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issue is the gestational age at which the study is performed. In the Eurofetus Study, for example, 38.5% of
the anomalies were diagnosed after 29 weeks’ gestation.
Other factors influencing sensitivity of prenatal sonography include the quality of equipment, prevalence of
a particular defect, maternal body habitus, and examination protocol.
19,28,29
Many of the benefits of ultrasound are nonquantifiable. Having time to adjust prenatally to information
about an anomaly can improve both the clinician’s and
the parents’ approach to the pregnancy and birth, as well
as their abilities to make decisions about prenatal and
postnatal treatment.
30
It is important for patients and
their physicians to understand the limitations of ultrasound. Not all abnormalities can be detected. The accuracy of prenatal ultrasound is variable and often depends
on where and by whom it is being performed.
Three- and Four-Dimensional
Ultrasound
In addition to two-dimensional (2-D) images, 3-D and
4-D imaging allow for reconstructed images in planes
that were not previously available. This allows for
improved visualization of facial anomalies
lies of the hands, feet, and spine.
images may be more comprehensible to the patient,
allowing for better understanding of the abnormality.
Cervical assessment is also thought to be more complete
with volume imaging.
to assess the lungs,
33
Volume imaging can be used
34,35
which is used in fetuses with
suspected pulmonary hypoplasia. Reconstructed images
can be helpful to image portions of the brain.
31
32
and anoma-
In addition, 3-D
36
Sub-
31,32
sequent chapters integrate 3-D and 4-D images as
appropriate.
Prudent Use of Ultrasound
The AIUM, ACR, and American College of Gynecologists (ACOG) collaborative guidelines state that “Fetal
ultrasound should be performed only when there is a
valid medical reason, and the lowest possible ultrasonic
exposure settings should be used to gain the necessary
diagnostic information.”
6
Although there is no reliable
evidence of physical harm to human fetuses from diagnostic ultrasound imaging using current technology,
public health experts, clinicians, and industry representatives agree that casual use of sonography, especially
during pregnancy, should be avoided. The U.S. Food
and Drug Administration (FDA) views the promotion,
sale, or lease of ultrasound equipment for making “keepsake” fetal videos as an unapproved use of a medical
37
device.
Medically indicated obstetric imaging can easily
integrate making copies of key images for parents who
want an early view of their baby.
Chapter 28 ■ Overview of Obstetric Imaging 1057
MAGNETIC RESONANCE IMAGING
Ultrasound is the screening modality of choice for fetal
imaging. However, when additional information regarding fetal anatomy or pathology is needed, fast MR
imaging is increasingly being used as a correlative imaging
modality in select cases (Fig. 28-17). MRI is useful in
these cases because it has no ionizing radiation, provides
excellent soft tissue contrast, has multiple planes for
reconstruction, and has a large field of view, allowing
for improved depiction of many complex fetal
abnormalities.
It is important to tailor the examination to answer
specific questions raised either by patient history or by
prior sonographic examination. In the past decade, software and hardware have allowed for fetal MR images to
be obtained in about 400 milliseconds. This allows for
fetal imaging to be performed without maternal or fetal
sedation. The ease of performing these examinations and
the superb contrast resolution afforded by T2-weighted
MRI have popularized the use of this imaging tool to
improve prenatal diagnosis.
There are no known biologic risks from MRI. The
MR procedure is not believed to be hazardous to the
38-50
fetus.
No delayed sequelae from MR examination
have been encountered, and it is expected that the potential risk for any delayed sequelae is extremely small or
nonexistent.
Gadolinium is the contrast typically used for MR
studies, but it is not recommended for fetal examination.
Gadolinium crosses the placenta and appears within the
fetal bladder soon after intravenous administration. The
contrast is excreted from the fetal bladder into the amniotic fluid, where it is then swallowed and potentially
reabsorbed from the gastrointestinal tract. Because of
this reabsorption, the half-life of gadolinium in the fetal
circulation is not known.
51
This drug has been shown to
have adverse effects on the fetus in animal models.
Gadopentetate dimeglumine has been shown to impair
development slightly in rats (at 2.5 times the human
dose, 0.1 mmol/kg), and in rabbits (at 7.5 times the
human dose).
52,53
It is considered a pregnancy category
C drug, meaning that it should be given only if potential
benefit outweighs the risk; animal studies have revealed
adverse effects, but no controlled studies have been performed in humans.
52
Therefore, we do not use contrast
for fetal examinations at our institution.
CONCLUSION
Ultrasound is a readily available, noninvasive, and safe
means of evaluating fetal health, determining gestational
age, and assessing the intrauterine environment. It is
an indispensable tool for the practice of obstetrics.
