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Obstetrical Applications for 3D Ultrasonography
Wesley Lee, M.D.
Dolores Pretorius, M.D.
CHAPTER CONTENTS
A. INTRODUCTION
B. IMPORTANT CONCEPTS FOR VOLUME SONOGRAPHY
C. EARLY PREGNANCY EVALUATION USING 3DUS
early fetal anatomic evaluation
genetic risk assessment
nuchal translucency
nasal bone assessment
frontomaxillary facial angle
fetal pelvic angle
embryonic volume
D. SELECTED 3DUS APPLICATIONS FOR LATER PREGNANCY
face
eyes and ears
metopic suture
cleft lip and palate
jaw abnormalities
brain
spina bifida
skeletal dysplasia
E. TISSUE VASCULARIZATION ASSESSMENT
F. FETAL GROWTH AND WEIGHT ESTIMATION
G. OTHER CONSIDERATIONS
safety issues
parental bonding
medicolegal issues
ultrasound for entertainment
H. EMERGING CONCEPTS
I. CONCLUSIONS
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A.
INTRODUCTION
Three-dimensional ultrasonography (3DUS) can be combined with conventional twodimensional ultrasonography (2DUS) for the evaluation of normal and abnormal fetal
anatomy. Development of cost-effective high performance computers and sophisticated
image analysis software now makes it practical for 3DUS to be conveniently integrated
with standard diagnostic imaging equipment. The previous chapter summarized basic
concepts regarding the acquisition and fundamental concepts of ultrasound volume data.
This overview will describe how this information can be applied to specific problems
during pregnancy.
Although 3DUS applications have been described for over two decades, one of our initial
challenges was to evaluate their clinical value against a backdrop of emerging
technology. In 2005, a literature review of more than 500 related articles suggested that
additional diagnostic information was particularly useful for facial anomalies, neural tube
defects, and skeletal malformations (1). Other potential benefits involved early pregnancy
evaluation, nuchal translucency measurements, weight estimation, fetal lung volumetry,
growth evaluation, and possibly maternal fetal bonding. Technical developments, such as
spatiotemporal image correlation (STIC) algorithms, were also cited for improving our
ability to examine rapid changes in the fetal heart. The following chapter by Dr. DeVore
will more closely examine the emerging field of four-dimensional ultrasonography.
B.
IMPORTANT CONCEPTS FOR VOLUME SONOGRAPHY
We have witnessed an impressive refinement of image analysis tools and their migration
from dedicated image workstations to notebook computers. This technology permits the
examiner to choose among many different visualization techniques with a variety of
output display modes as summarized by Dr. Bega’s preceding chapter. In the most cases,
volume sonography can be generally considered as an important diagnostic technique
that is complementary to conventional 2D imaging. Before specific examples of how
3DUS can be applied to pregnant women are reviewed, we will first describe a few
general concepts for how 3DUS can be best applied during pregnancy.
1.
Use 2D ultrasonography for an initial diagnostic impression. Health care
professionals are classically trained to translate 2D images into volume reconstructions
for an improved understanding of spatial relationships and image patterns that suggest
congenital abnormalities. Volume sonography provides the examiner with an opportunity
to systematically evaluate anatomic structures with less inter-observer dependency,
sometimes in ways that are not possible through conventional 2D methods. A preliminary
2D sonographic scan for suspected fetal abnormalities can be very useful and the results
can be used to guide the subsequent 3D study. Once an initial differential diagnosis has
been generated, the examiner should be able to formulate pending questions about the
initial diagnostic impression that may or may not be satisfactorily addressed using 3DUS.
If spina bifida is detected, for example, there may be a need to more precisely define the
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anatomic level of the defect. This information would help the clinician to estimate the risk
of problems related to ambulation and bowel or bladder function.
In order to better understand the contribution of conventional imaging to 3DUS,
Gonçalves and colleagues (2) compared both modalities in a blinded manner for 99
fetuses at a mean menstrual age of 24.4 ± 6.5 weeks. Complete agreement between
2DUS and 3DUS was observed for 90.4% of the findings. Six anomalies were missed by
volume sonography, including ventricular septal defects (n=2), interrupted inferior vena
cava with azygous continuation (n=1), tetralogy of Fallot (n=1), and cystic adenomatoid
malformation (n=1). There were 12 discordant diagnoses between 2D and 3D
ultrasonography. When compared to postnatal diagnoses (n=106), the sensitivity and
specificity of volume sonography was 92.2% and 76.4%, respectively. However, no
significant differences in the diagnostic conformity to neonatal outcomes were found when
the 3DUS results were compared to the sensitivity (96.1%) and specificity (72.7%) from
2DUS (p = 0.23). This study concluded that the information provided by 2D
ultrasonography is consistent, in most cases, with the diagnostic results from 3DUS.
2.
Match the 3DUS technique with a specific clinical question that is being
asked. The diagnostic benefit of volume sonography critically depends upon expectations
of the examiner and the precise reason why the scan itself is being performed. Although
most patients relate to this technology from its ability to display a fetal face for bonding
purposes, this is not a recognized medical indication in low-risk pregnancies. In this
context, one must recognize that 3DUS has the potential of revealing much more than a
fetal face. The fundamental technologies, as described in the preceding chapter, actually
represents several different image visualization tools that may or may not apply to the
question being asked. They include multi-planar imaging, surface rendering, volume
rendering, thick slice scanning, tomographic slices, inversion mode, and 3D Doppler
ultrasonography (Figures 1-7). As one example, the maximum intensity projection
algorithm might be most appropriate to analyze a possible hemi-vertebra that is
suspected on the 2D scan. Complementary display modes, such as multi-planar imaging
or the use of parallel tomographic slices, might also offer benefit. By comparison, a
surface-rendering algorithm would not expected to provide useful information for bony
structures such as cranial sutures or spinal abnormalities. This modality would be better
suited for delineation of soft tissue problems such as cleft lip. Some volume analysis
software packages allow the examination of volume reconstructions using a combination
of different rendering algorithms (Figure 8). Others may use 4DUS for evaluating the
status of joint movement of the wrist in a fetus suspected to have arthrogryposis. Hence,
the examiner must remember to formulate one or more specific questions that are based
on the initial 2D scan in order to choose the most appropriate type of image analysis.
3.
Do not underestimate the diagnostic value of 3D multi-planar imaging.
Although much emphasis has been placed on volume rendering, one must appreciate
how useful it is for an examiner to analyze multi-planar image slices from standardized
orthogonal views. In our practices, it is not uncommon that we might use this modality as
the initial method of fetal organ evaluation. After standardized orthogonal planes are
displayed, it is possible to systematically "march" through a volume of interest in order to
better characterize the anatomy. One of the most common applications for this modality
will be demonstrated for the fetal face evaluation. From these views, it will also be
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possible to make a wide variety of quantitative distance, angle, and area measurements
as needed.
4.
Good two-dimensional imaging is likely to translate to satisfactory threedimensional volume acquisitions. The most useful volume data sets will be acquired
when optimal sonographic technique is used in pregnancies where technical factors do
not degrade the image. Remember the basics by adjusting scanning parameters such as
system gain and acoustic focus. A reasonable goal is to adjust the region of interest in
the rendering box so that it fills about two-thirds of the available display screen. Scan from
different viewing perspectives for optimal images of the specific region of interest. For
example, the fetal spine and overlying skin line should be obtained from a prone fetus, not
from the supine position.
We are often asked, "Is the sonographer's job at risk if all one needs to do is to place a
transducer on the maternal abdomen and push a start button? The answer is
emphatically, "NO!" because the likelihood that volume sonography will provide an
adequate means for diagnostic interpretation is really dependent on the original quality of
the images. The examiner should be able to optimize the image by utilizing the proper
probe position while making certain that excessive pressure is not placed on the maternal
abdomen. There are several ways to analyze good quality volume data sets if the original
acquisition is obtained under optimal conditions. Careful attention should be made for
adjusting image depth, acoustic focus, and signal gain at a time when fetal movement is
minimal for acquisition of this image data. Both 2D and 3D ultrasonographic techniques,
however, are sensitive to the potentially detrimental effects of maternal obesity, fetal
movement, early fetal age, presence of maternal abdominal scars, and oligohydramnios.
With these caveats in mind, some of the more common diagnostic applications will now
be reviewed to further demonstrate basic approaches for using volume sonography
during pregnancy.
C.
EARLY PREGNANCY EVALUATION USING 3DUS
Early Fetal Anatomic Evaluation
The first trimester 2D scan is mainly performed for dating early pregnancies, confirming
cardiac activity, and to measure nuchal translucency as part of risk assessment for
aneuploidy. Relatively fewer investigators have used conventional 2D imaging techniques
to evaluate anatomic structures of the developing embryo. An important advantage of
accurate early diagnosis would include parental reassurance that a major abnormality
was not present. Earlier anomaly detection would provide more time for defining
pregnancy options, prenatal care, delivery plans, and prognosis. As the field of fetal
therapy develops, the earlier diagnosis of certain types of anomalies may even allow
treatment at a time when chances for salvaging the fetus may be higher at an earlier
stage of disease progression.
