Fleischer’s Sonography in Obstetrics & Gynecology [8th ed.] 9781259641350

The most authoritative guide to sonography in obstetrics and gynecology—completely revised to reflect the latest technol

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Fleischer’s Sonography in Obstetrics & Gynecology [8th ed.]
 9781259641350

Table of contents :
Cover......Page 1
Tribute......Page 2
I. General Obstetric Sonography......Page 4
1. Ultrasound Bioeffects and Safety: What the Practitioner Should Know......Page 5
2. Normal Pelvic Anatomy as Depicted with Transvaginal Sonography......Page 28
3. Transvaginal Sonography of Early (First Trimester) Intrauterine Pregnancy......Page 48
4. Transvaginal Sonography of Ectopic Pregnancy......Page 84
5. Ultrasound of the Fetus at 11 to 18 Weeks......Page 112
6. Fetal Biometry......Page 140
7 Placenta, Cord, and Membranes......Page 164
8. Sonographic Diagnosis of Abnormally Adherent Placenta......Page 196
9. Enhanced Myometrial Vascularity: The Role of Ultrasound in the Diagnosis and Treatment......Page 206
10. Fetal Growth Restriction......Page 212
11. Uterine Artery Doppler......Page 242
12. Doppler Interrogation of the Fetal Circulation......Page 258
13. Doppler Ultrasonography for the Diagnosis and Management of Fetal Anemia, Hydrops, and Fetal Lung Maturity......Page 306
14. Color Doppler Sonography in Obstetrics......Page 324
15. Sonography in Multiple Gestation......Page 352
16. Ultrasound Evaluation in the Modern Labor Delivery Unit: An Important Diagnostic and Management Tool......Page 392
II. Fetal Anomalies and Disorders......Page 400
17. Fetal Anomalies: Overview......Page 401
18. Prenatal Diagnosis of Cerebrospinal Anomalies......Page 440
19. Fetal Neck and Chest Anomalies......Page 466
20. Prenatal Assessment of Congenital Heart Disease......Page 486
21. Fetal Gastrointestinal Anomalies......Page 520
22. The Fetal Genitourinary System......Page 570
23. Prenatal Diagnosis of Skeletal  Anomalies......Page 590
24. Ultrasound Detection of Chromosomal Anomalies, Congenital Infections, and Syndromes......Page 666
III. Risk Assessment and Therapy......Page 726
25. First Trimester Screening......Page 727
26. Fetal Biophysical Profile Score: Theoretical Considerations and Practical Application......Page 756
27. Invasive Diagnosis of The Fetus......Page 768
28. Minimally Invasive Fetal Therapy and Open Fetal Surgery......Page 850
IV. Maternal Conditions and Disorders......Page 868
29. Sonographic Examination of the Uterine Cervix......Page 869
30. Sonography of Trophoblastic Diseases......Page 902
31. Postpartum Ultrasound......Page 912
32. Sonography of Maternal Disorders Encountered During Pregnancy......Page 924
V. Gynecologic Sonography......Page 938
33. Sonographic Evaluation of Pelvic Masses......Page 939
34. Sonographic Evaluation of Uterine Disorders......Page 968
35. Transvaginal Sonography of Endometrial Disorders......Page 998
36. Sonographic Techniques for Early Detection of Ovarian and Endometrial Cancers......Page 1018
37. Sonographic Evaluation of Acute and Chronic Pelvic Pain......Page 1040
38. Contrast-Enhanced Gynecologic Sonography......Page 1058
39. Transvaginal Sonography in Gynecologic Infertility......Page 1076
40. Sonohysterography and Sonohysterosalpingography......Page 1108
41. Guided Procedures using Transvaginal, Transabdominal, and Transrectal Sonography......Page 1128
42. Pelvic Floor Ultrasound......Page 1154
43. Basic Breast Sonography......Page 1186
44. Breast Sonography: Advanced......Page 1194
VI. Complementary Imaging Modalities......Page 1202
45. Volume Sonography: Core Concepts for Clinical Practice......Page 1203
46. Obstetrical Applications for 3D Ultrasonography......Page 1242
47. The Screening Examination of the Fetal Heart: A Practical Approach......Page 1282
48. Magnetic Resonance Imaging in Obstetrics......Page 1316
49. Three-Dimensional Volumetric Sonography in Gynecology......Page 1354
50. Gynecologic MRI: Problem Solving Sonographic Uncertainties......Page 1396
Teaching Cases......Page 1423
Self-Assessment Modules......Page 1424
Supplemental Videos......Page 1425

Citation preview

TRIBUTE This book, previously entitled simply Sonography in Obstetrics and Gynecology, is now entitled Fleischer’s Sonography in Obstetrics and Gynecology, in honor of the lead author, Arthur C. Fleischer, MD, whose brilliance, intellect, and experience have spanned eight editions. Arthur C. Fleischer was born in Miami, Florida in 1952. His parents were Lucille and Eugene. Lucille was a lifelong learner and educator, graduating from Hunter College in 1942 (when she was 17), obtaining a Master’s in Education from the University of Miami in 1951, and graduating first in her class at the University of Miami School of Law in 1958. Eugene attended the University of Miami after military service, became a general contractor in Miami, and was instrumental in starting a new Reform Jewish congregation, Temple Beth Am in Kendall, Florida. Art Fleischer’s grandparents were Hungarian immigrants who came to New York City from Budapest in 1921. As a child, Art was fortunate to excel at equestrian competitions and was state champion from 11 to 18 years of age. At Emory University, he completed his thesis on ultrasound enhancement of treatments and received his BS degree, magna cum laude, in biology in 1973. He met Lynn in 1974 through the introduction from a mutual medical school friend, and they were married in 1975. In 1976, he received the MD degree from the Medical College of Georgia at Augusta, and in 1980, he completed the Radiology Residency/Fellowship at Vanderbilt University Medical Center inNashville, Tennessee. Dr. Fleischer began his medical career in 1974 as the Acting Director of Diagnostic Ultrasound at the Medical College of Georgia. He came to Vanderbilt University School of Medicine in 1976 and has held the following positions: Acting Director of Diagnostic Ultrasound; Clinical Fellow in Ultrasound; Assistant Professor (Radiology and Obstetrics and Gynecology); and Associate Professor (Radiology and Obstetrics and Gynecology). Additionally, Dr. Fleischer was Visiting Professor in Radiology (Diagnostic Ultrasound) at Thomas Jefferson University Hospital. Presently, he is Professor of Radiology and Radiological Sciences (1987); Professor of Obstetrics and Gynecology (Secondary) (1987); Medical Director of the Sonography Training Program (1981); and Medical Director of Ultrasound. Dr. Fleischer has been active in several specialty societies, including the American Institute of Ultrasound in Medicine (Board of Governors, Fellow), the American College of Radiology (Fellow), the Society of Radiologists in Ultrasound (Fellow), and the Society for the Advancement of Women’s Imaging (Cofounder and President). Professor Fleischer has authored more than 200 research papers regarding clinical aspects of diagnostic ultrasound and 23 textbooks involving the use of diagnostic sonography in obstetrics/gynecology. He has received numer-

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ous awards and honors, among them are the Larry Mack Award for Best Research Paper by the Society of Radiologists in Ultrasound in 1998, the William Fry Award for Outstanding Contributions to Ultrasound by the American Institute of Ultrasound in Medicine in 1999, the Frank H. Boehm Award for Contribution to Continuing Medical Education by Vanderbilt University School of Medicine in 2005, and the Distinguished Alumnus Award from the Medical College of Georgia in 2007. In 2011, Dr. Fleischer was honored with the Cornelius Vanderbilt Chair in Radiology. Art and Lynn have three children, Braden, Jared, and Amy, and one grandson, Jakob. When asked about her father, Amy had the following words: The essence of Dr. Fleischer (our dad, or “Daddio,” as we know him) is exemplified by an unconditional love of learn­ ing. Whether our family discussions took place at the dinner table or at his favorite lunch spot (let’s be honest, most of our chats involved food), he always exuded an enthusiasm for learning. In fact, the most valuable gift our dad gave us (besides life itself!) is his infectious curiosity. His passion for new technology is not only evidenced by the every-growing stack of medical and academic publications he has authored (during his 40-year career) but also by the abundant sea of gadgets in his office! His thirst for innovative tools and tech­ nology is unquenchable, even when our mom threatens to purge his “toys” in order to make a path through the house. In amongst these toys, a plethora of textbooks, articles, pho­ tos, and old x-ray films make our home a monument to his staggering medical career. To us, such tangible evidence—of which this book is now a vital part—will always serve to represent his most deeply held belief in the value of asking good questions while seeking new understanding about the world. Amy Fleischer, MS, OTR/L, on behalf of Art’s three children

Luis Gonçalves, MD, has the following observations: There are moments in life when one wonders about how the Universe conspires to align with perfection those people who eventually become a permanent part of our path on Earth. I would like to take this moment to acknowledge the oppor­ tunity of having Arthur Fleischer cross my path 24 years ago at Vanderbilt University. Art has certainly inspired me then and will continue to inspire those of us who have been fortunate enough to have crossed his path and know firsthand the enormity of the human being who teaches and leads with a light heart.

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Tribute xxii Eugene C. Toy, MD, on behalf of the tens of thousands of physicians, sonographers, residents and students who have been touched by Dr. Art Fleischer, has these words: Art Fleischer has been a tremendous inspiration to everyone around him. He has an amazing sense of humor, a consci­ entiousness that goes far beyond the normal “call of duty,” and a dedication to women’s health through imaging and the prevention and diagnosis of disease. Art is an amazing educator, and I have sat in his conferences amazed at how much he is able to teach—from the anatomical structures, to the imaging, to the disease. More than all of this, Art has a tremendous love for people and cares so deeply about all of those who are fortunate enough to cross paths with him. One physician who was in a medical school radiology rota­ tion with Art summed it up: “I don’t know how so much

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knowledge, and so much zeal, and so much compassion can be in one person!” Dr. Fleischer has been one the cor­ nerstones in advancing imaging in women’s health over the past 40 years, particularly in the areas of gynecologic ultra­ sound. Not only has he propelled this embryologic science into a maturing and exciting field in science and informa­ tion, he has also put his own personal heart and soul into gynecologic sonography. I feel so fortunate to be able to call Art Fleischer my friend, mentor, and inspiration. For the tens of thousands who use imaging to help treat women, and the millions of women who are dependent on this modal­ ity for their care, we pause a moment to give tribute to a man who worked tirelessly in his significant contributions to the science and art of gynecologic sonography. For this reason, we have entitled this book, Fleischer’s Sonography in Obstetrics and Gynecology.

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PART 1

GENERAL OBSTETRIC SONOGRAPHY

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Part 1 GENERAL OBSTETRIC SONOGRAPHY

Chapter 1

ULTRASOUND BIOEFFECTS AND SAFETY: WHAT THE PRACTITIONER SHOULD KNOW Jacques S. Abramowicz  ●  Eyal Sheiner Key Terms1 1.  Acoustic streaming: movement of tissue or fluid, resulting from the passage of alternating positive and negative pressures of the ultrasound wave. Can also result from movements of bubbles, as a result of changes in pressure. 2.  ALARA principle: stands for As Low As Reasonably Achievable, a way to obtain the best, clinically relevant image while keeping ultrasound intensity and exposure as low as possible. 3.  Cavitation: bubble activity, secondary to ultrasound insonation. The positive aspect of the ultrasound pressure wave causes compression of the bubble while the negative part, also called rarefactional, causes production of the bubbles or expansion of existing ones. Cavitation can be stable or inertial. • Stable cavitation: bubble activity where bubble does not collapse (see inertial cavitation) but is moving back and forth in the tissue or fluid, thus potentially causing the surrounding medium to flow (ie, stream, hence the term streaming). • Inertial (previously known as transient) cavitation: bubbles that are compressed and expanded but with each compressing (positive) component, causing the volume to diminish ever more, until collapse occurs. This collapse can generate tremendously elevated temperature and pressure for an extremely short time and over an extremely short space (called an adiabatic reaction). This can result in production of several more bubbles, local cell damage, and/or generation of free radicals. 4.  Derating: action of multiplying a value measured in water with standard methods by a correction factor to account for the attenuation of the ultrasound field by the tissue traversed by the beam (usually 0.3 dB/ cm/MHz). 5.  Dwell time: the time during which the ultrasound beam impinges on a specific organ, body part, or entire organism. 6.  Mechanical index (MI): expresses the potential for nonthermal (also known as mechanical) effects in tissues traversed by the ultrasound wave. Depends on the pressure and the frequency ( = P/ f ).

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7.  Output Display Standard (ODS): actual name— Standard for Real-Time Display of Thermal and Mechanical Acoustic Indices on Diagnostic Ultrasound Equipment. Introduced to make end users aware, in real time, of the potential effects of ultrasound in tissues. See also mechanical index and thermal index. 8.  Radiation force: force resulting from absorption of some of the energy of the acoustic wave by tissue and transformation into heat. 9.  Scanned mode: refers to the ultrasound beam moving through the field, with energy distributed over a large volume, such as in B-mode and colorflow Doppler. 10.  Thermal index (TI): expresses the potential for temperature increase in tissues traversed by the ultrasound wave. It is given by the ratio of the power emitted by the transducer to the ultrasonic power required to raise tissue temperature by 1°C for the specific exposure conditions. This is a relative indication and does not necessarily correspond to the actual temperature increase. One of three thermal indices is displayed, based on whether soft tissue (TIS, mostly first and early second trimesters), bone (TIB, late second and third trimesters), or adult cranium (TIC) is being scanned. 11.  Unscanned mode: the ultrasound beam is stationary with power concentrated along a single line, such as in M-mode and spectral Doppler.

INTRODUCTION “Is this safe for my baby?” Ultrasound practitioners hear this question almost every day in clinical practice. The answer generally given is: “Of course. Ultrasound is not x-rays, it is not invasive; it has been used for close to sixty years and is perfectly safe.” While this answer may, in fact, contain some correct facts (ultrasound is not x-rays), the concept of perfect safety is not scientifically valid, and furthermore, the level of knowledge regarding potential effects of ultrasound in tissues is, by and large, very low among end-users of this technology. Ultrasound in obstetrics is convenient, painless, and results are available immediately. The belief exists that is does not pose any risk

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Ultrasound Bioeffects and Safety: What the Practitioner Should Know

to the pregnant patient or her fetus. Ultrasound, however, is a form of energy and, as such, has effects in biological tissues (bioeffects). The physical mechanisms responsible for these effects are nonthermal (mechanical) or thermal. The nonthermal mechanisms can further be separated into acoustic cavitation (inertial and noninertial) and noncavitational mechanisms, ie, acoustic radiation force (time-averaged force exerted by the ultrasound beam), acoustic radiation torque (producing in the insonated tissue a tendency to rotate or spin), and acoustic streaming (circulatory flow). It is the role of science to show whether any of these bioeffects may be harmful. The question has been debated since the introduction of ultrasound in clinical obstetrics, particularly as it relates to the fetal nervous system2,3 and continues to be discussed currently.4-9(1) This chapter presents basic notions of acoustics and physics as they relate to ultrasound, examines some literature on bioeffects and the safety of ultrasound, reviews statements of various ultrasound organizations, and affords a practical approach to limit the potential risks to the fetus of exposure to diagnostic ultrasound (DUS).

BASIC PHYSICS OF ULTRASOUND A detailed description of ultrasound physics can be found in various publications.10-12 However, certain properties of ultrasound are very important when trying to understand safety and bioeffects. Equally important are tissue characteristics, such as attenuation coefficient. A basic knowledge of instrument controls (“knobology”) is essential not only for appropriate clinical usage, but it is imperative to avoid potential harm.

The Ultrasound Wave Sound is a mechanical vibratory form of energy. It propagates through a medium by means of the motions of the particles in the medium, under the influence of the alternating positive and negative components of the wave. Megapascal (MPa) is the unit for pressure. Ultrasound instrumentation can generate peak pressures of 5 MPa and above. This is in comparison to the atmospheric pressure, which is 0.1 MPa. Several other characteristics define the ultrasound beam. The ultrasonic wave progresses in the insonated tissue at a velocity that is related to the sound characteristics as well as the tissue properties. For practical purposes, the average speed of sound propagation in biological tissues is estimated at 1540 ms/sec. Frequency is the number of cycles per second, measured in hertz (Hz). The limits of human hearing spans from approximately 20 to 20,000 Hz. Diagnostic ultrasound is, generally, 2 to 10 million Hz (megahertz, MHz). Wavelength is the distance between 2 corresponding points on a particular wave. It is inversely proportional to the frequency. Equipment resolution (the shortest distance between 2 objects or parts of an object to be represented by 2 separate echoes) depends on the wavelength: axial resolution ranges between 2 and 4 wavelengths. Hence, the shorter the wavelength (ie, the higher the frequency), the better the resolution (the distance between 2 points is smaller). The trade-off is that the higher the frequency

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3

6 Resolution Penetration 5

4

3

2

1

0

Figure 1-1.  Resolution (solid line) and penetration (dotted line) as a function of increasing frequency, represented by the x-axis. Units on the y-axis are not actual but representative of increasing values. The green arrow represents the goal of improving penetration at high frequencies.

(better resolution), the lower the penetration of the beam through a given tissue (Figure 1-1). Diagnostic ultrasound is pulsed, ie, pulses of acoustic energy separated by “silent” gaps. The number of pulses occurring in 1 second is the pulse repetition frequency (PRF) and is controlled by the instrument in B-mode. In Doppler mode, it can be altered by the end user. Another important parameter is the duty factor: this is the fraction of time that the pulsed ultrasound is on. With an increase in PRF, the duty factor increases. The pulse amplitude reflects pressure and is the maximum variation from the baseline, expressed in MPa’s. Since the ultrasound wave is sinusoidal, there are periods of positive and negative pressure. When the ultrasound wave exerts pressure on the resisting insonated tissue, work is produced. The ability of the wave to do work is its energy (in joules). The rate at which the energy is transformed from one form to another is the power (in watts or milliwatts). Intensity represents the rate at which energy passes through area unit. Average intensity of a beam is expressed by the beam power (in milliwatts, mW), divided by the cross-sectional area of the beam (in cm2) and is, therefore, expressed in mW/cm2. As stated earlier, DUS is performed with a pulsed wave. The intensity is proportional to the square of the instantaneous ultrasound wave pressure. There are pulses of energy intermingled with periods where no energy is emitted. Depending on the time and location of the measurement, several parameters can be described in relation to time or space: temporal peak intensity (the greatest intensity), average intensity over time, ie, including “silent” time between pulses (temporal-average intensity), maximal intensity at a particular location (spatial-peak intensity), as well as average-spatial intensity. By combining time and space, 6 intensities can be described: spatial average– temporal average (ISATA), spatial average–pulse average

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Part 1 GENERAL OBSTETRIC SONOGRAPHY Table 1-1

 VALUES OF ISPTA BY MODALITY AND YEAR OF DEFINITION

Modality/ Application

1976 Values

1986 Values

1992 Values

Fetal imaging

46

94

720

Cardiac

430

430

720

Peripheral vessel

720

720

720

Ophthalmic

17

17

17

Note: All are derated values in mW/cm . Data from Nyborg WL. Biological effects of ultrasound: development of safety guidelines. Part II: general review. Ultrasound Med Biol. 2001;27:301-333; Abramowicz JS. Prenatal exposure to ultrasound waves: is there a risk? Ultrasound Obstet Gynecol. 2007;29:363-367; Gressens P, Huppi PS. Are prenatal ultrasounds safe for the developing brain? Pediatr Res. 2007;61:265-266. 2

(ISAPA), spatial average–temporal peak (ISATP), spatial peak– temporal average (ISPTA), spatial peak–pulse average (ISPPA), and spatial peak–temporal peak (ISPTP). The most practical, and commonly referred to, is the ISPTA. The maximal permitted value varies by clinical application. This had been determined in 1976 by the US Food and Drug Administration (FDA),13 but was modified in 1986.14 The most recent definition dates from 1992.15 These values are shown in Table 1-1. One can observe from the table that, for fetal imaging, the ISPTA has been allowed to increase by a factor of almost 16-fold from 1976 and almost 8-fold from 1986 to 1992, yet, all epidemiological information available regarding fetal effects predates 1992. A remarkable fact is that intensity for ophthalmic examination has not changed from the original 17 mW/cm2, a value approximately 42.5 times lower than the present allowed value for fetal scanning. This will be addressed in more detail further in the chapter.

Tissue Characteristics When the ultrasound wave travels through a medium, its intensity diminishes with distance.16 In completely homogeneous, idealized materials, the signal amplitude would be reduced only because the wave is spreading. Biologic tissues, however, are different and induce further weakening by absorption and scattering (an effect called attenuation) and by reflection. Many models have been described to help calculate attenuation, particularly in obstetrical scanning,17 but the most commonly used model uses an average attenuation of 0.3 dB/cm/MHz.18 It is important to note that the attenuation increases logarithmically with frequency and distance traveled. Technically, many measurements of acoustic power are performed in water, which has almost no attenuation. To apply these calculations to tissues, values are multiplied by this factor, an action called derating.19 Absorption is the sound energy being converted to other forms of energy, and scattering is the sound being reflected in directions other than its original direction of propagation. Since attenuation is proportional to the square of sound frequency, it becomes evident why higher frequency transducers have less penetration (but better resolution; see Figure 1-1). One needs, therefore, to be closer to the organ of interest, such as through

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transesophageal or, in obstetrics and gynecology, transvaginal scanning. Another possibility is increasing the power of the instrument, resulting in improved resolution, as depicted by the green arrow in Figure 1-1. This is seemingly simple, but instrument outputs are regulated in the United States (see The Output Display Standard section). Another important parameter is acoustic impedance, which can be described as the opposition to transmission or progression of the ultrasound wave. It is proportional to the velocity of sound in the tissue (estimated at 1540 ms/sec) and to the tissue density.