1058 PART IV ■ Obstetric Sonography
A
B C
D E F
G H I
FIGURE 28-17. Normal fetal MRI: representative T2-weighted images. A, Sagittal view of fetal head with fetal body
in coronal plane. B, Sagittal view of fetal head. Note normal appearance of corpus callosum and soft palate, with fluid outlining the soft
palate above the tongue. C, Coronal view of the brain, chest, and abdomen. Note normal appearance to the lungs, diaphragm, stomach,
and kidneys. D, Axial view of brain with normal-appearing lateral ventricles. E, Oblique axial view of brain shows normal cerebellar
hemispheres and vermis. F, Axial view at level of globes. Note the dark lens in each globe. G, Axial view at level of palate. Note that
majority of the alveolar tooth-bearing ridge is well depicted. H, Axial view at level of stomach and gallbladder. Note spinal cord outlined
by fluid in thecal sac. I, Axial view at level of bladder.
Ultrasound is also a screening test, yielding results that
must be interpreted and integrated in a knowledgeable
way. As with physical examination, the ultrasound study
is most helpful when performed in a consistent and
reproducible fashion, carefully documenting positive
and negative findings important in clinical decision
making. The information gained from routine obstetric
ultrasound may provide reassurance, guide therapy, or
identify a pathologic condition that merits further
investigation.
Chapter 28 ■ Overview of Obstetric Imaging 1059
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5. Abuhamad AZ, Benacerraf BR, Woletz P, Burke BL. The accreditation
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17. Bakketeig LS, Eik-Nes SH, Jacobsen G, et al. Randomised controlled
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18. Blondel B, Ringa V, Breart G. The use of ultrasound examinations,
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19. Levi S, Hyjazi Y, Schaapst JP, et al. Sensitivity and specificity of routine
antenatal screening for congenital anomalies by ultrasound: the
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1:102-110.
20. Bucher HC, Schmidt JG. Does routine ultrasound scanning improve
outcome in pregnancy? Meta-analysis of various outcome measures.
BMJ 1993;307:13-17.
21. Lys F, De Wals P, Borlee-Grimee I, et al. Evaluation of routine
ultrasound examination for the prenatal diagnosis of malformation.
Eur J Obstet Gynecol Reprod Biol 1989;30:101-109.
22. Rosendahl H, Kivenen S. Antenatal detection of congenital malformations by routine ultrasonography. Obstet Gynecol 1989;73:
947-951.
23. Shirley IM, Bottomley F, Robinson VP. Routine radiographer screening for fetal abnormalities by ultrasound in an unselected low-risk
population. Br J Radiol 1992;65:564-569.
24. Luck CA. Value of routine ultrasound scanning at 19 weeks: a fouryear study of 8849 deliveries. BMJ 1992;304:1474-1478.
25. Chitty LS, Hunt GH, Moore J, Lobb MO. Effectiveness of routine
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26. Levi S, Montenegro NA. Eurofetus: an evaluation of routine ultrasound screening for the detection of fetal defects—aims and method.
Ann NY Acad Sci 1998;847:103-117.
27. Fadda GM, Capobianco G, Balata A, et al. Routine second trimester
ultrasound screening for prenatal detection of fetal malformations in
Sassari University Hospital, Italy: 23 years of experience in 42,256
pregnancies. Eur J Obstet Gynecol Reprod Biol 2009;144:110-
114.
28. Grandjean H, Larroque D, Levi S. The performance of routine ultrasonographic screening of pregnancies in the Eurofetus Study. Am J
Obstet Gynecol 1999;181:446-454.
29. Crane JP, LeFevre ML, Winborn RC, et al. A randomized trial of
prenatal ultrasonographic screening: impact on the detection, management, and outcome of anomalous fetuses. The RADIUS Study
Group. Am J Obstet Gynecol 1994;171:392-399.
30. Berwick DM, Weinstein MC. What do patients value? Willingness to
pay for ultrasound in normal pregnancy. Med Care 1985;
23:881-893.
31. Johnson DD, Pretorius DH, Budorick NE, et al. Fetal lip and primary
palate: three-dimensional versus two-dimensional ultrasound. Radiology 2000;217:236-239.
32. Dyson RL, Pretorius DH, Budorick NE, et al. Three-dimensional
ultrasound in the evaluation of fetal anomalies. Ultrasound Obstet
Gynecol 2000;16:321-328.
33. Bega G, Lev-Toaff A, Kuhlman K, et al. Three-dimensional multiplanar transvaginal ultrasound of the cervix in pregnancy. Ultrasound
Obstet Gynecol 2000;16:351-358.
34. Gerards FA, Engels MA, Twisk JW, van Vugt JM. Normal fetal lung
volume measured with three-dimensional ultrasound. Ultrasound
Obstet Gynecol 2006;27:134-144.
35. Jani J, Cannie M, Sonigo P, et al. Value of prenatal magnetic
resonance imaging in the prediction of postnatal outcome in fetuses
with diaphragmatic hernia. Ultrasound Obstet Gynecol 2008;32:
793-799.
