First-Trimester Ultrasound: A Comprehensive Guide

1. Ultrasound in the First Trimester and Earlier: How to Keep It Safe

Jacques S. Abramowicz 

(1)

Department of Obstetrics and Gynecology, Wayne State University School of Medicine, 3990 John R. Street, Detroit, MI 48201, USA

Jacques S. Abramowicz

Email: jabramow@med.wayne.edu

Keywords

Artificial reproductive technologies (ART)BioeffectsDopplerFetusFirst trimesterMechanical IndexPregnancyRiskSafetyTeratologyThermal IndexUltrasound

“Ultrasound is safe. Ultrasound is not X-rays. Our machines are FDA-approved.” These are the statements most commonly made when initiating a conversation on safety of ultrasound. This is one of the reasons cited for its becoming an essential tool in medicine (together with its relatively low cost and immediate results availability). Diagnostic ultrasound (DUS) has been in use for over half a century in obstetrics and gynecology [1] and the benefits of this technology are multiple [2]. Most pregnant women have 2–3 ultrasound examinations (and many more in certain countries) during their pregnancies. In early pregnancy and before (i.e., in Artificial Reproductive Technologies [(ART]), these include serial scans of the developing follicles during ovulation induction [3] and in the earliest stages of gestation [4], first-trimester ultrasound for viability and/or aneuploidy screening (nuchal translucency, NT) and, more and more, early anatomy survey [5]. Such is the widespread enthusiasm and the generally accepted notion of safety that its use has spilled into the commercial world with mall stores offering non-medical ultrasound or “souvenir” scans. The record of safety of DUS is excellent: there are no epidemiological studies demonstrating harmful effects in human fetuses [6]. Most human epidemiological studies, however, published so far are based on information obtained with pre-1991/1992 machines. Around that time, the US Federal Drug Administration (FDA) allowed the acoustic output of ultrasound machines for fetal use to be increased from 94 to 720 mW/cm2, a factor of almost 8 [78]. Is there enough evidence to validate the use of ultrasound imaging in general and Doppler in particular in the first trimester [9] and could ultrasound have detrimental effects on the fetus in the first trimester, a time of maximal susceptibility to external factors? If there are clinical indications to perform these scans (and if there were none, there would be no raison-d’être for this book) safety must be guaranteed by educating the end-users on ways to limit the possible hazards of exposure of the follicles/ova and the fetus at early stages of gestation [2].

Bioeffects of Ultrasound

Ultrasound is a waveform with a succession of positive and negative pressures [10]. Whenever an ultrasound beam traverses biological tissues, two major mechanisms are operative: thermal and non-thermal (also known as mechanical). This will occur every time ultrasound is used. As the waveform travels through tissue, it loses amplitude by absorption and scatter. With absorption, energy is converted into heat, hence a thermal effect [11], an indirect effect of the waveform. A direct effect of the passage of the waveform, secondary to the succession of positive and negative pressures is non-thermal or mechanical [12].

Thermal Effects

Human body normal core temperature is generally accepted to be 37 °C with a diurnal variation of ±0.5–1 °C [12]. Temperature in the human fetus is slightly higher than maternal body temperature by 0.3–0.5 °C during the early gestation (two first trimesters). During the third trimester fetal temperature is higher by 0.5 °C than that of its mother. Ultrasound may cause a rise in temperature in insonated tissues [13]. This rise will be small and, most likely, clinically insignificant, if certain precautions are respected (as detailed below). Why is this important? Because specific structural abnormalities have been shown to be produced by increased temperature in many pregnant animal studies, as well as several controlled human studies [14], but not by ultrasound. Elevated maternal temperature in early gestation, secondary to viral infection, for instance, has been associated with a higher than expected incidence of congenital anomalies [15]. Edwards and others have demonstrated that hyperthermia is teratogenic for many animal species (such as guinea pigs, rats, monkeys, and more), including the human [1416]. Major anomalies observed included microcephaly, encephalocele, microphthalmia, skeletal anomalies as well as growth delay. It was suggested that a 1.5 °C temperature elevation above the normal body temperature should be considered a universal threshold [17]. The acceptance of a threshold forms the basis for the ALARA (As Low As Reasonably Achievable) principle: keep the exposure as low as possible, for the least amount of time possible, but yet enough to get adequate diagnostic images [18]. Some scientists, however, assert that any temperature increment for any period of time has some effect, the higher the temperature differential or the longer the temperature increment the greater the likelihood of producing an effect, i.e., there is no thermal threshold for hyperthermia-induced birth defects [1920]. Whether a threshold exists or not, two facts are undeniable: ultrasound has the potential to elevate the temperature of the tissues being scanned [2124] and elevated maternal temperature, whether from illness or exposure to heat, can produce teratologic effects [142527]. Consequently, the obvious question that emerges is: can diagnostic ultrasound produce harmful/teratological temperature rise in the fetus [112228]? Some believe that such a temperature rise is, in effect, the major operational mechanism for ultrasound bioeffects [1229]. For prolonged exposures, temperature elevations of up to 5 °C have been obtained [28]. The actual in situ temperature change in insonated tissues depends on the balance between heat production and heat loss. Local perfusion is a specific tissue condition that strongly influences the amount of heat loss and which very clearly diminishes the risk, if present. In early pregnancy, under 6–8 weeks, there appears to be minimal maternal–fetal circulation and minimal fetal perfusion, which may potentially reduce heat dispersion [30]. Only at about weeks 10–11 does the embryonic circulation actually link up with the maternal circulation [31]. The early absence of perfusion may thus lead to some underestimation of the actual ultrasound-induced temperature in early gestation. Interestingly, this lack of perfusion, which also exists in the eye, 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 (Table 1.1). One should note that 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 proportion in the fetus). At about gestational weeks 4–5, 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 [32]. Ultrasound imaging in these early stages of gestation involves “whole body” scanning since the fetal size is less than the cross section of the beam (Fig. 1.1). An additional factor, virtually ignored clinically, is modifications of tissue temperature due to ambient maternal and fetal temperatures. Elevated maternal temperature is immediately translated into a similar increase in the fetus which may compound the ultrasound-induced heat burden [33]. On the other hand, 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’s and the fetus’) tend to spread the region being heated. However, for spectral (pulsed) Doppler studies, conditions may be different (see below). As mentioned above, there is a mathematical/physical relation between temperature elevation and several beam characteristics. The elevation is proportional to the product of the wave amplitude, length of the pulse and pulse-repetition frequency (PRF). Hence, manipulating any of these via instrument controls will alter the in situ conditions. Temperature increases of 1 °C are easily reached in routine scanning [34]. A general threshold of temperature elevation of 1.5–2 °C has been suggested before any evidence of developmental effect occurs [12]. An increase of 2.5 °C and above is possible with 1 h of exposure to ultrasound [12]. When using an abdominal probe, the skin surface is close to room temperature and heat is removed by air convection but in the case of endovaginal scanning, tissues are at an average temperature of 37 °C—or possibly higher in febrile patients—and there is very little heat removal [35]. In addition, the surface of all ultrasound transducers, including endovaginal probes, self-heats [36], and particular attention is necessary during ART procedures and the first 10–12 weeks of gestation, when endovaginal scanning is often the favored method. As was concluded by the World Federation for Ultrasound in Medicine and Biology (WFUMB), exposure that produces a maximum temperature elevation of no more than 1.5 °C above normal physiological levels may be used without reservation on thermal ground [37].