Instrument Outputs Although some publications of various instrument outputs are available,20-22 these are generally quickly outdated, since manufacturers introduce new commercial machines to the market (or modify existing ones) at a rate too fast for immediate objective evaluation. From a clinical standpoint, there is no easy way to verify the actual output of the instrument in use. In addition to the variety of instruments, each attached transducer will generate a specific output, further complicated by the different modes that may be applied.23 When comparing modes, the ISPTA increases from B-mode (34 mW/ cm2, average) to M-mode to color Doppler to spectral Doppler (1180 mW/cm2). Average values of the temporal averaged intensity are 1 W/cm2 in Doppler mode but can reach 10 W/cm2.23 Therefore, caution should be exercised when applying Doppler mode, particularly in the first trimester. Color Doppler, while having higher intensities than B-mode, is still much lower than spectral Doppler. This is mainly due to the mode of operation—sequences of pulses, scanned through the region of interest (ROI or “box”). Most measurements are obtained from manufacturers’ manuals, having been derived in laboratory conditions. Real-life conditions may be different.24 Furthermore, machine controls can alter the output. If one keeps in mind that, for instance, the degree of temperature elevation is proportional to the product of the amplitude of the sound wave by the pulse length and the PRF, it becomes immediately evident why any change (augmentation) in these properties can add to the risk of elevating the temperature, a potential mechanism for bioeffects (see Thermal Effects). The 3 important parameters under end-user control are the scanning (or operating) mode, including transducer choice; the system setup and output control; and the dwell time. 1. Scanning mode: as mentioned previously, B-mode carries the lowest risk, and spectral Doppler carries the highest (with M-mode and color Doppler in between). High pulse repetition frequencies are used in pulsed Doppler techniques, generating greater temporal average intensities and powers than B- or M-mode, and hence greater heating potential. An additional risk is that since, in spectral Doppler, the beam needs to be held in relatively constant position over the vessel of interest, there may be a further increase in temporal average intensity. Naturally, transducer choice is of great consequence since it will determine frequency, penetration, resolution, and field of view. 2. System setup: starting or default output power and, particularly, mode (B-mode, Doppler, etc) control changes. A subtler element is fine tuning performed

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Ultrasound Bioeffects and Safety: What the Practitioner Should Know

by the examiner to optimize the image and influence output but with no visible effect (except if one follows thermal index [TI] and/or mechanical index [MI] displays). Controls that regularize output include focal depth (usually with greatest power at deeper focus but occasionally, on some machines, with highest power in the near field); increasing frame rate; and limiting the field of view, for instance, by high-resolution magnification or certain zooms (Figure 1-2). 3. In Doppler mode, changing sample volume and/or velocity range (all done to optimize received signals) changes output. Video Clip 1 demonstrates change in output (as observable by change in TI) when changing the focal distance. A very important control in every mode is receiver gain. It often has similar effects to the above controls on the recorded image but none on the output of the outgoing beam, and is therefore completely safe to manipulate (Figure 1-3). In other words, the receiver gain should be maximized before output is increased. In addition, over the years, output of instruments has increased.22, 25

5

A

B

A

C B Figure 1-2.  Acoustic output changes (as reflected by changes in TI). A: Nonzoomed image. Please note TI = 0.2. B: Zoomed image. Please note TI = 1.0 (arrow).

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Figure 1-3.  A: Image obtained with 100% power (blue arrow). Note MI = 1.2 and TI + 0.1 (yellow arrow). B: Power has been reduced to 85% (blue arrow). Note MI = 0.7 and TI + 0.0 (yellow arrow). This image is less diagnostic. C: Receiver gain has been increased. Power is unchanged from B (nor are MI and TI) but image is as diagnostic as A.

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6

Part 1 GENERAL OBSTETRIC SONOGRAPHY 4. Dwell time: is directly under the control of the examiner. Interestingly, dwell time is not taken into account in the calculation of the safety indices (thermal index, TI and mechanical index, MI,) nor, in general, until now, reported in clinical or experimental studies. However, one needs to remember that it takes only one pulse to induce cavitation, and about a minute to raise temperature to its peak. Directly related with dwell time is examiner experience: knowledge of anatomy, bioeffects, instrument controls, and scanning techniques. It can be safely assumed that the more experienced the examiner, the less scanning time will be needed to obtain the needed diagnostic images.

A standardized method of providing the end user a parameter related to acoustic output and expressing potential for bioeffects is clearly needed; hence, the generation of the Output Display Standard, based on the 2 most likely interactions of ultrasound with tissues: thermal and nonthermal or mechanical.26

THERMAL EFFECTS Normal core human body temperature is generally accepted to be 37°C (98.6°F) with a diurnal variation of ±0.5°C to 1.0°C, although 36.8°C ± 0.4°C (95% confidence interval) may be closer to the actual mean for large populations.27 During the entire gestation, temperature of the human embryo/ fetus is higher than maternal core body temperature28 and gradually rises until the final trimester (near term). The fetal temperature generally exceeds that of the mother by 0.5°C.29 Thermally induced teratogenesis (production of congenital malformations in an embryo or fetus) has been demonstrated in many animal studies, as well as several controlled human studies.30 While elevated maternal temperature in early gestation has been associated with an increased incidence of congenital anomalies,31 the majority of these studies do not involve ultrasound-induced temperature elevation. Edwards and others have demonstrated that hyperthermia is teratogenic for numerous animal species, including humans,32 and suggested a 1.5°C temperature elevation above the normal value as a universal threshold.33 Some scientists believe that there are, indeed, temperature thresholds for hyperthermia-induced birth defects, hence the As Low As Reasonably Achievable (ALARA) principle. There is, however, some evidence that any positive temperature differential for any period of time has some effect. In other words, that there may be no thermal threshold for hyperthermia-induced birth defects.34 From careful thermal dose determinations, derived from published literature in this area, it may be that hyperthermia-induced birth defects are produced in accordance with an Arrhenius relation for chemical rate effects, and thus have no threshold.35 Any temperature increment for any period of time has some effect. Likewise, the higher the temperature differential or the longer the temperature increment, the greater the likelihood of producing an effect. Gestational age is a vital factor: milder exposure during the preimplantation period can have similar consequences to more severe exposures during embryonic and fetal development and can result in prenatal death and abortion or a wide range of structural and functional defects.

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The organ at greatest risk is the central nervous system (CNS) due to a lack of compensatory growth of damaged neuroblasts. In experimental animals the most common defects are of the neural tube, microphthalmia, cataract, and microencephaly, with associated functional and behavioral problems.32 Defects of craniofacial development including clefts,36 the axial and appendicular skeleton,37 the body wall, teeth, and heart38 are also commonly found. Hyperthermia in utero (due to maternal influenza) has been described as a risk factor for congenital anomalies39,40 and subsequent childhood psychological/behavioral disturbances41 and, more particularly, schizophrenia.42 Nearly all these defects have been found in human epidemiological studies following maternal fever or hyperthermia during pregnancy. It should be emphasized that these investigations have not involved ultrasound-induced hyperthermia effects. Yet, there are data on the effects of hyperthermia and measurements of in vivo temperature induced by pulsed ultrasound, but not in human beings.43-46 These data have been widely reviewed.32,35,47-49 There is, however, a serious lack of data that examine the effects of ultrasound while rigorously excluding other confounding factors. Two widely accepted facts are that ultrasound has the potential to elevate the temperature of the tissues being scanned,50-53 and elevated maternal temperature, whether from illness or exposure to heat, can produce teratologic effects.31,32,35,54-56 The major question is, therefore, whether DUS can induce a harmful rise in temperature in the fetus.57-59 Some believe that this temperature rise is, in fact, a major mechanism for ultrasound bioeffects.30,35 Temperature elevation in the insonated tissue can be calculated and estimated fairly accurately if the field is sufficiently well characterized.60,61 For prolonged exposures, temperature elevations of up to 5°C have been obtained.57 Temperature change in insonated tissues depends on the balance between heat production and heat loss. A particular tissue property that strongly influences the amount of heat transported is local perfusion, which very clearly diminishes the risk, if present. Similar experimental conditions caused a 30% to 40% lower maximal temperature increase in live versus dead sheep fetuses exposed in the near field,45 while in guinea pig fetuses exposed at the focus the difference was approximately 10%.46 These findings were estimated to be secondary to vascular perfusion in live animals. A significant cooling effect of vascular perfusion was observed only when the guinea pig fetuses reached the stage of late gestation near term, when the cerebral vessels were well developed. In the midterm, there was no significant difference when guinea pig fetal brains were exposed, alive (perfused) or postmortem (nonperfused), in the focal region of the ultrasound beam.46 In early pregnancy, under 6 weeks gestation, there appears to be minimal maternal-fetal circulation, that is, minimal fetal perfusion, which may potentially reduce heat dispersion.62 The lack of perfusion is one reason why the spatial peak-temporal average intensity (ISPTA) for ophthalmic applications has been kept very low, in fact much lower than peripheral, vascular, cardiovascular, and even obstetric scanning, despite the general increase in acoustic power that was allowed after 1992 (see Table 1-1). There are some similarities in physical characteristics between the early, first-trimester embryo and the eye. Neither is perfused; they can be of similar size; and protein is present (in an increasing

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Figure 1-4.  First trimester (11 weeks) measurement of the crownrump length: the entire fetus is within the ultrasound beam (“whole body scanning”).

proportion in the fetus). As mentioned previously, one must then wonder why, from the time intensities were checked and recommended in clinical practice, ISPTA was from the beginning and has continued to be maintained at 17 mW/ cm2, while for fetal imaging it was allowed to reach 720 mW/cm2, up from 46 mW/cm2. At about weeks 4 to 5, the gestational sac is about the size of the eye (2.5 cm in diameter), and by week 8 it is around 8 cm in diameter. This may allow whole-body fetal scanning (and possibly temperature increase), a concept that is generally ignored in the literature dealing with thermal effects of ultrasound (Figure 1-4). The issue of transducer heating, which may be particularly relevant in the first trimester, specifically if performing endovaginal scanning, is also often ignored.63,64 There are additional concerns in early gestation because of minimal or lack of perfusion. Only at about weeks 10 to 11 does the embryonic circulation actually linkup with the maternal circulation.65 There may thus be some underestimation of the actual DUS-induced temperature in early gestation, mainly because of the absence of perfusion. The perfusion issue is in addition to modifications of tissue temperature due to ambient maternal and fetal temperatures. Furthermore, motions (even very small) of the examiner’s hand as well as the patient’s breathing and body movements (in the case of obstetric ultrasound, both the mother and the fetus) tend to spread through the region being heated. However, for spectral (pulsed) Doppler studies, it is necessary to have the transducer as steady as possible. This is because, in general, blood vessels are small in comparison to the general organ or body size being scanned with B-mode imaging, and hand movements while performing Doppler studies will have more undesired effects on the resulting image. As described earlier, the intensity (ISPTA) and acoustic power associated with Doppler ultrasound are the highest of all the generaluse categories. Ziskin66 reported that among 15,973 Doppler ultrasound examinations, the average duration was 27 minutes (and the longest 4 hours!). There is a mathematical/physical relation between temperature elevation and several beam characteristics. The

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elevation is proportional to the product of the wave amplitude, length of the pulse, and PRF. Hence, manipulating any of these via instrument controls will alter the in situ conditions. It is clear that temperature increases of 1°C are easily reached in routine scanning.67 Elevation of up to 1.5°C were obtained in the first trimester and up to 4°C in the second and third trimesters, particularly with the use of pulsed Doppler.68 There is a large body of literature on heat shock proteins (HSPs), the production of which is triggered by a core temperature increase and the function of which is to protect against hazardous effects of elevated temperature as well as to induce some thermotolerance, ie, the ability to withstand higher elevations than in the past, with no harmful results.69 While their production is activated by whole-body temperature elevation, and may be speculated in ultrasound-induced thermal effects, it has not been shown to actually occur during experimental (or clinical) insonation.

MECHANICAL EFFECTS Ultrasound bioeffects also occur through mechanical mechanisms.70,71 These are interactions between the ultrasound wave and the tissue that do not cause a significant degree of temperature increase (less than 1°C above physiologic temperature). These include acoustic cavitation as well as radiation torque and force, and acoustic streaming secondary to propagation of the ultrasound waves. While included in this category, some effects are, in fact, the result of the mechanical interaction but are actually physical (shock wave) or chemical (release of free radicals) effects. Table 1-29 summarizes nonthermal effects described in the literature in laboratory or animal experiments—and not in humans— which may be pertinent to fetal ultrasound. Investigations with laboratory animals clearly indicate that nonthermal interactions of ultrasound fields with tissues can produce biological effects in vivo.71 It is interesting

Table 1-2

 MAJOR NONTHERMAL EFFECTS OF ULTRASOUND OBSERVED IN THE LABORATORY AND IN ANIMALS AND WITH THE POTENTIAL TO AFFECT THE FETUS

Free-radical generation Increase in cell membrane permeability Erythrocyte agglutination Growth restriction (transient decrease) DNA single-strand break Increased sister chromatid exchange Increased mutation frequency Capillary petechiae Vasoconstriction Lung microvascular hemorrhage Intestine microvascular hemorrhage Neuronal migration delay Auditory tract stimulation Tactile radiation pressure perception effect Cardiac, premature contractions Modified with permission from Stratmeyer ME, Greenleaf JF, Dalecki D, et al. Fetal ultrasound: mechanical effects. J Ultrasound Med. 2008 Apr;27(4):597-605.

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to note that chemical effects of ultrasound were described more than 80 years ago!72 Cavitation seems to be the major factor in mechanical effects73 as it has been demonstrated to occur in living tissues under ultrasound insonation.74,75 Two types of cavitation can be described—stable and inertial (previously defined as transient)—both of which need the presence of gas bubbles to occur. Stable cavitation indicates vibrations or small backward and forward movements with possible resulting microstreaming. Inertial cavitation indicates expansion and reduction in volume, secondary to alternating positive and negative pressures generated by the ultrasound wave. Expansion in growth is less with each cycle until collapse occurs with production of very high pressure (hundreds of atmospheres) and very elevated temperature (thousands of degrees), but on such a small area (less than 100 nm) and for such a brief time (few tens of nanoseconds) that it will not be felt and is very hard to measure (adiabatic reaction—occurring without the gain or loss of heat) but can produce microstreaming—a phenomenon that has been described also with no clear involvement of bubbles,76-78 or even release of free radicals.79,80 Acoustic streaming is easily demonstrated by watching ultrasound-induced movements of solid-mattercontaining fluids in insonated cavities (see Video 1). Radiation torque refers to the induction, in objects found in the acoustic field, of rotation or of the tendency to rotate. Biological effects of ultrasound in animals such as local intestinal,81 renal,82 and pulmonary83 hemorrhages have been attributed to mechanical effects, although cavitation could not always be implicated. Furthermore, since gas bubbles do not seem to be present in fetal lungs or bowels (where effects have been described in neonates or adult animals), the risk from mechanical effect secondary to cavitation appears to be minimal.84 There are several other effects that 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.85 It seems, however, that the presence of some cavitation nuclei is necessary for hemolysis to occur. At present, there is no clear clinical indication for the use of ultrasound contrast agents (a source of cavitation nuclei, when injected into the body before ultrasound examination) in fetal ultrasound, and to date, no studies have specifically investigated the interaction of ultrasound and microbubble contrast agents in fetal tissues in vivo. Nevertheless, it should be noted that in the presence of such contrast agents, fetal red blood cells are more susceptible to lysis from ultrasound exposure in vitro.86 Additionally, fetal stimulation caused by pulsed ultrasound insonation has been described, with no apparent relation to cavitation.87 This effect may be secondary to radiation forces associated with ultrasound exposures. These forces were suspected at the earliest stages of ultrasound research88 and are known to possibly stimulate auditory,89 sensory,90 and cardiac tissues.91 No harmful effects of DUS, secondary to nonthermal mechanisms, have been reported in human fetuses. A very intriguing nonthermal effect of ultrasound is acceleration of bone fractures healing in animals and humans.92 Because of these known effects of ultrasound in living tissues and the fact that pressures involved with Doppler propagation are much higher than B-mode, caution is further recommended, based on

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scientific evidence of potential effect, particularly in the first trimester.93

THE OUTPUT DISPLAY STANDARD In 1992, the FDA yielded to pressure from ultrasound clinical users as well as manufacturers to increase the power output of instruments. The rationale for this request was that higher outputs would generate better images, and thus improve diagnostic accuracy. To allow clinical users of ultrasound to use their instruments at higher powers than originally intended and to reflect the two major potential biological consequences of ultrasound (mechanical and thermal, see above), the American Institute of Ultrasound in Medicine (AIUM), the National Electrical Manufacturers’ Association (NEMA), and the FDA (with representatives from the Canadian Health Protection Branch, the National Council on Radiation Protection and Measurements,94 and 14 other medical organizations30) developed a standard related to the potential for ultrasound bioeffects. The full name was the Standard for Real-Time Display of Thermal and Mechanical Indices on Diagnostic Ultrasound Equipment, generally known as the Output Display Standard or ODS.15 The importance of this document and what it describes is that it represents historically the first attempt at providing the end user with quantitative safety-related information. One important result is that the end users are able to see how manipulation of the instrument controls during an examination causes alterations in the output and, thus, on the exposure. As a consequence, for fetal imaging the output, as expressed by the ISPTA, went from a previous value of 92 to 720 mW/cm2 (see Table 1-1). To allow the output to reach such levels, the manufacturers were requested to display, on screen and in real-time, two types of indices with the intent of making the user aware of the potential for bioeffects, as described earlier. These indices are the thermal index (TI), to provide some indication of potential temperature increase, and the mechanical index (MI), to provide indication of potential for nonthermal (ie, mechanical) effects15,30,95 (Figure 1-5). The TI is the ratio of total acoustic power to the acoustic power estimated

Figure 1-5.  Onscreen TI (= 0.3, red arrow) and MI (= 1, yellow arrow).

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to be required to increase tissue temperature by a maximum of 1°C. It is an estimate of the maximal temperature rise at a given exposure. There are 3 variants: for soft tissue (TIS), to be used mostly in early pregnancy when ossification is low; for bones (TIB), to be used when the ultrasound beam impinges on bone at or near the beam focus, such as late second and third trimesters of pregnancy; and for transcranial studies (TIC) when the transducer is essentially against bone, mostly for examinations in adult patients, but also in neonatal scanning, which is an area that is, generally, ignored. These indices were required to be displayed if equal to or over 0.4. It needs to be made very clear that TI does not represent an actual or an assumed temperature increase. It bears some correlation with temperature rise in degrees Celsius but in no way allows an estimate or a guess as to what that temperature change actually is in the tissue.95 The MI represents the potential for nonthermal damage in tissues but is not based on actual in-situ measurements. It is a theoretical formulation of the ratio of the pressure to the square root of the ultrasound frequency (hence, the higher the frequency, the lesser risk of mechanical effect). Both the TI and MI can and should be followed as an indication of change in output during the clinical examination with higher values indicating the potential for higher thermal and nonthermal effects than lower values. A clear mandate in the ODS original document was education of the end user as a major part in the implementation of the indices. Attempts have been made to educate the end users,96 but, unfortunately, this aspect of the ODS does not seem to have succeeded as end users’ knowledge of bioeffects, safety, and output indices is found lacking.97,98 In a questionnaire that was distributed to ultrasound end users (82% were obstetricians) attending review courses and hospital grand rounds, only 17.7% gave the correct answer of the definition of the TI, and only 3.8% described MI properly. Almost 80% of end users did not know where to find the acoustic indices when various responses included the machine documentation, a textbook, a complicated calculation or in real time on the ultrasound monitor (the correct answer).97 Similar results were recorded in surveys abroad, performed in Europe, Asia, or the Middle East98,99,100,101 indicating that clinical end users worldwide show poor knowledge regarding safety issues of ultrasound during pregnancy.102,103 More recently, knowledge of residents in obstetrics and gynecology was also found to be grossly lacking 104 and, furthermore, similar results were obtained when surveying sonographers, with no difference in years of experience.105 Compliance with the ALARA (as low as reasonably achievable) principle by practitioners seeking credentialing for nuchal translucency (NT) measurement between 11 and 14 weeks’ gestation was evaluated. Only 5% of the providers used the correct TI type (TIb) at lower than 0.5 for all submitted images, 6% at lower than 0.7, and 12% at 1.0 or lower. A TI (TIb or TIs) higher than 1.0 was used by 19.5% of the providers. Proficiency in NT measurement and educational background (physician or sonographer) did not influence compliance with ALARA. The authors concluded that clinicians seeking credentialing in NT do not demonstrate compliance with the recommended use of the TIb in monitoring acoustic output.106

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Furthermore, several assumptions were made, which prompts some questions on the clinical value of these indices. Maybe the most significant (from a clinical aspect) is the choice of the homogeneous attenuation path model (defined as the H3 model), with an attenuation coefficient of 0.3 dB/cm/MHz, as detailed previously in Tissue Characteristics. The reason to employ models of that nature is the impossibility, for obvious reasons, to perform certain measurements in pregnant women. This coefficient may be an overestimation of the attenuation in many clinical scenarios, a situation that would underestimate the actual exposure. In National Council on Radiation Protection and Measurements (NCRP) report number 140,30 there is an entire chapter (Chapter 9) indicating conditions where both indices may be inaccurate, eg, long fluid path (full bladder, amniotic fluid, ascites, or hydrocephalus) or path through increased amounts of soft tissue such as obese patients. Because of these uncertainties, the accuracy of the TI and MI may be within a factor of 2 or even 6.107 For example, an on-screen TI of 1 may correspond to an actual value of 0.5°C or 2°C if the error factor is 2, but possibly 0.33°C or 6°C, if the error factor is 6 (as previously stated, these are not actual temperature indications). A further disturbing and confusing element is that outputs reported by manufacturers are not necessarily equivalent to those calculated in the laboratory.108

Risk Assessment Risk means the chance or the possibility of loss or bad consequence. It refers to the possibility, with a certain degree of probability, of damage to health, environment, and objects, in combination with the nature and magnitude of the damage.109 These are the 3 important characteristics of risk: probability of occurrence, and nature and magnitude of harm. It has been, specifically, applied to the use of medical instruments.110 A complicating factor that makes definition and classification difficult is that the concept of risk means various things to different people. Age, background, education, morals, religion, and many other traits will direct this evaluation and not only the absolute possible result of the activity, putting the participant at risk. For instance, in bungee jumping, rupture of the elastic cord and subsequent death may be, indisputably, the worst possible outcome, but different people evaluate this and make decisions that are not necessarily based on this absolute result. Furthermore, the reason to take a possible risk has to be taken in consideration. Two approaches are possible in risk evaluation: how much harm is acceptable to obtain the desired results (risk-benefit ratio) or how much harm can be avoided by withholding the action or modifying it (the precautionary principle). The risk-benefit principle is what is almost universally used in medicine to justify a medical diagnostic procedure (such as ultrasound) or a therapeutic intervention. If the benefit to be obtained from the procedure in terms of diagnosis (ultrasound) or intervention (a newly discovered and not yet commercialized cancer or AIDS drug, for instance) is deemed to be sufficient, then, even if this diagnostic or interventional procedure carries some risks (recognized or presumed to be possible),