36. Zalel Y, Yagel S, Achiron R, et al. Three-dimensional ultrasonography
of the fetal vermis at 18 to 26 weeks’ gestation: time of appearance
of the primary fissure. J Ultrasound Med 2009;28:1-8.
37. US Food and Drug Administration. Fetal keepsake videos. Washington, DC, 2005, FDA.
Magnetic Resonance Imaging
38. Wolff S, Crooks LE, Brown P, et al. Tests for DNA and chromosomal
damage induced by nuclear magnetic resonance imaging. Radiology
1980;136:707-710.
39. Kanal E, Gillen J, Evans JA, et al. Survey of reproductive health
among female MR workers. Radiology 1993;187:395-399.
40. Baker PN, Johnson IR, Harvey PR, et al. A three-year follow-up of
children imaged in utero with echo-planar magnetic resonance. Am
J Obstet Gynecol 1994;170:32-33.
41. Chew S, Ahmadi A, Goh PS, Foong LC. The effects of 1.5T magnetic
resonance imaging on early murine in-vitro embryo development.
J Magn Reson Imaging 2001;13:417-420.
42. Clements H, Duncan KR, Fielding K, et al. Infants exposed to MRI
in utero have a normal paediatric assessment at 9 months of age. Br
J Radiol 2000;73:190-194.
43. Glover P, Hykin J, Gowland P, et al. An assessment of the intrauterine
sound intensity level during obstetric echo-planar magnetic resonance
imaging. Br J Radiol 1995;68:1090-1094.
44. Kok RD, de Vries MM, Heerschap A, van den Berg PP. Absence of
harmful effects of magnetic resonance exposure at 1.5 T in utero
during the third trimester of pregnancy: a follow-up study. Magn
Reson Imaging 2004;22:851-854.
45. Levine D, Zuo C, Faro CB, Chen Q. Potential heating effect in the
gravid uterus during MR HASTE imaging. J Magn Reson Imaging
2001;13:856-861.
46. Merkle EM, Dale BM, Paulson EK. Abdominal MR imaging at 3T.
Magn Reson Imaging Clin N Am 2006;14:17-26.
1060 PART IV ■ Obstetric Sonography
47. Myers C, Duncan KR, Gowland PA, et al. Failure to detect intrauterine growth restriction following in utero exposure to MRI. Br J Radiol
1998;71:549-551.
48. Schwartz JL, Crooks LE. NMR imaging produces no observable
mutations or cytotoxicity in mammalian cells. AJR Am J Roentgenol
1982;139:583-585.
49. Shellock FG, Crues JV. MR procedures: biologic effects, safety, and
patient care. Radiology 2004;232:635-652.
50. US Food and Drug Administration. Guidance for content and review
of a magnetic resonance diagnostic device 510 (k) application. Washington, DC: FDA; 1988.
51. Shellock FG, Kanal E. Bioeffects and safety of MR procedures. In:
Edelman RR, Hesselink JR, Zlatkin MB, editors. Clinical magnetic
resonance imaging. 2nd ed. Philadelphia: Saunders; 1996. p. 429.
52. Magnevist product information. Wayne, NJ: Berlex Laboratories;
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53. Runge VM. Safety of approved MR contrast media for intravenous
injection. J Magn Reson Imaging 2000;12:205-213.
CHAPTER 29
Bioeffects and Safety of
Ultrasound in Obstetrics
Jacques S. Abramowicz
Chapter Outline
INSTRUMENT OUTPUTS
Scanning Mode
System Setup
Dwell Time
THERMAL EFFECTS
MECHANICAL EFFECTS
BIOEFFECTS OF ULTRASOUND
Animal Research
Human Studies
Birth Weight
Delayed Speech
Dyslexia
Non-Right-Handedness
Neurologic Development and
Behavioral Issues
Half a century of extensive use in clinical obstetric and
radiologic practice has shown that ultrasound does not
cause major abnormalities in the fetus. Ultrasound is a
form of energy, however, and one must consider whether
subtle effects are possible when such energy penetrates
living tissues. Although some effects have been described
in animals, no immediate human correlation can be
made. Conversely, “no effects detected so far” does not
necessarily means “no effect.” Only large, epidemiologic
studies can solve this problem. In the United States,
most women who receive prenatal care are referred for
at least one ultrasound scan; in many other countries,
almost 100% of these women are exposed to ultrasound.
Multiple examinations are often performed, with or
without clear indication. Because of this near-universal
exposure of pregnant women and their unborn child to
ultrasound, the issues of possible effects and safety need
to be addressed.
Whether short-term or long-term adverse bioeffects to
the fetus may result from exposure to ultrasound is a
major issue. It is well established that under certain conditions, ultrasound can have undesirable side effects.