Table 1.1

Changes over the years in I SPTA (in mW/cm2) in various medical applicationsa

Ultrasound clinical application

1976

1986

1991

Ophthalmic

17

17

50

Fetal, neonatal, pediatric imaging

46

94

720

Cardiac (adult)

430

430

720

Peripheral vascular

720

720

720

aAdapted from various sources [81259166170]

A328333_1_En_1_Fig1_HTML.jpg

Fig. 1.1

In early pregnancy the entire fetus is within the ultrasound beam. Gestational age of 12 weeks

Non-thermal Effects

Ultrasound bioeffects may also occur through non-thermal or mechanical processes [3839]. These include acoustic cavitation, if gas bubbles are present, as well as radiation torque and force and acoustic streaming secondary to propagation of the ultrasound waves. Included in this category are physical (shock wave) or chemical (release of free radicals) effects. Bubble cavitation seems to be the major factor in mechanical effects [4041], as it has been demonstrated to occur in living tissues when insonated [4243]. Non-thermal mechanisms have been implicated in biological effects of ultrasound in animals, such as local intestinal [44], renal [45], and pulmonary hemorrhages [46], although cavitation could not always be incriminated. Furthermore, since there does not seem to be gas bubbles in the ovarian vasculature or parenchyma, nor the fetal lungs or bowels (where effects have been described in neonates or adult animals), the risk to the ovum and fetus from mechanical effect appears to be minimal [47]. However, the use of contrast agents (including agitated saline) to image the fallopian tubes or the endometrial cavity for instance, introduces these potential cavitation foci [48]. Details on the cavitation phenomenon can be found in various publications [3840434950]. Another described result of mechanical energy is hemolysis [51]. Again, it is evident, however, that the presence of some cavitation nuclei is necessary for hemolysis to occur. In the presence of such contrast agents, fetal red blood cells are more susceptible to lysis from ultrasound exposure in vitro [52]. In addition to the above, fetal stimulation caused by ultrasound (Doppler) insonation has been described, with no apparent relation to cavitation [53]. This effect may be secondary to radiation forces associated with ultrasound exposures. These forces were suspected at the earliest stages of ultrasound research [54] and are known to possibly stimulate auditory [55] and other sensory tissues [56]. The main effects of non-thermal damage have been demonstrated in mammalian tissues containing gas where capillary bleeding has been observed [394257]. This potentially pertains to the neonatal lung, intestine and also, as noted above, in the presence of ultrasound microbubble contrast agents. Several non-thermal mechanisms, not related to cavitation have also been described: radiation force, acoustic streaming, modification of electrical potentials, effect on cardiac performance and stimulation of bone repair [12]. None of these have been demonstrated in humans and no harmful effects of diagnostic ultrasound, secondary to non-thermal mechanisms have been reported in human fetuses.

The Output Display Standard (OSD)

Until 1992 acoustic outputs of clinical ultrasound machines had specific limits. For instance, the upper limit of the spatial peak temporal average intensity or ISPTA (the most clinically useful intensity used to determine acoustic power of the ultrasound beam) for adult use was 720 mW/cm2 and for fetal use, 94 mW/cm2, which in fact, already had been increased from a previous maximum value of 46 mW/cm2. It was assumed that higher outputs would generate better images and, thus, improve diagnostic accuracy. Hence, end-users required ultrasound manufacturers to increase their machines output. Some worry, however, was expressed regarding the actual amount of energy absorbed by a human fetus during an ultrasound examination. This amount cannot be measured precisely. Not only the lack of an internal recording device is a major issue but, in addition, elements such as variations in maternal body habitus, fetal position changes, and gestational age progression render such a task impossible. 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 (thermal and mechanical), the American Institute of Ultrasound in Medicine (AIUM), the National Electrical Manufacturers’ Association (NEMA) and the US food and Drug Administration (FDA), with representatives from the Canadian Health Protection Branch, the National Council on Radiation Protection and Measurements (NCRP) and 14 other medical organizations developed a standard related to the potential for ultrasound bioeffects [12]. The Standard for Real-Time Display of Thermal and Mechanical Indices on Diagnostic Ultrasound Equipment, generally known as the Output Display Standard or ODS, 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, on the exposure, providing, from a clinical standpoint, a rough estimate to compare various modes of examination. As a consequence, the acoustic output for fetal use, as expressed by the ISPTAwent from a previous value of 94–720 mW/cm2 (see Table 1.1). It is interesting to observe from the table that, for fetal imaging, the ISPTA was allowed to increase by a factor of almost 16 from 1976 to the most recent values in 1992; yet virtually all epidemiological information available regarding fetal effects predates 1992. A further remarkable fact is that intensity for ophthalmic examination was increased from the original 17–50 mW/cm2, a value approximately 12 times lower than the present allowed maximal value for fetal scanning. Furthermore, the clinical categories included in the analysis consisted of ophthalmic, fetal (without specification of gestational age), cardiac, and peripheral vascular examinations. Pelvic imaging (abdominal or transvaginal), including, naturally, examination of ovaries in ovulation induction, is not mentioned. The indices to appear on-screen (Fig. 1.2) were 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 [5859]. The TI calculation is based on the formula:

A328333_1_En_1_Fig2_HTML.jpg

Fig. 1.2

The TI and MI acoustic indices as demonstrated on the monitor screen during routine ultrasound examination. In this picture, the MI is 0.9 and the TIS, 0.1

 $$ \mathrm{T}\mathrm{I}=W/{W}_{\deg } $$

where W is the acoustic power while scanning and Wdeg is the acoustic power required to achieve an increase in temperature of 1 °C under similar conditions [60]. The TI has three variants [35]: TI for soft tissue (TIS), to be used mostly in early pregnancy when ossification is low (as well as in ART for ovulation studies), 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, but in no way allowing an estimate or a guess as to what that temperature change actually is in the tissue. The TI represents reasonable “worst-case” estimate of the temperature rise resulting from the exposure. It can, thus, be used to assess the potential for harm via a thermal mechanism, the higher the TI, the higher this potential. Calculations are also on the ultimate temperature reached after prolonged exposure. This time will be short (less than 5 min) with a narrow beam and good tissue perfusion, as is the case in late first-trimester scanning. When bone is present, this time is very short, approximately 30 s. An important point to remember is that experimental data has clearly demonstrated that this worst-case elevation of temperature may be a gross underestimation, by as much as a factor of 2 or even 6, and, more rarely, an overestimation [12]. Furthermore, exposure time is not part of the equation, nor is it in the second index, the MI, which represents the potential for cavitation in tissues, but is not based on actual in situ measurements. The MI is defined as:

 $$ \mathrm{M}\mathrm{I}=p/\sqrt{f} $$

It is a theoretical formulation of the ratio of the peak rarefaction pressure to the square root of the ultrasound frequency (hence, the higher the frequency, the lesser risk of mechanical effect, which is an advantage in endovaginal scanning). As for the TI, exposure time is not part of the calculation. Both the TI and MI can and should be followed as an indication of change in output during the clinical examination. A major component of the implementation of the ODs was supposed to be education of the end-user. Unfortunately, this aspect of the ODS does not seem to have succeeded as end-users’ knowledge of bioeffects, safety, and output indices is lacking. Both in Europe [61] and the USA [62], approximately 70 % of clinicians (physicians and sonographers, including nurses who perform ultrasound) show very poor, or no knowledge of bioeffects and safety issues, do not know what TI and MI represent and do not even know that these appear on-screen during clinical ultrasound examinations. This is true in several other countries [6365] as well as among residents/fellows [66] and sonographers, regardless of their seniority [67]. Furthermore, several assumptions were made when formulating the indices, which bring questions on their clinical value [68]. Details can be found in the NCRP report 140 [12]. These indices, however, are the best mean we have, nowadays, to estimate, in real time, changes occurring in acoustic output of the instrument, although various modifications have been offered, in particular in regard to exposure time [6970]. There is, in fact, little information on energy output and exposure in clinical obstetrical ultrasound. Only relatively recently has it been shown that, if one considers TI and MI to be some indication of acoustic output, then the levels are low in the first [7172], second and third trimesters [73], and even Doppler studies [74]—although higher levels of TI can be reached in this modality—as well as 3D/4D examinations [75]. 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 [76].