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the benefit overrides these risks, assuming the subject understands those risks and is willing to take them. The precautionary principle (PP) is a diametrically opposed ethical, political, and economic approach stating that if a certain action may cause severe damage to the public, in the absence of a scientific consensus that harm would not ensue, the burden of proof falls on those who would advocate taking that action.111 This principle is much less familiar to the medical field, although “first do no harm” is its direct application, but it may be extremely relevant when considering safety and risks of a procedure, such as prenatal ultrasound. The concept originated in the 19th century when John Snow, a London, UK, physician, determined that cholera was due to the extensive, common use of an unclean water supply and recommended closing of this source of water, although it was the sole one in a large vicinity.112 This may have been the first epidemiological analysis of a disease. Although the beginning of the PP was medical, it became a social idea in Germany in the 1930s as Vorsorge, “forecaring.” This later became the Vorsorgeprinzip, the forecaring or precautionary principle, in West German environmental law in the 1970s.113 The idea was adopted by decision and policy makers but, remarkably, much more extensively in Europe than in the United States. Some key concepts in the original formulation were environmental harm to a population and responsibility: “When an activity raises threats of harm to human health or the environment, precautionary measures should be taken even if some cause and effect relationships are not fully established scientifically. In this context the proponent of an activity, rather than the public, should bear the burden of proof” (the Wingspread Statement on the Precautionary Principle114). From environmental research it spread to toxicology and was first applied only recently in the United States to a clinical medical field.115 However, several medical mishaps clearly belong to the history of the development of the PP—from the diethylstilbestrol debacle116 to the thalidomide tragedy.117 While referring mostly to environmental issues, such as global warming, the PP can certainly be extended to other medical activities (such as diagnostic ultrasound) and be applied to individuals (such as fetuses). The simple enunciation of the principle, particularly in reference to diagnostic ultrasound in general, and entertainment ultrasound in particular, is that even if a particular action or procedure has not been proven to be harmful, it is better to avoid it so as not to take the risk until safety is established through clear, scientific evidence, popularly expressed as “better safe than sorry.”118 This is also the basis of the Hippocratic Oath, which includes the recommendation to first do no harm. A major difference with the risk-benefit principle is that proponents of the PP believe that public action is necessary if there is any evidence of likely or substantial harm, however limited but plausible, and the burden of proof is shifted from showing the presence of risk to demonstrating its absence.119 As such, epidemiologic research on chronic diseases and the use of surrogates for human studies (eg, animal research or tissue cultures) have been shown to be uncertain.120 There are several variations of the PP, but all have some common key elements:

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1. There must be scientific uncertainty about nature of harm, probability, magnitude, and causality (fulfilled by DUS). 2. Mere speculation is not enough to invoke the PP. Scientific analysis must have triggered the process (also fulfilled by DUS). 3. Per definition, the PP deals with procedures with probability of unclear outcome, in that it is different from prevention or from risk-benefit assessment where some clear knowledge or precise suspicion exists, and where decision may be made to go ahead despite this risk by, for instance, taking additional measures to attempt and limit the danger. Clearly, the ALARA principle is the exact application of this element121,122 (fulfilled by DUS). 4. In general, the PP applies to unacceptable (“serious,” “irreversible,” “global”) high levels of risk to large populations, present or future, local or distant123 (may not be the case for DUS). 5. One needs to intervene (not observe or procrastinate) before damage has been demonstrated (eg, “do not perform DUS”). 6. The intervention must be proportional to the possible risk: indicating DUS may be acceptable but not nonclinical use of DUS. A level of “zero risk” is probably never attainable. Those who support the PP make the following very strong argument for precaution: serious damage may be caused if one uses a risk-based approach. A well-known example is what constitutes toxic levels of lead in paint. As early as 1897, it was known that lead may be toxic, but at first the upper limit of safety for children was assumed to be 60 μg/dL of blood, and this had terrible results. The “safe” level was reduced over the years to 40, then 20, then 10, which it is today, although some scientists feel that even 2 μ/dL may pose some risk.124 The basic conclusion of risk analysis with the PP is that measures against a possible risk should be taken (such as exposure avoidance) even if the available evidence is weak (or maybe absent) regarding the existence of that risk as a scientifically established fact.125 In many European countries this “stop first then study” approach (a clear application of the PP) has been adopted (particularly for chemicals). The exact opposite is often true in the United States where something, once introduced, has to be proven harmful by science before being removed or forbidden. A major goal of the PP is to help delineate (preferably quantitatively) the possibility that some exposure is hazardous, even in cases where this is not established beyond reasonable doubt.126 The classical statistical approach to hypothesis testing is unhelpful because lack of significance can be due to either uninformative data or genuine lack of effect (type II error).127 There are many critics of the PP because of the risk of exaggeration in caution and slowing down of scientific progress.128,129 A major issue is that the PP relies very heavily on a single conjecture: prevention is better than cure. There is no scientific evidence for this. Furthermore, it may be true that, often, it is better to be “safe than sorry” and the primum non nocere (first do no harm) principle is a direct application of this, but preventative measures can

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be long lasting and possibly incapacitating, whereas cures can be targeted and effective.128 What is more, no moral opinion is formed of people when treating them, but if the main focus is upon precaution, then it can be deemed morally wrong not to take preventative measures. The whole precaution approach is imbued with what may appear to many as an excessively moralistic tone and a “I am the expert and therefore know what is best for you” attitude.130 Furthermore, the probability of a problem occurring that one tries to avoid has to be high (which does not apply, as far as we know, to ultrasound) and preventative measures have to be effective. Hence this approach may be adopted with some restrictions and this is, in fact, exactly what ALARA recommends.122 Most scientists and professional organizations have recommended such a practice in clinical obstetrical ultrasound.131-133

HISTORICAL RESEARCH The first descriptions of ultrasound as an imaging mode date from the 19th century.134 The French engineer Paul Langevin designed an ultrasound machine using Pierre Curie’s principle of the piezoelectric effect. During World War I, he attempted to use this instrument to detect submarines through echo location (hence the later coined term SONAR: Sound Navigation And Ranging). He also demonstrated that the waves produced by his machine could kill small animals in an insonated water bath, and could cause pain to his assistants when they were required to plunge their hands in the water bath in the path of the beam. Other bioeffects observed included the searing of skin when touching a resonant quartz bar, and explosive atomization (!) of fluid drops from the end of the rod. Since that time, the question of effects and safety has been on the minds of researchers88 and has given rise to literature too extensive to review in detail.2,3,6,49,131,135-147 Initially, cell suspensions and cell and tissue cultures were employed, and many reports described clear effects of the ultrasound waves on these, mostly secondary to cavitational and other nonthermal mechanisms, such as cell aggregation,148 membrane damage,149 and cell lysis.150 Plants were another extensively studied organism for effects of ultrasound,151 particularly the Elodea leaf, since internal gas channels are present.152 Insects have been exposed to ultrasound with significant effects, such as death of eggs and larvae as well as abnormal development, presumably secondary to the presence of gas-filled channels.153 Additionally, alterations at the chromosomal and even DNA levels have been described.154 These effects have been reviewed extensively elsewhere,5,30 and while they are of major scientific and historical importance, they are not of major relevance to clinical exposure of human fetuses.

Animal Research Effects of ultrasound were demonstrated in animals more than 80 years ago.88 Since then, multiple studies have been performed with ultrasound on a wide variety of species. Studies of gross effects on the brain and liver of cats were first performed with well-defined lesions and demyelination in the brain155 and tissue damage in the

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liver,156 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,157,158 as well as lesions in the liver, kidney, and testicles of rabbits.159 While some effects are likely due to mechanical influences, very high temperature elevations (much higher than anything reachable with diagnostic ultrasound) have also been observed and may be more directly involved with the tissue damage. Effects in muscles have been obtained, but with outputs much higher than those usually generated in clinical studies,160 and so have intestinal81 and lung161 hemorrhages, also at acoustic pressures well above those generated by ultrasound fields. These are helpful in understanding the mechanisms involved with possible bioeffects of DUS. It should also be noted that some similar effects have also been demonstrated with acoustic fields much closer to clinically pertinent ones, in particular lung and intestinal hemorrhage.81 Several major clinical end points for bioeffects that could have direct relevance to human studies include fetal growth and birth weight, effects on brain and CNS function, and change in hematological function, and these will be considered in more detail. Decreased birth weight after prenatal exposure to ultrasound has been reported in the monkey162,163 and the mouse,164,165 but not convincingly in the rat.166 Therefore, clear species differences seem to exist,167 making it difficult to generalize, and even more difficult to extrapolate, to humans. Tarantal and Hendrickx162 evaluated 30 pregnancies in monkeys, half of which were exposed to ultrasound. The scanned fetuses had lower birth weights and were shorter than the control group. No significant differences were noted between the groups with regard to the rate of abortions, major malformations, or stillbirths. Moreover, all showed catch-up growth when examined at 3 months of age.162 It should be noted that in-situ intensities were higher than what is considered routine in clinical obstetrical imaging in humans. Hande and Devi168 evaluated the effect of prenatal exposure to diagnostic ultrasound on the development of mice. Swiss albino mice were exposed to diagnostic ultrasound for 10 minutes on day 3.5 (preimplantation period), 6.5 (early organogenesis period), or 11.5 (late organogenesis period) of gestation. Sham-exposed controls were maintained for comparison. Fetuses were dissected out on the 18th day of gestation, and changes in total mortality, body weight, body length, head length, brain weight, sex ratio, and microphthalmia were recorded. Exposure on day 3.5 of gestation resulted in a small increase in the resorption rate and a significant reduction in fetal body weight. Low fetal weight and an increase in the incidence of intrauterine growth-restriction were produced by exposure on day 6.5 postcoitus.168 Others have also demonstrated restricted growth in newborns after in utero exposure to DUS.169 Subtler findings have also been described. Pregnant Swiss albino mice were exposed to diagnostic ultrasound (3.5 MHz, 65 mW, ISPTP = 1 W/cm2, ISATA = 240 W/cm2) for 10, 20, or 30 minutes on day 14.5 (fetal period) of gestation.170 Shamexposed controls were studied for comparison. There were significant alterations in behavior in the exposed groups as revealed by decreased locomotor and exploratory activity,

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and an increase in the number of trials needed for learning. No changes were observed in physiological reflexes and postnatal survival. The authors concluded that ultrasound exposure during the early fetal period can impair brain function in the adult mouse.170 Likewise, Hande et al171 found that anxiolytic activity and latency in learning were more noticeable in ultrasound-treated animals. The authors exposed pregnant Swiss mice to diagnostic levels of ultrasound (3.5 MHz, maximum acoustic output: ISPTP = 1 W/cm2 and ISATA = 240 mW/cm2, acoustic power = 65 mW) for 10 minutes on postcoital day 11.5 or 14.5. At 3 and 6 months postpartum, offspring were subjected to behavioral tests. The effect was more pronounced in the 14.5 days postcoital group than in the 11.5 days group. They concluded that exposure to diagnostic ultrasound during late organogenesis period or early fetal period in mice may cause changes in postnatal behavior.171 Temperature elevations were induced by ultrasound in guinea pig fetal brains.46 In fact, mean temperature increases of 4.9°C close to parietal bone and 1.2°C in the midbrain were recorded after 2-minute exposures, albeit at exposure conditions higher than what is usually employed in clinical examinations.46 This greatest temperature rise recorded close to the skull correlated with both gestational age and progression in bone development.43 The skull bone becomes progressively thicker and denser between 30 and 60 days’ gestational age (normal gestation for guinea pigs is 66 to 68 days). After only 2 minutes of insonation with an ISPTA of 2.9 W/cm2 (about 4 times higher than currently permitted by the FDA for diagnostic use), mean maximum temperature increases varied from 1.2°C at 30 days to 5.2°C at 60 days. It is important to note that most of the heating (80% of the mean maximum temperature increase) occurred within 40 seconds. The 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. However, milder insults early in gestation may be as significant (or more) than more severe ones in later stages. Neurons of the cerebral neocortex in mammals, including humans, are generated during fetal life in the brain proliferative zones and then migrate to their final destinations by following an inside-to-outside sequence. Ang et al172 evaluated the effect of ultrasound waves on neuronal positioning within the embryonic cerebral cortex in mice. Neurons generated at embryonic day 16 and destined for the superficial cortical layers were chemically labeled in over 335 animals. A small, but statistically significant, number of neurons failed to acquire their proper position and remained scattered within inappropriate cortical layers and/or in the subjacent white matter when exposed to ultrasound for a total of 30 minutes or longer during the period of their migration. The magnitude of dispersion of labeled neurons was variable but systematically increased with duration of exposure to ultrasound (although not linearly, with some extended exposure yielding less effect than lower ones). These investigators concluded that

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further research in larger and slower-developing brains of nonhuman primates and continued scrutiny of unnecessarily long prenatal ultrasound exposure is warranted. It is unclear whether a relatively small misplacement in a relatively small number of cells that retain their origin cell class is of any clinical significance. It is also important to note that there are several major differences between the experimental setup of Ang et al172 and the clinical use of ultrasound in humans.6 The most noticeable difference was the length of exposure of up to 7 hours in the setup of Ang et al. No real mechanistic explanation was given for the findings, and furthermore, there was no real dose effect with high effects at the penultimate high dose, but less so at the highest dose. Moreover, scans were performed over a small period of several days. The experimental setup was such that embryos received whole-brain exposure to the beam, which is rare in humans, although quite possible in the earliest stages of gestation. In addition, brains of mice are much smaller than those in humans, and develop over days. This should not completely deter from the study, but encourages caution. It should be noted that some have described a complete lack of effects of prenatal ultrasound exposure on postnatal development and growth173 or behavior.174 The influence of prenatal ultrasound exposure on the blood–brain barrier (BBB) integrity as measured by the permeation of Evans blue (EB) through the BBB during the postnatal development of 139 rats was evaluated by Yang et al.175 Diagnostic levels of ultrasound (2.89 MHz, mechanical index = 1.1, acoustic output power = 70.5 mW) for 1 and 2 hours per day, for 9 consecutive days were used on Sprague-Dawley rats. Offspring were assessed postnatally on days 10, 17, 24, and 38. A statistically significant amount of EB extravasation into the cerebrum and cerebellum could be detected on postnatal day 10 (but not later), following exposure to diagnostic levels of ultrasound during embryonic development. The authors concluded there is a need for further investigation of the effects of ultrasound exposure during the potentially vulnerable period of intense BBB development in the human fetus. This study did not provide clear evidence that there is cause for concern for clinical prenatal diagnostic imaging in humans. The study had several methodological flaws, and specifically, the acoustic exposure was intense and untranslatable to clinical practice.176 In another study177 chick brains were exposed, in ovo, on day 19 of a 21-day incubation period to B-mode (5 or 10 minutes), or to pulsed Doppler (1, 2, 3, 4, or 5 minutes) ultrasound. After hatching, learning and memory function were assessed at day 2 post hatch. B-mode exposure did not affect memory function. However, significant memory impairment occurred following 4 and 5 minutes of pulsed Doppler exposure. Short-, intermediate-, and long-term memory was equally impaired, suggesting an inability to learn. Chicks were also unable to learn with a second training session. In this study, exposure to pulsed Doppler ultrasound adversely affected cognitive function in chicks. Although some methodological issues exist and extrapolation to humans is unwarranted, these findings justify further investigations. The hematological system is the second major system to be investigated for ultrasound effects. The following have

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been assessed: hemolysis, coagulation factors and platelets, and leukocyte production and function.178 Increased hemolysis has been demonstrated for ultrasound in (human) fetal cells as compared to adult cells, but only in the presence of ultrasound contrast agents, with human cells being less fragile than certain tested animals.86,179 Other alterations have been described in the hemolytic system180 but appear to be of minimal, if any, clinical significance.

Human Research and Epidemiology In 2005, the American Institute of Ultrasound in Medicine (AIUM) published the following statement: “Based on the epidemiological data available and on current knowledge of interactive mechanisms, there is insufficient justification to warrant a conclusion of a causal relationship between diagnostic ultrasound and recognized adverse effects in humans. Some studies have reported effects of exposure to diagnostic ultrasound during pregnancy, such as low birth weight, delayed speech, dyslexia, and non–right-handedness. Other studies have not demonstrated such effects. The epidemiological evidence is based on exposure conditions prior to 1992, the year in which acoustic limits of ultrasound machines were substantially increased for fetal/ obstetrical applications.”181 Applied to ultrasound, epidemiology is the study of effects on human populations as a result of ultrasound scanning and, in the case of obstetrical ultrasound, this should include the pregnant patient as well as her infant. Laboratory animal experiments under similar diagnostic exposure levels have shown some effects from ultrasound, under certain conditions. Effects have also been reported in humans, but a definitive statement regarding risk should, ideally, include direct analysis of the effects in human populations. Several epidemiological studies have been published.4,49,182 For an extensive discussion, including elements of statistics, see Chapter 12 in NCRP report number 140,30 an extensive review by Newnham,143 and AIUM document, Conclusions Regarding Epidemiology for Obstetric Ultrasound.183,184. Relevant details will be summarized. Several biological end points have been analyzed in the human fetus/neonate in an attempt to determine whether prenatal exposure to diagnostic ultrasound had observable effects: intrauterine growth restriction (IUGR) and low birth weight, delayed speech, dyslexia, neurological and mental development or behavioral issues, and, more recently, non–right-handedness. Occasional studies report an association between diagnostic ultrasound and some specific abnormalities such as lower birth weight,182 delayed speech,185 dyslexia,186 and non–right-handedness.187,188 With the exception of low birth weight (also demonstrated in monkeys,179) these findings have never been duplicated, and the majority of studies have been negative for any association. Moore et al189 examined a large number of infants (over 2000, half of them exposed to ultrasound) and found a small but statistically significant lower mean birth weight of exposed versus nonexposed infants. However, information was collected several years after exposure, no indications for the examination are known, and no exposure information is available. This lack of detail about the exposure parameters is, very often, the major problem in analyzing these reports.

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13

In a later study, the authors concluded that the relationship of ultrasound exposure and reduced birth weight may be due to shared common risk factors, which lead to both exposure and a reduction in birth weight.190 Another retrospective study, with Moore as a coauthor, reported a 2.0 greater risk of low birth weight after 4 or more exposures to diagnostic ultrasound.144 These results were not reproduced in other retrospective studies.189 In a large study (originally 10,000 pregnancies exposed to ultrasound matched with 500 controls) with a 6-year follow-up, Lyons et al191 did not find differences in birth weight (nor increased congenital malformations, chromosomal abnormalities, infant neoplasms, speech or hearing impairment, or developmental problems). Newnham et al192 performed a randomized control trial including more than 2800 parturients. Of these, about half received 5 ultrasound imaging and Doppler flow studies at 18, 24, 28, 34, and 38 weeks’ gestation, and half received a single ultrasound imaging at 18 weeks. They found an increased risk of IUGR when exposed to frequent Doppler examinations, possibly via some effects on bone growth. However, when children from the previously mentioned study 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, no evidence of long-term adverse impact in neurological outcome was noted by the same group.192 Similarly, no harmful effect of a single or 2 prenatal scans on growth were found in several randomized studies.193,194 In fact, in some studies, birth weight was slightly higher in the scanned group, but not significantly so, except in one.195 In conclusion, decreased birth weight has been extensively analyzed after DUS exposure in utero, and it does not appear that such exposure is associated with reduced birth weight, although Doppler exposure may have some risks.147 In a few studies that appear to favor such an effect, a major problem is that there is an important confounding factor: many studies include pregnancies at risk for IUGR due to existing maternal or fetal conditions. A second major potential effect extensively evaluated is delayed speech. In an attempt to determine if there is an association between prenatal ultrasound exposure and delayed speech in children, Campbell et al185 studied 72 children with delayed speech and found a higher rate of ultrasound exposure in utero than the 144 control subjects. Some issues render these results less valid: there was neither a dose-response effect nor any relationship to time of exposure, and many of the records were more than 5 years old. Another study of over 1100 children exposed to ultrasound in utero and over 1000 controls found no significant differences in delayed speech, limited vocabulary, or stuttering.196 Dyslexia is another widely studied subject. In one study over 4000 children, aged 7 to 12, exposed to ultrasound in utero were used as a study group and compared to matched controls to evaluate the appearance of adverse effects.186 Seventeen outcomes measures were examined, at birth (APGAR scores, gestational age, head circumference, birth weight, length, congenital abnormalities, neonatal infection, and congenital infection) or in early infancy (hearing, visual

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Part 1 GENERAL OBSTETRIC SONOGRAPHY

acuity and color vision, cognitive function, and behavior). No significant differences were found, except for a significantly greater proportion of dyslexia in those children exposed to ultrasound. The authors, however, indicated that this could be an incidental finding, given the design of the study and the presence of several confounding factors that could have contributed to the possible dyslexia finding. On the other hand, it should be noted that exposure conditions were probably much lower than modern ultrasound systems, given that the fetal examinations were performed from 1968 to 1972. Subsequently, a long-term follow-up study was performed on over 2100 children.193,197 End points included evaluation for dyslexia along with additional hypotheses, including an examination of non– right-handedness said to be associated with dyslexia. These studies198-200 included the specific examination of more than 600 children with various tests for dyslexia such as spelling and reading. No statistically significant differences were found between ultrasound-exposed children and controls for reading, spelling, arithmetic, or overall performance as reported by teachers. Specific dyslexia tests showed similar rates of occurrence among scanned children and controls in reading, spelling, and intelligence scores, and no discrepancy between intelligence and reading or spelling. Since the original finding of dyslexia was not confirmed in subsequent randomized controlled trials, it is considered unlikely that routine ultrasound screening exams can cause dyslexia. However, these studies did raise the issue of laterality (in terms of handedness). The topic of non–right-handedness as a result of prenatal exposure has caused much ink to be used in extensive discussions and reports. The first report of a possible link between prenatal exposure to ultrasound and subsequent non–right-handedness in insonated children was published in 1993 by Salvesen et al,198 but according to the authors, “only barely significant at the 5% level.” In a later analysis of the data, they described that the association was restricted to males.193 A second group of researchers (with Salvesen, the main author of the first study, included but with a new population, in Sweden as opposed to Norway) published similar findings of a statistically significant association between ultrasound exposure in utero and non–right-handedness in males.187 Salvesen then published a meta-analysis of these 2 studies and of previously unreported results.188 No difference was found in general, but a small increase in non–righthandedness was present when analyzing boys separately. No valid mechanistic explanation is given in the studies to explain the findings. In conclusion, although there may be a small increase in the incidence of non–right-handedness in male infants, there is not enough evidence to infer a direct effect on brain structure or function or even that non–righthandedness is an adverse effect. An intriguing recent study showed that fetuses self-touched their faces more often with the left hand than the right, as observed by ultrasound, in correlation to stress levels of the mother.189 Furthermore, laterality is, mostly, genetically determined.190 Other end points that have been considered but not found to be associated with ultrasound exposure include congenital malformations, hearing problems and malignancies.204,205 There has been no published epidemiological study that found negative effects of obstetrics ultrasound in

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populations scanned after 1992, when regulations were altered and acoustic output of diagnostic instruments were permitted to reach levels many times higher than previously allowed (from 94 to 720 mW/cm2 ISPTA for fetal applications). There are no epidemiological studies related to the output display standard (thermal and mechanical indices) and clinical outcomes. The safety of new technologies such as harmonic imaging and three-dimensional (3D) ultrasound, as well as that of probe self-heating, needs to be investigated.