Two conflicting points need clarification: (1) to date, no
evidence has been found of harmful effects of ultrasound
in humans at clinical exposure levels, but (2) all available
published epidemiologic data are from before 1992.
Since then, acoustic output of diagnostic systems for
fetal use was increased by a factor of almost 8, from
94 mW/cm2 to 720 mW/cm2, and, in reality, a factor of
16 (from 46 mW/cm2) based on earlier regulations.26
Additional concerns follow:
• An increasing number of fetuses in the first
trimester, a time of maximal susceptibility to
1
2-25
Congenital Malformations
Childhood Malignancies
SAFETY GUIDELINES
CONCLUSION
external insults, are exposed to ultrasound,
particularly spectral Doppler.
27
• “Entertainment” ultrasound, scanning to obtain
pictures or videos of the fetus (fetal “keepsake”
video) without a medical indication has burgeoned
despite calls for avoidance of unnecessary
exposure.
29-31
• Clinical users of obstetric ultrasound appear to have
limited knowledge and awareness of bioeffects and
32
safety.
Thus the main goals of this chapter are as follows:
1. Summarize the literature on bioeffects in
experimental settings as well as the available
knowledge on bioeffects in the human fetus.
2. Analyze changes that occurred over time in energy
levels of ultrasound machines and the regulations
involved.
3. Describe how manipulation of many
instrument controls alters acoustic energy and
thus exposure.
4. Educate sonographers and physicians on how best
to minimize fetal exposure without sacrificing
diagnostic quality.
INSTRUMENT OUTPUTS
Over the years, output of ultrasound instruments has
increased.
alter the output. For example, keeping in mind that
the degree of temperature elevation is proportional to the
product of the amplitude of the sound wave times the
pulse length and the pulse repetition frequency, it
33
Furthermore, many machine controls can
28
1061
1062 PART IV ■ Obstetric Sonography
A B
FIGURE 29-1. Effect of changing power setting on thermal index of bone (TIB) during spectral Doppler
velocity measurements of umbilical artery. A, The output power is high, and the thermal index (TI) is 1.7 (see highlighted
gray box, upper right). B, The power has been lowered; the TI is now 0.1, and the tracing is still diagnostic.
becomes immediately evident why any change (augmentation) in these characteristics can add to the risk of
elevating the temperature, a potential mechanism for
bioeffects. Three important parameters under end-user
control are the (1) scanning/operating mode (including
transducer choice), (2) system setup and output control,
and (3) dwell time.
Scanning Mode
When comparing modes, the spatial peak, temporal
average intensity (I
) increases from B-mode (34 mW/
SPTA
cm2, average) to M-mode to color Doppler to spectral
Doppler (1180 mW/cm2, average).34 Average I
SPTA
values
are 1 W/cm2 in Doppler mode but can reach 10 W/cm2.
Caution is therefore recommended when applying this
mode. Color Doppler has higher intensities than B-mode
but is still much lower than spectral Doppler, mainly
because of the mode of operation: sequences of pulses,
scanned through the area of interest (“box”). High pulse
repetition frequencies (PRFs) are used in pulsed Doppler
techniques, generating greater temporal average intensities and power than B-mode or M-mode and thus greater
heating potential. Also, because the beam needs to be
held in relatively constant position over the vessel of
interest in spectral Doppler ultrasound, temporal average
intensity may further increase. This is particularly concerning in first-trimester applications. In addition,
transducer choice is important because it will determine: frequency, penetration, resolution, and field
of view.
System Setup
Starting or default output power is another important
ultrasound parameter. Some manufacturers “boot” their
machines with high power, which supposedly produces
a better image, and the sonographer must act to decrease
that power. Other systems boot up with low power and,
only if judged necessary, the sonographer will increase
that power. In Figure 29-1, for example, the Doppler
signal in A was obtained with a high power, whereas in
B the power was greatly reduced, and the image is still
diagnostic. Also, the examiner fine-tunes to optimize the
image, influencing output but with no visible effect,
except to change thermal index (TI) and mechanical
index (MI), as discussed in Chapter 2.
Controls that regulate output include focal depth,
usually with greatest power at deeper focus but occasionally with highest power in the near field; increasing
frame rate; and limiting the field of view, as by highresolution magnification or certain zooms. In Doppler
mode, changing sample volume and velocity range (to
optimize received signals) will change output. In Figure
29-2, only the size of the color box is smaller, which
caused increased TI on the output. It should be remembered that receiver gain often has similar effects as these
controls on the recorded image, but no effect on the
output of the outgoing beam, and therefore it is completely safe to manipulate.