Several investigators have used 2D endovaginal scans to visualize fetal anatomy before
14 weeks, menstrual age (3-5). First trimester pregnancies can also be evaluated using
3DUS although recent improvements in high frequency probe technology have made it
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increasingly feasible to visualize cross-sectional and surface anatomy of the embryo
(Figure 9). Blaas and co-workers (6) were among the first groups to use 3DUS for
volume reconstruction of embryos between 7-10 weeks, menstrual age. They used a
customized 7.5 MHz annular array vaginal probe and a VingMed system to trace contours
of embryonic brain structures that permitted volume calculations as well.
Normal embryonic anatomy has also been studied using 3DUS (7). One investigator
threaded a catheter-based 20 MHz ultrasound transducer through the maternal cervix and
endometrial cavity to demonstrate the embryonic face, limbs, and brain (8). Benoit et al
(9) introduced the term, "sonoembryology" for describing the specific use of volume
sonography of the developing fetus. He later demonstrated the evolving changes in
embryonic brain development and reported that the optimal time to use 3DUS was
between 7-12 weeks (10). Twelve representative images of the rendered volume provided
an informative timeline of embryonic brain development (Figure 10). There have also
been several related reports of conjoined twins (11-13), spina bifida (14),
holoprosencephaly (10, 15-18), sirenomelia (19), and sacrococcygeal teratoma (20).
Although the sensitivity of 2DUS for the detection of major fetal anomalies between 11
and 14 weeks has been reported to be approximately 50 percent (21), there are many
factors that can affect diagnostic results. They include the population being studied, type
of equipment used, examiner experience, exam duration, and the gestational age at
which the scan is performed. Unfortunately, no large scale comparative studies have
been performed that can clearly define the role of 3DUS for the systematic detection of
fetal anomalies during early pregnancy as compared to 2DUS. Technical improvements,
such as the development of more sophisticated image analysis tools or the commercial
availability of higher frequency transducers, are likely to result in more accurate and
earlier diagnoses over time. The best diagnostic technology in the world, however, will not
be translated into improved outcome unless clinical management protocols are also
capable of taking advantage of this information.
How much additional benefit is actually provided by 3DUS over conventional 2DUS during
early pregnancy? Michailidis and co-workers (22) compared real-time 2D scans (5 MHz
transabdominal and 7 MHz transvaginal probes) to 3DUS (7 MHz transvaginal probe) for
early fetal anatomic assessment. The anatomic survey included the head, face, stomach,
abdominal wall, kidneys, bladder, spine, and extremities in 159 consecutive women at
12.0 to 13.9 weeks gestation. Two 3D volumes were obtained at the end of the
procedure and they were subsequently analyzed for the same anatomic features that
were examined using 2DUS. A "complete" anatomic survey was possible in 93.7% of the
2D scans which was a higher visualization rate than 80.5% of fetuses that were
satisfactorily examined using 3DUS (p < 0.001). The mean time to perform a 2D scan
was 12.2 ± 3.4 minutes (SD) as compared to the greater time it took to acquire and
analyze 3D volume datasets for the same information (8.4 ± 1.5 minutes) (p<0.001). They
concluded that real-time 2DUS was the best way to examine first trimester embryonic
anatomy. Volume sonography provided occasional views that were not possible using
2DUS, was associated with less scanning time, and provided a mechanism where
scanned data could be stored for subsequent review.
Fauchon (23) recently performed a prospective study where an examiner acquired
transabdominal 3DUS of the entire fetus from 273 singleton pregnancies between 11.0
5
and 13.9 weeks, menstrual age. Each dataset was manipulated and analyzed by two
independent examiners who were blinded to each other's results. The requirements for
sonographic visualization of 12 anatomic structures were strictly defined. Crown-rump
length and nuchal translucency were measured with a high degree of agreement between
both investigators in 100% and 84.6% of cases, respectively. Negligible clinical
differences in either measurement resulted among all three examiners. In this study, a
single abdominal 3DUS acquisition of a fetus between 11-13.0 weeks gestation usually
provided satisfactory views for both the anatomic survey and nuchal translucency
measurement of the embryo. Increasing maternal weight was an important factor that
prevented adequate visualization of embryonic anatomy whereas longer crown rump
length increased the odds of the examiners being able to identify half of these anatomic
characteristics.
The aforementioned studies indicate that the entire fetus can usually be satisfactorily
screened for an anatomic survey during early pregnancy. Factors such as embryonic
position, bladder filling, examiner experience, type of equipment used, menstrual age,
limited range of probe movement, transducer frequency, and even maternal obesity can
greatly influence the examiner's ability to complete this transvaginal study. The
advantages for using a high frequency transvaginal probe to improve image resolution is
offset by relatively limited tissue penetration. It also becomes increasingly difficult to
capture the entire fetus after approximately 14 weeks, menstrual age. After this time, it
may be necessary to acquire more than one volume data sets due to the technical
specifications of most mechanical volume probes. Accordingly, one could subsequently
attempt volume acquisitions with a lower frequency abdominal probe. More studies are
required to characterize the normal appearance and evolution of embryonic structures on
the basis of 3DUS. For example, the physiologic mid-gut herniation and its relationship to
development of ventral wall defects is well known. This normal finding is typically very
prominent in a 10 week fetus (Figure 9).
Genetic Risk Assessment
Several sonographic markers of genetic risk have included an evaluation of nuchal
translucency (NT), nasal bone, frontomaxillary facial angle, fetal pelvic measurements,
and embryonic volume. Key questions must be considered before these new techniques
are introduced into clinical practice. First, the technique must be relatively simple to
perform, affordable, and reproducible among different examiners. Second, the
relationship of these measurements to menstrual age must be established. Third, the new
marker should be able to distinguish between normal and pathologic pregnancies with
good sensitivity and relatively low false positive rate. Fourth, any potential advantages
over the use of conventional 2DUS and any technical limitations of the new technique
should be described.
Nuchal Translucency
At least six reports have examined how 3DUS can be used to evaluate nuchal
translucency (24-29). Paul et al. (27) studied 40 consecutive uncomplicated pregnancies
who underwent first trimester screening for Down syndrome at 11-14 weeks. Nuchal
translucency was measured using both transabdominal 2DUS and 3DUS. Two volume
data sets were acquired - one that included a mid-sagittal plane and a second one that
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was obtained from a random initial plane. This detail is important because images that are
analyzed from the original plane of acquisition are usually the clearest because they do
not require reconstruction. Small, but significant errors can occur if the nuchal
translucency thickness is in the range of the ultrasound beam's lateral resolution of 1-2
mm. They found that nuchal translucency thickness could be repeated in 38/40 (95%) of
the volumes that were acquired from a sagittal view of the fetus. By contrast, the random
volumes yielded only 24/40 embryos with satisfactory nuchal translucency
measurements. The mean difference between results from 2DUS and those obtained
from reslicing "sagittal" volume datasets was -0.097 mm (95% limits of agreement from 0.481 to 0.675) and 0.225 mm (95% limits of agreement from -0.369 to 0.819) when
random volumes were analyzed. Their results underscored the fact that the analysis of
3D volume datasets can be reliably used to replicate nuchal translucency measurements
only when the nuchal skin line is also seen on the 2D scan. If visualization of the posterior
neck is obscured by acoustic shadowing, one would not expect a well-defined nuchal
translucency on the multi-planar reconstruction.
Clementschitsch and co-workers (28) also prospectively examined 229 unselected
pregnancies to compare the use of 2DUS and 3DUS for NT measurements. Satisfactory
nuchal translucency measurements were obtained using 2DUS in 96.8% of cases as
compared to 3DUS (98.6% transabdominal). Suboptimal fetal position was the main
reason why 2DUS failed to provide satisfactory measurements. In some cases, it was
difficult to precisely distinguish between fetal skin and amnion or uterine wall (6.3% for
2DUS, 3.3% for 3DUS). Fetal movement was the main reason for measurement failure
using 3DUS. The mean time for either method was similar (9 minutes for 2DUS versus 10
minutes for 3DUS). Finally, the correlation between these measurements was very high (r
= 0.97).
Both studies suggest that reliable nuchal translucency measurements are feasible with
transabdominal 3DUS during the 11-14 week embryo, especially if the original plane of
volume acquisition contains a midsagittal view of the embryonic neck. Of course, it would
be prudent to follow technical guidelines for 2DUS that are recommended by the
Foundation for Fetal Medicine (http://www.fetalmedicine.com/downs/nuchal.htm) or the
Nuchal Translucency Quality Review (NTQR, http://www.ntqr.org) programs to assure
adequate quality control of these precise measurements. Presently, only the latter
program addresses the use of 3DUS for NT measurement. The NTQR guidelines suggest
that volume data acquisitions for this purpose are most reliable from a sagittal sweep of
the embryonic face. Examiners are also cautioned about the potential limitations of lateral
resolution for their ultrasound system.
Can reliable NT measurements be obtained from volume data that are not originally
acquired from a sagittal plane? Shipp and associates (30) addressed this question by
analyzing NT measurements of 29 consecutive fetuses between 11.4 and 13.9 weeks,
menstrual age. The 2DUS results were compared to 3D based measurements from a
median sagittal plane of the embryonic neck. A sagittal plane was obtained by navigating
through 3D multi-planar views using volume data sets that had been initially acquired
from a coronal sweep of the embryo. The mean measurement (± SD) between 2DUS (1.7
± 1.4 mm) was not statistically different from use of a reconstructed sagittal plane (1.8 ±
1.6 mm) (p = 0.4) and these results were highly correlated (r = 0.98, p < 0.001). Their
findings suggest that nuchal translucency measurements are feasible from 3D data,
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despite the original volume was initially acquired from a coronal plane. They also
concurred with an earlier report that emphasized the importance of satisfactorily
visualizing the neck region using 2DUS before initiating the volume sweep procedure
(27). The interpretation and practical implementation of their findings warrant further
investigation in a larger group of patients. Furthermore, the study did not consider the skill
of the examiner for satisfactory manipulation of these volume data sets in a reproducible
manner.