Clinical Exposimetry There is, unfortunately, no way to perform actual sonographic exposure measurements in the human fetus. Pressure, intensity, and power are not measured in situ, but are estimated from laboratory obtained measurements. Several tissue models have been developed to help with this estimation, depending mostly on approximate attenuation coefficients for various tissues or beam paths.30,50 A large range of variation is expected secondary to individual patient characteristics, such as weight and thickness of tissues.206 Because of these possible variations, the reasonable worst-case scenario is usually considered. There are scarce data on instruments’ acoustic output (nor patient acoustic exposure) for routine clinical ultrasound examinations. Acoustic output was recorded in several prospective observational studies investigating first-trimester ultrasound,207,208 Doppler studies,209 and 3D/four-dimensional (4D) studies.210 Basically, first-trimester ultrasound was associated with very low TI values (with a mean of 0.2 ± 0.1).207 The TI was significantly higher in the pulsed wave Doppler (mean 1.5 ± 0.5, range 0.9-2.8) and color flow imaging studies (mean 0.8 ± 0.1, range 0.6-1.2) as compared to B-mode ultrasound (mean 0.3 ± 0.1, range 0.1-0.7; P < .01).209 In the same study, TI was above 1.5 in 43% of the Doppler studies.209 Mean TI during the 3D (0.27 ± 0.1) and 4D examinations (0.24 ± 0.1) was comparable to the TI during the B-mode scanning (0.28 ± 0.1; P = .343).210 There is ever-increasing use of 3D/4D ultrasound in clinical

Figure 1-6. TI and MI during M-mode examination. Please note TI = 0.8 (arrow).

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Figure 1-7.  TI and MI during color Doppler exam. Please note TI = 0.6

Figure 1-8.  TI and MI during spectral Doppler examination. Please

medicine, thus knowledge about bioeffects and safety is mandatory.211 Figures 1-6 through 1-9 are examples of actual screen shots during clinical exams, for M-mode, color Doppler, spectral Doppler, and 3D acquisition, respectively. Figure 1-10 demonstrates that extremely elevated TIs are easily reachable with spectral Doppler, although in manufacturer’s fetal setting. Adequate diagnostic information may be obtained with low output levels (as documented by values of the TI). This is seen in Figure 1-11 and Video 1. This has been reported in the literature, specifically for Doppler, the mode with the highest output, both in early and later pregnancy.212,213 It should be noted that, under pressure

from Bioeffects and Safety Committees of various professional organizations (American Institute of Ultrasound in Medicine-AIUM, European Federation of Ultrasound in Medicine and Biology-EFSUMB, International Society for Ultrasound in Obstetrics and Gynecology-ISUOG, and World Federation for Ultrasound in Medicine and Biology-WFUMB), several manufacturers have changed their default settings, specifically for pulsed Doppler in fetal mode, from very high (as it was originally, presumably in an attempt to obtain better images) to very low, with the end user capable or raising the output, if desired. Since acoustic output is high in Doppler, special precaution is recommended, particularly in early gestation.214

(arrow).

note TI = 2.4 (arrow).

Figure 1-9.  TI and MI during multiplanar acquisition in 3D scanning. Please note TI = 0.4 (arrow).

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Part 1 GENERAL OBSTETRIC SONOGRAPHY Because of the possible errors inherent in the calculation of the TI and MI, various attempts have been made to find a better quantification of the potential risk.215 These have not been adopted by the clinical community. The other side of the equation is, “What are we looking for?” Ultrasound is neither radiation nor thalidomide, and it is certain that ultrasound does not kill fetuses, does not cause limb amputations, and does not cause gross structural anomalies.216 But are we looking where we should, and have we studied enough cases in a scientific fashion, looking at subtle changes? The answer is clearly, “No.” We have been looking for macroscopic, gross findings and have not found any, but is it possible that harmful effects of ultrasound have been missed because the wrong time frame reference was used? Two possible factors are described for such errors.217 If one uses a term human pregnancy (280 days [40 weeks]) to life expectancy of 70 years (25,550 days) ratio, then 7 in utero days are comparable to about 631 ex-utero days. Therefore, it is conceivable that a much shorter time interval (1 day) should be used to group fetuses to evaluate

Figure 1-10.  Second-trimester spectral Doppler. Please note TI = 3.3 (arrow). This is with the instrument on “fetal” setting.

A

B

C

D

Figure 1-11.  Color and spectral Doppler of umbilical artery. A: Color Doppler with high output power (as reflected by TI = 0.7). B: Lower output power (TI = 0.1). C: Spectral Doppler with high output power (as reflected by TI = 2.4). D: Lower output power (TI = 0.6). Image is equally diagnostic.

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effects, not intervals of 1 or more weeks as is usually done. Furthermore, there is also a potential “dilution error.” Assuming an event has a background rate of 10% in the general population but occurs in 100% of fetuses exposed on day 35, if a large number (for instance, 1000) of fetuses exposed on that particular day are examined, the incidence will be 100%, ie, 90% increase over the control population (background rate of 10%). But if we assume 1000 fetuses are exposed per day for 12 weeks, this represents 84,000 scans, and only 11.1% will be affected (all 1000 scanned on day 30 and 10% [the background rate] of all 83,000 others [8300], or 9300 total), an increase of only 1.1% (1.07 to be precise) over the background rate of 8400 (10% of 84,000), which is very difficult to extract and observe, but still present in 100% of the fetuses exposed at the critical time (day 35 in the above example). The actual numbers are probably even more complicated since more than 1000 fetuses are scanned every day, the background rate of major anomalies is 3% to 4% in the general population and much lower for nongross macroscopic findings, and furthermore, the hit rate of any teratological agent is rarely 100%. This points to the need for extensive, well-planned research—a goal very difficult to accomplish, given that the majority of pregnant women who receive prenatal care will have 1 or several DUS scans during their pregnancy. It has been shown that subtle changes can be observed in animals.218 As detailed previously, there is a possible male preponderance of non–right-handedness after in utero ultrasound exposure. In addition, an increased prevalence of autism exists in males, and there are reports of excess non–right-handedness in this population. Pregnant mice were exposed to 30 minutes of diagnostic ultrasound at embryonic day 14.5. Social behavior of their male pups was analyzed 3 weeks after birth. Ultrasound-exposed pups were significantly (P < 0.01) less interested in social interaction than sham-exposed pups and demonstrated significantly (P < 0.05) more activity relative to the sham-exposed pups, but only in the presence of an unfamiliar mouse.218 These results suggest that social behavior in young mice was altered by in utero fetal exposure to diagnostic ultrasound. The authors conclude that this may be relevant for autism but that major differences between the exposure of DUS of mice and humans preclude conclusions regarding human exposure and require further studies.

Nonmedical Ultrasound Nonmedical ultrasound refers to the performance of obstetrical ultrasound with no medical indication but to provide the mother/parents-to-be with images or video clips of the fetus (on hard copy, tape, CD, DVD, tablet or cell-phone), also called “scanning for pleasure.”219 There are several reasons why most official organizations are opposed to this practice, such as issues of training of the providers, quality and nature of the scans, feedback to the “customers,” and risks that these customers will not have a regular, clinical exam. But perhaps the most obvious reason for the resistance to these scans is the safety issue. For instance, the FDA is strongly opposed, stating, “… ultrasound energy delivered to the fetus cannot be regarded as completely innocuous. Laboratory studies have shown that diagnostic levels of ultrasound can produce physical effects in tissue,

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such as mechanical vibrations and rise in temperature. Although there is no evidence that these physical effects can harm the fetus, public health experts, clinicians and industry agree that casual exposure to ultrasound, especially during pregnancy, should be avoided.”220 The FDA goes further and indicates, “Persons who promote, sell or lease ultrasound equipment for making ‘keepsake’ fetal videos should know that the FDA views this as an unapproved use of a medical device. In addition, those who subject individuals to ultrasound exposure using a diagnostic ultrasound device (a prescription device) without a physician’s order may be in violation of state or local laws or regulations regarding use of a prescription medical device.”220 Equally opposed to the nonclinical use of DUS are the American Institute of Ultrasound in Medicine (AIUM), the American College of Obstetrics and Gynecology (ACOG), the European Committee for Medical Ultrasound Safety (ECMUS), and the World Federation for Ultrasound in Medicine and Biology (WFUMB). The AIUM’s most recent statement is, “The AIUM advocates the responsible use of diagnostic ultrasound . . . [and] strongly discourages the non-medical use of ultrasound . . . . The use of either two-dimensional (2D) or three-dimensional (3D) ultrasound to only view the fetus, obtain a picture of the fetus or determine the fetal gender without a medical indication is inappropriate and contrary to responsible medical practice. Although there are no confirmed biological effects on patients caused by exposures from present diagnostic ultrasound instruments, the possibility exists that such biological effects may be identified in the future. Thus, ultrasound should be used in a prudent manner to provide medical benefit to the patient.”221 Similarly, the ECMUS’s statement includes the following: “The embryonic period is known to be particularly sensitive to any external influences. Until further scientific information is available, investigations should be carried out with careful control of output levels and exposure times. With increasing mineralization of the fetal bone as the fetus develops the possibility of heating fetal bone increases.”222 More recently the WFUMB and the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) issued a joint statement with identical conclusions: “The WFUMB and ISUOG disapprove of the use of ultrasound for the sole purpose of providing souvenir images of the fetus . . . . Furthermore, ultrasound should be employed only by health professionals who are well trained and updated in ultrasound clinical usage and bioeffects.”223

Official Positions Many national and international organizations or societies have issued official statements regarding the epidemiology, bioeffects, and safety of ultrasound, as well as the nonmedical usage of ultrasound such as the AIUM, WFUMB, British Medical Ultrasound Society (BMUS), and European Committee of Medical Ultrasound Safety (ECMUS). They all state, in one way or another, that ultrasound appears safe if performed for clinical indications by appropriately trained personal, but that prudence is recommended because of the possibility of yet unknown deleterious effects. For instance, the AIUM has several statements available on its Web site for epidemiology,180 prudent

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Part 1 GENERAL OBSTETRIC SONOGRAPHY Table 1-3

TI

 MAXIMAL ALLOWED EXPOSURE TIME AS A FUNCTION OF TI Maximum Exposure Time (min)

0.7

60

1.0

30

1.5

15

2.0

4

2.5

1

use,221 and keepsake fetal imaging.223 The Keepsake Fetal Imaging statement contains a clear “safety clause” particularly addressing pulsed Doppler: “Although the general use of ultrasound for medical diagnosis is considered safe, ultrasound energy has the potential to produce biological effects. Ultrasound bioeffects may result from scanning for a prolonged period, inappropriate use of color or pulsed Doppler ultrasound without a medical indication, or excessive thermal or mechanical index settings.”223

RECOMMENDATIONS The sonographer and sonologist are interested in knowing how to keep the examination safe. One needs to provide recommendations based on scientific evidence. This is a difficult task. In terms of clinical exposure, what should be recommended? A general recommendation is that DUS should be used only when indicated and minimal exposure should be used to obtain the diagnostic images. Furthermore, exposure time should be kept as short as possible.123 Precautions are, naturally, of particular importance in early gestation224 and for Doppler exposure.225 Several organizations have actually published recommendations, based more or less on scientific data.226 The most rigorous is the BMUS, as can already be inferred by its title: Statement on the Safe Use, and Potential Hazards of Diagnostic Ultrasound.227 Their 1999 statement declares, “For equipment for which the safety indices are displayed over their full range of values, the TI should always be less than 0.5 and the MI should always be less than 0.3*.” When the safety indices are not displayed, Tmax should be less than 1°C and MImax should be less than 0.3. Frequent exposure of the same subject is to be avoided.”223 They have very strict recommendations for maximum allowed exposure time, depending on the TI (Table 1-3). In 2012, they updated their recommendations, and these are, at the moment, the most detailed guidelines for safe use of DUS in medicine in general and obstetrics in particular.228 The 2015 AIUM Statement on Mammalian Biological Effects of Heat229 is a must read for all ultrasound practitioners and states: “Acoustic output from diagnostic ultrasound devices is sufficient to cause temperature elevations in fetal tissue.” The WFUMB offers some scientific rationalization, stating that diagnostic exposure resulting in a *Italics ours.

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temperature rise of no more than 1.5°C above normal physiological levels (37°C) may be used clinically without reservation on thermal grounds. Furthermore, diagnostic exposure that elevates embryonic and fetal in situ temperature above 41°C (4°C above normal temperature) for 5 minutes or more should be considered potentially hazardous.48 In addition, in febrile patients, extra precaution may be needed to avoid unnecessary additional embryonic and fetal risk from ultrasound examinations. Precautions are much softer regarding mechanical phenomena, which, in the absence of gas nuclei (as is the case in fetal lungs and bowels and assuming no use of contrast agents) are probably negligible. Hence, BMUS, despite its very cautionary statements also published a statement directed at the public, stating: “the British Medical Ultrasound Society considers ultrasound imaging to be safe when it is performed prudently, for a clear medical purpose, by properly trained professionals, using well maintained equipment.”230

FUTURE DIRECTIONS Scientists continue to be interested in biophysics of ultrasound and remain worried about potential harmful effects. Hence, research in this area is continuing. Ideally, epidemiological studies should be performed on large populations, blindly randomizing 50% to ultrasound testing and 50% to no testing. Given the extensive indications for DUS in pregnancy and the fact that most (and in certain countries, all) pregnant patients are referred for one ultrasound examination (or many more), this would be extremely difficult to realize in a human population. More accurate techniques to measure in vivo real exposure may appear, allowing more precise assessment of safety, possibly by generating actual safety indices, correlated with actual length of exposure. In the meantime, areas of uncertainty persist and caution is justified, particularly in Doppler mode early in pregnancy, but also when insonating the fetal skull for relatively long periods. Education of the end users will continue to be vital to maintaining the good safety record of ultrasound and preventing possible harmful bioeffects. KEY POINTS 1.  Know the machine you use. 2.  Perform a scan only when indicated. 3.  Keep the examination as short as possible. The longer the exposure, the higher the risk. 4.  Always start a scan at the lowest possible output (default) and increase only if necessary. 5.  Use receiver gain, PRF, and amplitude change output. Output and receiver gain can affect the image in the same way, and receiver gain changes are without any effect on the intensity of the outgoing beam (and hence are completely safe). 6.  Follow the ALARA principle. 7.  Keep track of the TI and MI values on the screen. 8.  Keep TI below 1. 9.  Keep MI below 1 (although some recommend 0.5). 10.  Be extremely cautious when using Doppler in the first trimester.

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REFERENCES 1. AIUM. Medical Ultrasound Safety. 3rd ed. Laurel, MD: American Institute of Ultrasound in Medicine, 2014. 2. Donald I. The safety of using sonar. Dev Med Child Neurol. 1974;16:90-92. 3. Nyborg WL. Safety of ultrasound diagnosis. Science. 1974;186:1074. 4. Salvesen KA, Eik-Nes SH. Is ultrasound unsound? A review of epidemiological studies of human exposure to ultrasound. Ultrasound Obstet Gynecol. 1995;6:293-298. 5. Nyborg WL. Biological effects of ultrasound: development of safety guidelines. Part II: general review. Ultrasound Med Biol. 2001;27:301-333. 6. Abramowicz JS. Prenatal exposure to ultrasound waves: is there a risk? Ultrasound Obstet Gynecol. 2007;29:363-367. 7. Gressens P, Huppi PS. Are prenatal ultrasounds safe for the developing brain? Pediatr Res. 2007;61:265-266. 8. Abramowicz JS, Barnett SB, Duck FA, Edmonds PD, Hynynen K, Ziskin MC. Fetal thermal effects of diagnostic ultrasound. J Ultrasound Med. 2008;27:541-559. 9. Stratmeyer ME, Greenleaf JF, Dalecki D, Salvesen KA. Fetal ultrasound: mechanical effects. J Ultrasound Med. 2008;27:597-605. 10. Nyborg WL. Physical principles of ultrasound. In: Fry FJ, ed. Ultrasound: Its Application in Medicine and Biology, Part I. New York: Elsevier Publishing Company, 1978. 11. Kremkau FW. Diagnostic Ultrasound. Principles and Instruments. Philadelphia: W.B. Saunders Company (an Elsevier Company), 2006. 12. Duck FA, Starritt HC, Aindow JD, Perkins MA, Hawkins AJ. The output of pulse-echo ultrasound equipment: a survey of powers, pressures and intensities. Br J Radiol. 1985;58:989-1001. 13. FDA, Center for Devices and Radiological Health. 501(k) Guide for Measuring and Reporting Acoustic Output of Diagnostic Ultrasound Medical Devices. 1985. 14. US Food and Drug Administration (FDA). Diagnostic Ultrasound Guidance Update. Rockville, MD: Center for Devices and Radiological Health, 1987. 15. AIUM/NEMA. American Institute of Ultrasound in Medicine and the National Electrical Manufacturers’ Association: Standard for Real-Time Display of Thermal and Mechanical Acoustic Output Indices on Diagnostic Ultrasound Equipment. Laurel, MD; 1992 (revised 1996). 16. Insana MF. Sound attenuation in tissue. In: Goldman LW, Fowlkes JB, eds. Medical CT and Ultrasound: Current Technology and Applications. College Park, MD: American Association of Physicists in Medicine, 1995. 17. Siddiqi TA, O’Brien WD Jr, Meyer RA, Sullivan JM, Miodovnik M. Human in situ dosimetry: differential insertion loss during passage through abdominal wall and myometrium. Ultrasound Med Biol. 1992;18:681-689. 18. US Department of Health and Human Services-Food and Drug Administration (FDA). Revised 510(k) Diagnostic Ultrasound Guidance for 1993. Rockville, MD: Food and Drug Administration, 1993. 19. Siddiqi TA, O’Brien WD Jr, Meyer RA, Sullivan JM, Miodovnik M. In situ human obstetrical ultrasound exposimetry: estimates of derating factors for each of three different tissue models. Ultrasound Med Biol. 1995;21:379-391. 20. Carson PL, Fischella PR, Oughton TV. Ultrasonic power and intensities produced by diagnostic ultrasound equipment. Ultrasound Med Biol. 1978;3:341-350. 21. Henderson J, Willson K, Jago JR, Whittingham TA. A survey of the acoustic outputs of diagnostic ultrasound equipment in current clinical use in the Northern Region. Ultrasound Med Biol. 1995;21:699-705. 22. Duck FA, Martin K. Trends in diagnostic ultrasound exposure. Phys Med Biol. 1991;36:1423-1432. 23. Duck FA, Henderson J. Acoustic output of modern instruments: is it increasing? In: Barnett SB, Kossoff G, eds. Safety of Diagnostic Ultrasound. New York, London: The Parthenon Publishing Group, 1998. 24. Jago JR, Henderson J, Whittingham TA, Willson K. How reliable are manufacturer’s reported acoustic data? Ultrasound Med Biol. 1995;25:135-136.

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25. CibullSL, Harris GR, Nell DM. Trends in diagnostic ultrasound acoustic output from data reported to the US Food and Drug Administration for device indications that include fetal applications. J Ultrasound Med. 2013 Nov;32(11):1921-1932. 26. O’Brien WD Jr. Ultrasound-biophysics mechanisms. Prog Biophys Mol Biol. 2007;93:212-255. 27. Mackowiak PA, Wasserman SS, Levine MM. A critical appraisal of 98.6 degrees F, the upper limit of the normal body temperature, and other legacies of Carl Reinhold August Wunderlich. JAMA. 1992;268:1578-1580. 28. Asakura H. Fetal and neonatal thermoregulation. J Nippon Med Sch. 2004;71:360-370. 29. Macaulay JH, Randall NR, Bond K, Steer PJ. Continuous monitoring of fetal temperature by noninvasive probe and its relationship to maternal temperature, fetal heart rate, and cord arterial oxygen and pH. Obstet Gynecol. 1992;79:469-474. 30. NCRP (National Council on Radiation Protection and Measurements). Exposure Criteria for Medical Diagnostic Ultrasound: II. Criteria Based on All Known Mechanisms. Report No. 140. Bethesda, MD, 2002. 31. Shaw GM, Todoroff K, Velie EM, Lammer EJ. Maternal illness, including fever and medication use as risk factors for neural tube defects. Teratology. 1998;57:1-7. 32. Edwards MJ, Saunders RD, Shiota K. Effects of heat on embryos and foetuses. Int J Hyperthermia. 2003;19:295-324. 33. Edwards MJ. Hyperthermia as a teratogen: a review of experimental studies and their clinical significance. Teratog Carcinog Mutagen. 1986;6:563-582. 34. Miller MW, Miller HE, Church CC. A new perspective on hyperthermia-induced birth defects: the role of activation energy and its relation to obstetric ultrasound. J Therm Biol. 2005;30:400-409. 35. Miller MW, Nyborg WL, Dewey WC, Edwards MJ, Abramowicz JS, Brayman AA. Hyperthermic teratogenicity, thermal dose and diagnostic ultrasound during pregnancy: implications of new standards on tissue heating. Int J Hyperthermia. 2002;18:361-384. 36. Toneto AD, Lopes RA, Oliveira PT, Sala MA, Maia Campos G. Effect of hyperthermia on rat fetus palate epithelium. Braz Dent J. 1994;5:99-103. 37. Martinez-Frias ML, Garcia Mazario MJ, Caldas CF, Conejero Gallego MP, Bermejo E, Rodriguez-Pinilla E. High maternal fever during gestation and severe congenital limb disruptions. Am J Med Genet. 2001;98:201-203. 38. Tikkanen J, Heinonen OP. Maternal hyperthermia during pregnancy and cardiovascular malformations in the offspring. Eur J Epidemiol. 1991;7:628-635. 39. Luteijn JM, Brown MJ, Dolk H. Influenza and congenital anomalies: a systematic review and meta-analysis. Hum Reprod. 2014 Apr;29(4):809-823. 40. Dreier JW, Andersen AM, Berg-Beckhoff G Systematic review and meta-analyses: fever in pregnancy and health impacts in the offspring. Pediatrics. 2014 Mar;133(3):e674-688. 41. Dombrowski SC, Martin RP, Huttunen MO. Association between maternal fever and psychological/behavior outcomes: a hypothesis. Birth Defects Res A Clin Mol Teratol. 2003;67:905-910. 42. Edwards MJ. Hyperthermia in utero due to maternal influenza is an environmental risk factor for schizophrenia. Congenital Anomalies. 2007;47:84-89. 43. Bosward KL, Barnett SB, Wood AK, Edwards MJ, Kossoff G. Heating of guinea-pig fetal brain during exposure to pulsed ultrasound. Ultrasound Med Biol. 1993;19:415-424. 44. Tarantal AF, O’Brien WD, Hendrickx AG. Evaluation of the bioeffects of prenatal ultrasound exposure in the cynomolgus macaque (Macaca fascicularis): III. Developmental and hematologic studies. Teratology. 1993;47:159-170. 45. Duggan PM, Liggins GC, Barnett SB. Ultrasonic heating of the brain of the fetal sheep in utero. Ultrasound Med Biol. 1995;21: 553-560. 46. Horder MM, Barnett SB, Vella GJ, Edwards MJ, Wood AK. Ultrasound-induced temperature increase in guinea-pig fetal brain in utero: third-trimester gestation. Ultrasound Med Biol. 1998;24: 1501-1510. 47. Barnett SB, Rott HD, ter Haar GR, Ziskin MC, Maeda K. The sensitivity of biological tissue to ultrasound. Ultrasound Med Biol. 1997;23:805-812.