Dwell Time
Dwell time is the actual scanning time and thus directly
under control of the examiner. Dwell time is not taken
into account in the calculation of the safety indices and
generally is not reported in clinical or experimental
studies. However, it takes only one pulse to induce cavitation, and about a minute to raise temperature to its
peak. Directly correlated with dwell time is examiner
experience: knowledge of anatomy, bioeffects, instrument controls, and scanning techniques.
Chapter 29 ■ Bioeffects and Safety of Ultrasound in Obstetrics 1063
A B
FIGURE 29-2. Effect of changing size of color box on thermal index of bone (TIB) during color Doppler
examination of umbilical cord. Changing the size of the box from large (A) small (B) changes the TI (red squared number at top
right) from 0.2 to 0.5.
gens, the central nervous system (CNS) is most at risk
THERMAL EFFECTS
because of a lack of compensatory growth by undamaged
neuroblasts. In experimental animals the most common
Thermal changes induced by ultrasound have been demonstrated in various animals, with hyperthermia clearly
shown to be teratologic to many species.
maternal temperature, whether from illness or exposure
to heat, can produce teratogenic effects.
rise less than 2° C is thought to be safe,
temperature increase for any amount of time may have
some effect,
significant.
48,60
and a rise of 2.5° C may be considered
61
A major question is whether diagnostic
ultrasound can induce a rise in temperature in the fetus
that could reach dangerous levels.
elevation in the human fetus cannot be exactly measured
but can be estimated fairly accurately.
ultrasound exposures, temperature elevations of up to
5° C have been obtained.
59
Thus, any temperature incre-
35-44
17,38,40-43,45-58
59
although any
19,59,62
Temperature
63,64
For prolonged
Elevated
A
ment for any period of time has some effect; the higher
the temperature differential or the longer the temperature increment, the greater is the likelihood of producing
an effect. Although these assumptions cannot be demonstrated in diagnostic ultrasound and no human data
exist, clinicians should keep these facts in mind when
performing obstetric ultrasound. This also forms part of
the argument against nonmedical or nonindicated ultrasound examinations.
As with any external influence on the pregnancy, ges-
tational age is a vital factor. Milder (in time or inten-
sity) exposures during the preimplantation period (very
early gestational age) could have similar or worse consequences than more severe exposures during embryonic
and fetal development and could result in fetal demise
and abortion or structural and functional defects. Such
a dose analysis is not available. As for many other terato-
defects associated with temperature increase are of the
neural tube (anencephaly, microencephaly) and the
eyes (microphthalmia, cataract). Associated with CNS
defects are functional and behavioral problems.
organ defects secondary to hyperthermia include defects
of craniofacial development(e.g., clefts
of the axial and appendicular skeleton,
teeth, and heart.
67
65
) and anomalies
66
46
Other
the body wall,
Gestational age is critical when considering heat
dispersion. In midterm, there was no significant differ-
ence when guinea pig fetal brains were exposed, alive
(perfused) or postmortem (non-perfused), in the focal
region of the ultrasound beam. However, a significant
cooling effect of vascular perfusion was observed when
the fetuses reached the stage of late gestation near term,
when the cerebral vessels were well developed.
human pregnancy, less than 6 weeks, the minimal fetal
perfusion may reduce heat dispersion.
68
In early
69
The increased
sensitivity of Doppler devices suggests evidence of blood
flow within embryonic vesicles after heart formation,
with the simultaneous development of a uterine circulatory pathway in the developing placenta. The flow is
often termed “nonpulsatile” or “percolating”
70,71
with
near-minimal Doppler-measured velocities, as opposed
to later in pregnancy. At about week 12 of gestation, the
plugs of the spiral arteries are “loosened” and allow for
freer blood circulation.
72,73
Thus, perfusion status is far from approaching that for
normal tissue levels (as assumed in the TI algorithm) for
much of the first trimester. Only later, when “free circulation” is established (about week 11-12 of gestation),
does the tissue become normally perfused, when the
1064 PART IV ■ Obstetric Sonography
embryonic circulation actually links up with the maternal circulation.
73
This absence of perfusion may result
in underestimation of the actual ultrasound-induced
temperature in early gestation. This warrants extreme
caution in first-trimester scanning, particularly with the
recent increase in utilization of Doppler in the first
trimester.
74-77
Also, the issue of transducer heating may be particularly relevant in the first trimester, if performing endovaginal scanning.
76,78
A mitigating factor is motion (even
very small) of the examiner’s hand, as well as the patient’s
breathing and body movements (in obstetric ultrasound,
both mother and fetus), which tend to spread the region
being heated. However, for spectral (pulsed) Doppler
studies, it is necessary to have the transducer as steady as
possible. Because the intensity and acoustic power associated with Doppler ultrasound are the highest of all the
general-use categories, time spent scanning with Doppler
ultrasound mode is crucial. Ziskin
79
reported that average
duration of 15,973 Doppler ultrasound examinations
was 27 minutes (longest, 4 hours!). It is clear that temperature increases of 1° C are easily reached in routine
scanning.
the first trimester and up to 4° C in the second and third
trimesters, particularly with the use of pulsed Doppler.