Ultrasound and the Ovum

Ultrasound has permeated the field of infertility and reproductive endocrinology, from diagnosing uterine anomalies [77], following development of the follicle [78], evaluating tubal patency [79], to its use in embryo transfer [80]. A study from 1982 demonstrated premature ovulation in women who underwent ultrasound examination of the ovaries (B-mode) in the late follicular phase [81]. The authors compared patients in induced ovulation cycles, followed by ultrasound (study group) or only by hormone levels (control group). They investigated timing of follicle rupture after the onset of LH surge or administration of hCG. Rupture never occurred before the 37th hour in control patients (no ultrasound in the follicular phase). However, (premature) ovulation was observed at 26–36 h in about 50 % cases in the study group (ultrasound during the previous 3 days or in the 36 h immediately following the ovulatory stimulus). This study was very concerning but has never been reproduced. Ultrasound-guided oocyte aspiration for in vitro fertilization and embryo transfer was reported in the early 1980s [8283]. It has now become routine [84]. There are only a few, relatively dated, studies aimed at determining the interaction between ultrasound exposure and successful fertilization. Most are, in fact, concerned with success or lack thereof of the procedure in terms of pregnancy rates and not possible bioeffects. Some researchers have reported deleterious effects of ultrasound on the menstrual cycle, particularly decrease in ovulation rates in mice [85] and premature ovulation [81], as well as reduced cumulative pregnancy rates in mice [86] and in humans [87]. Others have demonstrated no effects on the ovulation process or egg quality, including DNA and RNA synthesis [88], or on fertilization rate and embryonic development following in vitro fertilization and embryo transfer [89]. In general, the clinically available data on ultrasound exposure of oocytes during meiosis are confusing. Some researchers reported a deleterious effect on the fertility of patients undergoing artificial insemination with a reduction in the cumulative rate of pregnancy [87]. A study of ultrasound exposure of meiotically active, preovulatory oocytes showed no differences between rats exposed to ultrasound after the LH surge and controls in terms of pregnancy rate, number of corpora lutea, implantations, pups, and mean pup and placental weights at autopsy on day 22 of pregnancy [90]. Others have claimed an increase in the success rate, allowing ultrasound monitoring of follicular growth [91], although, evidently, this is not a direct effect of ultrasound but of improved intervention timing. An attempt to clarify this was described by Mahadevan and colleagues [89]. They wanted to determine how oocytes obtained under ultrasound guidance affected the pregnancy rate. The results obtained with 3.5-MHz probes suggest that exposure of human oocytes to ultrasonic waves during the different phases of meiosis does not significantly influence the developmental potential of the in vitro fertilized embryos. Unfortunately, no researcher describes any of the relevant exposure parameters discussed earlier, except for ultrasound frequency.

Ultrasound in Early Gestation

There are many valid medical indications to perform ultrasound in early gestation [292]. These are described in various parts of this book and include, among others, pregnancy location, accurate gestation dating, confirmation of viability, verification of number of fetuses, and early anatomy survey. All of these examinations are, generally, performed with B-mode, a mode with relatively low acoustic output. However, more recently, screening for genetic abnormalities, such as NT and early assessment of structural abnormalities are described in the literature in early (11–15 weeks) pregnancy [59394]. While most of these are also performed with B-mode, often Doppler is used to detect blood vessels and/or to visualize and analyze cardiac valves [95], exposing the fetus to much higher energy levels (see below]. One needs to keep in mind that, even with B-mode, dwell time is important since prolonged examination can result in higher exposure levels [96]. Interesting, somewhat worrying and unexplained data have been published on an increased incidence of fetal anomalies in fetuses resulting from ART [9798]. Some concerning effects on the chorionic villi in women who had transvaginal ultrasound during the first trimester were reported [99]. There was a time–effect relation with activation of an enzyme pathway responsible for apoptosis through a mitochondrial pathway with exposures of 20 and 30 min but not 0 (control group) or 10 min.

Fetal Susceptibility to External Insults

The growing fetus is very sensitive to external influences. This is especially true in the first 10–12 weeks of gestation [100101]. 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 [102]. Gestational age is thus a vital factor when considering possible bioeffects: milder exposure during the preimplantation period or more severe exposures during embryonic and fetal development can have similar results and can result in embryonic/fetal 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 [14]. Other prominent defects are seen in craniofacial development, such as facial clefts [103], the skeleton [104], the body wall, teeth, and heart [105]. Hyperthermia in utero [due to maternal influenza for instance] was long known to potentially induce structural anomalies in the fetus [106108] but it has been described also as an environmental risk factor for psychological/behavioral disturbances [109] and, more particularly, schizophrenia [107]. It is stressed that these are not ultrasound-induced hyperthermia effects. Yet ultrasound has been shown to induce temperature increase in vivo [11212429110112], albeit not in humans. Subtle effects are possible, such as abnormal neuronal migration with unclear potential results [113]. One specific single specific effect has been described in various publications: a mild increase in the prevalence of non-right handedness among male children exposed to prenatal ultrasound with no other neurological, intellectual, behavioral, or physical anomalies [114116]. Ultrasound has been implicated, in chicks who were insonated in ovo, in learning and memory disturbances [117]. A study failed to demonstrate a relation between ultrasound insonation in utero and decreased intellectual performance [118]. In mice, the etiology of symptoms similar to those seen in autism was attributed to ultrasound [119]. Extrapolation to humans is not automatic, despite the argument, by some, that the increased incidence of this condition in children over the last 20 years or so is secondary to the similar increase in the use of ultrasound in obstetrics [120]. One study reported on approximately 750 children, half with autism spectrum disorders and half without [121]. The conclusion was that ultrasound in any of the three trimesters of pregnancy could not be correlated with an increased risk of ASD. In fact, there is a serious lack of data examining the role of ultrasound in the etiology of autism while rigorously excluding other confounding factors [122]. If one, however, considers together the facts that hyperthermia is potentially harmful to the fetus and that ultrasound 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).

Is Doppler Different and Can It Have Detrimental Effects on the Fetus in the First Trimester?

Ultrasound modalities can result in either scanned or unscanned exposure. Scanned conditions are associated with grey-scale B-mode images (the most commonly used real-time application), and Doppler images of tissue cross sections. Unscanned conditions are used for M-mode and pulsed-Doppler studies of tissue movement (such as cardiac valves) or blood velocity waveforms. This is clinically very important because for unscanned beams the power is limited to the area of the beam cross section, often very narrow (1 mm2) in the focal region. For scanned beams the acoustic power is not limited to a narrow area, but may cover large areas in the lateral direction, hence less risk of high exposure at a specific point. Furthermore, a variety of movements intervene during B-mode imaging, such as fetal body motion, observer’s hand movements, and maternal breathing. During a Doppler examination, however, it is necessary to have the transducer as steady as possible. This is because, in general, blood vessels or heart valves are small in comparison to the general organ or body size being scanned and even small movements will have more undesired effects on the resulting image. As described below, the most commonly used intensity (spatial peak temporal average intensity, ISPTA) associated with Doppler ultrasound is the highest of all the general-use categories, 1180 mW/cm2 for pulsed Doppler, as opposed to 34 mW/cm2 for B-mode, a 35-fold difference. Dwell time (duration of exposure) is also of major importance: Ziskin [123] reported that among 15,973 Doppler ultrasound examinations, the average duration was 27 min (and the longest 4 h!). A study in chicken seemed to clearly implicate Doppler [117]. Chicken eggs were insonated on day 19- of a 21-day incubation period. Exposure was to B-mode for 5 or 10 min or to pulsed Doppler for 1–5 min. 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 not observed 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. Hearing the fetal heart beat is certainly a very satisfying experience for the expecting parents. Often this is accomplished by using pulsed Doppler. This is so engrained in the minds of the public that each time ultrasound is mentioned in a television series or a movie, one can hear the heart beat in the background although the image on-screen is only of a B-mode exam. In fact, using Doppler to “listen” to the fetal heart is not new [124125]. This should be discouraged and replaced by M-mode assessment. If Doppler is used, it is sufficient to “hear” 3–4 heart beats and thus limit the exposure [126127]. One of the major uses of ultrasound is the prenatal detection of fetal abnormalities. The organ most commonly affected by major genetic disorders is the heart, and hence, extensive research is conducted in imaging and functional assessment of the heart. While B-mode is used to assess structure, Doppler (pulsed [spectral] and color) are the ideal techniques to examine heart function. A vast amount of literature has been published on the value of ultrasound examination of the fetal heart, using various techniques, including Doppler analysis of flow across the cardiac valves and Doppler velocimetry of various fetal vessels [128130]. The vast majority of published reports was, until recently, on B-mode examinations around 18–20 weeks. However, several authors have demonstrated the feasibility of examining the heart much sooner in pregnancy, beginning around 10 or 11 weeks [131134]. Doppler analysis has long been a tool to study cardiac function, although mostly in the placenta, umbilical or uterine arteries [135]. Studies have been published of Doppler study of flow through cardiac valves, beginning at 6 weeks [136137]. It should be noted that it is technically extremely difficult to obtain these tracings and, thus, very prolonged dwell times may be necessary. Some have described performing a measurement of the heart diameter, heart rate and inflow and outflow waveforms “after 5 weeks” [138]. No details are available on exposure levels. It should also be remembered that, at these early stages of pregnancy, fetuses measure 1–2 cm in length and are completely included in the beam, therefore generating “total body scanning” in B-mode, which is necessary to position the Doppler gate. Analysis of ductus venosus flow as well as characteristics of flow across the tricuspid valve have been shown to be helpful in screening for chromosomal anomalies in the first trimester of pregnancy, as an adjunct to measurement of the NT. Waveform analysis of the ductus venosus reduces the false-positive rate of the screening test [139140]. For example, in fetuses with increased NT but with normal karyotype, from 11 to 13 6/7 weeks, absent or reversed A-wave (atrial contraction) in the ductus venosus is associated with a threefold increase in the likelihood of a major cardiac defect, whereas normal ductal flow is associated with a 50 % reduction in the risk for such defects [141143]. It is clear that Doppler is an important tool to study fetal health in early (and late) pregnancy [130] but appropriate precautions need to be taken to limit exposure in terms of clear indication, time and acoustic output [144].

