There has been a rapid increase in the use of diagnostic ultrasound (DUS) in obstetrics since its introduction in the late 1950’s 1. Major improvements in imaging quality and the introduction of new technologies, such as 3D/4D are partly responsible. Other factors include immediate availability of results, relative low cost, when compared to other imaging modalities and, especially, assumed complete safety. As a result, a rapidly increasing number of pregnant women are exposed to ultrasound. In the United States, ultrasound is not recommended as routine in obstetrical care by any professional organization (American Institute of Ultrasound in Medicine [AIUM], American Congress of Obstetricians and Gynecologists [ACOG], American College of Radiology [ACR], for instance) nor recognized by third-party payers which require a clear indication for scanning. These indications were defined in 1984 (!) and never updated 2. However, de facto, most women who receive prenatal care will be referred for at least one scan, even with no declared clear medical indication. Since the introduction of ultrasound in clinical medicine- and more specifically in obstetrics- safety of this modality has been considered 3,4 If asked, the vast majority of end users (and patients) will respond that ultrasound is not X-rays and is completely safe. In reality, there is a marked lack of knowledge on effects of ultrasound in tissues being examined (bioeffects) among the majority of these end-users 5.
While it seems evident that DUS does not cause major structural/anatomic anomalies in the fetuses being scanned, more subtle effects cannot completely be ruled out and certain steps are recommended for the clinical end-user to assure safety. Furthermore, scanning should be performed only with a valid medical indication.
Basic Physics of Ultrasound
- The Ultrasound Beam
Ultrasound is a waveform. Several characteristics are used to describe this (or any other) waveform. The
speed of propagation is related both to the beam and several of the insonated tissue properties. 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). Human ears can discern sounds at approximately 20Hz to 20,000 HZ. Diagnostic ultrasound is, generally, 2-10 million Hz (megahertz, MHz).
Wavelength is the distance between two corresponding points on a particular wave. It is inversely proportional to the frequency.
Resolution (i.e. the shortest distance between two points which allows these two points to be seen separately) depends on the wavelength: the axial resolution ranges between 2-4 wavelengths. Therefore, the smaller the wavelength (which corresponds to the higher the frequency), the better the resolution (the distance between the 2 points is smaller) but the lower the penetration. This explains why endovaginal probes have better resolution (higher frequency) but lower penetration, hence the need to be closer to the organs being examined. Diagnostic ultrasound is not continuous but pulsed. There are pulses separated by silent intervals. The number of pulses occurring in one second is the pulse repetition frequency (PRF). The fraction of time that the pulsed ultrasound is on (duty factor) is very important from a potential bioeffect aspect. When the PRF increases, so does the duty factor. The pulse amplitude reflects pressure and is the maximum variation from the baseline, expressed in megapascals (MPa). Since the ultrasound wave is sinusoidal, there are alternating periods of positive and negative pressure which allow the wave to propagate through tissues by means of particles motions. Peak pressures of 5MPa and above can be generated by clinical instruments. This is considerable when comparing it to the atmospheric pressure which is 0.1 MPa. When pressure is exerted on the resisting insonated tissue, work is produced. The ability of the wave to do this is its energy (in joules) and the rate at which the energy is transformed from one form to another is the power (in watts or milliwatts, mW). When expressed as a function of area unit (in cm2), this is Intensity (generally in mW/cm2). The intensity is proportional to the square of the instantaneous ultrasound wave pressure. Bioeffects are conventionally related to the acoustic intensity. As stated above, pulses of energy are intermingled with periods where no energy is emitted. When describing an ultrasound wave, several parameters can be described in relation to time or space: the greatest intensity in time (temporal peak intensity or TP), the average intensity over time, which includes time between pulses when no energy is emitted (temporal-average intensity or TA), the maximal intensity at a particular spot (spatial-peak intensity or SP) and the average intensity at a particular spot (spatial intensity or SA). A combination of spatial and temporal intensities is needed to relate an observed tissue effect (bioeffect) to the physical parameters of the ultrasound field parameters. By combining peak and average values in time and space, six intensities can be defined: spatial average-temporal average (ISATA), spatial average-pulse average (ISAPA), spatial average-temporal peak (ISATP), spatial peak-temporal average (ISPTA), spatial peak-pulse average (ISPPA), and spatial peak-temporal average (ISPTA). The ISPTA is the most practical, and most commonly referred to and corresponds to the energy averaged over a period of time 6 . There are accepted maximal permitted values, based on the clinical application being considered. This had been determined in 1976 by the US Food and Drug Administration, FDA 7 but modified in 1986 8. The most recent definition dates from 1992 9. These values (in mw/cm2) are shown in the following table (modified from references 7,8,9).
*values in mW/cm2
It is interesting to observe from the above table that, for fetal imaging, the ISPTA was allowed to increase by a factor of almost 16 from 1976 and almost 8 from 1986 to 1992, yet, as will be described below, all epidemiological information available regarding fetal effects predates 1992. A further remarkable fact is that intensity for ophthalmic examination has not changed from the original 17mW/cm2, a value approximately 42.5 times lower than the present allowed maximal value for fetal scanning.
One aspect that is absent from all calculations but that is vital if one wants to perform accurate and complete ultrasound dosimetry, is information on exposure time, including dwell time. The dwell time is the time during which the ultrasound beam remains at the same point in the tissue. It is important and rather curious to note and remember that no epidemiological data available include dwell time, nor do any of the existing exposure indices (thermal and mechanical indices [vide infra]) take time into account.
These are very important when considering potential effects of the ultrasound beam 10. When the ultrasound wave travels through a medium, its intensity diminishes with distance 11.
Spreading of the wave would be the only phenomenon causing a reduction in the amplitude of the signal in a completely homogeneous medium. Biologic tissues, however, are non-homogeneous and further weakening (attenuation) results because of absorption and scattering, and by reflection. Several models have been used to help calculate attenuation, particularly in obstetrical scanning. The most commonly referred to model uses an average attenuation of 0.3dB/cm per MHz 7. 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 the above factor, an action called derating 12.
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). Acoustic impedance can be described as the opposition to transmission of the ultrasound wave. It is proportional to the velocity of sound in the tissue (estimated at 1540 ms/sec, see above) and to the tissue density.
3. Instruments Outputs
Publications of various instruments outputs are available 13. From a clinical standpoint, there is no easy way to verify the actual output of the instrument in use. In addition, each attached transducer will generate a specific output, further complicated by which mode is being applied14 . 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 10W/cm215. Therefore precaution is needed when applying this mode. Most measurements are obtained from manufacturers’ manuals, having been derived in laboratory conditions which may be different from real-life clinical conditions16. Furthermore, machine settings which are under the control of the clinician can alter the output. 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. Hence it is evident why any change (augmentation) in these properties can add to the risk of elevating the temperature, a potential mechanism for bioeffects (vide infra). The three important parameters under end-user control are the operating mode (including choice of transducer), the system setup/output control and the dwell time.
- Scanning mode: as mentioned above, B-mode carries the lowest risk, spectral Doppler 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. In spectral Doppler, the beam needs to be held in relatively constant position over the vessel of interest, which may add to the risk of a larger increase in temporal average intensity. Naturally, transducer choice is of great consequencesince transducer frequency will determine penetration, resolution and field of view. In addition, M-mode and color and power Doppler are scanned modes (as opposed to pulsed Doppler), meaning the beam is not immobile but scans through the region of interest, therefore, exposing each segment for much shorter periods.