80
Elevation of up to 1.5° C were obtained in
81
In many clinical machines, TI values of 5 or 6 can be
obtained in Doppler mode.
MECHANICAL EFFECTS
Although effects have been described in neonates or
adult animals, because gas bubbles are not present in
fetal lung or bowel, it is assumed that the risk from
mechanical effect secondary to cavitation is minimal.
Several other mechanical effects do not appear to involve
cavitation, such as tactile sensation of the ultrasound
wave, auditory response, cell aggregation, and cell
membrane alteration. Hemolysis has also been
reported,
82
although some cavitation nuclei must be
present for hemolysis to occur. Such microbubbles
would be provided by the introduction of ultrasound
contrast agents to the area under ultrasound examination. However, there is currently no clear clinical indication for the use of these agents in fetal ultrasound.
In addition, fetal stimulation caused by pulsed ultrasound insonation has been described, with no apparent
relation to cavitation.
85
This effect may be secondary to
radiation forces associated with ultrasound exposures.
No harmful effects of diagnostic ultrasound secondary
to nonthermal mechanisms have been reported in
human fetuses. However, because of these known
mechanical effects of ultrasound in living tissues, and
because pressures in Doppler propagation are much
higher than in B-mode, further caution is recommended
in the use of ultrasound, particularly in the first
trimester.
86
10
83,84
BIOEFFECTS OF ULTRASOUND
Animal Research
Multiple studies have shown effects of ultrasound in a
wide variety of species.
the brain and liver of cats showed well-defined lesions
and demyelination in the brain
the liver
92
resulting from ultrasound exposure of a few
seconds at 1 and 3 MHz, respectively. Other observed
effects include limb paralysis, as a result of spinal cord
injury in the rat,
93,94
and testes of rabbits.
strated in male mice after in utero ultrasound exposure
of the testes.
96
Although some effects are likely caused by
mechanical processes, very high temperature elevations
(much higher than with diagnostic ultrasound) may be
more directly involved with the tissue damage. It took
acoustic pressures generated by lithotripsy to obtain
effects in muscles,
and lungs.
99
These intensities are much higher than in
diagnostic ultrasound but are helpful in understanding
the mechanisms involved with possible bioeffects of
ultrasound.
Several major clinical end points for bioeffects in
animals that could have direct relevance to human
studies include fetal growth and birth weight, effects on
brain and CNS function, and change in hematologic
function. High-level exposures were associated with
decreased body weight at birth in exposed monkeys compared with controls, but all showed catch-up growth
when examined at 3 months of age.
weight after prenatal exposure to ultrasound has also
been reported in mice,
103
Clear species differences therefore seem to exist,
rats.
making it difficult to extrapolate to the human. In a
report of 30 pregnancies in monkeys, half were exposed
to ultrasound.
100
weights and were shorter than the control group. No
significant differences were noted in rate of abortions,
major malformations, or stillbirths. Moreover, all showed
catch-up growth when examined at 3 months of age.
In-situ intensities were higher than routinely used in
clinical obstetric imaging in the human. Studies in
mice have shown increased mortality, and decreased
body weight after in utero exposure to diagnostic ultra-
105,106
sound.
Gross lesions have been described in the
central nervous system
Neurologic or behavioral findings may be sensitive
markers of teratogenic effect.
mice were exposed to diagnostic ultrasound for 10, 20,
or 30 minutes on day 14.5 (fetal period) of gestation and
compared with sham-exposed controls.
behavioral alterations in the exposed groups included
decreased locomotor and exploratory activity and more
trials needed for learning. No changes were observed in
physiologic reflexes or postnatal survival. The authors
87-90
Studies of gross effects on
91
and tissue damage in
as well as lesions in the liver, kidney,
95
Changes in fertility were demon-
97
as well as hemorrhage in bowel98
100
Decreased birth
101,102
but not convincingly in
The scanned fetuses had lower birth
107
and the spine94 in mammals.
87,108
Pregnant Swiss albino
109
104
Significant
Chapter 29 ■ Bioeffects and Safety of Ultrasound in Obstetrics 1065
concluded that ultrasound exposure during the early
fetal period can impair brain function in the adult
109
mouse.
increased anxiolytic activity and learning latency in ultrasound-treated animals.
In another study, the same authors found
110
Pregnant Swiss albino mice
were exposed to similar diagnostic levels of ultrasound
for 10 minutes on days 11.5 or 14.5. Behavioral tests at
3 and 6 months postpartum showed more pronounced
effects in the 14.5-day than in the 11.5-day group. The
authors concluded that exposure to diagnostic ultrasound during the late organogenesis period or early
fetal period in mice may cause changes in postnatal
behavior.