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48. WFUMB. WFUMB Symposium on Safety of Ultrasound in Medicine: Conclusions and Recommendations on Thermal and NonThermal Mechanisms for Biological Effects of Ultrasound (Barnett SB, ed.) Ultrasound Med Biol. 1998;24:S1-S55. 49. Ziskin MC, Petitti DB. Epidemiology of human exposure to ultrasound: a critical review. Ultrasound Med Biol. 1988;14:91-96. 50. NCRP (National Council on Radiation Protection and Measurements). Biological effects of ultrasound. I. Criteria based on thermal mechanisms. NCRP Report number 113. Bethesda, MD, 1992. 51. Abraham V, Ziskin MC, Heyner S. Temperature elevation in the rat fetus due to ultrasound exposure. Ultrasound Med Biol. 1989;15:443-449. 52. Duck FA, Starritt HC. A study of the heating capabilities of diagnostic ultrasound beams. Ultrasound Med Biol. 1994;20:481-492. 53. Nyborg WL, Steele RB. Temperature elevation in a beam of ultrasound. Ultrasound Med Biol. 1983;9:611-620. 54. Layde PM, Edmonds LD, Erickson JD. Maternal fever and neural tube defects. Teratology. 1980;21:105-108. 55. Milunsky A, Ulcickas M, Rothman KJ, Willett W, Jick SS, Jick H. Maternal heat exposure and neural tube defects. JAMA. 1992;268:882-885. 56. Moretti ME, Bar-Oz B, Fried S, Koren G. Maternal hyperthermia and the risk for neural tube defects in offspring: systematic review and meta-analysis. Epidemiology. 2005;16:216-219. 57. Miller MW, Ziskin MC. Biological consequences of hyperthermia. Ultrasound Med Biol. 1989;15:707-722. 58. Barnett SB. Can diagnostic ultrasound heat tissue and cause biological effects? In: Barnett SB, Kossoff G, eds. Safety of Diagnostic Ultrasound. New York: Parthenon Publishing, 1998. 59. Abramowicz JS. Ultrasound in obstetrics and gynecology: is this hot technology too hot? J Ultrasound Med. 2002;21:1327-1333. 60. Nyborg WL, Steele RB. Temperature elevation in a beam of ultrasound. Ultrasound Med Biol. 1983;9:611-620. 61. Nyborg WL, O’Brien WD. An alternative simple formula for temperature estimate. J Ultrasound Med. 1989;8:653-654. 62. Jauniaux E, Gulbis B, Burton GJ. The human first trimester gestational sac limits rather than facilitates oxygen transfer to the foetus—a review. Placenta. 2003;24 (Suppl A):S86-93. 63. Duck FA. Is it safe to use diagnostic ultrasound during the first trimester? Ultrasound Obstet Gynecol. 1999;13:385-388. 64. Calvert J, Duck F, Clift S, Azaime H. Surface heating by transvaginal transducers. Ultrasound Obstet Gynecol. 2007;29:427-432. 65. Makikallio K, Tekay A, Jouppila P. Uteroplacental hemodynamics during early human pregnancy: a longitudinal study. Gynecol Obstet Invest. 2004;58:49-54. 66. Ziskin MC. Intrauterine effects of ultrasound: human epidemiology. Teratology. 1999;59:252-260. 67. O’Brien WD, Siddiqi TA. Obstetric sonography: the Output Display Standard and ultrasound bioeffects. In: Fleischer AC, Manning FA, Jeanty P, Romero R, eds. Sonography in Obstetrics and Gynecology— Principles and Practice. New York: McGraw-Hill, 2001. 68. Bly SH, Vlahovich S, Mabee PR, Hussey RG. Computed estimates of maximum temperature elevations in fetal tissues during transabdominal pulsed Doppler examinations. Ultrasound Med Biol. 1992;18:389-397. 69. Li GC, Mivechi NF, Weitzel G. Heat shock proteins, thermotolerance, and their relevance to clinical hyperthermia. Int J Hyperthermia. 1995;11:459-488. 70. Fowlkes JB, Holland CK. Mechanical bioeffects from diagnostic ultrasound: AIUM consensus statements. American Institute of Ultrasound in Medicine. J Ultrasound Med. 2000;19:69-72. 71. Dalecki D. Mechanical bioeffects of ultrasound. Annu Rev Biomed Eng. 2004;6:229-248. 72. Richards WT, Loomis AL. The chemical effects of high frequency sound waves. I. A preliminary survey. J Am Chem Soc. 1928;49: 3086-3100. 73. Carstensen EL. Acoustic cavitation and the safety of diagnostic ultrasound. Ultrasound Med Biol. 1987;13:597-606. 74. Holland CK, Deng CX, Apfel RE, Alderman JL, Fernandez LA, Taylor KJ. Direct evidence of cavitation in vivo from diagnostic ultrasound. Ultrasound Med Biol. 1996;22:917-925. 75. Kimmel E. Cavitation bioeffects. Crit Rev Biomed Eng. 2006;34:105-161.

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76. Rooney JA. Shear as a mechanism for sonically induced biological effects. J Acoust Soc Am. 1972;52:1718-1724. 77. Nyborg WL. Ultrasonic microstreaming and related phenomena. Br J Cancer Suppl. 1982;5:156-160. 78. Zauhar G, Starritt HC, Duck FA. Studies of acoustic streaming in biological fluids with an ultrasound Doppler technique. Br J Radiol. 1998;71:297-302. 79. Kondo T, Kano E. Effects of free radicals induced by ultrasonic cavitation on cell killing. Int J Radiat Biol. 1988;54:475-486. 80. Riesz P, Kondo T. Free radical formation induced by ultrasound and its biological implications. Free Radic Biol Med. 1992;13:247-270. 81. Dalecki D, Raeman CH, Child SZ, Carstensen EL. Intestinal hemorrhage from exposure to pulsed ultrasound. Ultrasound Med Biol. 1995;21:1067-1072. 82. Wible JH Jr, Galen KP, Wojdyla JK, Hughes MS, Klibanov AL, Brandenburger GH. Microbubbles induce renal hemorrhage when exposed to diagnostic ultrasound in anesthetized rats. Ultrasound Med Biol. 2002;28:1535-1546. 83. Hartman C, Child SZ, Mayer R, Schenk E, Carstensen EL. Lung damage from exposure to the fields of an electrohydraulic lithotripter. Ultrasound Med Biol. 1990;16:675-679. 84. Carstensen EL, Gates AH. The effects of pulsed ultrasound on the fetus. J Ultrasound Med. 1984;3:145-147. 85. Dalecki D, Raeman CH, Child SZ, et al. Hemolysis in vivo from exposure to pulsed ultrasound. Ultrasound Med Biol. 1997;23: 307-313. 86. Miller MW, Brayman AA, Sherman TA, Abramowicz JS, Cox C. Comparative sensitivity of human fetal and adult erythrocytes to hemolysis by pulsed 1 MHz ultrasound. Ultrasound Med Biol. 2001;27:419-425. 87. Fatemi M, Ogburn PL Jr, Greenleaf JF. Fetal stimulation by pulsed diagnostic ultrasound. J Ultrasound Med. 2001;20:883-889. 88. Harvey EN, Loomis AL. High frequency sound waves of small intensity and their biological effects. Nature. 1928;121:622-624. 89. Siddiqi TA, Plessinger MA, Meyer RA, Woods JR Jr. Bioeffects of diagnostic ultrasound on auditory function in the neonatal lamb. Ultrasound Med Biol. 1990;16:621-625. 90. Dalecki D, Child SZ, Raeman CH, Carstensen EL. Tactile perception of ultrasound. J Acoust Soc Am. 1995;97:3165-3170. 91. Dalecki D, Raeman CH, Child SZ, Carstensen EL. Effects of pulsed ultrasound on the frog heart: III. The radiation force mechanism. Ultrasound Med Biol. 1997;23:275-285. 92. Kristiansen TK, Ryaby JP, McCabe J, Frey JJ, Roe LR. Accelerated healing of distal radial fractures with the use of specific, low-intensity ultrasound. A multicenter, prospective, randomized, double-blind, placebo-controlled study. J Bone Joint Surg Am. 1997;79:961-973. 93. Duck FA. Acoustic streaming and radiation pressure in diagnostic applications: what are the implications? In: Barnett SB, Kossoff G, eds. Safety of Diagnostic Ultrasound. New York, London: The Parthenon Publishing Group, 1998. 94. NCRP. NCRP (National Council on Radiation Protection and Measurements) Implementation of the Principle of as Low as Reasonably Achievable (ALARA) for Medical and Dental Personnel. Report No. 107. Bethesda, MD: National Council on Radiation Protection and Measurements, 1990. 95. Abbott JG. Rationale and derivation of MI and TI—a review. Ultrasound Med Biol. 1999;25:431-441. 96. EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology). Thermal and mechanical indices: EFSUMB safety tutorial. Eur J Ultrasound. 1996;4:144-150. 97. Sheiner E, Shoham-Vardi I, Abramowicz JS. What do clinical users know regarding safety of ultrasound during pregnancy? J Ultrasound Med. 2007;26:319-325; quiz 326-327. 98. Marsal K. The output display standard: has it missed its target? Ultrasound Obstet Gynecol. 2005;25:211-214. 99. Piscaglia F, Tewelde AG, Righini R, Gianstefani A, Calliada F, Bolondi L. Knowledge of the bio-effects of ultrasound among physicians performing clinical ultrasonography: results of a survey conducted by the Italian Society for Ultrasound in Medicine and Biology (SIUMB). J Ultrasound. 2009 Mar;12(1):6-11. 100. Akhtar W, Arain MA, Ali A, et al. Ultrasound biosafety during pregnancy: what do operators know in the developing world?

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National survey findings from Pakistan. J Ultrasound Med. 2011 Jul;30(7):981-985. 101. Sharon N, Shoham-Vardi I, Aricha-Tamir B, Abramowicz JS, Sheiner E. What do ultrasound performers in Israel know regarding safety of ultrasound, in comparison to the end users in the United States? Harefuah. 2012 Mar;151(3):146-149. 102. Sheiner E, Abramowicz JS. Clinical end users worldwide show poor knowledge regarding safety issues of ultrasound during pregnancy. J Ultrasound Med. 2008 Apr;27(4):499-450. 103. Sheiner E, Abramowicz JS. A symposium on obstetrical ultra sound: is all this safe for the fetus? Clin Obstet Gynecol. 2012 Mar;55(1):188-198. 104. Houston LE, Allsworth J, Macones GA. Ultrasound is safe . . . right? Resident and maternal-fetal medicine fellow knowledge regarding obstetric ultrasound safety. J Ultrasound Med. 2011 Jan;30(1):21-27. 105. Bagley J, Thomas K, DiGiacinto D. Safety practices of sonographers and their knowledge of the biologic effects of sonography. J Diag Med Sonography. 2011;27:252-261. 106. Bromley B, Spitz J, Fuchs K, Thornburg LL. Do clinical practitioners seeking credentialing for nuchal translucency measurement demonstrate compliance with biosafety recommendations? Experience of the Nuchal Translucency Quality Review Program. J Ultrasound Med. 2014 Jul;33(7):1209-1214. 107. Jago JR, Henderson J, Whittingham TA, Mitchell G. A comparison of AIUM/NEMA thermal indices with calculated temperature rises for a simple third-trimester pregnancy tissue model. American Institute of Ultrasound in Medicine/National Electrical Manufacturers Association. Ultrasound Med Biol. 1999;25:623-628. 108. Jago JR, Henderson J, Whittingham TA, Willson K. How reliable are manufacturer’s reported acoustic output data? Ultrasound Med Biol. 1995;21:135-136. 109. http://unesdoc.unesco.org/images/0013/001395/139578e.pdf. 110. International Organization for Standardization (ISO): Medical devices—application of risk management to medical devices. ISO14971. Geneva, Switzerland, 2007. 111. Montague P. The precautionary principle in a nutshell, 2005. http:// www.precaution.org/lib/pp_def.htm. Accessed December 24, 2015. 112. Lilienfeld AM, Lilienfeld DE. John Snow, the Broad Street pump and modern epidemiology. Int J Epidemiol. 1984;13:376-378. 113. Christiansen SB. The precautionary principle: history and origins. In: O’Riordan T, Cameron J, eds. Interpreting the Precautionary Principle. London, UK: Earthscan Publications Ltd, 1994. 114. SEHN. Science and Environmental Health Network (SEHN): The Wingspread Statement on the Precautionary Principle, 1998. http:// www.sehn.org/state.html#w. Accessed December 24, 2015. 115. Stijkel A, Reijnders L. Implementation of the precautionary principle in standards for the workplace. Occup Environ Med. 1995; 52:304-312. 116. Ibarreta D, Swan S. The DES story: long-term consequences of prenatal exposure. In: Harremoës P, Gee D, MacGarvin M, et al, eds. Late Lessons from Early Warnings: The Precautionary Principle 1896-2000. Environmental Issue Report #22. Copenhagen: European Environmental Agency, 2002. 117. James WH. Teratogenetic properties of thalidomide. Br Med J. 1965;2:1064. 118. Ellman LM, Sunstein CR. Hormesis, the precautionary principle, and legal regulation. Hum Exp Toxicol. 2004;23:601-611. 119. Vineis P. Scientific basis for the precautionary principle. Toxicol Appl Pharmacol. 2005;207:658-662. 120. Weiss NS. When can the result of epidemiologic research not eliminate the need to invoke the precautionary principle? J Evid Based Dent Pract. 2006;6:16-18. 121. Stratmeyer ME, Christman CL. Biological effects of ultrasound. Women Health. 1982;7:65-81. 122. Lierman S, Veuchelen L. The optimisation approach of ALARA in nuclear practice: an early application of the precautionary principle. Scientific uncertainty versus legal uncertainty. Water Sci Technol. 2005;52:81-86. 123. Gilbert SG. Ethical, legal, and social issues: our children’s future. Neurotoxicology. 2005;26:521-530. 124. Rogan WJ, Ware JH. Exposure to lead in children—how low is low enough? N Engl J Med. 2003;348:1515-1516.

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125. Sandin P. A paradox out of context: Harris and Holm on the precautionary principle. Camb Q Healthc Ethics. 2006;15:175-183; discussion 184-187. 126. Tubiana M. Conclusions. The precautionary principle: its advantages and risks. Bull Acad Natl Med. 2000;184:969-993. 127. Keiding N, Budtz-Jorgensen E. The precautionary principle and statistical approaches to uncertainty. Int J Occup Med Environ Health. 2004;17:147-151. 128. Whelan EM. Can too much safety be hazardous? A critical look at the “Precautionary Principle.” Posted May 23, 2000. http://www. acsh.org/healthissues/newsID.236/healthissue_detail.asp. Accessed December 24, 2015. 129. Goldstein BD, Carruth RS. Implications of the precautionary principle: is it a threat to science? Int J Occup Med Environ Health. 2004;17:153-161. 130. Resnik DB. The precautionary principle and medical decision making. J Med Philos. 2004;29:281-299. 131. Kremkau FW. Biological effects and possible hazards. Clin Obstet Gynaecol. 1983;10:395-405. 132. Barnett SB, Maulik D. Guidelines and recommendations for safe use of Doppler ultrasound in perinatal applications. J Matern Fetal Med. 2001;10:75-84. 133. Church CC, Miller MW. Quantification of risk from fetal exposure to diagnostic ultrasound. Prog Biophys Mol Biol. 2007;93: 331-353. 134. Woo J. A short history of the development of ultrasound in obstetrics and gynecology, 2002. http://www.ob-ultrasound.net/history1. html. Accessed December 23, 2015. 135. Brown BS. How safe is diagnostic ultrasonography? Can Med Assoc J. 1984;131:307-311. 136. Lele PP. Safety and potential hazards in the current applications of ultrasound in obstetrics and gynecology. Ultrasound Med Biol. 1979;5:307-320. 137. Muggah HF. The safety of diagnostic ultrasonography. Can Med Assoc J. 1984;131:280-282. 138. O’Brien WD Jr. Ultrasonic bioeffects: a view of experimental studies. Birth. 1984;11:149-157. 139. Rott HD. [Diagnostic ultrasound: biological effects and potential risks]. Ultraschall Med. 1988;9:2-4. 140. Reece EA, Assimakopoulos E, Zheng XZ, Hagay Z, Hobbins JC. The safety of obstetric ultrasonography: concern for the fetus. Obstet Gynecol. 1990;76:139-146. 141. Merritt CR, Kremkau FW, Hobbins JC. Diagnostic ultrasound: bioeffects and safety. Ultrasound Obstet Gynecol. 1992;2:366-374. 142. Miller MW, Brayman AA. Biological effects of ultrasound. The perceived safety of diagnostic ultrasound within the context of ultrasound biophysics: a personal perspective. Echocardiography. 1997;14:615-628. 143. Newnham JP. Studies of ultrasound safety in humans: clinical benefit vs. risk. In: Barnett SB, Kossoff G, eds. Safety of Diagnostic Ultrasound. New York, London: The Parthenon Publishing Group, 1998. 144. Marinac-Dabic D, Krulewitch CJ, Moore RM Jr. The safety of prenatal ultrasound exposure in human studies. Epidemiology. 2002;13:S19-S22. 145. Bly S, Van den Hof MC. Obstetric ultrasound biological effects and safety. J Obstet Gynaecol Can. 2005;27:572-580. 146. Kieler H. Epidemiological studies on adverse effects of prenatal ultrasound—which are the challenges? Prog Biophys Mol Biol. 2007;93:301-308. 147. Salvesen KA. Epidemiological prenatal ultrasound studies. Prog Biophys Mol Biol. 2007;93:295-300. 148. Miller DL, Nyborg WL, Whitcomb CC. Platelet aggregation induced by ultrasound under specialized conditions in vitro. Science. 1979;205:505-507. 149. Williams AR. A possible alteration in the permeability of ascites cell membranes after exposure to acoustic microstreaming. J Cell Sci. 1973;12:875-885. 150. Kaufman GE, Miller MW, Griffiths TD, Ciaravino V, Carstensen EL. Lysis and viability of cultured mammalian cells exposed to 1 MHz ultrasound. Ultrasound Med Biol. 1977;3:21-25. 151. Miller DL. The botanical effects of ultrasound: a review. Environ Exp Botany. 1983;23:1-27.

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152. Carstensen EL, Child SZ, Crane C, Miller MW, Parker KJ. Lysis of cells in Elodea leaves by pulsed and continuous wave ultrasound. Ultrasound Med Biol. 1990;16:167-173. 153. Child SZ, Carstensen EL, Lam SK. Effects of ultrasound on Drosophila: III. Exposure of larvae to low-temporal-average-intensity, pulsed irradiation. Ultrasound Med Biol. 1981;7:167-173. 154. Barnett SB, Miller MW, Cox C, Carstensen EL. Increased sister chromatid exchanges in Chinese hamster ovary cells exposed to high intensity pulsed ultrasound. Ultrasound Med Biol. 1988;14:397-403. 155. Fry FJ, Kossoff G, Eggleton RC, Dunn F. Threshold ultrasonic dosages for structural changes in the mammalian brain. J Acoust Soc Am. 1970;48:Suppl 2:1413+. 156. Frizzell LA, Carstensen EL, Davis JD. Ultrasonic absorption in liver tissue. J Acoust Soc Am. 1979;65:1309-1312. 157. Frizzell LA, Lee CS, Aschenbach PD, Borrelli MJ, Morimoto RS, Dunn F. Involvement of ultrasonically induced cavitation in the production of hind limb paralysis of the mouse neonate. J Acoust Soc Am. 1983;74:1062-1065. 158. Borrelli MJ, Frizzell LA, Dunn F. Ultrasonically induced morphological changes in the mammalian neonatal spinal cord. Ultrasound Med Biol. 1986;12:285-295. 159. Frizzell LA, Linke CA, Carstensen EL, Fridd CW. Thresholds for focal ultrasonic lesions in rabbit kidney, liver, and testicle. IEEE Trans Biomed Eng. 1977;24:393-396. 160. Hynynen K. The threshold for thermally significant cavitation in dog’s thigh muscle in vivo. Ultrasound Med Biol. 1991;17:157-169. 161. Dalecki D, Child SZ, Raeman CH, Cox C, Carstensen EL. Ultrasonically induced lung hemorrhage in young swine. Ultrasound Med Biol. 1997;23:777-781. 162. Tarantal AF, Hendrickx AG. Evaluation of the bioeffects of prenatal ultrasound exposure in the cynomolgus macaque (Macaca fascicularis): II. Growth and behavior during the first year. Teratology. 1989;39:149-162. 163. Tarantal AF, Gargosky SE, Ellis DS, O’Brien WD Jr, Hendrickx AG. Hematologic and growth-related effects of frequent prenatal ultrasound exposure in the long-tailed macaque (Macaca fascicularis). Ultrasound Med Biol. 1995;21:1073-1081. 164. Hande MP, Devi PU. Effect of in utero exposure to diagnostic ultrasound on the postnatal survival and growth of mouse. Teratology. 1993;48:405-411. 165. O’Brien WD. Dose-dependent effects of ultrasound on fetal weight in mice. J Ultrasound Med. 1983;2:1-8. 166. Vorhees CV, Acuff-Smith KD, Schilling MA, et al. Behavioral teratologic effects of prenatal exposure to continuous-wave ultrasound in unanesthetized rats. Teratology. 1994;50:238-49. 167. O’Brien WD Jr, Januzik SJ, Dunn F. Ultrasound biologic effects: a suggestion of strain specificity. J Ultrasound Med. 1982;1:367-370. 168. Hande MP, Devi PU. Effect of prenatal exposure to diagnostic ultrasound on the development of mice. Radiat Res. 1992;130:125-128. 169. Rao S, Ovchinnikov N, McRae A. Gestational stage sensitivity to ultrasound effect on postnatal growth and development of mice. Birth Defects Res A Clin Mol Teratol. 2006;76:602-608. 170. Devi PU, Suresh R, Hande MP. Effect of fetal exposure to ultrasound on the behavior of the adult mouse. Radiat Res. 1995;141:314-317. 171. Hande MP, Devi PU, Karanth KS. Effect of prenatal ultrasound exposure on adult behavior in mice. Neurotoxicol Teratol. 1993;15: 433-438. 172. Ang ES Jr, Gluncic V, Duque A, Schafer ME, Rakic P. Prenatal exposure to ultrasound waves impacts neuronal migration in mice. Proc Natl Acad Sci U S A. 2006;103:12903-12910. 173. Jensh RP, Lewin PA, Poczobutt MT, Goldberg BB, Oler J, Brent RL. The effects of prenatal ultrasound exposure on postnatal growth and acquisition of reflexes. Radiat Res. 1994;140:284-293. 174. Jensh RP, Lewin PA, Poczobutt MT, et al. Effects of prenatal ultrasound exposure on adult offspring behavior in the Wistar rat. Proc Soc Exp Biol Med. 1995;210:171-179. 175. Yang FY, Lin GL, Horng SC, Chen RC. Prenatal exposure to diagnostic ultrasound impacts blood-brain barrier permeability in rats. Ultrasound Med Biol. 2012 Jun;38(6):1051-1057. 176. Bagley J, Thomas K, DiGiacinto D, et al. Bioeffects literature reviews. J Ultrasound Med. 2015 Aug;34(8):1-12. 177. Schneider-Kolsky ME, Ayobi Z, Lombardo P, Brown D. Ultrasound exposure of the fetal chick brain: effects on learning and memory. Internat J Develop Neuroscience. 2009;27: 677-683.