- System setup: starting or default output power is very often high to allow better imaging and end-users will, generally, keep it as such, mostly out of lack of concern for bioeffects. Excellent, diagnostic images can be obtained at lower output powers (see figure 1, a-b). Until recently, the default power setting for machines from most manufacturers was high, presumably to obtain optimal images at the exam onset. However, several major manufacturers have responded to requests from involved individuals and are now offering a low output power, particularly in Doppler as their default. Only if needed, can the power be increased. Fine tuning performed by the examiner to optimize the image influence output but with no recognizable effect in terms of the machine power output (except if one follows TI and/or MI displays, see below). 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, limiting the field of view (for instance by high-resolution magnification or certain zooms). In Doppler mode, changing sample volume and/or velocity range (all done to optimize received signals), change output. A very important control 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. In addition, over the years, output of instruments has increased 15.
- Dwell time is directly under control of the examiner. Interestingly, as stated above, dwell time is not taken into account in the calculation of the safety indices, nor, in general, until now, reported in clinical or experimental studies. Since it takes only one pulse to induce cavitation, and about a minute to raise temperature to its peak, time is very important. Directly associated with dwell time is examiner experience in terms of knowledge of anatomy, bioeffects, instrument controls and scanning techniques, since, presumably, the more experienced the examiner, the less scanning time is needed.
Figure 1a: Pulsed Doppler imaging of the umbilical artery. a. Default power.
Figure 1b: Pulsed Doppler imaging of the umbilical artery. b. Same patient, lower power. The image is still diagnostic.
Basic Elements of Teratology
The growing fetus is very sensitive to external influences. Important fundamentals to be considered when analyzing a potential teratogenic effect are 17:
- Stage sensitivity- Susceptibility of the fetus as well as the degree of the adverse effect caused by the external agent depend on the stage at which the exposure occurred. Three such developmental stages are defined: fertilization and implantation (until 4th menstrual week), organogenesis or embryonic period (until the end of menstrual week 10) and fetal period.
- Dose response relationships- A quantitative correlation exists between the magnitude of teratogenic effects and the dose of the teratogenic agent. The higher the dose, the more severe the teratogenic effect.
- Threshold effects- This is the level of exposure below which the incidence of malformations or death is not statistically greater than that of controls. This concept is of major importance when considering diagnostic procedures. Whether such a threshold exists or any exposure increases risk is a legitimate discussion.
- Genetic variability- There are major differences in various characteristics of species reactions to exposure, such as placental transport, absorption, distribution and metabolism of a specific agent and these differences must be accounted for when extrapolating data between different species and, specifically, to humans.
Known teratological agents include, for instance, certain medications or drug of abuse taken by the pregnant woman, exposure to X-rays and elevated temperature, secondary to infectious diseases or environmental factors (hot bath). This is especially true in the first 10-12 weeks of gestation. Gestational age is thus a vital factor when dealing with possible bioeffects: 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. Most at risk is the central nervous system (CNS) due to a lack of compensatory growth of undamaged neuroblasts. In experimental animals the most common defects are of the neural tube as well as microphthalmia, cataract, and microencephaly, with associated functional and behavioral problems 18 . More subtle effects are possible, such as abnormal neuronal migration which has been described in animals 19 but with unclear potential results. Other prominent defects are seen in craniofacial development (more specifically facial clefts), the skeleton, the body wall, teeth, and heart. Hyperthermia in utero (due to maternal influenza for instance) has long been known to potentially induce structural anomalies in the fetus20 but, relatively recently, it has been described as an environmental risk factor for psychological/behavioral disturbances 21 and, more particularly, schizophrenia 22. It is stressed that these effects are due to hyperthermia that was not ultrasound-induced. It is suggested that temperature elevation within the normal human diurnal range of 37+/-
1.5°C or under 38.9°C is probably not harmful. However, elevation of the embryonic or fetal temperature above 41°C for five minutes or more is regarded as potentially hazardous 23. Ultrasound has been shown to induce temperature increase in vivo 24, albeit not in humans. There is, however, a serious lack of data examining the effects of DUS while rigorously excluding other confounding factors. If one considers together the facts that hyperthermia is potentially harmful to the fetus and that DUS may, under certain circumstances, elevate tissue temperature, then precaution has to be recommended, particularly in early gestation and especially with modes known to emit higher acoustic energy levels (such as pulsed Doppler). In addition, in febrile patients, extra precaution may be needed to avoid unnecessary additional embryonic and fetal risk from the ultrasound examination, given the already elevated maternal and fetal core temperature, secondary to the disease process.
Bioeffects-Why Are We Concerned?
This is a legitimate question 25. Have there been descriptions of harmful effects of DUS in humans (children or adults) who were insonated in utero? The answer appears to be no, but a lack of demonstration does not equal a lack of effects. The concern stems from the knowledge that ultrasound is a form of energy with effects in tissues it traverses and from extensive literature published on the effects of ultrasound in cells 26-28, tissue cultures 29 and even DNA 31,31, as well as animals 32-38. Despite over 50 years of usage in clinical medicine, no clear, undisputable, reproducible harmful effects have been demonstrated as a result of DUS exposure in humans. There is, however, a paucity of rigorously conducted epidemiological studies to evaluate adverse outcomes of DUS in humans. Large epidemiological studies with half of the population exposed to ultrasound in utero and half not exposed would be the only way to demonstrate a clear effect or lack thereof 39. Such a study is very unlikely, from ethical and financial standpoints. A number of studies of the use of ultrasound in pregnancy, including some case-control and prospective randomized control studies have been performed over the last 30 years. Among all endpoints, several have been analyzed more in depth, including: intrauterine growth restriction (IUGR) and lower birth weight 40, delayed speech 41 , lower intellectual performance 42, dyslexia 43, childhood malignancies44 , neurological and mental development or behavioral issues 45 and, more recently, non-right-handedness, particularly in male infants 46,47. None has been reproduced nor has offered evidence-based information on a cause-effect relation, except, possibly, for non-right handedness. The first report of a possible link between prenatal exposure to ultrasound and subsequent non-right handedness in the insonated children was published in 1993 47 but, according to the authors “only barely significant at the 5% level”. In a later analysis of the data, the association was found to be restricted to males 48. Similar findings were reported by a second group of researchers in a different population (Sweden versus Norway) with a statistically significant association between ultrasound exposure in utero and non-right handedness in males 49. A meta-analysis of these 2 studies and of previously unreported results was then published 48. No difference was found in general but a small increase in non-right handedness was present when analyzing boys separately and this was later confirmed by further analysis 50. 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-right handedness is an adverse effect. 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. Recently the effects of ultrasound waves on neuronal position within the embryonic cerebral cortex were evaluated in mice19. Neurons generated at embryonic day 16 and destined for the superficial cortical layers were chemically labeled. 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 min or longer during the period of their migration. The authors’ conclusions were that this may be the mechanism for potential ultrasound-induced neurological damage. It is not clear 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 al. 19 and the clinical use of ultrasound in humans 51. The most noticeable difference was the length of exposure, of up to 7 hours in Ang’s setup. Moreover, scans were performed over a small period of several days. The experimental setup was such that embryos received whole-brain exposure to the bean, which is rare in humans. In addition, brains of mice are much smaller than those in humans, and develop over days. It should be noted that some have described a complete lack of effects on postnatal development and growth to prenatal ultrasound exposure on postnatal development and growth 52 or behavior 35 . With the exception of low birth weight, also demonstrated in monkeys 38 , these findings have not been duplicated and the vast majority of studies have been negative for any association. Caution in interpreting case-control studies is essential since the effect being studied (for instance low estimated weight) may be the reason for performing the ultrasound exam and may thus be found to be associated with it but not through a causal relationship. There have been several major reviews published of epidemiological studies conducted over more than 25 years 53-57 . Some of the studies have serious limitations such as small samples, poorly matched controls and, perhaps more importantly from a bioeffects standpoint, absence of information on acoustic output and quantification of exposure (number of episodes, duration or “dose” delivered to particular target). This is particularly relevant in today’s clinical situations because of the addition of new modalities, with potentially very high energy levels (such as spectral Doppler) and the expansion of diagnostic studies to the first trimester, which is known to be a period of high sensitivity of the fetus to teratological insults (see above). In addition, it must once more be stressed that there has been no epidemiological study published on populations scanned after 1992, when regulations were altered and acoustic output of diagnostic instruments 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. Among all ultrasound modalities, spectral (pulsed) Doppler is the one with the highest acoustic output and, thus, the one with the greatest potential for bioeffects 58. A recent animal study seems to justify this concern 59. Chicken eggs were insonated by B-mode or pulsed Doppler on day 19 of a 21 day incubation period. Exposure was to B-mode for 5 or 10 minutes or to pulsed Doppler for 1 to 5 minutes. Eggs were allowed to hatch and learning and memory tests were performed in the chicks on day 2. Impairment in ability to learn or in short, medium and long-term memory was absent after B-mode exposure but was clearly demonstrated for those exposed to Doppler, with a dose-effect relationship. Furthermore, the chicks were still unable to learn with a second training session 5 min after completion of the initial testing. This represents a dose-effect relationship with higher time exposure to Doppler associated with clear behavioral effects. This is an animal study and the AIUM conclusions on epidemiology for obstetric ultrasound still states that based on epidemiologic data available and on current knowledge of interactive mechanisms, one cannot demonstrate a causal relationship between diagnostic ultrasound and recognized adverse effects in humans 60.