110
A very intriguing paper was published on memory
changes in chicks after being insonated in ovo with
various levels of Doppler ultrasound.
111
Exposure was to
5 or 10 minutes of B-mode, or to 1, 2, 3, 4, or 5 minutes
of pulsed Doppler ultrasound. Two hours after hatching,
chicks were trained to recognize certain colors in relation
to some feeding procedures. B-mode exposure on day 19
(of a 21-day gestation) did not affect memory. However,
significant memory impairment occurred after 4 and 5
minutes of pulsed Doppler exposure, as expressed by the
inability to discern the colors. Short-, intermediate- and
long-term memory was equally impaired, suggesting an
inability to learn. The chicks were still unable to learn
with a second training session. While there are major
differences in terms of length of gestation, amount of
“energy received,” and other technical issues when compared with human fetal exposure, these findings raise
important questions on the potential effect of pulsed
Doppler ultrasound in utero exposure on cognitive
function.
As mentioned previously, ultrasound induces thermal
changes in various animals, and hyperthermia clearly is
teratogenic to many species.
35-44,68
In guinea pigs, mean
temperature increases of 4.9° C close to parietal bone
and 1.2° C in the midbrain were recorded after 2-minute
ultrasound exposures, although at exposure conditions
higher than usually employed in clinical examinations.
68
After only 2 minutes of insonation with an ISPTA of
2.9 W/cm2 (about four times higher than the current
FDA allowance for diagnostic use), mean maximum
temperature increases varied from 1.2° C at 30 days to
5.2° C at 60 days. Importantly, 80% of the mean
maximum temperature increase occurred within 40
seconds. This rapid rate of heating is relevant to the
safety of clinical examinations in which the dwell time
may be an important factor. Because maximal ultrasound-induced temperature increase occurs in the fetal
brain near bone, worst-case heating will occur later in
pregnancy, when the ultrasound beam impinges on
bone, and less will occur earlier in pregnancy, when bone
is less mineralized. This is one of the justifications to
utilize thermal index for bone (TIB) late in pregnancy
and thermal index for soft tissue (TIS) earlier.
In 2006, Ang et al.
112
evaluated the effect of ultra-
sound insonation in pregnant mice on neuronal position
within the embryonic cerebral cortex of the fetuses.
Neurons generated at embryonic day 16 that normally
migrate to the superficial cortical layers were chemically
labeled. A small but statistically significant number of
neurons remained scattered within inappropriate cortical
layers and in the subjacent white matter, failing to
acquire their proper position when exposed to ultrasound for a total of 30 minutes or longer during their
migration. However, several major differences exist
between this experimental setup and clinical ultrasound
in humans,
113
most notably the length of exposure (up
to 7 hours). No real mechanistic explanation was given
for the findings, there was no real dose-response effect,
and scans were performed over a short period of several
days. The experimental setup was such that embryos
received whole-brain exposure to the beam, which is rare
in humans (although possible very early in pregnancy),
and the small brains of mice develop over days. Thus,
although the study merits repeating, the applicability to
human embryology is questionable.
113
These animal studies suggest precaution with obstetric
ultrasound. However, the animal studies to date do not
implicate ultrasound used at daily clinical exposure levels
with major adverse fetal effects.
Human Studies
Several epidemiologic studies on obstetric ultrasound
exposure have been published,
21,51,114-117
although some
have serious limitations, such as lack of a testable hypothesis for causation of the studied effect, small samples,
poorly matched controls, and most often, lack of information on acoustic output and exact quantification of exposure (number of episodes, duration of exposure, and
inability to calculate “dose”). These limitations are a major
problem when analyzing published data,
118
with new imaging modalities that have potentially high
energy levels and new applications of existing modalities.
Typical examples are spectral Doppler ultrasound analysis
of the tricuspid artery at 11 to 14 weeks’ gestation in
screening for Down syndrome
heart anatomy and function during the first trimes-
75,119-122
ter.
There is no epidemiologic or other informa-
27
and studies of the fetal
tion on levels of exposure or possible effects at these early,
particularly susceptible gestational ages. Several “epidemiologic” reports are actually case-control studies and
require caution in interpretation. The effects being studied
(e.g., low estimated fetal weight) may be the same as the
clinical indication for performing the ultrasound examination (“suspected intrauterine growth delay”). Thus an
association may exist between the ultrasound and the
growth delay, but not a causal relationship.
A further crucial confounding factor is that major congenital anomalies occur in 3% to 5% of the general human
population. An increment of 1% to 2% over this “background” incidence would be a major clinical effect but
might go undetected as an individual finding in routine
clinical practice, and would be detectable only after
particularly
1066 PART IV ■ Obstetric Sonography
prolonged observation in large populations. Also, some
underreporting occurs; for example, a certain number of
birth defects is expected in any ultrasound study in relatively large (>1000) populations. Often, however, these
studies describe no anomalies in the study group or in the
control population; in a survey of more than 121,000
patients among 68 examiners, combining 292 instituteyears of experience, 3000 to 5000 anomalies would be
expected as background rate, but none were reported.