Nasal Bone Assessment
The fetal nasal bone also has been found to be a sonographic marker of genetic risk.
Cicero and co-workers (31) used conventional 2DUS to identify the absence or presence
of nasal bone in fetuses with trisomy 21 at 11 to 13 + 6 weeks gestation. The nasal bone
was absent in 113 (0.6%) of the 20,165 chromosomally or phenotypically normal fetuses
and in 87 (62.1%) of the 140 fetuses with Down syndrome. The inclusion of the nasal
bone in first trimester combined screening for trisomy 21 achieved a detection rate of 90%
for a false-positive rate of 2.5%. Another 2DUS study (32) observed a much lower rate of
absent nasal bone in an unselected (16.7%) and selected (46.7%) population of fetuses
between 11 to 13.9 weeks, menstrual age. Since this study did not utilize any formal
training or quality assurance program for the detection of nasal bone, Sonek et al. (33)
recommended that an ultrasound marker, such as the nasal bone, should not be used in
a screening program unless the examiners are adequately trained. In an earlier study,
Cicero et al (34) analyzed the ability of 15 sonographers for obtaining satisfactory views
of the nasal bone. They found that approximately 80 2D examinations were required to
achieve competency for nasal bone assessment during the routine 11-14 week scan. In
this context, Malone and colleagues (35) performed nasal bone imaging as a screening
tool for aneuploidy in 6,324 of 38,189 patients who were scanned at 10.4 to 13.9 weeks,
menstrual age. An acceptable nasal bone image was reported in 76% of cases. Nasal
bones were present in 4,779 (99.5%) of this subgroup and absent in 22 fetuses (0.5%).
Absence of nasal bones had sensitivity for aneuploidy of only 7.7% with a false positive
rate of 0.3% and positive value of 4.5%. They concluded that nasal bone evaluation was
not useful for population screening for trisomy 21, possibly because of the difficulty in
performing this assessment consistently in a general U.S. population setting. However,
one-quarter of these sonographers reported unsatisfactorily visualization of the nasal
bone despite specific training in first trimester sonography. These results seemed
contrary to their specific implementation of a quality control program to monitor on-going
performance of nasal bone sonography. Nonetheless, it is presently unclear as to why the
FASTER trial results in the United States did not confirm the utility of nasal bone
screening in the United Kingdom.
Does 3DUS provide additional diagnostic benefit for nasal bone evaluation during early to
mid pregnancy? Rembouskos and co-workers (36) found that a mid-sagittal view was the
best original plane of 3D volume acquisition and their results suggested that satisfactory
visualization of the nasal bone was optimal when the fetal profile was insonated at about
45 degrees. The likelihood of an adequately visualized nasal bone from a 3D volume
dataset was strongly related to the quality of the initial 2D image. Other investigators
(37,38) have used 3DUS to document the presence of a gap between the nasal bones
during early pregnancy. Peralta (38) used 2DUS and 3DUS to scan 450 fetuses between
11.0 to 13.9 weeks, menstrual age. They found sonographic evidence of this gap in about
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20 percent of fetuses. Furthermore, in about 40% of these cases, the nasal bone may
erroneously be interpreted to be absent in an optimal median sagittal plane.
Goncalves and associates (39) used 3DUS to evaluate nasal bones in 26 fetuses with
Down syndrome during the second trimester of pregnancy (Figure 11). Rendered facial
profile views demonstrated absent nasal bones in 18.9% of cases, of which 90% had
Down syndrome for an overall sensitivity of 34.6% and false positive rate of 3.7%. This
appearance was associated with a 9.3 fold increased risk for Down syndrome when
compared to the normal control group. By comparison, three ossification patterns were
demonstrated from coronal views of the rendered face: (1) normally developed, (2)
delayed ossification, and (3) absent nasal bones. Sensitivity, false positive rate, and
likelihood ratio of absent nasal bones for detecting Down syndrome were 34.6%, 3.7%,
and 9.0 (95% CI, 1.3–68.7), respectively. These investigators identified nasal bones with
delayed ossification by using this maximum intensity projection algorithm. Similar to
findings from 2DUS, the absence of nasal bones was associated with the highest risk of
Down syndrome. Delayed nasal bone ossification patterns were associated with a
somewhat lower risk for these abnormal fetuses. The sensitivity, false positive rate, and
likelihood ratio of delayed ossification for detecting Down syndrome were 42.3%, 22%,
and 1.83 (95% CI, 0.8–4.4), respectively. This “hypoplasic” pattern probably reflects
shortened nasal bones that have been described using 2DUS (40). Benoit et al. (41)
subsequently used the 3D maximum intensity projection algorithm to demonstrate
unilateral absence or hypoplasia of nasal bones during the second trimester of
pregnancy. An analysis of these nasal bone patterns may improve our ability to identify
fetuses at risk for Down syndrome. However, more experience with these methods is
required for an unselected patient population before the diagnostic significance of 3DUS
can be established for this purpose.
Frontomaxillary Facial Angle
Frontomaxillary facial angle (FMF) is another sonographic marker of fetal aneuploidy that
has been studied in both the first and second trimesters of pregnancy. This measurement
is defined as the angle between the upper surface of the upper palate and the frontal
bone from a median sagittal view of the fetal face (Figures 12 and 13). Sonek and
associates (42) used 3DUS to standardize this measurement, based on the hypothesis
that the maxilla is dorsally displaced in relation to the forehead in fetuses with trisomy 21
between 11.0 to 13.9 weeks, menstrual age. The FMF angle was significantly larger in the
abnormal group of 100 fetuses with Down syndrome (mean 88.7, range 75.4 – 104
degrees) as compared to 300 chromosomally normal controls (mean 78.1, range 66.6 –
89.5 degrees). This angle was also not significantly associated with NT. Subsequent work
by the same group (43) underscored the importance of standardizing the FMF
measurement using 3D multi-planar views of the facial profile that includes the tip of the
nose and the rectangular shape of the maxillary bone. This approach was used to
demonstrate very reproducible results and they were able to prospectively demonstrate
that experienced examiners can alternatively measure the FMF angle using 2DUS as well
(44). Furthermore, an increased FMF angle in fetuses at 11.0 to 13.9 weeks, menstrual
age is increased in cases of trisomy 13 but, only when associated holoprosencephaly is
present (45). A prospective study of 782 euploid and 108 fetuses with Down syndrome
combined the FMF with biochemical screening tests (46). The inclusion of FMF angle to
first-trimester combined screening increased the estimated detection rate from 90 to 94%
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for a false positive rate of 5%.
Molina and co-workers (47) also applied the FMF angle to 150 normal fetuses and 23
fetuses with Down syndrome between 16 – 24 weeks, menstrual age. In the normal
group, the FMF angle did not change with menstrual age and the 95 th centile was 88.5.
By comparison, the FMF angle was greater than 88.5 degrees in 65.2% of abnormal
fetuses and inter-observer analysis indicated that in 95% of cases, the difference in
measurements between examiners was less than 5 degrees. Technically, one must
differentiate between the bony palate and vomer from a median sagittal view of the facial
profile for optimal FMF measurements (Figures 14 and 15).
Fetal Pelvic Angle
Since the late 1990's, several studies have correlated iliac angles - from a 2D axial view
of the fetal pelvis - with the risk of Down syndrome (48-50). Bork and colleagues (50)
prospectively scanned 377 singleton fetuses, of which karyotypes were available for only
128 cases. The mean iliac angle for normal fetuses (68.2 ± 15.4 degrees) was
significantly lower than observed in abnormal fetuses (98.5 ± 11.3 degrees). A receiver
operator curve for their high-risk population identified an optimal cut-off of 90 degrees for
a detection rate of 90.9% (5.5% false positive rate). By comparison, Shipp and associates
(51) prospectively measured iliac angles for all fetuses undergoing second trimester
amniocentesis over a 17-month period. Nineteen fetuses with Down syndrome and 1167
normal controls were scanned with a mean iliac angle was 80.1 ± 19.7 degrees for
abnormal cases as opposed to normal controls (63.1 ± 20.3 degrees). The iliac angle was
at least 90 degrees in 36.8 percent (7 of 19 fetuses) with Down syndrome and in 12.8%
(64 of 500 fetuses) with normal karyotype. Despite their results, it was concluded that the
iliac angle alone was not useful in a high-risk population because of the high falsepositive rate of 12.9%. French investigators also found a similar high false positive rate of
20% for use of the iliac angle as a single marker for trisomy 21 (52). Massez and coworkers (53) examined the effect of fetal position on the iliac angle measurement using
2DUS in 695 fetuses during the midtrimester. In euploid fetuses, the mean iliac wing
angle was 83.7 degrees in decubitus and 68.7 degrees in the lateral position. In fetuses
with trisomy 21, the mean angles were 104.9 and 102.5 degrees, respectively.