The Output Display Standard (ODS)
The Standard for Real-Time Display of Thermal and Mechanical Indices on Diagnostic Ultrasound Equipment, generally known as the Output Display Standard or ODS dates from 1992-1993. Ultrasound clinical users requested improved imaging and they as well as manufacturers compelled the US regulating bodies (principally the FDA) to allow the power output of diagnostic instruments to be increased. The (generally unproven) assumption was that higher outputs would allow better images and, thus, improve diagnostic accuracy. To allow this (but only up to 720 mW/cm2) 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 [NCRP] and 14 other medical organizations 61 developed a standard related to the potential for ultrasound bioeffects. This was an attempt to provide quantitative safety-related information. This information was to appear on-screen during an exam so that the end-users would be able to see how manipulation of the instrument controls during an examination causes alterations in the output and thus, presumably, on the exposure, as explained above. The information to appear on-screen consisted of two indices: the thermal index (TI) to provide some indication of potential temperature increase and the mechanical index (MI) to provide indication of potential for non-thermal (i.e. mechanical) effects 61,62. TI is defined as the ratio of the current instantaneous acoustic power output from the transducer to the power theoretically required to cause a maximum tissue temperature rise of 10C. The TI has 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. 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 such that a higher TI can be assumed to be associated with a higher temperature rise than a lower TI, but does not allow an estimate or a guess as to what that temperature change actually is in the tissue. The MI represents the potential for cavitation 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. Both indices generally appear on-screen in all modalities. Figure 2 a-g are examples of actual screen shots during clinical exams, for B-mode, M-mode, pulsed Doppler, color Doppler, power Doppler, 3D acquisition and 3D color Doppler, respectively. A very clear stipulation for the dissemination of the ODS was that education of the end user should be a major part in its implementation. Unfortunately, as described below, this aspect of the ODS does not seem to have succeeded as end users’ knowledge of bioeffects, safety and output indices is lacking 63,34. Additionally, several assumptions- on sound attenuation in tissue for instance- were made when formulating the indices, which raise some questions on their clinical value. For details, see NCRP report number 140 61. Based on mechanisms involved, as far as is known, non-thermal (mechanical) effects of ultrasound in the fetus are probably negligible, if they exist at all. This is because cavitation, which is a major mechanical effect of the ultrasound wave, occurs virtually only in the presence of bubbles (although spontaneous occurrence has also been occasionally observed [Charlie Church, personal communication]) and there are no naturally occurring gas bodies present in the fetal lungs and bowels. It should be noted, however, that some non-thermal effects have been described in animals but at exposures well above the upper limit (MI=1.9) imposed by the FDA. There is, in fact, little information on energy output and exposure in clinical obstetrical ultrasound. Only relatively recently e several studies were published regarding one possible indication of the acoustic power changes during clinical exams as mirrored by changes in the TI and MI. Acoustic output was recorded in several prospective observational studies investigating first trimester ultrasound 65, Doppler studies66and 3D/four-dimensional (4D) studies 67. First trimester ultrasound was associated with very low TI values, with a mean of 0.2 ± 0.1 65. 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) 66. In the same study, TI was above 1.5 in 43% of the Doppler studies 66. Mean TI during 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) 67. The above-mentioned studies should be viewed with some caution since they were performed in units where end-users (sonographers) were knowledgeable of bioeffects and safety, although they were not aware of the goals of these studies. As already noted, the maximal acoustic intensity for fetal use, as expressed by the estimated in-situ ISPTA went from a previous value of 94mW/cm2 to 720mW/cm2 (see table 1). This represents worst-case scenario and is probably, not consistently sustained in real clinical situations. Martin 14 compared various machines and obtained the following results for the ISPTA worst-case values (in mW/cm2) : for B-mode, a range of 2.4-440 in 1991 and 19.8-1100 in 2010 (the mean went from 17 to 341), for pulsed Doppler: 110-4520 to 271-2830 (mean from 1430 to 860) and for color Doppler, 25-256 to 51-1480 (mean 96 to 466). When examining TI, values range from 0.5 to 4.1 for the TIS in B-mode and 0.08 to 5.0 in pulsed Doppler and for the TIB, 0.02 to 4.0 for B-mode and 0.26 to 7.0 in pulsed Doppler 14. Obviously, the upper values are extremely concerning. It is unknown whether new technologies such as elastography, supersonic shear wave imaging or acoustic radiation force imaging (ARFI) have higher outputs or not. It should also be noted that in some countries, the number of prenatal ultrasound examinations has reached 10 per pregnancy and it is presently unknown whether there is a cumulative dose effect to exposure. A further point of major importance is the lack of consideration of length of exposure in the calculation of the exposure indices. The fact that time is a very important factor in terms of thermal exposure was shown clearly by Miller and Ziskin 68. Attempts have been made to modify this, particularly in regards to the TI 69-76. However, these new or modified indices are still not in clinical use.
Figure 2a. Output Display Standard (ODS) as demonstrated in various modalities. a. B-mode.
Figure 2b. Output Display Standard (ODS) as demonstrated in various modalities. b. M-mode.
Figure 2c. Output Display Standard (ODS) as demonstrated in various modalities. c. Pulsed Doppler
Figure 2d. Output Display Standard (ODS) as demonstrated in various modalities. d. Color Doppler
Figure 2e. Output Display Standard (ODS) as demonstrated in various modalities. e. Power Doppler
Figure 2f. Output Display Standard (ODS) as demonstrated in various modalities. f. 3D reconstruction
Figure 2g. Output Display Standard (ODS) as demonstrated in various modalities. g. 3D color Doppler.
What Determines Acoustic Output During an Exam?
As described above, acoustic output depends on beam characteristics, such as PRF, pulse length (a function of the frequency being used) and area being scanned (intensity is power per area unit, see above). Many of the controls used during a clinical examination to improve the image quality will alter the acoustic output but changing beam characteristics with no clear indication to the end-user that this is happening. One of the major issues is that different machines behave differently: for example some will increase the output when focus is in the near field; some will do this for far field. Following TI and MI on screen is the only (imperfect) way to assure that excessive values are not reached. In addition, time, as previously stated, is an important component of the exposure. This forms the basis of detailed recommendations 58,77-79. On all machines, receiver gain affect quality of the image without effect on the intensity (acoustic output) of the outgoing beam, since it is a post-processing change. Pulse repetition frequency and amplitude change output. Receiver gain and output can affect the image in the same way but receiver gain is completely safe.