123
In fact, rigorous epidemiologic studies of the adverse
bioeffects of ultrasound are scarce. Several biologic end
points have been analyzed in the human fetus or neonate
to determine whether prenatal exposure to diagnostic
ultrasound had observable effects: intrauterine growth
restriction (IUGR) and low birth weight,
125
speech,
and mental development or behavioral issues,
malignancies,
vision and hearing,
130
and non-right-handedness.
126
dyslexia,
124
delayed
127
neurologic
131,132
Most
128,129
findings have never been duplicated, and the majority of
studies have been negative for any association, with the
possible exception of low birth weight.
There are no epidemiologic studies related to the
output display standard (thermal and mechanical indices)
and clinical outcomes. Only a few clinical studies describe
routine scan,
nuchal translucency screening,
and 3-D/4-D ultrasound.
some studies address the issue of repeat scans,
133
first-trimester scan,
135
137
Furthermore, although
134
particularly,
as well as Doppler
138,139
it was
136
not as an analysis of potential cumulative effects for
which no information is available.
Birth Weight
In one often-quoted study in of more than 2000 infants,
a small (116 grams at term) but statistically significant
lower mean birth weight was found in the half exposed
to ultrasound compared with the nonexposed group.
140
However, information was collected several years after
exposure, with no indications known and no exposure
information available. Moreover, in a later study, the
authors concluded that the relationship of ultrasound
exposure to reduced birth weight may be caused by
shared common risk factors, which lead to both exposure and a reduction in birth weight,
141
an association
but not a causal relationship.
A twice-greater risk of low birth weight was reported
in another retrospective study after four or more exposures to diagnostic ultrasound.
21
These results were not
reproduced in another retrospective study with a large
population, originally of 10,000 pregnancies exposed to
ultrasound matched with 500 controls and with 6-year
follow-up.
142
No increased congenital malformations,
chromosomal abnormalities, infant neoplasms, speech or
hearing impairment, or developmental problems were
observed in this latter study.
In a randomized controlled trial of more than 2800
pregnant women, about half received five ultrasound
imaging and Doppler flow studies at 18, 24, 28, 34, and
38 weeks of gestation, and half received a single ultrasound imaging at 18 weeks.
143
An increased risk of IUGR
was detected in those exposed to frequent Doppler ultrasound examinations, possibly through effects on bone
growth. However, when children were examined at 1
year of age, there were no differences between the study
and control groups. In addition, after examining their
original subjects after 8 years, the investigators found no
evidence of adverse neurologic outcome.
other randomized studies found no harmful effect of
one or two prenatal scans on growth.
144,145
Curiously, in
some studies, birth weight was slightly higher in the
scanned group, but not significantly, except in one group
of newborns exposed to ultrasound in utero who weighed
on average 42 g (75 g in reported smokers) more than
the control group.
Although extensively analyzed, ultrasound exposure in
145
utero does not appear to be associated with reduced birth
weight, although Doppler ultrasound exposure may have
some risks.
116
Delayed Speech
To determine if an association exists between prenatal
ultrasound exposure and delayed speech in children,
Campbell et al.
125
studied 72 children with delayed
speech and found a higher rate of ultrasound exposure
in utero than the 144 control subjects. However, this
retrospective study used records more than 5 years old,
with neither a dose-response effect nor any relationship
to time of exposure. A much larger study of more than
1100 children exposed in utero and 1000 controls found
no significant differences in delayed speech, limited
vocabulary, or stuttering.
Dyslexia
146
Dyslexia has been extensively studied. Stark et al.
compared more than 4000 children (ages 7-12 years)
exposed to ultrasound in utero to matched controls,
analyzing outcome measures at birth (Apgar scores, gestational age, head circumference, birth weight, length,
congenital abnormalities, neonatal/congenital infection)
or in early infancy (hearing, visual acuity/color vision,
cognitive function, behavior). No significant differences
were found, except for a significantly greater proportion
of dyslexia in children exposed to ultrasound. Given the
design of the study and the presence of several possible
confounding factors, the authors indicated that dyslexia
could be incidental.
Subsequently, long-term follow-up studies of more
than 600 children with various tests for dyslexia (e.g.,
spelling, reading) were performed.
147-151
End points
included evaluation for dyslexia along with examination
of non-right-handedness, said to be associated with dyslexia. No statistically significant differences were found
between ultrasound-exposed children and controls for
reading, spelling, arithmetic, or overall performance,
139
Similarly,
127
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