A relatively high false positive rate of prior studies that utilized 2DUS may have been
largely attributed to the complex structure of the fetal pelvis. To address this possibility,
Lee et al. (54) used 3DUS to standardize iliac angle measurements from multi-planar
views of the fetal pelvis. Thirty-five normal fetuses and 16 fetuses with trisomy 21 were
scanned during second trimester amniocentesis. The mean iliac angle for normal fetuses
was 79 ± 5.5 degrees, which was significantly less than the abnormal fetuses (87.7 ± 4.9
degrees) (P < 0.001). Intraclass correlation analysis suggested that this technique was
reproducible between examiners. For a false-positive rate of 5%, an axial iliac angle
threshold of 87 degrees alone correctly classified 56 percent of fetuses with trisomy 21 in
this high-risk group. Further studies will be required to improve our understanding of the
potential utility for iliac angle measurements for an unselected low-risk population during
the second trimester of pregnancy.
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Embryonic Volume
Falcon and colleagues (55) used 2DUS and 3DUS to measure fetal trunk and head
volume in 140 chromosomally abnormal fetuses at 11.0 to 13.9 weeks, menstrual age
and compared them to 500 normal controls. In 72 fetuses with trisomy 21 and 14 fetuses
with Turner syndrome, the CRL for gestation was similar, but the fetal trunk and head
volume was about 10–15 percent lower. In fetuses with trisomy 18 (n = 29), trisomy13 (n
= 14) and triploidy (n = 11), the deficit in volume was about 45 percent, as compared to
crown-rump length, which was lower by less than 15 percent. These results raised the
possibility that fetal trunk and head volume measurements may have advantages over
2DUS for the identification of early fetal growth abnormalities. The same research group
used similar techniques to show that early asymmetric growth restriction between the
trunk and head was characteristic of triploidy, trisomy 13, and trisomy 18 (56). By
comparison, the growth abnormalities equally affected the head and abdominal volumes
in fetuses with trisomy 21 and Turner syndrome.
D.
SELECTED 3DUS APPLICATIONS FOR LATER PREGNANCY
Several 3D volume analysis tools can be applied to the fetus. Although we are trained to
mentally translate 2D images into 3D representations, this traditional approach is limited
by the examiner’s prior experience and ability to interpret this information. Furthermore,
there are new volume analysis tools that permit us to visualize images in ways that are
not possible using conventional methods. Despite these possible advantages, many
diagnostic imaging cases can be simply evaluated from using only 2DUS. In some
instances, 3DUS offers a complementary approach that may improve diagnostic
confidence for the diagnostic impression that is initially based on conventional
sonography.
We currently use 2DUS for the prenatal detection of most congenital anomalies, with a
targeted application of 3DUS to answer specific questions that are raised from the initial
diagnostic impression. As more applications for 3DUS are described against an emerging
backdrop of technological improvements, the paradigm for how volume sonography is
applied to obstetrical practice may also evolve (57). For example, Benacerraf and coworkers (58) have described how 3DUS improved the workflow of clinical practices by the
efficient acquisition and review of volume data sets. Although this is not a focus of the
current chapter, several investigations have also proposed automating the analysis for
data sets for the fetal heart (59-62). Others have reported remote sonographic diagnosis
for telemedicine applications, using 3DUS in areas that are remote from the expert
consultant (63-66). Volume sonography has also been used to assess fetal urine
production in both normal fetuses (67, 68) and after laser surgery for a case of twin-twin
transfusion (69).
Many scientific articles have been published over the past decade as a result of the
ultrasound manufacturing industry’s successful efforts to commercialize 3DUS technology
into clinical practice. This process has not only included improved image quality, smaller
transducers, and faster computers but, also the development of volume data analysis
tools as well. Potential advantages and technical limitations of 3DUS will now be reviewed
for selected obstetrical problems.
11
Face
The fetal face is important because it can provide diagnostic clues for the presence of
isolated abnormalities and genetic syndromes. Although many patients immediately
recognize facial features from the surface rendered display, we believe that 3D multiplanar images are often the most helpful for medical diagnosis. However, the most
appropriate selection of volume analysis tools critically depends on the question being
asked. For example, one would use the maximum intensity projection algorithm to
visualize problems with bony structures such as the cranial sutures. Soft tissue clefts
might be well visualized with surface rendering. The lips and hard palate could be
systematically evaluated by using multi-planar images as well. This modality allows one to
use a reference dot to improve their understanding of complex anatomic relationships that
are being investigated. Others might want to confirm a specific finding by using a parallel
slice display (e.g. tomographic ultrasound imaging, multi-slice, i-Slice) or even thick slice
scanning of the fetal lips (e.g. volume contrast imaging). Therefore, one must choose the
most appropriate set of volume analysis tools on the basis of the diagnostic questions that
are clinically relevant.
Many early investigators pointed out the benefits of 3DUS in evaluating the fetal face (7072). Pretorius and associates (73) described their preliminary experiences with visualizing
the fetal face and lips using surface rendering and multi-planar views. In a subgroup of
fetuses at less than 24 weeks gestation, 3DUS confirmed a normal lip in 93% (58 of 63
cases) as compared with 76% (48 of 63 cases) using 2DUS. At that time, they noted that
the 3D images of cleft lip were easier to understand for both the family and clinical
colleagues. Merz and colleagues (74) used multi-planar views of the face and found that
the facial profile that was obtained by 2DUS represented the true mid-sagittal profile in
only 69.6 percent of cases. In the remaining 30.4 percent, the profile view deviated from a
true mid-sagittal section by up to 20 degrees in one or two planes. In this series, they
found 20 of 25 facial anomalies that were demonstrated using both 2DUS and 3DUS. In
the remaining five cases, 3DUS revealed additional anomalies that included two cases of
narrow cleft lip as well as single examples of unilateral orbital hypoplasia, cranial
ossification defect, and flat facial profile with decreased amniotic fluid volume. Such
preliminary observations were quite extraordinary for the level of 3D technological
development at that time. It was not until approximately 3 years later that the “electronic
scalpel” image segmentation tool became commercially available on desktop computers
(75). This tool permits the examiner to selectively remove surrounding voxels that prevent
the precise display of volume-rendered structures.
One approach initiallty applies 4DUS to confirm recognizable features of the fetal face.
The rendered algorithms provided by the equipment vendors are often excellent and
provide a rapid acquisition of the face (Figure 16). Movement of the mouth is also easily
demonstrated. Acquisition is optimal when the fetal face is acquired from the sagittal or
profile view by placing the region of interest box (ROI) directly over the face, with the
rendering line just anterior to the nose (Figure 17). The rendering line may be straight or
curved to optimize the image. Occasionally it is necessary to increase the threshold knob
to take away unwanted echoes, particularly in heavier patients. If the face cannot be
positioned in a sagittal orientation, a frontal view (coronal) can be obtained, resulting in a
rendered image that displays the profile of the fetus.
12
Static 3DUS acquisitions of the fetus generally provide better resolution than 4DUS
acquisitions and are used for diagnostic evaluation. The face can be acquired from any
orientation but sagittal and slightly oblique off sagittal are optimal for seeing the rendered
face en face. Optimal planes of acquisition for various facial structures are summarized
in Table 1.
Manipulation of the 3DUS volume should begin with attempting to get the face into a
standard, symmetrical orientation. The cursor dot should be placed on a midline structure,
preferably the nose or the region in between the orbits. The volumes should be rotated in
all three planes until the orbits are symmetrical. It can then be evaluated by moving up
and down in parallel slices in each plane.
The face can also be displayed using a multi-slice technique that is similar to MRI imaging
or computed tomography where parallel slices at discrete intervals are varied to
demonstrate the anatomy. In a series of 142 patients, McGahan et al. (76) found that if
you started at 3 mm intervals there was minimal manipulation needed to show in the axial
plane the orbits, maxilla (primary palate) and mandible on one screen. Finally, Rotten and
colleagues (77) have nicely described how 2DUS and 3DUS can be systematically used
to evaluate the fetal face
Eyes
Although there are no published series of cases of abnormal orbits, case reports and
images in review articles have been published (78-80). The orbits can be measured from
volumes acquired of the face to identify hypotelorism (Figure 18), hypertelorism and
microopthalmia. We have found 3DUS very helpful when the orbits are absent or very
small (Figure 19).
Periorbital masses such as dacrocystocele (81), frontal encephalocele, glioma,
hemangioma and teratoma may be difficult to evaluate with 2DUS and 3DUS can be
helpful (82-84). Several authors have reported that 3DUS was useful in evaluating these
entities and for showing parents the 3D images for counseling (82-84).
Ears
Fetal ear abnormalities are often associated with aneuploidy (e.g. Trisomy 13,18,21) as
well as genetic syndromes such as Treacher-Collins Syndrome, Fraser syndrome,
CHARGE association and VACTERL association (85,86). The ears may be small, large,
abnormal shape and abnormal position. Although 2DUS can be used to assess the fetal
ears, 3DUS has been found to be extremely helpful (Figure 20). Shih et al. (85) evaluated
18 fetuses with abnormal ears and using 3DUS and found the ear shape, ridge pattern
and helix development as well as cranial location, axis and orientation of the ear was
better recognized on 3DUS compared to 2DUS. Case reports of abnormal ears seen
using 3DUS in fetuses with Treacher Collins syndrome have also been reported (87,88).
Nomograms for ear length and width measurements obtained with 3DUS have been
reported as a potential screening test for aneuploidy (86).