Knowledge of Clinical End-Users
Unfortunately, this is one of the most problematic aspects of the issue. While it seems safe to assume that clinicians utilizing a particular technology will be familiar with indications, limitations and possible side-effects, this is not the case for ultrasound. Research in Europe 64, the USA 63, Israel 80 and Pakistan 81 has clearly shown that, on average, less than 25% of clinicians know what TI and MI signify and even more concerning that 80% do not know where to find these indices during a clinical exam. This was determined by asking questions with multiple choice answers (e.g. : where can you find the TI and MI during an exam? The responses offered were: a. in a textbook; b.in the manufacturer manual; c. it can be calculated from the transducer information and d. you can read it on the monitor [obviously, the right answer]). This lack of knowledge was universal, for physicians but also for sonographers82as well as physicians in training, both residents and fellows83. It is worth noting that in most publications, the authors specifically included only people actively performing daily obstetrical scans.
How to Keep it Safe
In the USA, ultrasound machines are “FDA approved”, so why should there be a concern? While it is correct that the FDA has imposed limits to the acoustic outputs of ultrasound instruments, the power emitted by the machine is under direct control of the examiner, as clearly shown above and, based on the application chosen (whether B-mode or spectral Doppler for instance) and control changes (e.g. focal length or gate size), this output can vary greatly, to levels potentially known to have detrimental consequences. In Europe, the Medical Devices Directive requires manufacturers to demonstrate that their products meet essential requirements for safety and effectiveness before they can be offered for sale in any country of the European Community84. Acoustic output values must be demonstrated to be compliant with international standards such as IEC 60601-2-3785 which are standard format for acoustic output reporting, including a requirement to display safety indices but with no specification of maximum permitted levels for acoustic parameters.
Despite the fact that no harm has been demonstrated in humans from the use of DUS, several measures can be taken to minimize risks. The most important ones are to perform DUS only when medically indicated, using the lowest acoustic output, compatible with accurate diagnosis and for the shortest exposure time possible. This corresponds to the ALARA (As Low As Reasonably Achievable) principle. This was originally related to nuclear radiation86 and expended first to radiology (X-rays) and then DUS. However, it must be emphasized that neither theoretic calculations nor experimental results can yield unambiguous and definite evidence that fully guarantees the safety of ultrasound diagnostics, particularly in regards to delayed, subtle effects. Such effects would be very difficult to detect, given that the incidence of congenital abnormalities in the general population is about 3%. Even a relatively large number of additional problems might be missed: for instance if a population of 1 million children is born in a certain year and 3% are affected, this represents 30,000 infants. If 1000 are affected by some subtle ultrasound-induced anomaly (0.1% of exposed), the percentage of population affected in now 3.1%, a percentage that it most likely not statistically different form 3%. Because DUS an extremely powerful tool in the hands of experienced physicians and sonographers, the final decision regarding the risks and benefits can be made only by the individual responsible for applying the ultrasound to the patient. This is a clinical responsibility but also an ethical and legal one. Education of end users is primordial in this regard. Ideally large epidemiological studies might help answer the question in a more scientific way but these would probably be prohibitively complex and expensive. In the meantime, the best recommendation is to be aware of bioeffects, to perform ultrasound only with a clear medical indication and to watch TI, MI and the clock. One of the most detailed TI/time tables can be found in the Safety Group of the British Medical Ultrasound Society guidelines for the safe use of diagnostic ultrasound equipment77. The obstetrical part of this table was recently recommended for approval by the Bioeffects Committee of AIUM (personal communication).
Practical recommendations can be summarized as follows78:
- Perform a scan only when indicated.
- Know the machine you use.
- Keep the examination as short as possible.
- Always start a scan at the lowest possible output (default) and increase only if necessary.
- Follow the ALARA principle.
- Use receiver gain to optimize image.
- Keep track of the TI and MI values on the screen.
- Keep TI below 1.
- Keep MI below 1 (although some recommend 0.5).
- Be extremely cautious when using Doppler in the first trimester.
Ultrasound has physical properties which lead to biological effects in tissues that the beam traverses. The major mechanisms for these bioeffects are thermal and non-thermal (mechanical). Epidemiological evidence thus far is not sufficient to establish a causal relationship between ultrasound and harmful effects87. Biological effects have been demonstrated using some forms of ultrasound in animal and in vitro models. Subtle or transient effects in humans are possible, but none proven so far. Furthermore, while not always relevant in an analysis of epidemiological data, risk-benefit issues are extremely important in clinical practice. Since risks of adverse effects appear so low and clinical benefits so great, there is no justification to withhold the prudent use of diagnostic ultrasound in medically indicated conditions. Knowledge of bioeffects and safety measures are imperative and education of end users should remain a major focus of professional organizations.
Appendix: Statements from Various Organizations
AIUM AS LOW AS REASONABLY ACHIEVABLE (ALARA) PRINCIPLE 88
Approved March 2008
The potential benefits and risks of each examination should be considered. The ALARA (As Low As Reasonably Achievable) Principle should be observed when adjusting controls that affect the acoustical output and by considering transducer dwell times. Further details on ALARA may be found in the AIUM publication "Medical Ultrasound Safety”.
CONCLUSIONS REGARDING EPIDEMIOLOGY FOR OBSTETRIC ULTRASOUND 60
Approved March 2010
Based on the epidemiologic data available and on current knowledge of interactive mechanisms, there is insufficient justification to warrant 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 epidemiologic evidence is based primarily on exposure conditions prior to 1992, the year in which acoustic limits of ultrasound machines were substantially increased for fetal/obstetric applications.
PRUDENT USE AND CLINICAL SAFETY 89
Approved April 2012
Diagnostic ultrasound has been in use since the late 1950s. Given its known benefits and recognized efficacy for medical diagnosis, including use during human pregnancy, the American Institute of Ultrasound in Medicine herein addresses the clinical safety of such use:
No independently confirmed adverse effects caused by exposure from present diagnostic ultrasound instruments have been reported in human patients in the absence of contrast agents. Biological effects (such as localized pulmonary bleeding) have been reported in mammalian systems at diagnostically relevant exposures but the clinical significance of such effects is not yet known. Ultrasound should be used by qualified health professionals to provide medical benefit to the patient. Ultrasound exposures during examinations should be as low as reasonably achievable (ALARA).
PRUDENT USE IN PREGNANCY 90
Approved April 2012
The AIUM advocates the responsible use of diagnostic ultrasound and strongly discourages the non-medical use of ultrasound for entertainment purposes. The use of ultrasound without a medical indication to view the fetus, obtain imges of the fetus or determine the fetal gender is inappropriate and contrary to responsible medical practice. Ultrasound should be used by qualified health professionals to provide medical benefit to the patient 90.
KEEPSAKE FETAL IMAGING 91
Approved April 2012
The AIUM advocates the responsible use of diagnostic ultrasound for all fetal imaging. The AIUM understands the growing pressures from patients for the performance of ultrasound examinations for bonding and reassurance purposes largely driven by the improving image quality of 3D sonography and by more widely available information about these advances. Although there is only preliminary scientific evidence that 3D sonography has a positive impact on parental-fetal bonding, the AIUM recognizes that many parents may pursue scanning for this purpose.
Such "keepsake imaging" currently occurs in a variety of settings, including the following:
1. Images or video clips given to parents during the course of a medically indicated ultrasound examination;
2. Freestanding commercial fetal imaging sites, usually without any physician review of acquired images and with no regulation of the training of the individuals obtaining the images; these images are sometimes called "entertainment videos"; and
3. As added cost visits to a medical facility (office or hospital) outside the coverage of contractual arrangements between the provider and the patient’s insurance carrier
The AIUM recommends that appropriately trained and credentialed medical professionals (licensed physicians, registered sonographers, or sonography registry candidates) who have received specialized training in fetal imaging perform all fetal ultrasound scans. These individuals have been trained to recognize medically important conditions, such as congenital anomalies, artifacts associated with ultrasound scanning that may mimic pathology, and techniques to avoid ultrasound exposure beyond what is considered safe for the fetus. Any other use of "limited medical ultrasound" may constitute practice of medicine without a license. The AIUM reemphasizes that all imaging requires proper documentation and a final report for the patient medical record signed by a physician.