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178. Williams AR. Effects of ultrasound on blood and the circulation. In: Nyborg WL, Ziskin MC, eds. Clinics in Diagnostic Ultrasound: Biological Effects of Ultrasound. New York: Churchill Livingstone, 1985 (vol 16). 179. Abramowicz JS, Miller MW, Battaglia LF, Mazza S. Comparative hemolytic effectiveness of 1 MHz ultrasound on human and rabbit blood in vitro. Ultrasound Med Biol. 2003;29:867-873. 180. Tarantal AF. Effects of ultrasound exposure on fetal development in animal models. In: Barnett SB, Kossoff G, eds. Safety of Diagnostic Ultrasound. New York: The Parthenon Publishing Group, 1998. 181. AIUM: Conclusions Regarding Epidemiology for Obstetric Ultrasound. Reapproved 2010. http://www.aium.org/officialStatements/16. Accessed December 24, 2015. 182. Naumburg E, Bellocco R, Cnattingius S, Hall P, Ekbom A. Prenatal ultrasound examinations and risk of childhood leukaemia: casecontrol study. BMJ. 2000;320:282-283. 183. Newnham JP, Evans SF, Michael CA, Stanley FJ, Landau LI. Effects of frequent ultrasound during pregnancy: a randomized controlled trial. Lancet. 1993;342:887-891. 184. Abramowicz JA, Fowlkes JB, Skelly AC, Stratmeyer ME, Ziskin MC. Conclusions regarding epidemiology for obstetric ultrasound. J Ultrasound Med. 2008; 27: 637-644. 185. Campbell JD, Elford RW, Brant RF. Case-control study of prenatal ultrasonography exposure in children with delayed speech. CMAJ. 1993;149:1435-1440. 186. Stark CR, Orleans M, Haverkamp AD, Murphy J. Short- and longterm risks after exposure to diagnostic ultrasound in utero. Obstet Gynecol. 1984;63:194-200. 187. Kieler H, Axelsson O, Haglund B, Nilsson S, Salvesen KA. Routine ultrasound screening in pregnancy and the children’s subsequent handedness. Early Hum Dev. 1998;50:233-245. 188. Salvesen KA, Eik-Nes SH. Ultrasound during pregnancy and subsequent childhood non-right handedness: a meta-analysis. Ultrasound Obstet Gynecol. 1999;13:241-246. 189. Reissland N, Aydin E, Francis B, Exley K. Laterality of foetal selftouch in relation to maternal stress. Laterality. 2015;20(1):82-94. 190. Hepper PG. The developmental origins of laterality: fetal handedness. Dev Psychobiol. 2013 Sep;55(6):588-595. 191. Moore RM Jr, Barrick MK, Hamilton TM. Effect of sonic radiation on growth and development. Am J Epidemiol. 1982;116:571. 192. Moore RM Jr, Diamond EL, Cavalieri RL. The relationship of birth weight and intrauterine diagnostic ultrasound exposure. Obstet Gynecol. 1988;71:513-517. 193. Lyons EA, Dyke C, Toms M, Cheang M. In utero exposure to diagnostic ultrasound: a 6-year follow-up. Radiology. 1988;166: 687-690. 194. Newnham JP, Doherty DA, Kendall GE, Zubrick SR, Landau LL, Stanley FJ. Effects of repeated prenatal ultrasound examinations on childhood outcome up to 8 years of age: follow-up of a randomised controlled trial. Lancet. 2004;364:2038-2044. 195. Bakketeig LS, Eik-Nes SH, Jacobsen G, et al. Randomised con trolled trial of ultrasonographic screening in pregnancy. Lancet. 1984;2:207-211. 196. Saari-Kemppainen A, Karjalainen O, Ylostalo P, Heinonen OP. Ultrasound screening and perinatal mortality: controlled trial of systematic one-stage screening in pregnancy. The Helsinki Ultrasound Trial. Lancet. 1990;336:387-391. 197. Waldenstrom U, Axelsson O, Nilsson S, et al. Effects of routine onestage ultrasound screening in pregnancy: a randomised controlled trial. Lancet. 1988;2:585-588. 198. Salvesen KA, Vatten LJ, Bakketeig LS, Eik-Nes SH. Routine ultrasonography in utero and speech development. Ultrasound Obstet Gynecol. 1994;4:101-103. 199. Eik-Nes SH, Okland O, Aure JC, Ulstein M. Ultrasound screening in pregnancy: a randomised controlled trial. Lancet. 1984;1:1347. 200. Salvesen KA, Bakketeig LS, Eik-nes SH, Undheim JO, Okland O. Routine ultrasonography in utero and school performance at age 8-9 years. Lancet. 1992;339:85-89. 201. Salvesen KA, Vatten LJ, Jacobsen G, et al. Routine ultrasonography in utero and subsequent vision and hearing at primary school age. Ultrasound Obstet Gynecol. 1992;2:243-4, 245-247. 202. Salvesen KA, Vatten LJ, Eik-Nes SH, Hugdahl K, Bakketeig LS. Routine ultrasonography in utero and subsequent handedness and neurological development. BMJ. 1993;307:159-64.

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Ultrasound Bioeffects and Safety: What the Practitioner Should Know

203. Salvesen KA, Eik-Ness SH, Vatten LJ, Hugdahl K, Bakketeig LS. Routine ultrasound scanning in pregnancy. Authors’ reply. BMJ. 1993;307:1562. 204. Newnham JP. Studies of ultrasound safety in human: clinical benefit vs. risk. In: Barnett SB, Kossoff G, eds. Safety of Diagnostic Ultrasound. New York, London: The Parthenon Publishing Group, 1998. 205. Harbarger CF1, Weinberger PM, Borders JC, Hughes CA. Prenatal ultrasound exposure and association with postnatal hearing outcomes. J Otolaryngol Head Neck Surg. 2013 Jan 31;42:3. 206. Kossoff G, Griffiths KA, Garrett WJ, Warren PS, Roberts AB, Mitchell JM. Thickness of tissue intervening between the transducer and fetus and models for fetal exposure calculations in transvaginal sonography. Ultrasound Med Biol. 1993;19:59-65. 207. Sheiner E, Shoham-Vardi I, Hussey MJ, et al. First-trimester sonography: is the fetus exposed to high levels of acoustic energy? J Clin Ultrasound. 2007;35:245-249. 208. Sheiner E, Abramowicz JS. Acoustic output as measured by thermal and mechanical indices during fetal nuchal translucency ultrasound examinations. Fetal Diagn Ther. 2009;25(1):8-10. 209. Sheiner E, Shoham-Vardi I, Pombar X, Hussey MJ, Strassner HT, Abramowicz JS. An increased thermal index can be achieved when performing Doppler studies in obstetric sonography. J Ultrasound Med. 2007;26:71-76. 210. Sheiner E, Hackmon R, Shoham-Vardi I, et al. A comparison between acoustic output indices in 2D and 3D/4D ultrasound in obstetrics. Ultrasound Obstet Gynecol. 2007;29:326-328. 211. Pooh RK, Maeda K, Kurjak A, et al. 3D/4D sonography—any safety problem. J Perinat Med. 2016 Mar;44(2):125-129. 212. Sande RK, Matre K, Eide GE, Kiserud T. Ultrasound safety in early pregnancy: reduced energy setting does not compromise obstetric Doppler measurements. Ultrasound Obstet Gynecol. 2012 Apr;39(4):438-443. 213. Sande RK, Matre K, Eide GE, Kiserud T. The effects of reducing the thermal index for bone from 1.0 to 0.5 and 0.1 on common obstetric pulsed wave Doppler measurements in the second half of pregnancy. Acta Obstet Gynecol Scand. 2013 Jul;92(7):790-796. 214. ter Haar GR, Abramowicz JS, Akiyama I, Evans DH, Ziskin MC, Maršál K. Do we need to restrict the use of Doppler ultrasound in the first trimester of pregnancy? Ultrasound Med Biol. 2013 Mar;39(3):374-380. 215. Bigelow TA, Church CC, Sandstrom K, et al. The thermal index: its strengths, weaknesses, and proposed improvements. J Ultrasound Med. 2011 May;30(5):714-734. 216. Cardinale A, Lagalla R, Giambanco V, Aragona F. Bioeffects of ultrasound: an experimental study on human embryos. Ultrasonics. 1991;29:261-263. 217. Bello SO. How we may be missing some harmful effects of ultrasound—a hypothesis. Med Hypotheses. 2006;67:765-767. 218. McClintic AM, King BH, Webb SJ, Mourad PD. Mice exposed to diagnostic ultrasound in utero are less social and more active in social situations relative to controls. Autism Res. 2014 Jun;7(3):295-304. 219. Chudleigh T. Scanning for pleasure. Ultrasound Obstet Gynecol. 1999;14:369-371. 220. Rados C. FDA cautions against ultrasound “keepsake” images. FDA Consumer Magazine: U.S Food and Drug Administration, JanuaryFebruary 2004. 221. AIUM. Prudent Use in Obstetrics: American Institute of Ultrasound in Medicine, Approved 4/1/2012. http://www.aium.org/ officialStatements/33. Accessed December 24, 2015. 222. Thermal teratology. European Committee for Medical Ultrasound Safety (ECMUS). Eur J Ultrasound. 1999;9:281-283.

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223. AIUM. Keepsake Fetal Imaging, reapproved 2012. http://www.aium. org/officialStatements/31. Accessed December 23, 2015. 224. Lees C, Abramowicz JS, Brezinka C, et al. Ultrasound from conception to 10+0 weeks of gestation. Scientific impact paper no. 49. Royal College of Obstetricians and Gynaecologists, London, UK, 2015. 225. Abramowicz JS. Fetal Doppler: how to keep it safe? Clin Obstet Gynecol. 2010 Dec;53(4):842-850. 226. Harris GR, Church CC, Dalecki D, Ziskin MC, Bagley JE. Comparison of thermal safety practice guidelines for diagnostic ultrasound exposures. Ultrasound Med Biol. 2016 Feb;42(2):345-357. 227. BMUS. Statement on the safe use, and potential hazards of diagnostic ultrasound. 2000, reapproved 2012. https://www.bmus.org/static/ uploads/resources/STATEMENT_ON_THE_SAFE_USE_AND_ POTENTIAL_HAZARDS_OF_DIAGNOSTIC_ULTRASOUND. pdf. Accessed December 23, 2015. 228. ter Haar G. The Safe Use of Ultrasound in Medical Diagnosis. 3rd ed. London, UK: The British Institute of Radiology; 2012: 173. 229. AIUM. Statement on Mammalian Biological Effects of Heat. Approved 2015. http://www.aium.org/officialStatements/17. Accessed December 23, 2015. 230. BMUS. Statement for the General Public on the Safety of Medical Ultrasound Imaging. Approved 2012. https://www.bmus.org/static/ uploads/resources/Statement_for_the_General_Public_on_the_ Safety_of_Medical_Ultrasound_Imaging.pdf. Accessed December 23, 2015.

Highlighted References 1. Tarantal AF, O’Brien WD, Hendrickx AG. Evaluation of the bioeffects of prenatal ultrasound exposure in the cynomolgus macaque (Macaca fascicularis): III. Developmental and hematologic studies. Teratology. 1993;47:159-170. A classical animal study of the bioeffects of ultrasound. The authors published several such reports detailing the possible effects of ultrasound in monkeys. 2. Miller MW, Ziskin MC. Biological consequences of hyperthermia. Ultrasound Med Biol. 1989;15:707-722. One of the studies that formed the basis of modern analysis of ultrasound bioeffects. It solidified the notions of a correlation between duration of exposure and temperature increase. 3. Sheiner E, Shoham-Vardi I, Abramowicz JS. What do clinical users know regarding safety of ultrasound during pregnancy? J Ultrasound Med. 2007;26:319-325; quiz 326-327. A very disturbing study demonstrating a general lack of knowledge about bioeffects and safety of ultrasound among users of this technology in obstetrics in the United States of America (#95 is a study with similar results from Europe). 4. ter Haar GR, Abramowicz JS, Akiyama I, Evans DH, Ziskin MC, Maršál K. Do we need to restrict the use of Doppler ultrasound in the first trimester of pregnancy? Ultrasound Med Biol. 2013 Mar;39(3):374-380. An important discussion on the use of Doppler in early gestation. 5. Lees C, Abramowicz JS, Brezinka C, et al. Ultrasound from conception to 10+0 weeks of gestation. Scientific impact paper no. 49. Royal College of Obstetricians and Gynaecologists, London, UK, 2015. A document published by the RCOG on the use of ultrasound in the first trimester, with specific emphasis on bioeffects and safety.

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Chapter 2

Normal Pelvic Anatomy as Depicted with Transvaginal Sonography

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Chapter 2

NORMAL PELVIC ANATOMY AS DEPICTED WITH TRANSVAGINAL SONOGRAPHY Arthur C. Fleischer  ●  Lori Deitte   ●  Jill Trotter Key Terms 1.  Coronal: images obtained in the “elevational” plane. 2.  Curved (convex) array transducer: transducer elements arranged in curved fashion. 3.  Linear array: transducer elements linearly arranged. 4.  Phased array transducer: aims beam by selective activation of transducer elements. 5.  Sagittal: images obtained in the long axis of the body. 6.  Sector transducer: provides a pie-shaped field of view. 7.  Transverse: images obtained in the short axis of the body.

INTRODUCTION Transvaginal sonography (TVS) affords improved resolution of the uterus and ovaries over the conventional transabdominal sonography (TAS) approach. Although TVS allows a closer proximity of the transducer to the pelvic organs and more detailed depiction, it may be more difficult for the sonographer to become oriented to the images when compared with conventional TAS because of the limited field of view and unusual scanning planes depicted with TVS. As one develops a systematic approach to the examination of the uterus and adnexal structures with TVS, however, the examination becomes much easier to perform. Appendix 2-1 lists the American Institute of Ultrasound in Medicine (AIUM) guidelines for a complete pelvic sonogram. In this chapter, the sonographic appearances of the uterus, ovary, and other pelvic structures will be described, with particular emphasis on how they are best depicted in a real-time TVS examination.

SCANNING TECHNIQUE AND INSTRUMENTATION (Figures 2-1 to 2-3) The 3 scanning maneuvers that are used in TVS include: 1. Vaginal insertion of the transducer with side-toside angulation within the upper vagina for sagittal imaging.

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2. Transverse orientation of the transducer for imaging in various degrees of semiaxial to semicoronal planes. 3. Variation in depth of transducer insertion for optimal imaging of the fundus to the cervix by gradual withdrawal of the transducer into the lower vagina for imaging of the cervix. In contrast to conventional TAS, bladder distention is not necessary for TVS. In fact, overdistention can hinder TVS by placing the desired field of view outside the optimal focal range of the transducer. Minimal distention is useful in a patient with a severely anteflexed uterus to straighten the uterus relative to the imaging plane. As is true for conventional sonographic equipment, the highest-frequency transducer possible should be used that allows adequate penetration and depiction of a particular region of interest. Thus, transducers with a highcentral frequency are preferred (broadband 5.5-7.8 MHz). Higher-frequency (>8 MHz) transducers may limit the field of view to within only 6 cm of the transducer. The major types of transducers that are used for TVS include those that contain a single-element oscillating transducer, multiple small transducer elements that are arranged in a curved linear array, and those that consist of multiple small elements steered by an electronic phased array. All of these transducers depict the anatomy in a sector format that usually encompasses 100 to 120 degrees. In our experience, the greatest resolution is achieved with a curved linear array that contains multiple (up to 200) separate transmit-receive elements. Mechanical transducers may be subject to minor image distortions at the edges of the field due to the hysteresis (lag in effect when stopping and starting) that occurs with an oscillating element. Reverberation artifacts can be created by suboptimal coupling of the condom/transducer/vagina surfaces. Although degradation of image quality by side-lobe artifacts can occur in the far field in a phased array transducer, they do not significantly degrade the image in the near field. Therefore, phased array transducers have similar resolution capabilities to sector as curved linear array transducers for use in transvaginal examinations. Transvaginal equipment that utilizes a mechanical transducer is relatively rarely used today when compared to electronic transducers.

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Part 1 GENERAL OBSTETRIC SONOGRAPHY

Long axis

Short axis

A

A

Long axis

Short axis

B

B

C Figure 2-2. Major scanning planes for transabdominal sonography

C Figure 2-1.  Scan planes (A) and representative transabdominal pelvic

(TAS) and transvaginal sonography (TVS). A: Normal adult, parous uterus in long and short axis as depicted with transabdominal sonography (TAS) through a fully distended urinary bladder. B: Transvaginal sonography (TVS) of an anteflexed uterus in long axis. The hand not holding the probe can be used to gently manipulate the uterus and ovaries to an optimal position for scanning. C: TVS of a patient with a retroflexed uterus. The probe is within the posterior fornix of the vagina and is in direct line of the uterine corpus and fundus.

sonograms (B and C). Transabdominal Sonograms (TAS) in long (B) and short (C) axis with accompanying typical sonograms showing uterus and right ovary in sagittal plane and right ovary and uterus in transverse plane (between cursors). By convention, the left of the image depicts the cephalic or superior of the patient whereas the right of the patient is depicted on the left of the image of the transverse scans.

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A

B

C

D

Figure 2-3.  Typical scan planes used for TVS of the uterus. A: First, the long axis of the uterus is imaged. B: The probe is angled toward the right, then

the left, cornu in the semisagittal plane. A sonohysterography catheter is shown in its long axis. C: Next, the probe is rotated to image the uterus in short axis, sweeping from fundus to cervix. D: Additional views can be obtained by directing the probe in a semicoronal plane. In this plane, the transverse endometrial width is obtained.

Practitioners should follow the AIUM guidelines for the disinfection of transvaginal transducers. These guidelines are included as Appendix 2-2. The more recent widespread use of the Trophon device has extended disinfection capabilities to include the human papilloma virus (HPV) virus. There is evidence that some disinfectants such as glutaraldehyde and ortho-phthalaldehyde are ineffective against HPV16, the leading cause of cervical cancer.1-3 The Trophon system has been shown to be effective against HPV16 and HPV18.4 This is considered a major advantage since HPV contamination was identified in up to 7% of disinfected transducers used in TVS.2 HPV has been shown to account for up to 5% of all cancers worldwide and is responsible for almost all cases of cervical cancer. The HPV virus is a leading cause of oral, throat, anal, and genital cancers. In addition, the design of the Trophon

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unit affords disinfection of the handle of the transvaginal transducer, which has been shown to be a reservoir for pathogens.4-6 For infection control purposes, a disposable protective sheath is used to cover the transducer. After completely covering the transducer with a sheath such as a condom and securing the sheath to the shaft of the transducer with a rubber band, the transducer is lubricated on its tip and periphery and then inserted into the vagina and manipulated around the cervical lips and into the fornix to depict the structures of interest in best detail. When the transducer is oriented in the longitudinal or sagittal plane, the long axis of the uterus can usually be depicted by slight angulation off midline. The uterus is used as a landmark for depiction of other adnexal structures. Once the uterus is identified, the transducer can be

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Part 1 GENERAL OBSTETRIC SONOGRAPHY

A Left

A Right

B Left

B Right

C Left

C Right

Figure 2-4.  TVS of normal uterus. A:Transducer/probe motion to enhance depiction of the uterus and endometrium in an anteflexed uterus. The

probe is placed in the anterior vaginal fornix and directed anteriorly. B: Midline sagittal view (left) depicting uterus is long axis with accompanying transvaginal sonogram. The sagittal image (right) is oriented with anterior or superior aspect of the patient to left of image. C: Transducer probe showing direction of probe used to enhance depiction of a retroflexed uterus. Corresponding TVS of drawing shown in C showing retroflexed uterus with secretory phase endometrium (between cursors).

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Chapter 2

Normal Pelvic Anatomy as Depicted with Transvaginal Sonography

D Left

D Right

E Left

E Right

29

Figure 2-4.  (Continued) D: Diagram showing short-axis image of endometrium. Corresponding TVS of image plane in D showing short-axis view of

the endometrium with surrounding hypoechoic inner myometrium. E: Diagram (left) and TVS (right) showing angled imaging of cervix. The TVS probe is inserted into the anterior vornix of the vagina.

directed to the right or left of midline in the sagittal plane to depict the ovaries. The internal iliac artery and vein appear as tubular structures along the pelvic side wall. Low-level blood echoes can occasionally be seen streaming within these vessels. The ovaries typically lie medial to those vessels. After appropriate images are obtained in the sagittal plane, the transducer can be turned 90 degrees counterclockwise to depict these structures in their axial or semicoronal planes. Particularly in larger patients, it is helpful for the sonographer to use one hand to scan while the other is used for gentle abdominal palpation to move structures, such as the ovaries, as close as possible to the transducer.