13
Metopic Sutures
The metopic suture lies in the midline of the face above the nasal bone and is the space
where the frontal bones comes together (Figure 21). Abnormal development of the
metopic sutures has been associated with facial dysmorphism, fetal brain malformations,
chromosomal defects and genetic syndromes (89).
The use of 3DUS to evaluate cranial sutures and fontanelles was first reported in 1994 by
Pretorius and Nelson (90). Visualization of normal sutures has been reported in 120
cases by Dikkeboom et al (91) and in 120 patients by Faro et al (92). In general, it is
easier to visual the sutures at earlier gestational ages. The metopic sutures have also
been evaluated in the first trimester (93,94). Holoprosencephaly is associated with an
accelerated development of frontal bones and premature closure of the metopic sutures
(93). Similar changes were not observed in fetuses with trisomy 21 (94). Faro and
colleagues (95) have also described the presence of a widened metopic suture in fetuses
with Aperts syndrome.
Chaoui and co-workers (89) later described four patterns of abnormal metopic suture
development. The first pattern involved delayed development with a V- or Y-shaped open
suture in normal fetuses at 12-16 weeks. A second pattern was a U-shaped open suture.
The third pattern was premature closure of the suture in normal fetuses after 32 weeks.
The fourth pattern resulted from additional bone between the frontal bones in fetuses with
holoprosencephaly and agenesis of the corpus callosum. The other three patterns were
observed in fetuses with facial defects involving the orbits, nasal bones, lip, palate and
mandible.
Cleft Lip and Palate
Despite some geographic differences, oral cleft defects are among the most common
congenital abnormalities with a prevalence of approximately 2.0 per 1000 births during
the mid-trimester of pregnancy (96). One large Norwegian study recently reported 101
fetuses or newborns with facial clefts for 49,314 deliveries. Twelve percent of affected
cases were associated with chromosomal abnormalities and 18% were documented with
syndromes (97). Cleft lip and palate were probably the main reasons that 3DUS was
initially developed for the detection of fetal anomalies. Many papers have been written on
the technique and benefits of 3DUS in evaluating the lip and palate. It assists in
evaluating the presence, the extent and the appearance for communication with the
patient and her family. Subtle deformities can be precisely evaluated using a stationary
volume, rather than a moving fetus. Chmait et al. (98) showed that even clefts, thought to
be isolated on 2DUS and 3DUS, were found to associated abnormalities at birth in 22%
(8/37) of fetuses.
Volumes are acquired from static 3DUS volumes to evaluate the lip and palate. Axial
acquisitions angled slight upward toward the top of the mouth are optimal for evaluation of
the primary and secondary palate. Rendered images of the face are helpful to
demonstrate the cleft lip to the family (Figure 22). Multi-planar imaging can be used to
evaluate the primary palate and lip. Many of the early articles only used the multi-planar
reconstruction to evaluate for cleft lip and palate (99,100). Johnson et al (101) studied 28
fetuses with cleft lip with or without palate and found that 3DUS was able to identify the
14
cleft palate more frequently (19/22) than 2DUS (9/22). They also found that management
was changed using 3DUS in that some patients elected to terminate the pregnancy and
others elected to carry the pregnancy when they had planned otherwise. In another
study, Chmait and co-workers (102) evaluated 53 fetuses with cleft lip with or without cleft
palate and found that the diagnostic accuracy was improved for cleft lip to 100% (53/53)
using 3DUS vs. 91% (48/53) using 2DUS and or cleft palate it was 89% (47/53) for 3DUS
vs 57% (30/53) for 2DUS. An isolated cleft lip is shown in video 3 using both multi-planar
and rendered displays. Wang (103) also demonstrated how the use of a parallel image
slice display format (“extended imaging”) can also be used to evaluate fetal cleft lip and
palate.
The rendered display can also be used to evaluate the secondary (hard and soft) palate.
Campbell et al. (104) first published the demonstration of the hard palate using a
‘reversed face’ technique. He later wrote an informative editorial discussing issues related
to evaluation of the hard palate with various rendering techniques (105). Platt and
colleagues (106) described the ‘flipped face’ technique to display the primary (alveolar
ridge) and secondary (hard and soft) palate. This view emphasizes the palate with an
upright face and viewing from an inferior direction, rather than superiorly (Figures 23 and
24). Faure (107) described a similar technique to display the primary and secondary
palate in 100 low-risk fetuses that showed how 3D reconstruction of the fetal palate can
be correlated to anatomic specimens. Pilu and co-workers (108) studied 15 normal
fetuses and one fetus with cleft lip and palate and showed that the secondary palate
could be evaluated if the face was insonated at a 45 degree angle in the sagittal plane; in
addition, they showed that the palate could be displayed on both axial and coronal planes
(Figures 25 and 26). Faure (109) also found that a 30 degree inclined axial plane
appears to be useful for assessing the integrity of the fetal soft palate (Figure 27).
These examples serve to demonstrate the versatility of high quality voxel-based images
for providing several options for the analysis of fetal anomalies. It is important to
remember that scanning artifacts may lead to misinterpretation of these images. For
example, Nelson et al. (110) have reported several artifacts related to both 2DUS artifacts
being propagated through the volume and new artifacts related to 3D reconstruction,
display and scanning.
Jaw Abnormalities
An evaluation of the median facial profile can be performed using both multiplanar and
rendered displays (Figure 28). The face should be rotated into a standard, anatomic
orientation so that the face is symmetrical. 3DUS has been shown to be useful in
identifying abnormal profiles such as micrognathia (Figure 29), retrognathia, midface
hypoplasia and frontal bossing (Figure 30). Lee and co-workers (111) evaluated 9 cases
of micrognathia and found that an oblique plane can lead to misinterpretation of a normal
chin to be abnormal, that prominent cheeks (e.g. in diabetic mothers) and retrognathia
can lead to an overcall of micrognathia.
Evaluation of the fetal mandible can provide important diagnostic clues to the presence of
genetic syndromes. By mid-2008, the Online Mendelian Inheritance in Man (OMIM)
database cited 328 syndromes for micrognathia (small jaw) and 53 syndromes for
retrognathja (posteriorly displaced jaw). From a clinical perspective, these jaw
15
abnormalities can also be associated with obstructed airways and problems with feeding
after birth. Toward this end, Rotten and co-workers (112) have described an objective
approach for the assessment of abnormal jaw size and position using 3DUS.
Micrognathia was defined on the basis of a ratio between the mandibular width (MD) to
the maxillary width (MX). Both parameters can be measured on an axial plane, caudal to
the cranial base, at the level of the maxillary or mandibular tooth buds. From an axial
plane, a line was extended posteriorly, one centimeter from the anterior border of the
tooth buds. The MD/MX ratio was obtained from these two measurements (Figure 31).
Retrognathia was defined by an inferior facial angle (IFA) that resulted from the crossing
of two lines (Figure 32):
1. a ‘reference line’, orthogonal to the vertical part of the forehead, drawn at the level
of the synostosis of the nasal bones.
2. A ‘profile line’, joining the tip of the mentum and the anterior border of the more
protrusive lip.
Their results demonstrated that micrognathia and retrognathia can be distinguished by
the methods in this paper. The MD/MX ratio assesses mandible size, whereas, the IFA
evaluates mandible position. Although it is possible to obtain these measurements using
2DUS, the Authors believed that 3DUS could be applied more easily for this analysis.
Such improvements in our ability to more precisely diagnose congenital abnormalities
may translate into improved therapeutic approaches and outcome.
Brain
Three-dimensional ultrasound images of the embryonic brain (6,9) have offered a
fascinating insight into normal and abnormal development of the central nervous system.
Similar to 2DUS, however, the fetal brain can be poorly visualized as a result of acoustic
shadowing from the bony calvarium during the second and third trimester of pregnancy. A
successful sonographic study of the brain often relies on the use of transvaginal
sonography through a suitable acoustic window such as the anterior fontanelle.
Some of the earliest reports on the use of 3DUS for the diagnosis of fetal brain
abnormalities included unilateral megalencephaly, hydrocephalus, anencephaly,
holoprosencephaly, Dandy-Walker cyst, enlarged cisterna magna, periventricular
leukomalacia, agenesis of the corpus callosum, and cerebellar fusion (113-115).
Subsequent investigators have described 3DUS with varying degrees of successful
visualization for fetal brain evaluation. One important technique for fetal brain evaluation
was originally introduced by Timor-Tritsch (116) as the ‘three-horn view”. This view can
be used to demonstrate the anterior, posterior, and inferior horns by either 2DUS or
3DUS scans. This 3D technique requires acquisition of a volume dataset, orthogonal
multi-planar display of brain structures, and by rotating or tilting the mid-coronal section to
the left or right. The examiner is able to navigate through the volume data for an improved
understanding of these anatomic relationships for telemedicine, consultative, and
teaching purposes (117). Another approach, the transfrontal view, uses the frontal cranial
suture as an acoustic window to examine midline cerebral structures with abdominal
16
3DUS (118). This view was easily obtained in 89 percent of 124 healthy fetuses beween
19 to 24 weeks, menstrual age. Anatomic findings were similar to a median sagittal scan
through the anterior fontanelle. The trans-frontal approach can also be used to evaluate
the fetal facial profile. Correa et al. (119) prospectively scanned 202 fetuses using
abdominal 3DUS between 16 and 24 weeks, menstrual age. Acceptable cerebral multiplanar views were satisfactorily viewed by a sonologist who had expertise in neonatal
cranial sonography in 92% of cases. The visualization rate for brain structures are
summarized for the “3D multi-planar neuroscan” in Table 2. Pilu and colleagues (120)
have also presented a very informative review that demonstrates how they use 3DUS to
systematically evaluate the fetal brain.