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. The AIUM encourages patients to make sure that practitioners using ultrasound have received specific training in fetal imaging to ensure the best possible results.
The AIUM also believes that added cost arrangements other than those of providing patients images or copies of their medical records at cost may violate the principles of medical ethics of the American Medical Association (E-8.0621,2 and E-8.0632,3) and the American College of Obstetricians and Gynecologists. 4 The AIUM therefore reaffirms the Prudent Use in Pregnancy Statement5 and recommends that only scenario 1 above is consistent with the ethical principles of our professional organizations.
The market for keepsake images is driven in part by past medical approaches that have used medicolegal concerns as a reason not to provide images to patients. Sharing images with patients is unlikely to have a detrimental medicolegal impact. Although these concerns need further analysis and evaluation, we encourage sharing images with patients as appropriate when indicated obstetric ultrasound examinations are performed. 5
1. American Medical Association. E-8.062: Sale of Non-Health-Related Goods From Physician’s Offices. Chicago, IL: American Medical Association; 1998.
2. American Medical Association. Addendum III: Council on Ethical and Judicial Affairs Clarification on Sale of Products from Physicians’ Offices (E-8062 and E-8.063). Chicago, IL: American Medical Association; 2000.
3. American Medical Association. E-8.063: Sale of Health-Related Products From Physician’s Offices. Chicago, IL: American Medical Association; 1999.
4. Commercial enterprises in medical practice. ACOG Committee Opinion No. 359. American College of Obstetricians and Gynecologists. Obstet Gynecol 2007;109:243-5.
5. American Institute of Ultrasound in Medicine. Prudent Use in Pregnancy. Laurel, MD: American Institute of Ultrasound in Medicine; 2012.
IN VITRO BIOLOGICAL EFFECTS 92
Approved April 2012
It is often difficult to evaluate reports of ultrasonically induced in vitro biological effects with respect to their clinical significance. The predominant physical and biological interactions and mechanisms involved in an in vitro effect may not pertain to the in vivo situation. Nevertheless, an in vitro effect must be regarded as a real biological effect.
Results from in vitro experiments suggest new endpoints and serve as a basis for design of in vivo experiments. In vitro studies provide the capability to control experimental variables that may not be controllable in vivo and thus offer a means to explore and evaluate specific mechanisms and test hypotheses. Although they may have limited applicability to in vivo biological effects, such studies can disclose fundamental intercellular or intracellular effects of ultrasound.
While it is valid for authors to place their results in context and to suggest further relevant investigations, reports which do more than that should be viewed with caution.
SAFETY IN TRAINING AND RESEARCH 93
Approved April 2012
Diagnostic ultrasound has been in use since the late 1950s. There are no confirmed adverse biological effects on patients resulting from this usage. Although no hazard has been identified that would preclude the prudent and conservative use of diagnostic ultrasound in education and research, experience from normal diagnostic practice may or may not be relevant to extended exposure times and altered exposure conditions. It is therefore considered appropriate to make the following recommendation:
When examinations are carried out for purposes of training or research, ultrasound exposures should be as low as reasonably achievable (ALARA) within the goals of the study/training. In addition, the subject should be informed of the anticipated exposure conditions and how these compare with normal diagnostic practice. Repetitive and prolonged exposures on a single subject should be justified and consistent with prudent and conservative use.
STATEMENT ON THE SAFE USE OF DOPPLER ULTRASOUND DURING 11-14 WEEK SCANS (OR EARLIER IN PREGNANCY) 94
Approved April 2011
The use of Doppler Ultrasound during the first trimester is currently being promoted as a valuable diagnostic aid for screening for and diagnosis of some congenital abnormalities. The procedure requires considerable skill, and subjects the fetus to extended periods of relatively high ultrasound exposure levels. Due to the increased risk of harm, the use of spectral Doppler ultrasound with high TI in the first trimester should be viewed with great caution. Spectral Doppler should only be employed when there is a clear benefit/risk advantage and both TI and examination duration are kept low. Protocols that typically involve values of TI lower than 1.0 reflect minimal risk. In accordance with the WFUMB statement, we recommend that:
- Pulsed Doppler (spectral, power and color flow imaging) ultrasound should not be used routinely.
- Pulsed Doppler ultrasound may be used for clinical indications such as to refine risks for trisomies.
- When performing Doppler ultrasound, the displayed Thermal Index (TI) should be less than or equal to 1.0 and exposure time should be kept as short as possible (usually no longer than 5-10 minutes) and not exceed 60 minutes.
- When using Doppler ultrasound for research, teaching and training purposes, the displayed TI should be less than or equal to 1.0 and exposure time should be kept as short as possible (usually no longer than 5-10 minutes) and not exceed 60 minutes. Informed consent should be obtained.
- In educational settings, discussion of first trimester pulsed or color Doppler should be accompanied by information on safety and bioeffects (e.g. TI, exposure times, and how to reduce the output power).
- When scanning maternal uterine arteries in the first trimester, there are unlikely to be any fetal safety implications as long as the embryo/fetus lies outside the Doppler ultrasound beam.
STATEMENT ON MEASUREMENT OF FETAL HEART RATE 95
Approved November 2011
Besides watching the monitor and actually counting heartbeats, there are two ultrasonographic methods of measuring the fetal heart rate: M-mode and spectral Doppler. * The measurement of the rate, both in M-mode and spectral Doppler is performed by placing a pair of cursors to span a known number of heartbeats on the tracing. At a fetal size (crown-rump length) of 2 mm to 1 cm (approximately 5+ to 7 weeks), the heartbeat can be visualized by B-mode and then "heard" by spectral Doppler ultrasound.
*Hand-held Doppler instruments without imaging capability are not the topic of this statement.
When attempting to obtain fetal heart rate with a diagnostic ultrasound system, AIUM recommends using M-mode at first, because the time-averaged acoustic intensity delivered to the fetus is lower with M-mode than with spectral Doppler. If this is unsuccessful, spectral Doppler ultrasound may be used with the following guidelines: use spectral Doppler only briefly (e.g. 4-5 heart beats) and keep the thermal index (TIS for soft tissues in the first trimester, TIB for bones in second and third trimesters) as low as possible, preferably below 1 in accordance with the ALARA principle.
- International Society for Ultrasound in Obstetrics and Gynecology (ISUOG)
ISUOG STATEMENT ON THE SAFE USE OF DOPPLER IN THE 11 TO 13+6-WEEK FETAL ULTRASOUND EXAMINATION 96
- Pulsed Doppler (spectral, power and color flow imaging) ultrasound should not be used routinely.
- Pulsed Doppler ultrasound may be used for clinical indications such as to refine risks for trisomies.
- When performing Doppler ultrasound, the displayed thermal index (TI) should be =1. 0 and exposure time should be kept as short as possible (usually no longer than 5-10 min) and should not exceed 60 min.
- When using Doppler ultrasound for research, teaching and training purposes, the displayed TI should be =1. 0 and exposure time should be kept as short as possible (usually no longer than 5-10 min) and should not exceed 60 min. Informed consent should be obtained.
- In educational settings, discussion of first-trimester pulsed or color Doppler should be accompanied by information on safety and bioeffects (e.g. TI, exposure times and how to reduce output power).
- When scanning maternal uterine arteries in the first trimester, there are unlikely to be any fetal safety implications as long as the embryo/fetus lies outside the Doppler ultrasound beam.