Acoustic Output

Based on various sources, it appears that acoustic output (as expressed by various intensities) is much higher in Doppler than in B-mode: for instance, 34 mW/cm2 for the ISPTA in B-mode versus 1080 mW/cm2 for spectral Doppler [35145]. Furthermore, as demonstrated in Table 1.2, the output has increased in all modes over the years [35]. If one compares outputs (as expressed by TI and MI, a clinically easy-to-use but somewhat remote expression of output) between first, second and third trimesters, differences are not major [72] but higher TI values are obtained when switching to Doppler mode [74]. The increase in TI is, generally, small but with some new machines, TI’s of up to 5–6 are displayed in Doppler mode (Fig. 1.3). Research has shown that excellent, diagnostic images can be obtained at low outputs, as defined by the TI values of 0.5 or even 0.1 [146]. This is illustrated in Fig. 1.4. Therefore, the switch-on default should be set up such that a low acoustic output power is initiated for each new patient, when starting an examination. Only if images are not satisfactory from a diagnostic standpoint, should the output be increased. Under pressure from Safety Committees of various societies, several ultrasound manufacturers have implemented this recommendation. Concerns about the fact that outputs are much higher in Doppler applications were expressed in three editorials [9147148]. In one of these, the authors raised the question whether research involving Doppler in the first trimester should even be considered for publication [147]. Based on these considerations, some recommend extreme caution when employing Doppler in the first trimester [149]. Furthermore, acoustic outputs, as published by the various ultrasound instruments manufacturers may not always be adequate [150] and an additional cause for concern is the increase in instruments outputs over the years [151]. Despite this, as detailed above, in recent years there has been a major recrudescence in the usage of Doppler in very early pregnancy. Unfortunately, one of the reason for this is the ignorance of many end-users of potential bioeffects, based on the “nothing has been shown” principle. Therefore, the risk is that this will become a routine standard, secondary to the push to utilize this modality by certain individuals, not necessarily knowledgeable of potential safety issues and that inexperienced end-users, wishing to imitate and adulate these “experts” will attempt to perform these exams for extremely extended period of time at pregnancy stages which are very susceptible to external insults (Christoph Brezinka, pers. comm.). Indeed, as mentioned earlier, a major issue is the lack of knowledge of ultrasound clinical users on output, bioeffects and safety, both in the USA [62] and abroad [616364].

Table 1.2

Changes over the years in I SPTA (in mW/cm2), mean (and range) in various ultrasound modalitiesa

Ultrasound modality

1991

1995

1998

B-mode

17 (0.3–177)

34 (0.3–991)

94 (4.2–600)

Pulsed Doppler

1140 (110–4520)

1659 (173–9080)

1420 (214–7500)

Color Doppler

148 (25–511)

344 (21–2050)

470 (27–2030)

aAdapted from [35]

A328333_1_En_1_Fig3_HTML.jpg

Fig. 1.3

Very high TI (5.7) may be obtained in Doppler mode (not an actual clinical examination). Note that this is a general obstetrics setting

A328333_1_En_1_Fig4_HTML.jpg

Fig. 1.4

Doppler velocimetry in the umbilical artery. (a) TIB is 2.4. (b) The TIB is 0.4 and the image is equally diagnostic

3D/4D Ultrasound

Three-dimensional (3D) as well as four-dimensional (4D) ultrasound are gaining recognition in obstetrics and gynecology. In prenatal diagnosis it adds to the detection of a wide range of anomalies, such as those involving the face, skeleton and extremities. The usefulness in early gestation is less obvious [152]. Characteristics are short acquisition time and post processing analysis, hence decreased exposure. As determined by TI and MI, acoustic output during 3D/4D exams does not seem excessive [75]. Figure 1.5 demonstrates low TI and MI during a 3D acquisition. The resulting reconstructed image is, obviously, a post-processing process. Sheiner et al. have shown that mean TIs during the 3D (0.27 ± 0.1) and 4D examinations (0.24 ± 0.1) were comparable to the TI during the B-mode scanning (0.28 ± 0.1; P = 0.343) [75]. The 3D volume acquisitions added 2.0 ± 1.8 min of actual ultrasound scanning time (i.e., including neither data processing and manipulation, nor 3D displays, which are all post-processing steps). The 4D ultrasound added 2.2 ± 1.2 min to the examination time. Amount of additional scanning time needed to choose an adequate scanning plane and to acquire a diagnostic 3D volume was not noted. Attractive views of the face, for instance, have led to its popularity among pregnant women who ask for non-medically indicated ultrasound (“keepsake ultrasound”). This is often performed in non-medical facilities, not for diagnostic purposes, in order to provide images for the family photo album. The issue was addressed long ago [153] but the practice has been opposed by various authors and professional, scientific organizations [154164], although not by all [165] and with difference of opinions on whether practitioners involved in this activity should be sanctioned [166].

A328333_1_En_1_Fig5_HTML.jpg

Fig. 1.5

Three-D acquisition with three orthogonal planes and reconstructed volume. The output power is determined by the acquisition plane (in general plane A), since the two other planes (BC) and the reconstructed volume are computer-generated. In this acquisition, TIS was 0.5

How to Limit Fetal Exposure and Safety Statements

The answer is simple: perform ultrasound only with a clear indication, keep exposure to a minimum power and time, compatible with an adequate diagnosis (application of the ALARA principle), watch the TI (and, to a lesser degree) the MI on-screen and do not perform examinations with new techniques “simply because you can,” if they have not been scientifically shown to afford diagnostic advantages [96127144167]. In general, begin your exam with a low power output and increase only if necessary [167168]. Some scientists have clearly stated that Doppler should be avoided in the first trimester. Several ultrasound organizations, however, have publishing statements and/or guidelines specific for first-trimester ultrasound, with a particular emphasis on the use of Doppler in early pregnancy. The following statement which summarizes the various guidelines is copied from the AIUM’s website and is available to the public.

AIUM [169]: “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:

1.

2.

3.

4.

5.

6.

It should be noted that paragraphs 1 through 6 are common to AIUM, The European Federation of Ultrasound in Medicine and Biology (EFSUMB), the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) and the World Federation of Ultrasound in Medicine and Biology (WFUMB).

Summary

Ultrasound may, arguably, be the most important technology in the last 50 years in obstetrical clinical practice. Its advantages are numerous and its use has expanded from simply measuring a biparietal diameter to three-dimensional (3D) study of the brain or heart anatomy or “real-time 3D” (aka 4D) evaluation of fetal behavior. Not only is structural analysis possible but functional assessment of cardiac function is achievable with the use of Doppler applications. The fact this can be done is not a blanket permission to perform it with no control or limits, particularly in early pregnancy, a time when the fetus is very susceptible to external insults. No gross harmful bioeffects have been described in humans as a result of using DUS but indications to perform an examination should be clear and the lowest possible acoustic output power should be used, for the shortest possible time, yet compatible with accurate clinical diagnosis [18]. Clinical end-users should be educated in bioeffects and in ways to keep the fetus safe.