As the imaging resolution and visualization software improved, other investigators have
examined the fetal brain as well. Roelfsema and colleages (121) applied the VOCAL
technique to document median brain volume that increased from 34 mL at 18 weeks to
316 mL at 34 weeks, menstrual age. This represents a nearly 10-fold increase during the
second half of pregnancy. Viñals et al. (122) later applied a thick-slice scanning technique
(volume contrast imaging) to describe the normal appearance and dimensions of the fetal
cerebellar vermis. Paladini et al. (123) found that posterior fossa abnormalities can
usually be characterized using 3DUS on the basis of key findings that include upward
displacement of the tentorium, counterclockwise rotation, and vermian hypoplasia of the
cerebellum. One group has even described how 3DUS findings over time (i.e. 4D
ultrasonography or 4DUS) can be used to assess neurobehaviorial movements of the
fetus (124). Roeflsema and co-workers (125) described the normal development of the
fetal skull base and found that these measurements were reproducible between
examiners. In another study, serial volume measurements of the fetal cerebellum were
prospectively acquired in 52 normal pregnant women between 20 and 32 weeks,
menstrual age (126). These volume measurements were taken every two weeks as a
potential tool for fetal growth evaluation. All of these studies demonstrate the evolving
applications of 3DUS for fetal brain assessment. In many cases, the diagnostic results
from both 2DUS and 3DUS should be complementary to MRI studies of the fetal brain
(127).
Spina Bifida
The prenatal diagnosis of spina bifida has steadily improved as a result of maternal serum
alpha-fetoprotein screening and from the widespread use of ultrasonography.
Corresponding advances in patient management have greatly reduced mortality, but have
had minimal impact on long-term disability from neurological sequalae. This morbidity
includes paraplegia, sensory deficits, spinal deformity, bowel dysfunction, and urinary
incontinence.
Accurate characterization of spina bifida relies on sonographic recognition of disrupted
ossification centers and/or overlying skin from transverse and coronal views of the fetal
spine. Sonography predicts the clinical severity of open spina bifida because neurological
symptoms correlate with the anatomic level of the defect. Kollias et al. (128) reported that
two-dimensional ultrasonography (2DUS) estimated the defect to within one vertebral
segment in 79% of fetuses with spina bifida. However, one retrospective study of 171
consecutive cases of spina bifida found that only 29% of cases accurately identified the
17
specific upper level of a spinal lesion using 2DUS (129). Other investigators have
proposed that 3DUS may be used to further characterize spina bifida (130-133)
Optimal views can be generated by manipulation of a virtual cutting plane through a
volume reconstruction of the fetal spine. Lee and colleagues (134) has proposed that
3DUS can be used as a semi-quantitative technique for determining the anatomic level of
this lesion. Multi-planar views are acquired using a volume probe from an axial sweep of
the fetal spine (Figure 33). A coronal view of the lumbar and sacral spine is rendered with
a maximum intensity projection (MIP) algorithm that primarily displays the bony spine. An
electronic cutting plane is used to display orthogonal views of the volume-rendered spine,
beginning at the spinal segment that is contiguous with the last fetal rib. As the examiner
moves the cutting plane towards the sacral spine, simultaneous views of the axial spine
and over-lying skin line can be visualized. Other 3DUS techniques can be used to directly
render the bony and soft tissue defects (Figures 34-35). Spinal defect levels obtained in
this manner closely correlate with findings from both 2DUS and postnatal results.
Although multi-planar views are generally more informative than rendered views for
localizing these defects, their simultaneous use increases the likelihood that a spinal
defect will be appropriately analyzed. This approach may improve the characterization of
spina bifida by adding diagnostic information that is complementary to the initial
assessment by 2DUS.
Skeletal Dysplasias
Volume sonography offers an important method that allows the examiner to visualize fetal
skeletal structures on the basis of a maximum intensity projection (MIP) technique. This
software algorithm displays only the most echogenic structures and it is possible to mix
varying degrees of volume-rendered soft tissue for the final output display. Pretorius and
Nelson were among the first to use 3DUS to visualize cranial sutures and fontanelles
(135) as well as the thoracic skeleton (136). The same group later demonstrated the
value of stereoscopic imaging for these 3D reconstructions in order to better visualize
fetal bony structures (137).
One of the earliest applications of 3DUS for a fetal skeletal abnormality was described in
a fetus with platylospondylic lethal chondrodysplasia (138). Yanagihara et al (139)
subsequently reported early experiences with a specially developed abdominal 3D
transducer for visualizing skeletal structures in 42 normal fetuses and in 3 anencephalic
fetuses. Garjian and co-workers (140) reported a small series of fetuses with skeletal
dysplasia using this technology.The series included camptomelic dysplasia, thanatophoric
dysplasia, ostetogenesis imperfecta, arthrogryposis, and short limbed dysplasia. Surface
rendering, volume rotation, and multi-planar displays were especially helpful in 3 of 7
cases, when compared to 2DUS. Multi-planar imaging was helpful for displaying a true
median facial profile and volume sonography provided a more global assessment of the
skeletal anatomy. The MIP technique made it possible to identify scapular hypoplasia in a
fetus with campomelic dysplasia. The added depth perception cues and ability to rotate
volume data both facilitated increased appreciation of positional limb anomalies as well as
improved visualization of the spine. Another series from Cedars-Sinai Hospital further
described diagnostic advantages of 3DUS over 2DUS for additional skeletal dysplasias
for evaluating fetuses with facial dysmorphism, relative proportion of appendicular skeletal
elements, as well as the hands and feet (141). Benoit (142) provided additional examples
18
of the maximum intensity mode for displaying normal skeletal structures, hemivertebrae,
cranial sutures, spina bifida, hand digits, and cranial fontanelles (Figures 36-39).
Ruano and colleagues (143) have reported the use of a novel technology, 3D helical
computed tomography (CT) for the diagnosis of fetal skeletal anomalies between 27 and
36 weeks, menstrual age. There were three cases of achondroplasia, two cases of
osteogenesis imperfecta, Type II, and one case of chondrodysplasia punctata. The
correct diagnosis was made in four cases using 2DUS. Both 3DUS and 3D helical CT
were used to make the correct diagnosis in all cases. However, 3D helical CT provided an
advantage of imaging the entire fetus.
E.
TISSUE VASCULARIZATION ASSESSMENT
Tissue Perfusion Using 3D Vascular Flow Indices
3DUS and the VOCAL technique have been combined to estimate organ tissue perfusion
using vascular flow indices (4D View, version 7.0, GE Healthcare, Milwaukee, WI).
Pairleitner and co-workers (144) first introduced this approach for quantifying the degree
of vascularized tissue in adnexal masses. First, the VOCAL technique is used to define a
volume of interest that contains both gray-scale (nonvascular) and color voxels (vascular).
The fundamental principle is based on the use of histograms to analyze the ratio of
colored voxels to gray-scale voxels in the following manner.
1.
VI = vascularization index (standardized range 0 – 100)
Number of color voxels in relation to total number of voxels
Example:
2.
Number of color voxels = 1000
Total number of voxels = 5000
VI = 1000/5000 = 0.2 or 20%
FI = flow index (standardized range 0 – 100)
Average intensity value of color voxels contained in the volume.
Example:
3.
500 color voxels have a very high intensity = 80
500 color voxels have a lower intensity = 20
[(500 * 80) + (500*20)] / 1000 total voxels = FI = 0.50 or 50%
VFI = vascularization flow index = (VI *FI)/100
Example:
VFI = .2 x .5 = .10 or 10%
Several investigators have used vascular flow indices to study gynecologic conditions.
Pan et al. (145) studied differences in ovarian stromal flow in patients with polycystic
ovarian syndrome. The VI, FI, and VFI were significantly higher in affected women
19
compared with women having normal ovaries. Raine-Fenning and associates (146,147)
also examined periodic changes in endometrial development and subendometrial
vascularity during the normal menstrual cycle and found significantly reduced 3D vascular
flow indices in women with unexplained subfertility. Ng and co-workers (148) found
significantly higher endometrial and subendometrial vascularity in pregnant patients with a
live birth following in-vitro fertilization using frozen thawed-embryo transfer cycles as
compared to these women who experienced miscarriage.
Others have applied 3D vascular flow indices to the fetal liver (149), brain (150), kidneys
(151), and placenta (152). All flow indices significantly increase over time with advancing
pregnancy. Merce and colleagues (153) evaluated the reproducibility of placental vascular
flow indices on 30 normal singleton pregnancies from 14 to 40 weeks, menstrual age. All
3D power Doppler vascular indices (VI, FI and VFI) showed a correlation greater than
0.85, with a better intra-observer agreement for the flow indices (FI and VFI). They
subsequently described increases of placental vascular flow indices over time (154).
Power Doppler settings included a PRF 600 Hz; wall filter 40 Hz; and fixed 35 degree field
of view, although the overall gain settings were not reported. The FI, reflecting placental
flow, increased in a linear and progressive manner as compared to VI (number of
placental vessels) that increased up to the 30th week. The VI maintained a plateau up to
the 37th week and decreased afterwards.