SAFETY STATEMENT 97
2000 (reconfirmed 2003)
The thermal index (TI) and the mechanical index (MI) are not perfect indicators of the risks of thermal and nonthermal bioeffects, but currently they should be accepted as the most practical and understandable methods of estimating the potential for such risks.
B-mode and M-mode
Acoustic outputs are generally not high enough to produce deleterious effects. Their use therefore appears to be safe, for all stages of pregnancy.
Significant temperature increase may be generated by spectral Doppler mode, particularly in the vicinity of bone. This should not prevent use of this mode when clinically indicated, provided the user has adequate knowledge of the instrument’s acoustic output, or has access to the relevant TI. Caution is recommended when using color Doppler mode with a very small region of interest, since this mode produces the highest potential for bioeffects. When ultrasound examination is clinically indicated, there is no reason to withhold the use of scanners that have received current Food and Drug Administration clearance in tissues, which have no identifiable gas bodies. Since ultrasound contrast agents are mostly gas-carriers, the risk of induction and sustenance of inertial cavitation is higher in circumstances when these agents are employed.
Based on evidence currently available, routine clinical scanning of every woman during pregnancy using real time B-mode imaging is not contraindicated. The risk of damage to the fetus by teratogenic agents is particularly great in the first trimester. One has to remember that heat is generated at the transducer surface when using the transvaginal approach. Spectral and color Doppler may produce high intensities and routine examination by this modality during the embryonic period is rarely indicated. In addition, because of high acoustic absorption by bone, the potential for heating adjacent tissues must also be kept in mind. Exposure time and acoustic output should be kept to the lowest levels consistent with obtaining diagnostic information and limited to medically indicated procedures, rather than for purely entertainment purposes.
Education of ultrasound operators is of the utmost importance since the responsibility for the safe use of ultrasound devices is now shared between the users and the manufacturers, who should ensure the accuracy of the output display.
ISUOG-WFUMB STATEMENT ON THE NON-MEDICAL USE OF ULTRASOUND 98
The International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) and World Federation of Ultrasound in Medicine and Biology (WFUMB) disapprove of the use of ultrasound for the sole purpose of providing souvenir images of the fetus. There have been no reported incidents of human fetal harm in over 40 years of extensive use of medically indicated and supervised diagnostic ultrasound. Nevertheless, ultrasound involves exposure to a form of energy, so there is the potential to initiate biological effects. Some of these effects might, under certain circumstances, be detrimental to the developing fetus. Therefore, the uncontrolled use of ultrasound without medical benefit should be avoided. Furthermore, ultrasound should be employed only by health professionals who are trained and updated in the clinical usage and bioeffects of ultrasound
- World Federation for Ultrasound in Medicine and Biology (WFUMB)
CLINICAL SAFETY STATEMENT FOR DIAGNOSTIC ULTRASOUND 99
Diagnostic ultrasound has been widely used in clinical medicine for many years with no proven deleterious effects. However, investigations into the possibility of subtle or transient effects are still at an early stage. Biological effects (such as localized pulmonary capillary bleeding) have been reported in mammalian systems at diagnostically relevant exposures but the clinical significance of such effects is not yet known. Consequently, diagnostic ultrasound can only be considered safe if used prudently. Ultrasound examinations should only be performed by competent personnel who are trained and updated in safety matters. It is also important that ultrasound devices are appropriately maintained.
The range of clinical applications is becoming wider, the number of patients undergoing ultrasound examinations is increasing and new techniques with higher acoustic output levels are being introduced. It is therefore essential to maintain vigilance to ensure the continued safe use of ultrasound.
RECOMMENDATIONS ON NON-MEDICAL USE OF ULTRASOUND 100
- The WFUMB disapproves of the use of ultrasound for the sole purpose of providing keepsake or souvenir images of the fetus.
- Ultrasonography is a medical procedure that should only be carried out in the clinical setting where there is a medical indication and when carried out under the supervision of a physician or an expert.
- The use of ultrasound to provide keepsake images or videos of the fetus may be acceptable if it is undertaken as part of the normal clinical diagnostic ultrasound examination, provided that it does not increase exposure to the fetus.
- In the absence of supporting evidence of safety, caution should be used to minimize ultrasound exposure to the fetus.
- When using ultrasound for non-medical reasons the ultrasound equipment display should be used to ensure that TI<0.5 and MI<0.3.
- Ultrasound imaging for non-medical reasons is not recommended unless carried out for education, training or demonstration purposes.
- Live scanning of pregnant models for equipment exhibitions at ultrasound congresses is considered a non-medical practice that should be prohibited since it provides no medical benefit and affords potential risk to the fetus.
- Donald I, Macvicar J, Brown TG. Investigation of abdominal masses by pulsed ultrasound. Lancet. 1958;1(7032):1188-95. Epub 1958/06/07.
- NIH consensusDevelopment Conference: The Use of Diagnostic Ultrasound Imaging in Pregnancy. Vol 5, No 1. Washington, DC: US Government Printing Office, 1984 No. 84-667 Contract No. : Vol 5, No.1.
- Andrews DS. Ultrasonography in pregnancy-an inquiry into its safety. British Journal of Radiology. 1964;37:185-6.
- Duck FA. Hazards, risks and safety of diagnostic ultrasound. Medical engineering & physics. 2008;30(10):1338-48.
- Sheiner E, Abramowicz JS. Clinical end users worldwide show poor knowledge regarding safety issues of ultrasound during pregnancy. J Ultrasound Med. 2008;27(4):499-501.
- Nyborg WL, Wu J. Relevant parameters with rationale. In: Ziskin MC, Lewin PA, editors. Ultrasonic Exposimetry. Boca Raton, FL: CRC Press; 1993. p. pp 85 - 112.
- FDA, Center for Devices and Radiological Health: 501(k) Guide for Measuring and Reporting Acoustic Output of Diagnostic Ultrasound Medical Devices. 1985.
- US Food and Drug Administration (FDA):Diagnostic Ultrasound Guidance Update. Rockville, MD: Center for Devices and Radiological Health, 1987.
- 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 Devices. Laurel, MD and Rosslyn, VA. : 1992.
- Barnett SB, Rott HD, ter Haar GR, Ziskin MC, Maeda K. The sensitivity of biological tissue to ultrasound. Ultrasound in medicine & biology. 1997;23(6):805-12.
- Insana MF. Sound attenuation in tissue. In: Goldman IW, Fowlkes JB, editors. Medical CT and Ultrasound: Current technology and applications. College Park, MD: American Association of Physicists in Medicine; 1995.
- 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 in medicine & biology. 1995;21(3):379-91.
- Henderson J, Willson K, Jago JR, Whittingham TA. A survey of the acoustic outputs of diagnostic ultrasound equipment in current clinical use. Ultrasound in medicine & biology. 1995;21(5):699-705. Epub 1995/01/01.
- Martin K. The acoustic safety of new ultrasound technologies. Ultrasound. 2010;18:110-8.
- Duck FA, Henderson J. Acoustic output of modern instruments: is it increasing? In: Barnett SB, Kossoff G, eds, editors. Safety of Diagnostic Ultrasound. New York, London: The Parthenon Publishing Group; 1998.
- Jago JR, Henderson J, Whittingham TA, Willson K. How reliable are manufacturer's reported acoustic output data? Ultrasound in medicine & biology. 1995;21(1):135-6. Epub 1995/01/01.
- Brent RL, Beckman DA, Landel CP. Clinical teratology. Current opinion in pediatrics. 1993;5(2):201-11.
- Edwards MJ, Saunders RD, Shiota K. Effects of heat on embryos and foetuses. Int J Hyperthermia. 2003;19(3):295-324.
- Ang ESBC, Gluncic V, Duque A, Schafer ME, Rakic P. Prenatal exposure to ultrasound waves impacts neuronal migration in mice. Proc NY Acad Sci. 2006;103:12903-10.