Teaching Points

·               Biological effects have been demonstrated with the use of ultrasound in animals but not in humans.

·               Epidemiology data are from before 1992, when acoustic outputs were increased several folds.

·               The early fetal period is a time of increased susceptibility to external factors, such as hyperthermia, a recognized teratogen, with the central nervous system (CNS) being most at risk.

·               Bioeffects of ultrasound may be secondary to two major mechanisms: thermal (indirect, resulting from conversion of acoustic energy into heat) and non-thermal (also known as mechanical, direct effects caused by bubble cavitation and other mechanical phenomena).

·               The Output Display Standard (ODS) is designed to give the end-user an idea of exposure and includes the Thermal and Mechanical indices (TI and MI).

·               To ensure safety of ultrasound in early pregnancy, a clear and valid indication for use should exist.

·               New indications include screening for genetic disorders, ductus venosus and tricuspid Doppler and cardiac function analysis which have the potential for bioeffects, secondary to usage in early gestation, a time of increased susceptibility and/or increased acoustic power.

·               To limit exposure and potential harmful effects, use ultrasound only when indicated, keep the exam as short as possible, at lowest possible output for diagnostic accuracy (ALARA principle) and keep TI and MI below 1.

References

1.

Donald I, Macvicar J, Brown TG. Investigation of abdominal masses by pulsed ultrasound. Lancet. 1958;1(7032):1188–95.PubMed

2.

Abramowicz JS. Benefits and risks of ultrasound in pregnancy. Semin Perinatol. 2013;37(5):295–300.PubMed

3.

Baerwald AR, Walker RA, Pierson RA. Growth rates of ovarian follicles during natural menstrual cycles, oral contraception cycles, and ovarian stimulation cycles. Fertil Steril. 2009;91(2):440–9.PubMed

4.

Younis JS, Jadaon JE, Haddad S, Izhaki I, Ben-Ami M. Prospective evaluation of basal stromal Doppler studies in women with good ovarian reserve and infertility undergoing in vitro fertilization-embryo transfer treatment: patients with polycystic ovary syndrome versus ovulatory patients. Fertil Steril. 2011;95(5):1754–8.PubMed

5.

Timor-Tritsch IE, Fuchs KM, Monteagudo A, D'Alton ME. Performing a fetal anatomy scan at the time of first-trimester screening. Obstet Gynecol. 2009;113(2 Pt 1):402–7.PubMed

6.

Abramowicz JS, Fowlkes JB, Stratmeyer ME, Ziskin MC. Bioeffects and safety of fetal ultrasound exposure: why do we need epidemiology? In: Sheiner E, editor. Textbook of epidemiology in perinatology. New York, NY: Nova Science Publishers, Inc.; 2010.

7.

Abramowicz JS, Fowlkes JB, Skelly AC, Stratmeyer ME, Ziskin MC. Conclusions regarding epidemiology for obstetric ultrasound. J Ultrasound Med. 2008;27(4):637–44.PubMed

8.

FDA. US Food and Drug Administration. 510(k) diagnostic ultrasound guidance update of 1991. Rockville, MD: FDA; 1991.

9.

Duck FA. Is it safe to use diagnostic ultrasound during the first trimester? Ultrasound Obstet Gynecol. 1999;13(6):385–8.PubMed

10.

Duck F. The propagation of ultrasound through tissue. In: ter Haar G, editor. The safe use of ultrasound in medical diagnosis. 3rd ed. London: The British Institute of Radiology; 2012. p. 4–18.

11.

Abramowicz JS, Barnett SB, Duck FA, Edmonds PD, Hynynen KH, Ziskin MC. Fetal thermal effects of diagnostic ultrasound. J Ultrasound Med. 2008;27(4):541–59. quiz 60-3.PubMed

12.

NCRP (National Council on Radiation Protection and Measurements). Exposure criteria for medical diagnostic ultrasound: II. Criteria based on all known mechanisms. Report no. 140. Contract No.: 140. Bethesda, MD: NCRP; 2002.

13.

Duck FA, Starritt HC. A study of the heating capabilities of diagnostic ultrasound beams. Ultrasound Med Biol. 1994;20(5):481–92.PubMed

14.

Edwards MJ, Saunders RD, Shiota K. Effects of heat on embryos and foetuses. Int J Hyperthermia. 2003;19(3):295–324.PubMed

15.

Botto LD, Panichello JD, Browne ML, Krikov S, Feldkamp ML, Lammer E, et al. Congenital heart defects after maternal fever. Am J Obstet Gynecol. 2014;210(4):359e1–11.

16.

Clarren SK, Smith DW, Harvey MA, Ward RH, Myrianthopoulos NC. Hyperthermia – a prospective evaluation of a possible teratogenic agent in man. J Pediatr. 1979;95(1):81–3.PubMed

17.

Edwards MJ. Hyperthermia as a teratogen: a review of experimental studies and their clinical significance. Teratog Carcinog Mutagen. 1986;6(6):563–82.PubMed

18.

AIUM. AIUM as low as reasonably achievable (ALARA) principle 2014. http://www.aium.org/publications/viewStatement.aspx?id=39.

19.

Miller MW, Brayman AA, Abramowicz JS. Obstetric ultrasonography: a biophysical consideration of patient safety – the “rules” have changed. Am J Obstet Gynecol. 1998;179(1):241–54.PubMed

20.

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;30:400–9.

21.

Abraham V, Ziskin MC, Heyner S. Temperature elevation in the rat fetus due to ultrasound exposure. Ultrasound Med Biol. 1989;15(5):443–9.PubMed

22.

Barnett SB. Can diagnostic ultrasound heat tissue and cause biological effects. In: Barnett SB, Kossoff G, editors. Safety of diagnostic ultrasound. Canforth: Parthenon Publishing; 1998. p. 30–1.

23.

Barnett SB. Routine ultrasound scanning in first trimester: what are the risks? Semin Ultrasound CT MR. 2002;23(5):387–91.PubMed

24.

Nyborg WL, Steele RB. Temperature elevation in a beam of ultrasound. Ultrasound Med Biol. 1983;9(6):611–20.PubMed

25.

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(2):216–9.PubMed

26.

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):1–7.PubMed

27.

Dreier JW, Andersen AM, Berg-Beckhoff G. Systematic review and meta-analyses: fever in pregnancy and health impacts in the offspring. Pediatrics. 2014;133(3):e674–88.PubMed

28.

Miller MW, Ziskin MC. Biological consequences of hyperthermia. Ultrasound Med Biol. 1989;15(8):707–22.PubMed

29.

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(5):361–84.PubMed

30.

Jauniaux E. Intervillous circulation in the first trimester: the phantom of the color Doppler obstetric opera. Ultrasound Obstet Gynecol. 1996;8(2):73–6.PubMed

31.

Makikallio K, Tekay A, Jouppila P. Uteroplacental hemodynamics during early human pregnancy: a longitudinal study. Gynecol Obstet Invest. 2004;58(1):49–54.PubMed

32.

Bottomley C, Bourne T. Dating and growth in the first trimester. Best Pract Res Clin Obstet Gynaecol. 2009;23(4):439–52.PubMed

33.

Church CC, Barnett SB. Ultrasound-induced heating and its biological consequences. In: ter Haar G, editor. The safe use of ultrasound in medical diagnosis. 3rd ed. London: The British Institute of Radiology; 2012. p. 46–68.

34.

O'Brien WD, Siddiqi TA. Obstetric sonography: the output display standard and ultrasound bioeffects. In: Fleischer AC, Manning FA, Jeanty P, Romero R, editors. Sonography in obstetrics and gynecology – principles and practice. 6th ed. New York, NY: McGraw-Hill; 2001. p. 29–48.

35.

Shaw A, Martin K. The acoustic output of diagnostic ultrasound scanners. In: ter Haar G, editor. The safe use of ultrasound in medical diagnosis. 3rd ed. London: The British Institute of Radiology; 2012. p. 18–45.

36.

Calvert J, Duck F, Clift S, Azaime H. Surface heating by transvaginal transducers. Ultrasound Obstet Gynecol. 2007;29(4):427–32.PubMed

37.