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UTERUS (Figures 2-4 to 2-7) Examination of the uterus begins with its depiction in long axis. The endometrial interface, which is typically echogenic, is a useful landmark to depict in long axis. The actual sonographic texture of the endometrium varies according to its consistency, which is elaborated upon in other sections of this chapter. Once the endometrium is identified in long axis, images of the uterus can be obtained in the sagittal and semiaxial/coronal planes.7 It may be difficult to determine the flexion of the uterus with static images obtained solely from transvaginal scanning except in extreme cases of anteflexion or retroflexion;

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Part 1 GENERAL OBSTETRIC SONOGRAPHY

A Right A Left

B Right Figure 2-5.  A: Diagram (left) and TV-CDS (right) of the uterine arterial network. The arcuate arterioles branch into radial arteries that course across the myometrium ending in the spiral arteries within the endometrium B: Diagram (left) and TV-CDS (right) of arterial vascularity of the uterus. The main uterine artery branches from the hypogastric artery (internal iliac artery) and courses along the lateral edges of the uterus, branching off into the arcuates. The radial arteries then course toward the endometrium, branching into the basal and spiral arteries within the endometrium.

however, one can obtain an impression of uterine flexion during the examination by the relative orientation of the transducer needed to obtain optimal images of the uterus. For example, retroflexed uteri are best depicted when the transducer is in the anterior fornix and angulated in a posterior direction. The fundus of the retroflexed uterus is directed to the inferior right corner of the image. Conversely, the anteflexed uterus will demonstrate the fundus directed to the upper left corner of the image. The endometrium has a variety of appearances depending on its stage of development. The stages of endometrial development can be described in relation to oocyte maturation (follicular vs luteal) or endometrial development (proliferative vs secretory). In the proliferative phase, the endometrium measures 5 to 7 mm in anterior-posterior (AP) dimension. This measurement includes the 2 layers of endometrium. A hypoechoic

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interface can be seen within the luminal aspects of echogenic layers of endometrium in the peri-ovulatory phase and likely represents edema and increased glycogen and mucus in the inner layers of endometrium. In the few days after ovulation, a small amount of secretion into the endometrial lumen can be seen. During the secretory phase, the endometrium typically measures between 6 and 12 mm in bilayer thickness; is homogeneously echogenic, most likely as a result of multiple interfaces resulting from stromal edema; and is surrounded by a hypoechoic band, representing the inner layer of the myometrium. This inner layer of myometrium appears hypoechoic on TVS and corresponds roughly to the “junctional zone” seen on magnetic resonance imaging (MRI). The junctional zone, however, may be thicker than the hypoechoic band seen in TVS, perhaps because of different physical interaction with the myometrium in this

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Chapter 2

Normal Pelvic Anatomy as Depicted with Transvaginal Sonography

A

C

31

B

D

Figure 2-6.  Transvaginal sonography (TVS) planes for depiction of the endometrium A: Long axis of an anteflexed uterine showing orientation of the endometrium to the transducer. The transducer can be advanced into the anterior fornix for better delineation of the endometrium. The opposite is true for retroflexed uteri. B: Short-axis image of the endometrium. With pressure on the probe and placement of the probe head in the anterior fornix for an anteflexed uterus, the endometrium is imaged in its short axis. C: Coronal view depicting “endometrial width.” This plane is most readily obtained in a “neutral” positioned (neither ante- nor retroflexed) uterus. D: Long axis of endometrium in the retroflexed uterus. With pressure on the posterior fornix, the endometrium becomes more horizontal to the transducer, allowing better detection. (Used with permission from Paul Gross, MS.)

area.8 This layer is hypoechoic, probably due to the longitudinal arrangement of the myometrial fibers. Endometrial volume may be calculated by measuring its long axis and multiplying by the AP and transverse dimension.9 Alternatively, volumetric measurements can be made using 3D (see Chapter 49). One can use the axial plane landmark where the endometrium invaginates into the area of ostia in the region of the uterine cornu. This is also a useful landmark to denote the proximal portion of the tube. Because of the close proximity of the transducer to the cervix, the cervix is not as readily visualized as the remainder of the uterus. This may make exact measurement of the long axis of the uterus difficult due to the imprecision of its measurement. If one slightly withdraws the transducer into the vaginal canal, however, images of the cervix can easily be obtained. The mucus within the endocervical canal usually appears as an echogenic interface. This interface may become hypoechoic during the

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peri-ovulatory period because the cervical mucus has a higher fluid content.

OVARIES (Figure 2-8) Ovaries are typically depicted as oblong-shaped structures measuring approximately 3 cm in long axis and 2 cm in AP and transverse dimensions. On angled long-axis scans, they are immediately medial to the pelvic vessels. They are particularly well depicted when they contain a mature follicle that is typically in the 1.5- to 2.0-cm range. It is not unusual to depict multiple immature or atretic follicles in the 3- to 7-mm range. The size of an ovary is related to the patient’s age and phase of follicular development. When the ovary contains a mature follicle, it can become twice as large in volume as one that does not contain mature follicles. The greatest dimension of a normal ovary, however, is typically less than 3 cm.10,11 The ovaries of postmenopausal women may

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Part 1 GENERAL OBSTETRIC SONOGRAPHY

A

B

C Figure 2-7.  Normal endometrium. A: Three-dimensional diagram of endometrium (in blue). Note the configuration of the endometrium in the corpus is more linear than in the fundus, where it invaginates in the cornual regions and is more transversally oriented. B: Diagram showing layers of endometrium. The endometrium consists of a basal layer (in blue), which is not shed, and a functional layer (in pink), which thickens and sloughs. The functionalis layer consists of glands and stroma as well as spiral vessels. C: Diagrams and graph of normal range of endometrial thicknesses throughout cycle. Diagram and graph showing normal bilayer thicknesses of endometrium in different phases (mean and range).

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Chapter 2

Normal Pelvic Anatomy as Depicted with Transvaginal Sonography

D Left

D Right

E Left

E Right

F Left

F Right

33

Figure 2-7.  (Continued) D: Normal endometrium as depicted by TVS. Long (left) and short (right) axes of early proliferative endometrium. Transvaginal sonogram (left) and accompanying diagram show microscopic anatomy of the endometrium (right). E: Long axis of endometrium in midcycle (left). A multilayered appearance is seen with the outer echogenic interfact representing basalis, the inner layer funcationalis, and the median echo arises from refluxed mucus. Diagram of corresponding microscopic anatomy (right). F: The luteal phase endometrium appearing as thick (8 mm), regular, and echogenic (left). Diagram showing thickened stroma and distended glands (right). (Used with permission from Paul Gross, MS.)

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Figure 2-8.  Myometrial layers as depicted by TVS (left shows midline: right shows layers). The innermost layer of myometrium is hypoechoic and provides endometrial peristalsis (in light pink). The middle layer is the thickest and arranged in a spiral fashion (shown as muscle bundles). The outermost layer extends from the arcuate vessels to the serosa and is contiguous with the musculature of the tube.

be difficult to recognize because they are relatively small and usually do not contain follicles which enhance their sonographic recognition. Ovarian volumes can be estimated by measurement of the greater transverse, longitudinal, and AP dimensions. The average ovarian volumes measured in menstruating women were 9.8 cm3, in postmenopausal women were 5.8 cm3, and in premenarchal females were 3.0 cm3.11 There is a gradual decrease in ovarian volume after menopause except in women receiving hormone replacement.12 Echogenic foci can be seen on TVS within the center and/or periphery of the ovary. Most of the central echogenic foci are due to tiny cysts or calcifications within atretic follicles. Those that are peripherally located are probably of no clinical significance and represent calcified foci within superficial epithelial inclusion cysts.13,14 Recent studies have further elucidated the origin of echogenic foci within the ovary. Those without an associated shadow may represent specular reflections from unresolved microscopic (5 mm). Whether or not this finding is associated with a distinct clinical entity, such as “pelvic congestion syndrome,” is controversial because many women with distended veins do not experience pain. The nondistended fallopian tube is typically difficult to depict on TVS, which is related to its small intraluminal size, serpiginous course, and location in the cul-de-sac.18 Occasionally, one can identify the proximal segment of the

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Chapter 2

Normal Pelvic Anatomy as Depicted with Transvaginal Sonography

35

A

Right adnexal

B1

B2

Figure 2-9.  Normal ovaries. A: Diagram of adnexal view of ovary with accompanying transvaginal sonogram (B1) in semiaxial or transverse plane; the patient’s right is displayed on the left. B1: Right ovary containing a mature follicle (arrow) in a spontaneous cycle and diagram (B2).

fallopian tube by finding the invagination of endometrium into the cornua depicting the area of the tubal ostia and following these structures laterally in the axial or coronal plane. In some rare instances, in patients with markedly anteflexed uteri, the tube can be identified even without surrounding fluid. In most patients, the ovarian and infundibulopelvic ligaments usually cannot be depicted unless there is fluid surrounding these structures. Sonographic delineation of the tubes is facilitated by the presence of intraperitoneal fluid that may be present in the cul-de-sac.18 Placing the patient in a reverse Trendelenburg position (head higher than hips) may augment intraperitoneal fluid around the fallopian tubes. When surrounded by fluid, the normal tube appears as a 0.5- to 1-cm-wide tubular echogenic structure that usually arises from the

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lateral aspect of the uterine cornu posterolaterally into the adnexal regions and cul-de-sac. The flaring of the fimbriated end of the tube can be appreciated in some patients because it approximates its nearby ovary. Transvaginal sonographic depiction of the tubes is also facilitated when they contain intraluminal fluid. Rarely, small (6 mm) is associated with embryonic demise as well as those that are compromised and small.3,13 The embryo/yolk sac complex lies adjacent to the edge of the gestational sac and has been described as forming a “double bleb,” representing the amniotic sac-embryo/yolk sac complex.11 By the end of the first half of the embryonic period, the choriodecidua forms the boundaries of the gestational sac, which appears as an echogenic ring of tissue. At 4 weeks of menstrual age, the gestational sac measures only 3 to 5 mm in diameter and grows to approximately 1 cm at 5 weeks. During the early embryonic period, the embryo may be barely visible on TVS. Although many of the structures are present, they cannot be resolved sonographically. The neural tube is closed in its midportion but open at its rostral and caudal ends. Brachial arches form, and the somites develop as rounded surface elevations. Fortytwo or forty-four somites form; these paired structures eventually give rise to the axial skeleton and associated musculature.

7 to 8 Weeks During the latter half of the embryonic period, sonographic scanning can depict a gestational sac, the developing

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Part 1 GENERAL OBSTETRIC SONOGRAPHY

A

Inner cell mass

B

Endoderm

Connective tissue

Blastocoele

Amnion cavity Embryonic disc Entoderm

Chorion Uterine epithelium

C

Blood vessel Uterine gland Cellular trophoblast Mesoderm Primary yolk sac Syncytial trophoblast Coagulum at site of entry

D

Figure 3-1.  Diagrammatic representation of embryonic/early fetal development. A: Human oocyte in process of fertilization (×420). B: A preimplantation baboon embryo (similar to the human) as the morula is transforming into a blastocyst. Arrow: column segmentation cavity; PV, perivitelline space; ZP, zona pellucida. C: Line drawing of blastocyst showing early inner cell mass and trophoblast. D: Section of 11-day human embryo showing cellular and syncytial trophoblast. (Reproduced with permission from Arey B. Developmental Anatomy. Philadelphia: Saunders; 1962.)

embryo and its heartbeat, the surrounding membranes, and the choriodecidua. During this period, organogenesis of the major body viscera occurs (Figures 3-3 to 3-6). On both TVS and TAS, heart pulsations can be depicted during this period of gestation. Transvaginal sonography is most precise in depicting early heart pulsation after 6 postmenstrual weeks, when the developing embryo forms from 2 enfolding fusiform tubes and begins contractile activity. During the seventh postmenstrual week (fifth week of gestational age), the developing embryo grows from 6 to 11 mm in CRL. During this phase of development, the

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head growth is prominent relative to the rest of the body. A cystic area can be identified in the posterior aspect of the brain specifically the chorion fetus, representing the rhombencephalon.14 The yolk sac is relatively large, measuring less than 6 mm inner-to-inner dimensions, and floats within the gestational sac between the chorion and amnion, attached to the developing umbilical cord. During the eighth postmenstrual week of embryonic development (6 weeks of gestational age), the embryo grows from 14 to 21 mm in length. The head remains a large and prominent structure and is bent over the heart prominence. The yolk sac becomes progressively smaller,

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Chapter 3

Transvaginal Sonography of Early (First Trimester) Intrauterine Pregnancy MBC

Main-stem villus

49

Free-floating villus

Chorionic plate Intervillous space

d E e

L

EM

Basal plate

UE

Anchoring villus

E F

B S C

A

Y E

D T

G Figure 3-1.  (Continued) E: Twelve-day implanted embryo. a, Amnion and amniotic cavity; E, embryonic ectoderm; e, embryonic entoderm; EM, extra-

embryonic mesenchyme; L, maternal blood lacuna in the trophoblast; UE, uterine epithelium; MBC, maternal blood circulation. F: Cross section of early human placenta that demonstrates portions of the villous tree and stem villi anchored to the decidua basalis. G: Cross section through an early (16-day) gestational sac. B, decidual basalis; D, decidual capsularis; T, cytotrophoblast; C, chorion; S, secondary villus; A, amnion; Y, yolk sac; E, exocoelomic cavity. (Used with permission from Dr. A.T. Hertig and The Carnegie Institute of Washington.)

and the intestines enter the base of the umbilical cord, beginning the normal process of umbilical herniation. By the end of the ninth postmenstrual week (seventh week of gestational age), the embryo develops structures that are recognizable as uniquely human.15 The head, body, and

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extremities can be identified sonographically. The intestine of the developing fetus is still within the proximal portion of the umbilical cord. Occasionally, this physiologic umbilical herniation of bowel is particularly well depicted with TVS. Because this process of physiologic herniation

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50

Part 1 GENERAL OBSTETRIC SONOGRAPHY A.c. A.c.

Tr.v.

Y.s. Ed.

Ex-celom

Ex.

Ex-celom

Yolk sac

Tr.

(a)

Allantois

(b)

Excelom Ex. celom C.st.

C.st.

N.F.

NC EG

N.F.

H

M.G.

H.G.

Allantois

Allantois

N.C.

Ex. celom

Ex. celom

Ex. celom Yolk sac

Yolk sac

(c)

(d)

H U

AI

A YS

E

P

C

Y

I

J

Figure 3-1.  (Continued) H: Diagrams showing progressive growth (a through d) of the amniotic sac, yolk sac, and embryo. (Reproduced with permission from Arey B. Developmental Anatomy. Philadelphia: Saunders; 1962.) I: Diagram of J showing 10-mm human embryo with its membranes and surrounding villous trophoblast. AI, allantois; C, amniotic cavity; P, placenta; U, uterus; YS, yolk sac. J: E, 10-mm embryo; Y, yolk sac; and the chorionic villi (arrows).

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Chapter 3

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51

Fundus of uterus Embryo

Chorionic vesicle Uterine Mucosa (Decidua) Cervix of uterus

Myometrium

Amnion

Placenta

Decidua parietalis

Decidua basalis

Decidua capsularis

Yolk-sac Cervical canal

K

L

Anterior fornix of vagina

Figure 3-1.  (Continued) K: The external surface of a human chorionic sac showing both the chorion frondosum and chorion laeve areas. L: Diagrams in cross section of uterus at 6, 8, and 10 weeks’ menstrual age showing embryonic membranes and their development.

of bowel into the umbilical cord is normal, abnormalities of the ventral wall should be suspected only if the bowel remains outside of the abdomen at 12 weeks or beyond. Another structure that can be depicted in the late embryonic period is the amniotic membrane.16 The amniotic cavity forms from an area deep in the trilaminar

embryo, and the amniotic membrane can be seen on a fully floating linear interface in the outer portion of the amniotic cavity. The amnion approximates with the chorion only late in the first trimester of pregnancy (14 to 18 weeks).17 At 6 to 8 weeks, the membrane can be seen as a thin, rounded structure that encircles the embryo/fetus

A

B

Figure 3-2.  Normal 5-week intrauterine pregnancy (IUP). A: Transvaginal (TV) sonogram of 4-week, 6-day pregnancy demonstrating 5-mm anechoic sac (arrow) within decidua. B: Transabdominal (TA) sonogram of 5-week IUP (arrow) as depicted on magnified transverse scan. Normal 5-week IUP.

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Part 1 GENERAL OBSTETRIC SONOGRAPHY

C

D

E

F

G

H

Figure 3-2.  (Continued) C: TVS of 7- to 8-mm sac of 5-week IUP. D: TVS US of 5-week IUP appearing as anechoic area within the thickened decidualized endometrium. E: TVS of 5-week, 6-day intrauterine pregnancy in a retroflexed uterus, demonstrating an embryo/yolk sac complex (arrowhead). F: Magnified transverse TAS of 5- to 6-week IUP showing concentric layers of decidua (arrow) and a “double bleb.” G: TVS of 4-week IUP. The endometrium has undergone decidualization and the “chorionic sac” is just a few millimeters in size. H: Magnified TVS showing developing gestational sac of approximately 4 × 6 mm and surrounding choriodecidua in this 5-week pregnancy.

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Chapter 3

Transvaginal Sonography of Early (First Trimester) Intrauterine Pregnancy

A

B

C

D

E

F

53

Figure 3-3.  Normal 6- to 7-week IUP. A: Magnified TV sonogram of 3-mm embryo/yolk sac (arrow). Compare to Figure 3-1H. B: TV sonogram of 6-week IUP with 6-mm embryo (between x’s) adjacent to the yolk sac. C: Magnified TV scan of 6-week IUP demonstrating embryo within embryonic cavity (1), extraembryonic coelom (2), and yolk sac (3). D: Magnified TV sonogram of 6-week IUP demonstrating embryo/yolk sac complex and decidua capsularis and vera. Compare to Figure 3-1L. E: Yolk sac/embryo surrounded by choriodecidual layers. F: TVS showing embryo/yolk sac complex. The embryo is 3 mm in size, and heart motion was seen.

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Part 1 GENERAL OBSTETRIC SONOGRAPHY

G

H (a)

H (b)

H (c)

Figure 3-3.  (Continued) G: TVS of “deflated” gestational sac with enlarged yolk sac but no definite embryo. This is consistent with embryonic demise.  : Five- to six-week IUP in a bicorunate uterus. H(a): Transverse TVS showing gestational sac in right horn of a bicornate uterus. H(b): Sagittal TVS H through left nongravid horn. H(c): Sagittal TVS through right horn with gestational sac.

A

B

Figure 3-4.  Normal embryo at 7 to 8 weeks. A: TVS of 8-mm embryo with a yolk sac adjacent to embryo. B: Ten-millimeter embryo demonstrating limb and yolk sac.

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Chapter 3

Transvaginal Sonography of Early (First Trimester) Intrauterine Pregnancy

C

55

D

E Figure 3-4.  (Continued) C: TV scan of 8-week embryo in coronal plane, demonstrating early ossification of clavicle (arrow). D: Seven-week embryo with adjacent yolk sac. The arm buds are seen. E: Eight- to nine-week pregnancy showing the developing head (rhombencephalon). The choriodecidua now is intact.

A

B

Figure 3-5.  Normal fetal anatomy. A: TVS of 17-mm embryo demonstrating prominent cystic area of brain corresponding to rhombencephalon. B: TVS of 28-mm fetus.

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Part 1 GENERAL OBSTETRIC SONOGRAPHY

C

D

E

F

Figure 3-5.  (Continued) C: TV scan of 10-week fetus demonstrating arms and legs. D: Transverse of same fetus showing umbilical cord insertion

(arrow) within some physiologic herniation of bowel into base of umbilical cord. E: TVS showing hands (arrow) on or near face of 11-week fetus. F: TAS of 11-week fetus (between +’s).

on TVS. Prior to this, the amniotic membrane may appear as a linear echogenic interface projected within the gestational sac in proximity to the embryo. Besides depiction of the embryo/fetus, the choriodecidua is seen as it begins to thicken at the implantation site during the late embryonic and early fetal period. The anatomic and functional fusing of decidua basalis and chorion frondosum forms the future placenta at approximately 10 weeks. Certain parameters provide useful prognostic signs, including the heart rate and the relative size of the embryo to the prognostic size amniotic sac. A heart rate of less than 85 b/m at 6 to 8 weeks typically is a poor outcome.18 It is important to point out that 9% of fetuses with a heart rate of more than 85 had a normal pregnancy.19

9 to 11 Weeks After 9 weeks, the fetus is clearly depicted both with transabdominal sonography (TAS) and TVS. Nomograms for measurement of the embryo and fetus have been

Fleischer_CH03_p045-p080.indd 56

established. The fetus begins to move its trunk and extremities, and it can be seen to do an occasional somersault within the uterus. Movement is rapid in nature and often appears convulsive. Upper extremity movement is followed by lower extremity. The fetal brain has relatively large lateral ventricles that are mostly filled with choroid plexus (Figures 3-5 to 3-10). Small cysts within the umbilical cord can be seen but usually are resolved by 12 weeks.20 Herniated bowel also returns into the abdomen by 12 weeks. Before 12 weeks, however, the physiologically herniated bowel can measure up to 1.5 times the umbilical cord at its abdominal insertion. Color Doppler sonography may be used to assess the size of the herniated bowel in relation to the cord. Heart rate progressively increases to 120 to 160 beats per minute after 6 to 7 weeks.19 Heart rates of less than 85 beats per minute have been associated with pregnancy failure and necessitate follow-up sonograms.19 In another study, heart rates of less than 90 beats per minute in the first trimester were associated with a dismal diagnosis.21 Clearly, however, one could give the fetus the benefit of the

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Chapter 3

Transvaginal Sonography of Early (First Trimester) Intrauterine Pregnancy

A

B

C

D

57

Figure 3-6.  Other normal features. A: Hypoechoic lacunae (curved arrow) around decidual basalis of 10-week IUP. B: Magnified TVS of 11-week fetus with bowel herniated into base of cord. C: TAS of corpus luteum cyst of pregnancy (arrow). D: TAS showing unoccupied lumen (curved arrow) at 6 weeks.

doubt if slow heart rates are seen and confirm this finding on a follow-up study rather than terminate based on one abnormal examination.21 Another parameter that seems to have prognostic value is the size of the amniotic sac relative to the embryonic length. The yolk sac is typically 6 mm or less in normal pregnancies.13 An enlarged amniotic sac may be seen with embryonic demise as calculated by CRL − Da > 0.8 cm (diameter of the amniotic cavity).22 In normal pregnancies, the amniotic sac minus embryonic length should be greater than 5 mm.18 This measurement is less helpful because it may be difficult to completely visualize the amnion at this early stage of development. Several studies have shown a gradual increase in velocity and diastolic flow in choriodecidual (spiral) arteries in early pregnancies.23,24 However, the actual Doppler indices do not discriminate between viable and nonviable

Fleischer_CH03_p045-p080.indd 57

pregnancies. Increased venous flow within the choriodecidua can be seen in nonviable pregnancies associated with embryonic or early fetal demise. Failed or failing early pregnancies demonstrate increased “sparkly” flow around the gestational sac.25 One author suggests that color Doppler sonography (CDS) may help define the etiologic mechanism for early pregnancy failure.25 However due to concerns regarding potential bioeffects of CDS, it is only used in select cases such as defining whether an adnexal mass is intraovarian or potentially extraovarian. In a retrospective study it has been reported that pregnancy failure is more common when the retrochorionic hemorrhage is over two-thirds the size of the gestational sac, when the patient is over 35 years old, and when the pregnancy is less than 8 weeks.26

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Part 1 GENERAL OBSTETRIC SONOGRAPHY

E

F

G

H

I Figure 3-6.  (Continued) E: Same patient as shown in (D), 1 week later, showing embryo within sac and persistence of unobliterated lumen. F: TVS

showing amnion (arrow) surrounding 6-week embryo. G: Unfused chorioamnion (arrow) at 10 weeks shown on this magnified TAS. H: TAS of 6-week IUP within the right cornu of a bicornuate uterus. I: TAS showing prominent retrochorionic blood pool (curved arrow).