- Graham JM, Jr. , Edwards MJ, Edwards MJ. Teratogen update: gestational effects of maternal hyperthermia due to febrile illnesses and resultant patterns of defects in humans. Teratology. 1998;58(5):209-21.
- Stalberg K, Haglund B, Axelsson O, Cnattingius S, Pfeifer S, Kieler H. Prenatal ultrasound and the risk of childhood brain tumour and its subtypes. British journal of cancer. 2008;98(7):1285-7.
- Calvert J, Duck F, Clift S, Azaime H. Surface heating by transvaginal transducers. Ultrasound Obstet Gynecol. 2007;29(4):427-32.
- WFUMB. WFUMB symposium on safety of ultrasound in medicine recommendations on the safe use of ultrasound. Ultrasound in medicine & biology. 1998;24(Suppl. 1):15-6.
- Nyborg WL. History of the American Institute of Ultrasound in Medicine's efforts to keep ultrasound safe. J Ultrasound Med. 2003;22(12):1293-300.
- Sheiner E, Abramowicz JS. A symposium on obstetrical ultrasound: is all this safe for the fetus? Clinical obstetrics and gynecology. 2012;55(1):188-98. Epub 2012/02/22.
- Abramowicz JS, Miller MW, Battaglia LF, Mazza S. Comparative hemolytic effectiveness of 1 MHz ultrasound on human and rabbit blood in vitro. Ultrasound in medicine & biology. 2003;29(6):867-73.
- Ashush H, Rozenszajn LA, Blass M, Barda-Saad M, Azimov D, Radnay J, et al. Apoptosis induction of human myeloid leukemic cells by ultrasound exposure. Cancer research. 2000;60(4):1014-20.
- Kaufman GE, Miller MW, Griffiths TD, Ciaravino V, Carstensen EL. Lysis and viability of cultured mammalian cells exposed to 1 MHz ultrasound. Ultrasound in medicine & biology. 1977;3(1):21-5.
- Borrelli MJ, Bailey KI, Dunn F. Early ultrasonic effects upon mammalian CNS structures (chemical synapses). The Journal of the Acoustical Society of America. 1981;69(5):1514-6.
- Miller DL, Thomas RM, Frazier ME. Single strand breaks in CHO cell DNA induced by ultrasonic cavitation in vitro. Ultrasound in medicine & biology. 1991;17(4):401-6.
- Pinamonti S, Caruso A, Mazzeo V, Zebini E, Rossi A. DNA damage from pulsed sonication of human leukocytes in vitro. IEEE transactions on ultrasonics, ferroelectrics, and frequency control. 1986;33(2):179-85.
- Carnes KI, Hess RA, Dunn F. The effect of ultrasound exposure in utero on the development of the fetal mouse testis: adult consequences. Ultrasound in medicine & biology. 1995;21(9):1247-57.
- Fisher JE, Jr. , Acuff-Smith KD, Schilling MA, Vorhees CV, Meyer RA, Smith NB, et al. Teratologic evaluation of rats prenatally exposed to pulsed-wave ultrasound. Teratology. 1994;49(2):150-5.
- Hande MP, Devi PU. Effect of prenatal exposure to diagnostic ultrasound on the development of mice. Radiation research. 1992;130(1):125-8.
- Jensh RP, Lewin PA, Poczobutt MT, Goldberg BB, Oler J, Goldman M, et al. Effects of prenatal ultrasound exposure on adult offspring behavior in the Wistar rat. Proceedings of the Society for Experimental Biology and Medicine Society for Experimental Biology and Medicine (New York, NY. 1995;210(2):171-9.
- Nyborg WL. Biological effects of ultrasound: development of safety guidelines. Part II: general review. Ultrasound in medicine & biology. 2001;27(3):301-33.
- Sikov MR. Effect of ultrasound on development. Part 2: Studies in mammalian species and overview. J Ultrasound Med. 1986;5(11):651-61.
- 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(2):149-62.
- Abramowicz JS, Fowlkes JB, Stratmeyer ME, Ziskin MC. Epidemiology of ultrasound bioeffects. In: Sheiner E, editor. Textbook of Epidemiology in Perinatology. New York: Nova Science Publishers, Inc. ; 2010.
- Newnham JP, Evans SF, Michael CA, Stanley FJ, Landau LI. Effects of frequent ultrasound during pregnancy: a randomised controlled trial. Lancet. 1993;342(8876):887-91.
- Campbell JD, Elford RW, Brant RF. Case-control study of prenatal ultrasonography exposure in children with delayed speech. Cmaj. 1993;149(10):1435-40.
- Kieler H, Haglund B, Cnattingius S, Palmgren J, Axelsson O. Does prenatal sonography affect intellectual performance? Epidemiology (Cambridge, Mass. 2005;16(3):304-10.
- Stark CR, Orleans M, Haverkamp AD, Murphy J. Short- and long-term risks after exposure to diagnostic ultrasound in utero. Obstetrics and gynecology. 1984;63(2):194-200.
- Cartwright RA, McKinney PA, Hopton PA, Birch JM, Hartley AL, Mann JR, et al. Ultrasound examinations in pregnancy and childhood cancer. Lancet. 1984;2(8410):999-1000.
- Bricker L, Neilson JP, Dowswell T. Routine ultrasound in late pregnancy (after 24 weeks' gestation). Cochrane database of systematic reviews (Online). 2008(4):CD001451.
- Kieler H, Axelsson O, Haglund B, Nilsson S, Salvesen KA. Routine ultrasound screening in pregnancy and the children's subsequent handedness. Early human development. 1998;50(2):233-45.
- Salvesen KA, Vatten LJ, Eik-Nes SH, Hugdahl K, Bakketeig LS. Routine ultrasonography in utero and subsequent handedness and neurological development. BMJ (Clinical research ed. 1993;307(6897):159-64.
- Salvesen KA. Ultrasound and left-handedness: a sinister association? Ultrasound Obstet Gynecol. 2002;19(3):217-21.
- Kieler H, Cnattingius S, Haglund B, Palmgren J, Axelsson O. Sinistrality--a side-effect of prenatal sonography: a comparative study of young men. Epidemiology (Cambridge, Mass. 2001;12(6):618-23.
- Salvesen KA. Ultrasound in pregnancy and non-right handedness: meta-analysis of randomized trials. Ultrasound Obstet Gynecol. 2011;38(3):267-71. Epub 2011/05/18.
- Abramowicz JS. Prenatal exposure to ultrasound waves: is there a risk? Ultrasound Obstet Gynecol. 2007;29(4):363-7.
- 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. Radiation research. 1994;140(2):284-93.
- Kieler H. Epidemiological studies on adverse effects of prenatal ultrasound-which are the challenges? Progress in biophysics and molecular biology. 2007;93:301-8.
- Salvesen KA. EFSUMB: safety tutorial: epidemiology of diagnostic ultrasound exposure during pregnancy-European committee for medical ultrasound safety (ECMUS). Eur J Ultrasound. 2002;15(3):165-71.
- Salvesen KA. Epidemiological prenatal ultrasound studies. Progress in biophysics and molecular biology. 2007;93:295-300.
- Salvesen KA, Eik-Nes SH. Is ultrasound unsound? A review of epidemiological studies of human exposure to ultrasound. Ultrasound Obstet Gynecol. 1995;6(4):293-8.
- Ziskin MC, Petitti DB. Epidemiology of human exposure to ultrasound: a critical review. Ultrasound in medicine & biology. 1988;14(2):91-6.
- Abramowicz JS. Fetal Doppler: how to keep it safe? Clinical obstetrics and gynecology. 2010;53(4):842-50. Epub 2010/11/05.
- Schneider-Kolsky ME, Ayobi Z, Lombardo P, Brown D, Kedang B, Gibbs ME. Ultrasound exposure of the foetal chick brain: effects on learning and memory. Int J Dev Neurosci. 2009;27(7):677-83. Epub 2009/08/12.