Barnett SB. WFUMB symposium on safety of ultrasound in medicine. Conclusions and recommendations on thermal and non-thermal mechanisms for biological effects of ultrasound. Ultrasound Med Biol. 1998;24 Suppl 1:8.

38.

Dalecki D. Mechanical bioeffects of ultrasound. Ann Rev Biomed Eng. 2004;6:229–48.

39.

Fowlkes JB, Holland CK. Mechanical bioeffects from diagnostic ultrasound: AIUM consensus statements. American Institute of Ultrasound in Medicine. J Ultrasound Med. 2000;19(2):69–72.PubMed

40.

Carstensen EL. Acoustic cavitation and the safety of diagnostic ultrasound. Ultrasound Med Biol. 1987;13(10):597–606.PubMed

41.

Church CC. Spontaneous homogeneous nucleation, inertial cavitation and the safety of diagnostic ultrasound. Ultrasound Med Biol. 2002;28(10):1349–64.PubMed

42.

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(7):917–25.PubMed

43.

Kimmel E. Cavitation bioeffects. Crit Rev Biomed Eng. 2006;34(2):105–61.PubMed

44.

Dalecki D, Raeman CH, Child SZ, Carstensen EL. Intestinal hemorrhage from exposure to pulsed ultrasound. Ultrasound Med Biol. 1995;21(8):1067–72.PubMed

45.

Wible Jr JH, 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(11-12):1535–46.PubMed

46.

Dalecki D, Child SZ, Raeman CH, Cox C, Carstensen EL. Ultrasonically induced lung hemorrhage in young swine. Ultrasound Med Biol. 1997;23(5):777–81.PubMed

47.

Stratmeyer ME, Greenleaf JF, Dalecki D, Salvesen KA. Fetal ultrasound: mechanical effects. J Ultrasound Med. 2008;27(4):597–605. quiz 6-9.PubMed

48.

Bij de Vaate AJ, Brolmann HA, van der Slikke JW, Emanuel MH, Huirne JA. Gel instillation sonohysterography (GIS) and saline contrast sonohysterography (SCSH): comparison of two diagnostic techniques. Ultrasound Obstet Gynecol. 2010;35(4):486–9.PubMed

49.

Miller MW, Miller DL, Brayman AA. A review of in vitro bioeffects of inertial ultrasonic cavitation from a mechanistic perspective. Ultrasound Med Biol. 1996;22(9):1131–54.PubMed

50.

Wu J, Nyborg WL. Ultrasound, cavitation bubbles and their interaction with cells. Adv Drug Deliv Rev. 2008;60(10):1103–16.PubMed

51.

Dalecki D, Raeman CH, Child SZ, Cox C, Francis CW, Meltzer RS, et al. Hemolysis in vivo from exposure to pulsed ultrasound. Ultrasound Med Biol. 1997;23(2):307–13.PubMed

52.

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(6):867–73.PubMed

53.

Fatemi M, Ogburn Jr PL, Greenleaf JF. Fetal stimulation by pulsed diagnostic ultrasound. J Ultrasound Med. 2001;20(8):883–9.PubMed

54.

Harvey EN, Harvey EB, Loomis RW. Further observations on the effect of high frequency sound waves on living matter. Biol Bull. 1928;55:459–69.

55.

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(6):621–5.PubMed

56.

Dalecki D, Child SZ, Raeman CH, Carstensen EL. Tactile perception of ultrasound. J Acoust Soc Am. 1995;97(5 Pt 1):3165–70.PubMed

57.

Church CC, O'Brien Jr WD. Evaluation of the threshold for lung hemorrhage by diagnostic ultrasound and a proposed new safety index. Ultrasound Med Biol. 2007;33(5):810–8.PubMedCentralPubMed

58.

Abbott JG. Rationale and derivation of MI and TI – a review. Ultrasound Med Biol. 1999;25(3):431–41.PubMed

59.

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: AIUM/NEMA; 1992.

60.

National Council on Radiation Protection & Measurements (NCRP). Exposure criteria for medical diagnostic ultrasound: I. Criteria based on thermal mechanisms. Bethesda, MD: NCRP; 1992.

61.

Marsal K. The output display standard: has it missed its target? Ultrasound Obstet Gynecol. 2005;25(3):211–4.PubMed

62.

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.PubMed

63.

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.PubMed

64.

Meizner I. What do doctors understand regarding ultrasound safety during pregnancy? Harefuah. 2012;151(4):234–6, 52.PubMed

65.

Piscaglia F, Tewelde AG, Righini R, Gianstefani A, Calliada F, Bolondia 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 Med. 2009;12:6–11.

66.

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.PubMed

67.

Bagley J, Thomas K, DiGiacinto D. Safety practices of sonographers and their knowledge of the biologic effects of sonography. J Diagn Med Sonogr. 2011;27:252–61.

68.

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.PubMed

69.

Karagoz I, Kartal MK. A new safety parameter for diagnostic ultrasound thermal bioeffects: safe use time. J Acoust Soc Am. 2009;125(6):3601–10.PubMed

70.

Ziskin MC. The thermal dose index. J Ultrasound Med. 2010;29(10):1475–9.PubMed

71.

Sheiner E, Abramowicz JS. Acoustic output as measured by thermal and mechanical indices during fetal nuchal translucency ultrasound examinations. Fetal Diagn Ther. 2008;25(1):8–10.PubMed

72.

Sheiner E, Shoham-Vardi I, Hussey MJ, Pombar X, Strassner HT, Freeman J, et al. First-trimester sonography: is the fetus exposed to high levels of acoustic energy? J Clin Ultrasound. 2007;35(5):245–9.PubMed

73.

Sheiner E, Freeman J, Abramowicz JS. Acoustic output as measured by mechanical and thermal indices during routine obstetric ultrasound examinations. J Ultrasound Med. 2005;24(12):1665–70.PubMed

74.

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.PubMed

75.

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.PubMed

76.

Bellieni CV, Buonocore G, Bagnoli F, Cordelli DM, Gasparre O, Calonaci F, et al. Is an excessive number of prenatal echographies a risk for fetal growth? Early Hum Dev. 2005;81(8):689–93.PubMed

77.

Rackow BW. Congenital uterine anomalies. In: Stadtmauer LA, Tur-Kaspa I, editors. Ultrasound imaging in reproductive medicine. Heidelberg: Springer; 2014. p. 101–15.

78.

Wiser A, Gonen O, Ghetler Y, Shavit T, Berkovitz A, Shulman A. Monitoring stimulated cycles during in vitro fertilization treatment with ultrasound only – preliminary results. Gynecol Endocrinol. 2012;28(6):429–31.PubMed

79.

Vinayagam D, Ohja K. Evaluation of tubal patency (HyCoSy, Doppler). In: Stadtmauer LA, Tur-Caspa I, editors. Ultrasound imaging in reproductive medicine. Heidelberg: Springer; 2014. p. 179–87.

80.

Buckett WM. A meta-analysis of ultrasound-guided versus clinical touch embryo transfer. Fertil Steril. 2003;80(4):1037–41.PubMed

81.

Testart J, Thebault A, Souderes E, Frydman R. Premature ovulation after ovarian ultrasonography. Br J Obstet Gynaecol. 1982;89(9):694–700.PubMed

82.

Lenz S, Lauritsen JG, Kjellow M. Collection of human oocytes for in vitro fertilisation by ultrasonically guided follicular puncture. Lancet. 1981;1(8230):1163–4.PubMed

83.

Gleicher N, Friberg J, Fullan N, Giglia RV, Mayden K, Kesky T, et al. EGG retrieval for in vitro fertilisation by sonographically controlled vaginal culdocentesis. Lancet. 1983;2(8348):508–9.PubMed

84.

Wongtra-Ngan S, Vutyavanich T, Brown J. Follicular flushing during oocyte retrieval in assisted reproductive techniques. Cochrane Database Syst Rev. 2010;2010(9):CD004634.

85.

Heyner S, Abraham V, Wikarczuk ML, Ziskin MC. Effects of ultrasound on ovulation in the mouse. Gamete Res. 1989;22(3):333–8.PubMed

86.