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Chapter 3

Transvaginal Sonography of Early (First Trimester) Intrauterine Pregnancy

A

B

C

D

E

F

59

Figure 3-7.  Multifetal pregnancy. A: TAS of normal 7-week diamniotic, dichorionic twin IUP. B: TVS of demised embryo (between +’s) adjacent to

living twin at 7 weeks. C: TAS of “vanished” twin within an empty sac adjacent to a living embryo with an intact sac (between +’s). D: Diamniotic/dichorionic twin gestation showing thick interface between gestational sacs. E: Triplet intrauterine pregnancy showing thick membrane between sacs most likely representing trichorionic. F: Twin IUP with hypoechoic area to the left of the sacs most likely representing either unobliterated lumen or small retrochorionic hemorrhage.

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Part 1 GENERAL OBSTETRIC SONOGRAPHY

G H Figure 3-7.  (Continued) G: Intrauterine gestation with small sac, probably remnant of a second sac that contained an embryo. This most likely represents twin pregnancy with embryonic demise of one twin. H: Twin gestation with thin membrane most likely representing monoamniotic. The upper twin was adjacent to the choriodecidua and had a very short umbilical cord, suggesting the possibility of a body stalk anomaly.

A

B

C

D

Figure 3-8.  Complicated early pregnancy. A: TVS of an embryonic demise. B: Semiaxial TVS of incomplete abortion with irregular choriodecidua and deflated sac. C: TVS of retrochorionic hemorrhage (arrow) surrounding normal gestational sac with a living fetus. D: TV sonogram of retained choriodecidua within lower uterine lumen (curved arrow).

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Chapter 3

Transvaginal Sonography of Early (First Trimester) Intrauterine Pregnancy

E

F

G

H

61

I J Figure 3-8.  (Continued) E: TAS showing sloughed decidua (between arrows) in lower uterine lumen. F: TAS of extremely irregular sac. On repeat scan

2 weeks later, a living fetus was found. G: TVS of septated uterus with clot within right uterine lumen. The fetus (between +’s) within left side of uterus was living. H: TAS of completed abortion. Note thinness and regularity of endometrial interfaces (arrow). I: TVS of embryonic demise at 6 weeks. No heart activity was detected. J: TV scan of fetal demise at 9 weeks. No heart motion was detected.

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Part 1 GENERAL OBSTETRIC SONOGRAPHY

K

L

M (b) M (a) Figure 3-8.  (Continued) K: TAS showing retrochorionic hemorrhage surrounding an IUD (curved arrow). The deflated sac is seen inferior to the IUD.

L: TVS showing large fibroid on maternal right and normal gestational sac to the left of midline. M: IUD and 10 week IUP a: Transverse TAS showing IUD anterior to developing placenta. b: Composite (multiplanar reconstructions - MPR) top L = long axis; top R = short axis; bottom L = coronal; bottom R = 3D volume showing IUD.

A B Figure 3-9.  Gestational sac anomalies. A: Yolk sac within an overall small gestation sac. B: Large gestational sac. The amnion could be seen within the sac but no definite embryo. These are 2 ends of the spectrum seen in intrauterine fetal demise.

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Chapter 3

C

Transvaginal Sonography of Early (First Trimester) Intrauterine Pregnancy

63

D

F E Figure 3-9.  (Continued) C: Vitelline duct leading to a deflated yolk sac. D: Large sac size with deflated yolk sac indicating embryonic demise. E: Large

area of retrochorionic hemorrhage that extends behind the choriodecidua. F: TVS of a cervical inclusion cyst adjacent to gestational sac and embryo in a spontaneous abortion.

A

B

Figure 3-10.  Normal anatomy of embryo/fetus in first trimester of pregnancy. A: The stomach and umbilical cord seen in this 9-week pregnancy.

There is herniation of some bowel into the cord. B: Transverse TVS showing herniated bowel into the base of the cord, which is a physiologic process up to 12 weeks.

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Part 1 GENERAL OBSTETRIC SONOGRAPHY

C

D

E

F

G H Figure 3-10.  (Continued) C: TVS showing normal configuration of the abdominal wall of this 10- to 12-week fetus after bowel has returned into the

abdomen. D: The rhombencephalon is seen in this 8-week fetus. E: Fetal heart motion detected in this normal fetus. F: Rhombencephalon seen in this 9-week embryo showing measurement of crown-rump length. G: Amnion surrounding embryo should not to be mistaken for nuchal thickening. H: TVS of nuchal membrane. Although this multiloculated nuchal fluid collection looked like a cystic hygroma, it regressed, and the karyotype was normal.

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Chapter 3

Transvaginal Sonography of Early (First Trimester) Intrauterine Pregnancy

SONOGRAPHIC “MILESTONES” Most of the sonographic milestones used for assessment of early pregnancy can be established 1 week earlier with TVS than with conventional TAS.27 Typically, one expects to visualize a yolk sac and embryo in gestational sacs with a mean sac diameter of 8 mm. A fetal heartbeat is typically seen when the mean sac diameter is above 16 mm. In addition, the rule of “5-alive” denotes that a live embryo of 5 mm or more should demonstrate a heartbeat.27 Alternatively, a definitive diagnosis of embryonic/fetal demise should be reserved for those over 7 mm.28 This is the published guideline based on a recently convened consensus panel and takes into account variability of resolution of various scanners and the expertise of the operator and the interpreter. Besides these anatomic markers, another tool used by radiologists and clinicians is the maternal serum β-hCG level, which has traditionally helped to assess viability. The rule of “1-7-11” had been used to correlate a specific range of β-hCG with expected embryonic/fetal milestones.27 Specifically, this guideline has been used to indicate that with a β-hCG of 1000 mIU/mL, a fetal pole should be seen, and at 7000 mIU/mL a fetal pole and yolk sac with a fetal heartbeat seen at a threshold of 11,000 mIU/mL.27 Previously published guidelines have stated that an ectopic pregnancy is typically associated with a slower rise of serial β-hCG levels, when compared to normally progressing intrauterine pregnancies.29 However, recent data has shown that these general “rules” are not entirely valid. Silva reported that 70% of patients with an ectopic pregnancy have a slower decline in β-hCG values than those with a spontaneous miscarriage, and 15% to 20% have a seemingly normal rise30 (see Chapter 4). In fact, one study has reported that 15% of normal pregnancies can have seemingly abnormal rise of β-hCG.31 In a large retrospective series, Doubilet et al reported that there was no statistically significant relationship between initial β-hCG and outcome of pregnancy.32 They concluded that β-hCG “discriminatory” levels are not reliable indicators of normal versus abnormal early pregnancies. Therefore, they recommend that the actual β-hCG value should not be used to determine management of hemodynamically stable patient presenting with vaginal bleeding and no visible gestational sac on TVS. Recent research has also refined guidelines regarding the accuracy of early pregnancy assessment with TVS. One group found that an initial TVS could be used to determine the location of the sac (intra- or extrauterine) in 91% of a large cohort, whereas 8% were classified as pregnancy of unknown location (PUL) which resulted in 99% specificity and 99% positive and negative predictive values.33 Followup TVS in the remaining 8% of their series allowed for a definitive diagnosis.34 Further discussion of how this is pertinent in the evaluation of patients suspected of having an ectopic pregnancy is covered in detail in Chapter 4. One study found that 8% to 31% of early IUP are not visualized on initial TVS and the relative percentage of PUL versus IUP varies based on operator experience.34 In fact, in 15% to 35% of ectopics, the adnexal findings may not be appreciated on the initial TVS.35 Another factor in the serial evaluation of patients with β-hCG and TVS with an early pregnancy is that 15% of ectopic pregnancies resolve spontaneously.36

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Table 3-2

65

 HCG LEVELS IN EARLY PREGNANCY

Numbers of Weeks (LMP)

Levels of HCG (mIU/ml)

3 weeks

5 - 50

4 weeks

5 - 426

5 weeks

18 - 7,340

6 weeks

1,080 - 56,500

7 - 8 weeks

7,650 - 229,000

9 - 12 weeks

25,700 - 288,000

13 - 16 weeks

13,300 - 254,000

17 - 24 weeks

4,060 - 165,400

25 - 40 weeks

3,640 - 117,000

Data from Moshiri M, Katz D. New recommendations for evaluation of first trimester pregnancy, ARRS Bulletin. Spring. 2015;9(2)5-6,8.

A consensus statement from the Society of Radiologists in Ultrasound (SRU) uses terminology for patients presenting in the first trimester with vaginal bleeding and  pelvic pain, into categories of viable pregnancy, nonviable pregnancy, intrauterine pregnancy of uncertain viability, pregnancy of unknown location and ectopic pregnancy (see Tables 3-1 to 3-3).28

Table 3-3

 PREGNANCY OF UNKNOWN LOCATION

TVS Finding

Comment

An intrauterine saclike structure with no yolk sac or embryo and normal adnexa

Most likely an intrauterine pregnancy; however, ectopic pregnancy cannot be completely excluded

No intrauterine fluid collection with normal adnexa

1-If single hCG level is ≥3,000 and "empty uterus": Viable intrauterine pregnancy is unlikely; however, a single hCG level should not be used as a criterion for definitive exclusion of a potentially normal intrauterine pregnancy 2-In a hemodynamically stable patient, a single hCG level should not be used as the basis for distinguishing ectopic pregnancy from intrauterine pregnancy, or for determining treatment with methotrexate 3-hCG and sonographic follow-up, as appropriate, until definitive diagnosis 4-Most ectopic pregnancies have hCG levels 3,000, often 7 mm) Sustained bradycardia of less than 80 beats per minute Small sac size (mean sac diameter-crown-rump length 6 mm) endometrium, whereas the stripe is thinner with an ectopic pregnancy or spontaneous abortion.18 When ambiguity persists, serial hCG determinations should be drawn to look for a normal or abnormal progression, and the sonogram should be repeated once the level has risen above the discriminatory zone. It must be emphasized, however, that these criteria represent guidelines, not absolute end points.24 It is possible for a viable IUP to demonstrate a low hCG level and/or slow progression. Conversely, a normal rise in the hCG level may sometimes be associated with an ectopic pregnancy.24 Also, a multiple gestation or a heterotopic pregnancy may show an uncharacteristically elevated hCG level for any given gestational age.

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The amount of hCG produced by an ectopic pregnancy is generally less than that by a viable IUP of the same gestational age,25 which may be due to an unfavorable location for trophoblast proliferation or a difference in the implantation process. This fact is useful, however, only if the date of conception is known. It should be pointed out that the majority of these patients presented with the serum hCG level below the discriminatory zone, as defined at the time when the study was conducted. The level of serum hCG tends to be roughly proportional to the size of a tubal pregnancy and the extent of trophoblastic differentiation. A ruptured tubal pregnancy tends to be associated with a higher level than one that has not ruptured. The range of serum hCG levels for any given situation, however, is so broad that this observation has little clinical relevance. Sonographic visualization of an intrauterine sac when the serum hCG is below the discriminatory zone may signify an abnormal gestation (Figure 4-1). A nonviable IUP may appear this way. Also, there is the “pseudogestational sac,” which is sometimes associated with an ectopic pregnancy. A pseudogestational sac lacks the “double-sac” sign and is smaller and more irregular than a true gestational sac at a comparable gestational age. The reader is encouraged to realize the limitations of the use of the term “double-sac,” since it can be misleading. Serial determinations of the serum hCG level have proven useful in the clinically stable patient when ambiguity persists after a nondiagnostic TVS findings have been correlated with a single quantitative hCG. The first known value is placed on the standard line, and subsequent values are plotted accordingly. It is apparent that most patients showed a plateau or fall in the level during the period of preoperative evaluation. This plateau or fall is diagnostic of a nonviable pregnancy when it occurs at levels below 3000 mIU/mL during at least a 48-hour period. It does not, however, distinguish between a nonviable intrauterine and an ectopic pregnancy. It is also apparent that some ectopic pregnancies may show an initial “normal” rise in the level of hCG. This normal rise, however, is usually short-lived, and an abnormal progression often develops. Serial hCG determinations are also essential after treatment of an ectopic pregnancy by either medical or surgical means. A plateau or rise in the level may be the first indication of a persistent ectopic pregnancy indicating the need for further treatment.26 Furthermore, a negative hCG may signify a resolution of the ectopic pregnancy, which may precede normalization of any sonographic findings. An important term used to designate nondiagnostic TVS findings which represent a “pregnancy of unknown location” in those patients in whom an intrauterine or extrauterine pregnancy cannot be diagnosed. A repeat TVS in 2 to 5 days and a repeat hCG after 48 hours is often recommended to determine the exact nature of the pregnancy. In normal IUPs, hCG increases by an average of 66% in 48 hours. Not all IUPs have this expected increase, and up to 15% of normal IUPs will have less than the expected rise.26 Recent data, however, demonstrate that an increase in hCG of less than 53% in 48 hours confirms an abnormal pregnancy with 99% sensitivity.23

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Chapter 4 6,000 x

x

1,000 x x

Serum β-hCG in ng/mL

x

x x x

xx xx

100 x x x

x x

x x x x xx x xx

xx x

x x

10

x

xx

x

Transvaginal Sonography of Ectopic Pregnancy

85

the ability to detect ectopic pregnancies over techniques and tests available in the recent past. A very high degree of accuracy now exists in the ability to establish the presence or exclude the possibility of an ectopic pregnancy.28,30 (Please refer to the discussion in Chapter 3 for a more detailed description of normal and abnormal first trimester pregnancies.) As mentioned previously, TV-CDS may be a useful adjunct to TVS in that the “vascular ring” of the ectopic pregnancy can be visualized. Functioning corpora lutea may also have this appearance on TV-CDS and tend to have a more complete rim than that seen in ectopics. In most cases, the vascular ring of an ectopic pregnancy is sparser (discontinuous) than that of a functioning corpus luteum. Additionally, most nonviable ectopic pregnancies may not demonstrate flow. With methotrexate treatment, most ectopic pregnancies demonstrate increased vascularity as defined by the number of colorized pixel elements in the tubal ring. However, a recent case series showed no significant difference in the TV-CDS in responsive or nonresponsive ectopics. An increase in flow may reflect vasodilatation that occurs with effective treatment. CDS can be used to delineate the boundary of the extraovarian mass of the ectopic pregnancy from the ovary itself. Three-dimensional (3D) sonography may provide an additional means to depict the anatomic proximity of an ectopic pregnancy to the ovary.

SCANNING TECHNIQUE IUP

No IUP adnexal mass

No IUP NI adnexa

Figure 4-1.  β-hCG, ultrasound (TA) findings in 46 proven ectopic pregnancies. (Reproduced with permission from Cartwright PS, DiPietro DL. Ectopic pregnancy: changes in serum human chorionic gonadotropin concentration. Obstet Gynecol. 1984 Jan;63(1):76-80.) x, unruptured; •, ruptured (IRP).

SONOGRAPHIC EVALUATION The use of TVS has greatly enhanced the accuracy of sonographic evaluation of patients with suspected ectopic pregnancy over that possible with TAS.28,29 In particular, the presence or absence of an intrauterine gestation can be documented or excluded at an earlier stage (approximately 1 week) than with TAS. Most importantly, transvaginal transducer/probes typically allow accurate and definitive inclusion or exclusion of an IUP by demonstration of an intrauterine gestational sac. Transvaginal sonography can also be used to demonstrate an extrauterine gestational sac, corpus luteum, or both. TAS can be used to evaluate these parameters but is, in general, less accurate or definitive. In addition, adnexal masses and/or typical collections of intraperitoneal fluid created by ectopic pregnancies can more frequently be detected and identified by TVS. The use of TVS with highly sensitive pregnancy tests has markedly enhanced

Fleischer_CH04_p081_p108.indd 85

On both TAS and TVS, sonographic examinations should begin by delineation of the uterus in its long axis. One should carefully evaluate the endometrium for the presence or absence of a gestational sac or decidual thickening. Once the uterus is adequately evaluated, the adnexal region should be carefully examined. If possible, both ovaries should be identified because many ectopic pregnancies are associated with coexisting corpus luteum. On a transverse transvaginal scan, the relative position of the proximal segment of tube can be approximated by recognition of several anatomic landmarks. These include delineation of the round ligament as it courses directly anterior to the tube near the uterine fundus, and the location of the interstitial portion of the tube by its proximity to the endometrium, which invaginates into the uterine cornu on a transverse scan in the region of the tubal ostia. If color Doppler is used, the pulse repetition frequency should be low to maximize detection of slow flow. Acquisition of multiplanar images is needed for 3D reconstruction. The newer acquisition of 3D images can best be shown in the semicoronal plane so as to depict the area of the tube relative to the ovary.

SONOGRAPHIC FINDINGS The sonographic findings that are encountered in a patient with ectopic pregnancy differ according to the developmental stage of pregnancy in which the patient is

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In most ectopic pregnancies, the uterus contains thickened endometrium layer(s) due to its thickening related

to decidualization (Figure 4-2). Particularly with TVS, the increased fluid content of the decidualized endometrium can sometimes be appreciated due to enhanced through transmission distal to this layer. In more advanced ectopic pregnancies, fluid or blood may be present within the decidualized endometrium, simulating the appearance of an early gestational sac. In some cases, before sloughing of the decidua, a hypoechoic interface beneath the decidua can be seen that represents hemorrhage between the necrotic decidua and inner myometrium. In contradistinction to normal IUPs, where the gestational sac is spherical and well

A

B

C

D

examined, and to some degree whether or not rupture has occurred. One should be aware that the sonographic findings also depend on what type of transducer/probe is used. The following discussion is organized into uterine, adnexal, and peritoneal sonographic findings, even though multiple findings are usually present.

Uterus

Figure 4-2.  Ectopic pregnancy: uterine sonographic findings. A: Longitudinal TA sonogram of unruptured ectopic pregnancy appearing as a complex

retrouterine mass posterior to uterus (curved arrow). Uterus contains thickened, decidualized endometrium (arrow). B: Transverse TAS of (A) showing thickened endometrium (arrow) and left adnexal ectopic gestation (curved arrow). C: TVS of unruptured ectopic pregnancy. Long axis of uterus shows thickened decidualized endometrium (arrow). D: Semiaxial TVS of (C) showing right adnexal mass (arrow), which represents an unruptured ectopic pregnancy. A yolk sac is present within gestational sac.

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Transvaginal Sonography of Ectopic Pregnancy

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E

F

G

I

H

J

Figure 4-2.  (Continued) E: TVS of pseudogestational sac in a patient with proven ectopic pregnancy. The irregular sac (between +’s) was mistaken

for deformed intrauterine sac. F: Transverse TAS of a 6-week intrauterine pregnancy showing typically eccentric location of gestational sac (arrow) within uterine lumen. G: TAS showing irregularly thickened decidualized endometrium (curved arrow). H: TVS of patient in (G), more clearly showing irregular decidualized endometrium (arrow) of proven ectopic pregnancy. I: TVS of decidual cast (curved arrow) with blood-distended uterine lumen. Intraperitoneal fluid was also present in cul-de-sac. J, K, L: Unruptured left ectopic pregnancy demonstrating all of the typical sonographic findings. J: TVS of left adnexa showing adnexal “ring” (between +’s).

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Part 1 GENERAL OBSTETRIC SONOGRAPHY

K

L

M

N

Figure 4-2.  (Continued) K: TVS of right adnexa showing right corpus luteum (between +’s). L: TVS of uterus showing decidual thickening and small amount of intraluminal fluid or “pseudosac.” M: TVS of necrotic decidual cast showing irregular decidua and intraluminal fluid. N: TVS of decidual cysts associated with an ectopic pregnancy, which are thought to represent areas of decidual necrosis.

defined, the pseudogestational sac created by sloughing decidua found in some advanced ectopic pregnancies is more irregular and has angulated borders.31 For a more detailed discussion of the sonographic changes that occur within the uterus in early IUP, refer to Chapter 3. As opposed to the decidualized endometrium in normal IUP, the decidualized endometrium of ectopics usually demonstrates little or no diastolic flow on TV-CDS. The myometrium typically shows a poorly vascularized or “cold” pattern. The waveform from the decidualized endometrium of the ectopic pregnancy demonstrates little or no diastolic flow as compared with the decidua of an early IUP. Tiny (a few millimeters) cysts can be seen within the decidua, and they have been reported to correspond to areas of decidual necrosis.32

Adnexae Typically, ectopic pregnancies occur as rounded masses, from 1 to 3 cm in size, which are located in the parauterine region. Masses that result from an ectopic pregnancy

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typically consist of a central hypoechoic area surrounded by an echogenic rim of trophoblastic tissue and tubal wall, a so-called “adnexal ring.” An embryo can rarely be identified within the gestational sac of an early (.99