- AIUM. AIUM Official Statement: Conclusions Regarding Epidemiology for Obstetric Ultrasound. 2010 [5/1/2012]; Available from: http://www.aium.org/publications/statements/_statementSelected.asp?statement=16 .
- 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 Contract No. : 140.
- Abbott JG. Rationale and derivation of MI and TI--a review. Ultrasound in medicine & biology. 1999;25(3):431-41.
- Sheiner E, Shoham-Vardi I, Abramowicz JS. What do clinical users know regarding safety of ultrasound during pregnancy? J Ultrasound Med. 2007;26(3):319-25; quiz 26-7.
- Marsal K. The output display standard: has it missed its target? Ultrasound Obstet Gynecol. 2005;25(3):211-4.
- Kieler H, Cnattingius S, Palmgren J, Haglund B, Axelsson O. First trimester ultrasound scans and left-handedness. Epidemiology (Cambridge, Mass. 2002;13(3):370.
- 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(1):71-6.
- Sheiner E, Hackmon R, Shoham-Vardi I, Pombar X, Hussey MJ, Strassner HT, et al. A comparison between acoustic output indices in 2D and 3D/4D ultrasound in obstetrics. Ultrasound Obstet Gynecol. 2007;29(3):326-8.
- Miller MW, Ziskin MC. Biological consequences of hyperthermia. Ultrasound in medicine & biology. 1989;15(8):707-22.
- Bigelow TA, Church CC, Sandstrom K, Abbott JG, Ziskin MC, Edmonds PD, et al. The thermal index: its strengths, weaknesses, and proposed improvements. J Ultrasound Med. 2011;30(5):714-34. Epub 2011/04/30.
- Church CC. A proposal to clarify the relationship between the thermal index and the corresponding risk to the patient. Ultrasound in medicine & biology. 2007;33(9):1489-94. Epub 2007/05/22.
- Duck FA. Acoustic dose and acoustic dose-rate. Ultrasound in medicine & biology. 2009;35:1679-85.
- Karagoz I, Kartal MK. A new safety parameter for diagnostic ultrasound thermal bioeffects: safe use time. The Journal of the Acoustical Society of America. 2009;125(6):3601-10. Epub 2009/06/11.
- Lubbers J, Hekkenberg RT, Bezemer RA. Time to threshold (TT), a safety parameter for heating by diagnostic ultrasound. Ultrasound in medicine & biology. 2003;29(5):755-64. Epub 2003/05/20.
- Stalberg K. Prenatal ultrasound and X-ray-potentially adverse effects on the CNS. Upsalla, Sweden: Upsalla Universitet; 2008.
- Whelan EM. Can Too Much Safety be Hazardous? A Critical Look at the "Precautionary Principle". Posted May 23, 2000. . 2000 [09/03/2007]; Available from: http://www.acsh.org/healthissues/newsID.236/healthissue_detail.asp .
- Ziskin MC. The thermal dose index. J Ultrasound Med. 2010;29(10):1475-9. Epub 2010/09/30.
- Safety Group of the British Medical Ultrasound Society (BMUS)
- Guidelines for the safe use of diagnostic ultrasound equipment. Ultrasound 2010;18:52-9.
- Abramowicz JS, Sheiner E. Ultrasound Bioeffects and Safety: what the practitioner should know. In: Fleischer AC, Manning FA, Jeanty P, Romero R, editors. Sonography in Obstetrics and Gynecology-Principles and Practice. 7th ed. New York: McGraw-Hill; 2010.
- Nelson TR, Fowlkes JB, Abramowicz JS, Church CC. Ultrasound biosafety considerations for the practicing sonographer and sonologist. J Ultrasound Med. 2009;28(2):139-50.
- 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;151(3):146-9, 90. Epub 2012/04/24.
- Akhtar W, Arain MA, Ali A, Manzar N, Sajjad Z, Memon M, et al. Ultrasound biosafety during pregnancy: what do operators know in the developing world?: national survey findings from pakistan. J Ultrasound Med. 2011;30(7):981-5. Epub 2011/06/28.
- Bagley J, Thomas K, DiGiacinto D. Safety practices of sonographers and their knowledge of the biologic effects of sonography. Journal of Diagnostic Medical Sonography 2011;27:252-61.
- 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;30(1):21-7. Epub 2011/01/05.
- EEC. The Council of the European Communities directive 93/42/EEC concerning medical devices. 1993 [5/2/2012]; Official Journal L 169 , 12/07/1993 P. 0001 - 0043:[Available from: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CELEX:31993L0042:en:HTML .
- IEC. IEC 60601-2-37-2: Particular requirements for the basic safety and essential performance of ultrasonic medical diagnostic and monitoring equipment. GenevaEdition 2.0 2007-08.
- USRC. NRC Regulations, § 20.1003 Definitions. United States Regulatory Commission; [May 9, 2012]; Available from: http://www.nrc.gov/reading-rm/doc-collections/cfr/part020/part020-1003.html .
- Abramowicz JS, Fowlkes JB, Skelly AC, Stratmeyer ME, Ziskin MC. Conclusions regarding epidemiology for obstetric ultrasound. J Ultrasound Med. 2008;27(4):637-44.
- AIUM. AIUM As Low As Reasonably Achievable (ALARA) Principle. 2012; Available from: http://www.aium.org/publications/viewStatement.aspx?id=39 .
- AIUM. AIUM Official Statement: Prudent Use and Clinical Safety. 2012 [5/16/2012]; Available from: http://www.aium.org/publications/statements.aspx .
- AIUM. AIUM Official Statement:Prudent Use in Pregnancy. 2012 [5/16/2012]; Available from: http://www.aium.org/publications/viewStatement.aspx?id=33 .
- AIUM. AIUM Official Statement:Keepsake Fetal Imaging. 2012 [5/16/2012]; Available from: http://www.aium.org/publications/statements.aspx .
- AIUM. AIUM Official Statement: In-Vitro Biological Effects 2012 [5/16/2012]; Available from: http://www.aium.org/publications/guidelinesStatementsX.aspx#statements .
- AIUM. AIUM Official Statement: Safety in Training and Research 2012 [5/16/2012]; Available from: http://www.aium.org/publications/statements.aspx .
- AIUM. AIUM Official Statement: Statement on the Safe Use of Doppler Ultrasound During 11-14 week scans (or earlier in pregnancy). 2011 [5/16/2012]; Available from: http://www.aium.org/publications/statements.aspx .
- AIUM. AIUM Official Statement: Measurement of Fetal Heart Rate. 2011 [5/16/2012]; Available from: http://www.aium.org/publications/statements.aspx .
- Salvesen K, Lees C, Abramowicz J, Brezinka C, Ter Haar G, Marsal K, et al. ISUOG statement on the safe use of Doppler in the 11 to 13 +6-week fetal ultrasound examination. Ultrasound Obstet Gynecol. 2011;37(6):628. Epub 2011/05/28.
- Abramowicz JS, Kossoff G, Marsal K, Ter Haar G. Safety Statement, 2000 (reconfirmed 2003). International Society of Ultrasound in Obstetrics and Gynecology (ISUOG). Ultrasound Obstet Gynecol. 2003;21(1):100.
- Salvesen K, Lees C, Abramowicz J, Brezinka C, Ter Haar G, Marsal K. ISUOG-WFUMB statement on the non-medical use of ultrasound, 2011. Ultrasound in Obstetrics and Gynecology. 2011;38(5):608.
- WFUMB. WFUMB Clinical Safety Statement for Diagnostic Ultrasound. [5/16/2012]; Available from: http://www.wfumb.org/about/statements.aspx.
- WFUMB. WFUMB Recommendations on Non-medical Use of Ultrasound. Ultrasound Med Biol 2010;36(8):1210.