Bologne R, Demoulin A, Schaaps JP, Hustin J, Lambotte R. Influence of ultrasonics on the fecundity of female rats. C R Seances Soc Biol Fil. 1983;177(3):381–7.PubMed

87.

Demoulin A, Bologne R, Hustin J, Lambotte R. Is ultrasound monitoring of follicular growth harmless? Ann N Y Acad Sci. 1985;442:146–52.PubMed

88.

Heyner S, Abraham V, Wikarczuk ML, Ziskin MC. Effects of ultrasound on DNA and RNA synthesis in preimplantation mouse embryos. Mol Reprod Dev. 1990;25(3):209–14.PubMed

89.

Mahadevan M, Chalder K, Wiseman D, Leader A, Taylor PJ. Evidence for an absence of deleterious effects of ultrasound on human oocytes. J In Vitro Fert Embryo Transf. 1987;4(5):277–80.PubMed

90.

Williams SR, Rothchild I, Wesolowski D, Austin C, Speroff L. Does exposure of preovulatory oocytes to ultrasonic radiation affect reproductive performance? J In Vitro Fert Embryo Transf. 1988;5(1):18–21.PubMed

91.

Kerin JF. Determination of the optimal timing of insemination in women. In: Richardson D, Joyce D, Symonds M, editors. Frozen human semen. London: Royal College of Obstetrics and Gynaecology; 1979. p. 105–32.

92.

AIUM. AIUM practice guideline for the performance of obstetric ultrasound examinations 2007. http://www.aium.org/publications/guidelines.aspx. Accessed 20 Dec 2014.

93.

Ndumbe FM, Navti O, Chilaka VN, Konje JC. Prenatal diagnosis in the first trimester of pregnancy. Obstet Gynecol Surv. 2008;63(5):317–28.PubMed

94.

Nicolaides KH. First-trimester screening for chromosomal abnormalities. Semin Perinatol. 2005;29(4):190–4.PubMed

95.

Carvalho JS. Fetal heart scanning in the first trimester. Prenat Diagn. 2004;24(13):1060–7.PubMed

96.

ter Haar G. Guidelines and recommendations for the safe use of diagnostic ultrasound: the user’s responsibilities. In: ter Haar G, editor. The safe use of ultrasound in medical diagnosis. 3rd ed. London: British Institute of Radiology; 2012. p. 142–57.

97.

Allen VM, Wilson RD, Cheung A, Genetics Committee of the Society of O, Gynaecologists of C, Reproductive Endocrinology Infertility Committee of the Society of O, et al. Pregnancy outcomes after assisted reproductive technology. J Obstet Gynaecol Can. 2006;28(3):220–50.

98.

Budziszewska P, Wloch A, Rozmus-Warcholiniska W, Czuba B, Kuka-Panasiuk D, Ilski A, et al. Heart defects and other anomalies in fetuses conceived by assisted reproduction techniques. Ginekol Polska. 2007;78(11):865–8.

99.

Zhang J, Zhou F, Song Y, Ying W, Zhang Y. Long dwell-time exposure of human chorionic villi to transvaginal ultrasound in the first trimester of pregnancy induces activation of caspase-3 and cytochrome C release. Biol Reprod. 2002;67(2):580–3.PubMed

100.

Brent RL, Beckman DA, Landel CP. Clinical teratology. Curr Opin Pediatr. 1993;5(2):201–11.PubMed

101.

Thorpe PG, Gilboa SM, Hernandez-Diaz S, Lind J, Cragan JD, Briggs G, et al. Medications in the first trimester of pregnancy: most common exposures and critical gaps in understanding fetal risk. Pharmacoepidemiol Drug Saf. 2013;22(9):1013–8.PubMedCentralPubMed

102.

Barzilay E, Koren G. Elements of teratology. In: Abramowicz JS, editor. First-trimester ultrasound – a comprehensive guide. Heidelberg: Springer; 2015.

103.

Shahrukh Hashmi S, Gallaway MS, Waller DK, Langlois PH, Hecht JT, National Birth Defects Prevention S. Maternal fever during early pregnancy and the risk of oral clefts. Birth Defects Res A Clin Mol Teratol. 2010;88(3):186–94.PubMed

104.

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(2):201–3.PubMed

105.

Aoyama N, Yamashina S, Poelmann RE, Gittenberger-De Groot AC, Izumi T, Soma K, et al. Conduction system abnormalities in rat embryos induced by maternal hyperthermia. Anat Rec. 2002;267(3):213–9.PubMed

106.

Acs N, Banhidy F, Puho E, Czeizel AE. Maternal influenza during pregnancy and risk of congenital abnormalities in offspring. Birth Defects Res A Clin Mol Teratol. 2005;73(12):989–96.PubMed

107.

Edwards MJ. Hyperthermia in utero due to maternal influenza is an environmental risk factor for schizophrenia. Congenit Anom. 2007;47(3):84–9.

108.

Saxen I. The association between maternal influenza, drug consumption and oral clefts. Acta Odontol Scand. 1975;33(5):259–67.PubMed

109.

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(11):905–10.PubMed

110.

Atkins TJ, Duck FA. Heating caused by selected pulsed Doppler and physiotherapy ultrasound beams measured using thermal test objects. Eur J Ultrasound. 2003;16(3):243–52.PubMed

111.

Barnett SB. Intracranial temperature elevation from diagnostic ultrasound. Ultrasound Med Biol. 2001;27(7):883–8.PubMed

112.

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(9):1501–10.PubMed

113.

Ang ESBC, Gluncic V, Duque A, Schafer ME, Rakic P. Prenatal exposure to ultrasound waves impacts neuronal migration in mice. Proc N Y Acad Sci. 2006;103:12903–10.

114.

Kieler H, Cnattingius S, Palmgren J, Haglund B, Axelsson O. First trimester ultrasound scans and left-handedness. Epidemiology. 2002;13(3):370.PubMed

115.

Salvesen KA. Ultrasound in pregnancy and non-right handedness: meta-analysis of randomized trials. Ultrasound Obstet Gynecol. 2011;38(3):267–71.PubMed

116.

Salvesen KA, Vatten LJ, Eik-Nes SH, Hugdahl K, Bakketeig LS. Routine ultrasonography in utero and subsequent handedness and neurological development. BMJ. 1993;307(6897):159–64.PubMedCentralPubMed

117.

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.PubMed

118.

Kieler H, Haglund B, Cnattingius S, Palmgren J, Axelsson O. Does prenatal sonography affect intellectual performance? Epidemiology. 2005;16(3):304–10.PubMed

119.

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;7(3):295–304.PubMedCentralPubMed

120.

Rodgers C. Questions about prenatal ultrasound and the alarming increase in autism. Midwifery Today Int Midwife. 2006;80:16–9. 66-7.PubMed

121.

Grether JK, Li SX, Yoshida CK, Croen LA. Antenatal ultrasound and risk of autism spectrum disorders. J Autism Dev Disord. 2010;40(2):238–45.PubMed

122.

Abramowicz JS. Ultrasound and autism: association, link, or coincidence? J Ultrasound Med. 2012;31(8):1261–9.PubMed

123.

Ziskin MC. Intrauterine effects of ultrasound: human epidemiology. Teratology. 1999;59(4):252–60.PubMed

124.

Jouppila P, Piironinen O. Ultrasonic diagnosis of fetal life in early pregnancy. Obstet Gynecol. 1975;46(5):616–20.PubMed

125.

Resch B, Herczeg J, Altmayer P, Sztano P. The efficiency of Doppler-technique in the first trimester of pregnancy. Ann Chir Gynaecol Fenn. 1971;60(2):85–8.PubMed

126.

AIUM. AIUM official statement: measurement of fetal heart rate 2011. http://www.aium.org/publications/statements.aspx. Accessed 20 Dec 2014.

127.

WFUMB/ISUOG. WFUMB/ISUOG statement on the safe use of Doppler ultrasound during 11–14 week scans (or earlier in pregnancy). Ultrasound Med Biol. 2013;39(3):373.

128.

Herberg U, Breuer J, Gembruch U, Willruth A. Imaging in fetal cardiology. Minerva Pediatr. 2014;66(5):453–71.PubMed

129.