A few salient points are pertinent to this line of investigation. First, these noninvasive
Doppler techniques do not measure true tissue perfusion because this technique would
require knowledge regarding how fast blood volume moves through tissue. Secondly, the
reproducibility of vascular flow indices is dependent on several technical factors such as
system gain, pulse repetition frequency, angle of insonation, wall filter settings, and
examiner experience. In this regard, the use of vascular flow indices may be more suited
towards gynecological imaging, in which the proximity of the ovaries and endometrium to
the transvaginal probe almost eliminates the beam path (146,155). By contrast, the use of
standardized ultrasound system settings may not satisfactorily compensate for different
beam paths between obstetrical scans because of the signal attenuation that results from
insonating intervening tissue at various depths (156,157).
In order to address some of these concerns, Rubin and associates (158) have introduced
the concept of fractional moving blood volume. In this elegant in-vitro experiment, they
used power Doppler ultrasonography to detect moving scatterers in a flow tube as a
function of successive dilutions of a blood mimicking perfusate. Power Doppler
ultrasonography has advantages over color Doppler methods because of its low noise
variance, decreased electronic noise, greater dynamic range, and increased sensitivity to
the detection of blood flow. The fractional moving blood volume technique normalizes
power Doppler measurements to compensate for signal attenuation and insonation depth.
These signal intensities can be compared to similar measurements from the center of a
large blood vessel that is used to define the highest value for vascular amplitude
scanning. These colored voxels are set to a value of 100% and this normalized data
compensates for the attenuation of the Doppler signal through tissue. Fractional moving
blood volume has also been shown to correlate well with regional blood flow perfusion on
the basis of radioactive microspheres in exteriorized fetal lambs that were exposed to
experimentally induced asphyxia (159). This technique also appears to be reproducible in
the fetal lung during the third trimester of pregnancy (160). Furthermore, fractional moving
20
blood volume has more recently been used to study regional cerebral blood perfusion in
third trimester fetuses (161). Interobserver agreement showed a mean difference of -0.2
(SD 2.7) with 95% limits of agreement ranging from -5.6 to 5.2. Statistically significant
differences in fractional moving blood volume were also found between cerebellar and
complete sagittal planes of the frontal and basal ganglia regions. Future studies will need
to address the role of fractional moving blood volume analysis for standardized 3DUS as
well.
F.
FETAL GROWTH AND WEIGHT ESTIMATION
Abnormal fetal growth is associated with a significant proportion of newborn babies that
develop postnatal complications. Approximately 8.3 percent of babies are born with low
birth weight (< 2,500 gm) in the United States (162). These infants can experience a
broad range of problems that include respiratory distress syndrome, intraventricular
hemorrhage, patent ductus arteriosus, necrotizing entercolitis, and retinopathy of
prematurity. Furthermore, the National Center of Vital Statistics also reports that 10
percent of all live-born infants in this country weigh more than 4,000 grams. The most
serious complication of fetal macrosomia is shoulder dystocia during delivery, although
clavicular fractures, and brachial plexus injuries from birth trauma also occur (163, 164).
Contemporary obstetrical practice has heavily relied on a generalized assessment of fetal
nutritional status is based on either estimated weight or only a single abdominal
circumference measurement. Fetal weight estimation models typically include the
abdominal circumference with some combination of head or limb measurements.
However, these fetal growth parameters do not emphasize the degree of soft tissue
development. This issue is extremely important because there is mounting evidence that
indicates an association between low birth weight and health in later adult life.
The Barker Hypothesis has stimulated much interest regarding the fetal origins of adult
disease (165). This line of investigation proposes that some fetuses will respond
differently to an unfavorable intrauterine environment and that malnourished fetuses will
generally respond less favorably to these insults. Epidemiologic studies have found that
low birth weight infants are at increased risk for decreased longevity as well as the onset
of heart disease, diabetes, chronic renal disease, metabolic syndrome, and neurological
sequelae in adult life (165-168). Although many of these studies have been based on low
birth weight infants, obstetricians are now challenged with the task of separating fetuses
that are small, but otherwise normal from these that are truly malnourished. Early
identification of malnourished fetuses could potentially be used to guide timely prenatal
intervention, to minimize risk of adverse perinatal outcome, and possibly to reduce the
development of health problems in later adult life. Nonetheless, is it possible that 3DUS
could provide additional fetal size and growth parameters that will ultimately improve our
ability to detect and monitor malnourished fetuses?
Several studies have described the early use of 3DUS for measuring fetal limb volume
that includes soft tissue assessment (169-174). For example, Chang and colleagues
(169) investigated the relationship of fetal thigh volume to birth weight. The thigh volume
was measured by manually tracing transverse slices of the thigh at 3 mm intervals, a
process that usually took 10-15 minutes to complete for each limb. This information was
used to derive the best one-parameter regression model in 100 women who delivered at
term gestation. They prospectively compared their results in 50 additional Taiwanese
21
subjects against previously published fetal weight estimation models (175-177). Their new
model (birth weight = 1080.87350 + 22.447 x thigh volume) gave the most accurate and
precise results when the data was expressed as mean percent differences (1.5 ± 5.6
percent) as compared to the methods of Warsof (-4.2 ± 9.4%), Hadlock (-4.8 ± 9.4%), and
Thurnau (-19.2 ± 7.0%). Furthermore, they found no significant differences between the
inter- and intra- examiner errors of mean differences among 20 of their subjects. Similar
results with only fetal arm volume were prospectively obtained (0.35 ± 4.6%), although no
reproducibility testing was performed between examiners (Liang, 1997). German
investigators (172) subsequently reported new fetal weight estimation models that
combined upper arm and thigh volume measurements with BPD and abdominal volume.
The multiple parameter model prospectively yielded a mean percentage error of 1.9 ±
7.6%, as compared to results using the Hadlock model (0.8 ± 9.3%). No information was
provided about the time necessary to complete these measurements and only intraobserver reproducibility results were reported.
Unfortunately, two major technical limitations have prevented the practical application of
soft tissue measurements into obstetrical practice. First, limb volume measurements
originally required a series of tedious manual traces around the axial limb from one end of
the femur to the other. Secondly, soft tissue borders are often difficult to clearly visualize
at either end of the long bone shaft due to acoustic shadowing. This inherent limitation of
sonographic imaging can make manual tracing of soft tissue borders difficult from
overlying dense tissue. Lee and colleagues (178) addressed these technical concerns by
introducing the concept of fractional limb volume (Figure 40). A commercially available
software product (4D View, version 7.0, GE Healthcare, Milwaukee, WI) can be used to
measure fractional limb volume that is based on an analysis of a mid-section of arm or
thigh from a volume dataset (Figure 41). The examiner is able to more rapidly measure
soft tissue volume in the center of the limb, where the manual tracings around the soft
tissue borders are less likely to be obscured by acoustic shadowing. Manual fractional
limb volume measurements take approximately 2 minutes to complete and are
reproducible between observers throughout a broad range of pregnancy. A prospective
validation study of 55 fetuses (range 390 to 5143 gm) found a greater than 2-fold
improvement in the percentage of infants having predicted weight within 5% of actual birth
weight, when compared to more conventional 2D parameters alone (179). Fractional limb
volume has also been successfully applied to individualized fetal growth assessment
using the Rossavik fetal growth model (180,181) (Figures 42-43). Normal values for
fractional limb volume and the reproducibility of these measurements have now been
reported during pregnancy (182).
Another study used air displacement plethysmography for newborn infant body
composition to determine which prenatal growth parameters had the greatest correlation
to percent body fat (183). Fractional thigh volume (TVol) was the most significant
predictor of %BF and this parameter explained 46.1% of the variability in %BF. Actual
birth weight similarly explained 44.7% of the variation in %BF. By comparison, abdominal
circumference and estimated fetal weight accounted for only 24.8% and 30.4% of the
variance in %BF, respectively. Skeletal growth parameters, such as FDL (14.2%), HC
(7.9%), and BPD (4.0%), contributed the least towards explaining the variance in %BF
(Figure 44). If a major goal of prenatal care is to detect malnourished fetuses, the
rationale for using single parameters such as AC, or even EFW, to detect and monitor
fetal growth abnormalities may require critical re-examination. However, fractional thigh
22
volume still accounts for no more than one half of the variance in neonatal %BF. Other
novel fetal soft tissue parameters must be identified and validated to improve our
understanding of soft tissue development and, possibly, the subsequent risk for disease
in later life.
G.
OTHER CONSIDERATIONS
Safety Issues
The two main bioeffects of ultrasound exposure to fetuses are based on the possibility of
thermal effects and mechanical cavitation (184). Many professional organizations
encourage the prudent use of diagnostic sonography for medically indicated scans by
trained healthcare providers during pregnancy (185). Specific emphasis is placed on the
examiner for using acoustic power settings that are as low as reasonably achievable for
the acquisition of satisfactory diagnostic images (ALARA principle) with the corresponding
use of appropriate output display standards (186). A recent review of this topic suggests
that exposure to diagnostic ultrasound does not pose a significant health risk to either the
expectant mother or her fetus (184). Sheiner and co-workers (187) have performed a
prospective, longitudinal study of three commercially available 3D ultrasound systems to
examine the mechanical and thermal indices during pregnancy. Mean thermal indices
from volume sonography were comparable to corresponding values resulting from
conventional 2D ultrasound scans. However, the mechanical indices for volume
acquisitions were significantly lower than observed using 2D b-mode ultrasonography.
Parental Bonding
It has been known for some time the 2DUS imaging increases bonding between parents
and fetuses (188-190). As practitioners began using 3DUS, it appeared that there was an
even more obvious recognition of the fetus by parents, particularly images of the fetal
face and it appeared that there might be increased bonding between parents and their
fetus. Many physicians hoped that an increase in bonding might lead to a decrease in
abusive behaviors such as child abuse, spousal abuse, maternal smoking and use of
drugs and alcohol however no significant data has yet been published.
Several studies have now been published looking at bonding between parents and the
fetus after observing 3DUS images of their fetus. Certain subsets of patients appear to
benefit more from viewing the images and these include prior anomalies or fetal demise,
surrogate parents, hospice patients carrying fatal anomalies, infertility and family history
of anomalies (191). In a study of 100 patients, Ji and colleagues (192) looked at 50
patients having undergone 2-D ultrasound and 50 patients having undergone 3-D
ultrasound. They found that the patients with 3-D ultrasound shared their photographic
images with more people (median 27.5) than those who had 2-D ultrasound (median
11.0). In another study by Pretorius et al (193), 189 patients filled out, both before and
after 3DUS imaging, a validated questionnaire modified for pregnant parents and found
that bonding had increased.
Drawings of fetuses made by parents have been evaluated by two different teams of
investigators and appeared to increase bonding after undergoing 3DUS (194,195). It was
23
possible to predict which pictures were drawn before and after the 3DUS examination
primarily based on uterine context and positioning of the extremities (195). Parents
appear to have a more realistic view of their fetus after seeing three-dimensional
ultrasound images.
The data regarding bonding is however difficult to assess. Rustico et al (196) found that
facial expressions and hand-to-mouth movements were twice as likely after 4DUS in 48
patients (44%) compared to 2DUS in 52 patients (27%). The 4DUS group had more
women with positive quality, intensity, and global attachment although this was not
statistically significant. In addition, fetal structures and movements visualized were
similar between the two groups, as the face was visualizing 83% after 2DUS and 81%
after 4DUS.
Medicolegal Issues
A common question regarding medical legal use of 3DUS is related to whether the
volumes should be saved. It is clear that much information is within each data volume and
the examination of all data is not feasible for all possible planes. Diagnostic images that
are derived from volume data should be recorded as single images and saved. It is not
mandatory that volume data sets be saved unless there is a need to archive them for
research, consultative, or teaching purposes. This strategy is similar to how MRI and
computed tomography data are archived and stored in clinical practice.
Ultrasound for Entertainment
Patients and medical care providers have various opinions regarding whether parents
should be allowed to have 3DUS examinations for bonding alone. The question is
whether ultrasound examinations are entertainment or reassurance. 3DUS studies are
now being formed in commercial venues as well as pregnancy crisis centers after minimal
training, often at two weeks. The medical community is concerned about biohazards of
diagnostic ultrasound, including the understanding of power output, risk of Doppler to the
early embryo, length of time and frequency of scanning as well as misdiagnosis if
performed by non-skilled personnel outside the medical environment.
Both the Federal Drug Administration and the American Institute of Ultrasound in
Medicine have guidelines recommending that diagnostic ultrasound only be used when
there is a medical indication. The AIUM strongly discourages the nonmedical use of
ultrasound for psychosocial or entertainment purposes. Physicians have varied opinions
regarding the use of ultrasound for reassurance. Dr. Peter Doubilet (197) suggested that
to ban or condemn the use of ultrasound for entertainment is inconsistent with our
acceptance of many other goods and services that provide enjoyment while carrying a
small potential risk. Good examples of the computer, microscope and camera were
described that were all initially single use devices and only later were used for many
different purposes. This Editorial reminds us that we do not forbid airline travel for
pregnant women even though there is a cosmic ray related risk. Noting that our societal
approach is to warn mothers rather than to dictate actions, he also states that businesses
make it clear that entertainment ultrasound is not a diagnostic medical sonogram.
24
H.
EMERGING CONCEPTS
Future developments for volume sonography will include faster imaging systems with
improved detail resolution in both the original plane of volume acquisition as well as
reconstructed planes. Ultrasound volume probes will become smaller and may eventually
rely on the use of matrix array probes for real-time imaging, particularly of the fetal heart.
New software applications will allow us to analyze and quantify volume data in ways that
are currently not possible and the efficiency of clinical workflow will also be improved with
automated algorithms. It may eventually become practical to interactively explore fourdimensional volume data for the moving fetus within a virtual environment. This type of
“virtual ultrasound simulation” would allow improved depth perception and allow joint
discussion with colleagues for telemedicine applications, research, and training (198200).
I.
CONCLUSIONS
Volume sonography is an important complementary diagnostic technique to conventional
2D imaging (201). In this chapter, we have presented a perspective of the current medical
literature with our extensive experiences in this area. Remember that 3DUS is not just
one method, but it is based on a combination of several image visualization tools that
must be customized to answer the pertinent clinical questions being asked. This
technology can be used to improve diagnostic confidence as part of your problem-solving
process. Three-dimensional ultrasonography is still in its infancy as software tools
become more sophisticated and as we begin to apply these versatile capabilities for a
wide variety of clinical problems. Health care providers should be aware of these
emerging capabilities and their potential applications.
Key Points
3DUS uses several different types of image analysis techniques that are based
on the acquisition, processing, and manipulation of volume pixels (voxels).
2DUS and 3DUS are complementary diagnostic imaging modalities.
2DUS should be used to make an initial diagnostic impression and clinical
judgment will determine if there is likely to be a clinical advantage for the
application of 3DUS.
Match the 3DUS technique with a specific clinical question that is being asked.
Do not underestimate the diagnostic value of 3D multi-planar imaging.
Good two-dimensional imaging is likely to translate to satisfactory 3D volume
acquisitions.
25
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32
84. Petrikovsky BM, Kaplan GP. Fetal dacryocystocele: comparing 2D and 3D imaging
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87. Hsu TY, Hsu JJ, Chang SY, Chang MS. Letters to the Editor – Prenatal threedimensional sonographic images associated with Treacher Collins syndrome.
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88. Tanaka Y, Miyazaki T, Kanenishi K, Tanaka H, Yanagihara T, Hata T. Antenatal
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89. Chaoui R, Levaillant JM, Benoit B, Faro C, Wegrzyn P, Nicolaides KH. Threedimensional sonographic description of abnormal metopic suture in second- and
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90. Pretorius DH, Nelson TR. Prenatal visualization of cranial sutures and fontanelles
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91. Dikkeboom CM, Roelfsema NM, Van Adrichem LNA, Wladimiroff JW. The role of
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92. Faro C, Benoit B, Wegrzyn P, Chaoui R, Nicolaides KH. Three-dimensional
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93. Faro C, Wegrzyn P, Benoit B, Chaoui R, Nicolaides KH. Metopic suture in fetuses
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94. Faro C, Wegrzyn P, Benoit B, Chaoui R, Nicolaides KH. Metopic suture in fetuses
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95. Faro C, Chaoui R, Wegrzyn P, Levaillant JM, Benoit B, Nicolaides KH. Metopic
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96. Sivertsen Å, Wilcox A, Johnson GE, Åbyholm F, Vindenes HA, Lie RT.
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100. Rotten D, Levaillant JM. Two-and three-dimensional sonographic assessment of the
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101. Johnson DD, Pretorius DH, Budorick NE, Jones MC, Lou KV. Fetal lip and
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102. Chmait R, Pretorius D, Jones M, Hull A, James G, Nelson T, Moore T. Prenatal
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103. Wang LM, Leung KY, Tang M. Prenatal evaluation of facial clefts by threedimensional extended imaging. Prenat Diagn. 2007;27:722-729.
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105. Campbell S. Prenatal ultrasound examination of the secondary palate. Ultrasound
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This Editorial reviews the current state of knowledge regarding visualization of
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107. Faure JM, Captier G, Bäumler M, Boulot P. Sonographic assessment of normal
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This study describes how 3DUS can be used to examine the normal fetal
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108. Pilu G, Segata M. A novel technique for visualization of the normal and cleft fetal
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109. Faure JM, Bãumler M, Boulot P, Bigorre M, Captier G. Prenatal assessment of the
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111. Lee W, McNie B, Chaiworapongsa T, Conoscenti G, Kalache K, Vettraino IM,
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112. Rotten D, Levaillant JM, Martinez H, Ducou Le Pointe H, Vicaut É. The fetal
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114. Hata T, Yanagihara T, Matsumoto M, Hanaoka U, Ueta M, Tanaka Y, Kanenishi
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115. Pooh RK, Pooh KH, Nakagawa Y, Nishida S, Ohno Y. Clinical application of threedimensional ultrasound in fetal brain assessment. Croat Med J. 2000;41:245-251.
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117. Monteaqudo A, Timor-Tritsch ID, Mayberry P. Three-dimensional transvaginal
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Dr. Pilu and colleagues provide useful examples of how 3DUS can be
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151. Chang CH, Tsai PY, Yu CH, Ko HC, Chang FM. Predicting fetal growth restriction
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