Turan S, Turan O, Desai A, Harman C, Baschat A. First-trimester fetal cardiac examination using spatiotemporal image correlation, tomographic ultrasound and color Doppler imaging for the diagnosis of complex congenital heart disease in high-risk patients. Ultrasound Obstet Gynecol. 2014;44:562–7.PubMed

130.

Maulik D. The use of Doppler in early pregnancy. In: Abramowicz JS, editor. First-trimester ultrasound – a comprehensive guide. Heidelberg: Springer; 2015.

131.

Achiron R, Rotstein Z, Lipitz S, Mashiach S, Hegesh J. First-trimester diagnosis of fetal congenital heart disease by transvaginal ultrasonography. Obstet Gynecol. 1994;84(1):69–72.PubMed

132.

Carvalho JS. Screening for heart defects in the first trimester of pregnancy: food for thought. Ultrasound Obstet Gynecol. 2010;36(6):658–60.PubMed

133.

DeVore GR. First-trimester fetal echocardiography: is the future now? Ultrasound Obstet Gynecol. 2002;20(1):6–8.PubMed

134.

Gembruch U, Knopfle G, Chatterjee M, Bald R, Hansmann M. First-trimester diagnosis of fetal congenital heart disease by transvaginal two-dimensional and Doppler echocardiography. Obstet Gynecol. 1990;75(3 Pt 2):496–8.PubMed

135.

Dillon EH, Case CQ, Ramos IM, Holland CK, Taylor KJ. Endovaginal pulsed and color Doppler in first-trimester pregnancy. Ultrasound Med Biol. 1993;19(7):517–25.PubMed

136.

Leiva MC, Tolosa JE, Binotto CN, Weiner S, Huppert L, Denis AL, et al. Fetal cardiac development and hemodynamics in the first trimester. Ultrasound Obstet Gynecol. 1999;14(3):169–74.PubMed

137.

Makikallio K, Jouppila P, Rasanen J. Human fetal cardiac function during the first trimester of pregnancy. Heart (Br Cardiac Soc). 2005;91(3):334–8.

138.

Wloch A, Rozmus-Warcholinska W, Czuba B, Borowski D, Wloch S, Cnota W, et al. Doppler study of the embryonic heart in normal pregnant women. J Matern Fetal Neonatal Med. 2007;20(7):533–9.PubMed

139.

Borrell A, Grande M, Bennasar M, Borobio V, Jimenez JM, Stergiotou I, et al. First-trimester detection of major cardiac defects with the use of ductus venosus blood flow. Ultrasound Obstet Gynecol. 2013;42(1):51–7.PubMed

140.

Matias A, Gomes C, Flack N, Montenegro N, Nicolaides KH. Screening for chromosomal abnormalities at 10–14 weeks: the role of ductus venosus blood flow. Ultrasound Obstet Gynecol. 1998;12(6):380–4.PubMed

141.

Florjanski J, Fuchs T, Zimmer M, Homola W, Pomorski M, Blok D. The role of ductus venosus Doppler flow in the diagnosis of chromosomal abnormalities during the first trimester of pregnancy. Adv Clin Exp Med. 2013;22(3):395–401.PubMed

142.

Maiz N, Valencia C, Kagan KO, Wright D, Nicolaides KH. Ductus venosus Doppler in screening for trisomies 21, 18 and 13 and Turner syndrome at 11–13 weeks of gestation. Ultrasound Obstet Gynecol. 2009;33(5):512–7.PubMed

143.

Papatheodorou SI, Evangelou E, Makrydimas G, Ioannidis JP. First-trimester ductus venosus screening for cardiac defects: a meta-analysis. BJOG. 2011;118(12):1438–45.PubMed

144.

Abramowicz JS. Fetal Doppler: how to keep it safe? Clin Obstet Gynecol. 2010;53(4):842–50.PubMed

145.

Duck FA, Henderson J. Acoustic output of modern instruments: is it increasing? In: Barnett SB, Kossoff G, editors. Safety of diagnostic ultrasound. London: The Parthenon Publishing Group; 1998. p. 15–25.

146.

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;39(4):438–43.PubMed

147.

Campbell S, Platt L. The publishing of papers on first-trimester Doppler. Ultrasound Obstet Gynecol. 1999;14(3):159–60.PubMed

148.

Chervenak FA, McCullough LB. Research on the fetus using Doppler ultrasound in the first trimester: guiding ethical considerations. Ultrasound Obstet Gynecol. 1999;14(3):161.PubMed

149.

ter Haar GR, Abramowicz JS, Akiyama I, Evans DH, Ziskin MC, Marsal K. Do we need to restrict the use of Doppler ultrasound in the first trimester of pregnancy? Ultrasound Med Biol. 2013;39(3):374–80.PubMed

150.

Martin K. The acoustic safety of new ultrasound technologies. Ultrasound. 2010;18:110–8.

151.

Cibull SL, 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;32(11):1921–32.PubMed

152.

Goncalves L. Three-D ultrasound-a role in early pregnancy? In: Abramowicz JS, editor. First-trimester ultrasound – a comprehensive guide. Heidelberg: Springer; 2015.

153.

Furness ME. Fetal ultrasound for entertainment? Med J Aust. 1990;153(7):371.PubMed

154.

Abramowicz JS, Barnett SB. Isuog, Wfumb. The safe use of non-medical ultrasound: a summary of the proceedings of the joint safety symposium of ISUOG and WFUMB. Ultrasound Obstet Gynecol. 2009;33(5):617–20.

155.

ACOG. American College of Obstetricians and Gynecologists (ACOG) Committee Opinion. Number 297, August 2004. Nonmedical use of obstetric ultrasonography. Obstet Gynecol. 2004;104(2):423–4.

156.

AIUM. AIUM official statement: keepsake fetal imaging 2012. http://www.aium.org/publications/statements.aspx. Accessed 16 Dec 2014.

157.

BMUS. BMUS (British Medical Ultrasound Society) guidelines for the safe use of diagnostic ultrasound equipment 2009. http://www.bmus.org/ultras-safety/us-safety03.asp. Accessed 16 Dec 2014.

158.

Chudleigh T. Scanning for pleasure. Ultrasound Obstet Gynecol. 1999;14(6):369–71.PubMed

159.

Rados C. FDA cautions against ultrasound ‘Keepsake’ images 2004. http://www.fda.gov/FDAC/features/2004/104_images.html. Accessed 30 Aug 2007.

160.

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 Obstet Gynecol. 2011;38(5):608.PubMed

161.

Westin S, Bakketeig LS. Unnecessary use of ultrasound in pregnancy should be avoided. Probably safe, but new evidence suggests caution. Scand J Prim Health Care. 2003;21(2):65–7.PubMed

162.

WFUMB. WFUMB recommendations on non-medical use of ultrasound. Ultrasound Med Biol. 2010;36(8):1210.

163.

Greene N, Platt LD. Nonmedical use of ultrasound: greater harm than good? J Ultrasound Med. 2005;24(1):123–5.PubMed

164.

Chervenak FA, McCullough LB. An ethical critique of boutique fetal imaging: a case for the medicalization of fetal imaging. Am J Obstet Gynecol. 2005;192:31–3.PubMed

165.

Doubilet PM. Entertainment ultrasound. J Ultrasound Med. 2005;24(2):251–3.PubMed

166.

Wax JR, Cartin A, Pinette MG, Blackstone J. Nonmedical fetal ultrasound: knowledge and opinions of Maine obstetricians and radiologists. J Ultrasound Med. 2006;25(3):331–5.PubMed

167.

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.PubMed

168.

Abramowicz JS, Lewin PA, Goldberg BB. Ultrasound bioeffects for the perinatologist 2008. http://www.glowm.com/index.html?p=glowm.cml/print&articleid=204#r22. Accessed 12 Apr 2013.

169.

AIUM. AIUM official statement: statement on the safe use of Doppler ultrasound during 11–14 week scans (or earlier in pregnancy) 2011. http://www.aium.org/publications/statements.aspx. Accessed 20 Dec 2014.

170.

Carson PL, Fischella PR, Oughton TV. Ultrasonic power and intensities produced by diagnostic ultrasound equipment. Ultrasound Med Biol. 1978;3(4):341–50.PubMed

© Springer International Publishing Switzerland 2016


Previous
Page
Next
Page