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Safety of Ultrasound
Abstract & Commentary
By John C. Hobbins, MD, Professor of Obstetrics and Gynecology, University of Colorado School of Medicine, Aurora, Colorado, is Associate Editor for OB/GYN Clinical Alert.
Dr. Hobbins reports no financial relationships relevant to this field of study.
Synopsis: Two recent studies show that pulsed Doppler delivered at diagnostic levels can adversely affect liver cells in a fetal animal model, but standard 2-D ultrasound exposure in utero did not seem to have a significant effect on handedness in children — as suggested by other studies.
Sources: Pellicer P, et al. Ultrasound bioeffects in rats: Quantification of cellular damage in the fetal liver after pulsed Doppler imaging. Ultrasound Obstet Gynecol 2011;37:643-648. Heikkila K, et al. Handedness in the Helsinki ultrasound trial. Ultrasound Obstet Gynecol 2011;37:638-642.
Two recent studies have re-energized discussion regarding the safety of ultrasound — a subject that pops up periodically and then disappears until a new study surfaces. These new studies — one with provocative findings and the other with reassuring results — were published back-to-back in the June issue of Ultrasound in Obstetrics and Gynecology.1,2
Pellicer et al used a pregnant rat model to test whether pulsed Doppler ultrasound examination of the fetal ductus venosus will have a deleterious effect on fetal liver cells.1 Rat fetuses at 18 days gestation (analogous in size to first trimester human fetuses) were exposed to pulsed Doppler ultrasound at diagnostic levels (temperature index [TI] and mechanical index [MI] < 1.0 — more on this later) for varying lengths of time (600, 300, 60, 20, 15, 10, and 3 seconds). The animals were sacrificed at different intervals after exposure, and liver cell damage/death was assessed by the degree of apoptosis in the tissue.
They found that exposure to pulsed Doppler for 20 seconds or more resulted in significant fetal liver cell damage, and that there was a linear relationship between the apoptotic index and the exposure time. Interestingly, after 12 hours post-exposure there appeared to be a full recovery of the liver cells.
The second study (the famous Helsinki Study) involved patients enrolled in a randomized clinical trial in Finland between 1985 and 1987.2 The thrust of the initial trial was to determine the efficacy of screening all patients with ultrasound compared with using ultrasound only if there was a clinical indication (the analogous study in the USA was the RADIUS trial).3 Since data from a Norwegian trial4 with similar design suggested a small increase in left-handedness in boys exposed to ultrasound, the Finnish investigators decided to explore this interesting possibility in exposed children vs those completely unexposed in the Helsinki trial.
They sent questionnaires to 7773 mothers regarding the "handedness" of their, now, teenage children. Since many individuals have varying degrees of ambidexterity, the authors boiled their results down into only two categories: (completely) right-handed and non-right-handed (NRH).
The authors found that boys were 1.26 times more likely to be NRH than girls. However, there were no statistically significant differences between exposed and non-exposed children (odds ratio = 1.16; 95% confidence interval 0.98-1.37). When analyzed separately, neither boys nor girls had significant differences in NRH after ultrasound exposure.
To paraphrase the American Institute of Ultrasound in Medicine (AIUM) safety statement, which has been updated periodically over the last 20 years, "there is no independently confirmed evidence of harm from ultrasound when used at diagnostic dosage." However, as the authors of an excellent accompanying editorial in the same issue say, "an absence of evidence of harm is not equal to the absence of harm."5 Because of difficulties in extrapolating the findings of the above Doppler study in the rat to the human fetus, the findings in this animal study should not necessarily trigger alarm, but they should make us take stock of how we examine patients with ultrasound, especially in the first trimester.
Scores of studies have been conducted over the years in water baths, in animal models, and in humans that have shown no evidence of bioeffect when ultrasound is used at diagnostic dosage. Until now, there has been only one other credible animal study6 showing a possible effect from ultrasound exposure (on brain cell migration in rat fetuses). However, the experimental setting in that study certainly was not analogous to an exam in a human fetus. Regarding human investigation, other than an Australian study7 showing newborns to be on average 26 g lighter (with later catch-up) when exposed to repetitive Doppler investigations, the only unusual finding that has emerged in humans is a slightly increased chance of boys being left-handed.8 Although this finding has not been matched by data in the above study,2 a very recent meta-analysis9 that included the Finnish data showed a slight, but statistically significant, tendency for exposed boys to be NRH. Who knows whether this small difference is, in any way, meaningful? Some might point out that NRH has been linked with other brain migrational disorders, while others will counter that the difference between groups is so small that one has to accumulate huge patient numbers to find it, and some of our most creative individuals in history have been left handed.
Prior to 1992, the FDA rode herd over the intensity levels emanating from ultrasound machines. This caused clinicians to complain that, on occasion, one needed higher intensities than were previously allowed. So, in a rare capitulation (or, perhaps, in exasperation), the FDA decided to leave output levels to the discretion of the user. In order for clinicians to adjust the level to fit the clinical situation, the "output display standard" (ODS) was born.
There are two known mechanisms by which bioeffects can be produced by ultrasound at high intensities: through cavitation created by pulses of very high strength (like those used to desiccate renal stones) or through a mechanism involving a rise in temperature. Pulsed Doppler is particularly capable of increasing tissue temperatures because the pulses need to be longer in length in order to show a change in frequency. This results in higher average intensities. The peak pulse intensities are monitored by an ODS feature called the mechanical index (MI). The calculation to assess temperature rise is based on average intensities over time and is displayed as a temperature index (TI). Theoretically, a TI of 1.0 would mean that the ultrasound energy being used during an exam has the ability to raise the temperature of tissue at the target site by 1°C.
It has been mandated that both MI and TI be displayed simultaneously on the screen of every machine manufactured after 1992. Probably the most important index is the TI in bone (TIb) because it is affected most by Doppler intensities.
In any case, the modulation of power, with a default set only at very high intensities, has been left to us — the users — and the admonition by the AIUM is that we adjust the power levels to fit the clinical situation by using levels that are "as low as is readily achievable" (the ALARA principle). Simply put, TIs should not exceed 1.0 and MIs should not be above 1.4 in all but a few unusual circumstances where more penetration is needed (such as obesity).
Unfortunately, most users have a limited knowledge of these indices, and those who are informed tend to be complacent about monitoring intensities. For example, a U.S. survey of "end users" (60% physicians and 40% sonographers) showed that although 32% knew the term TI, only 18% knew what it represented.10 Only 4% knew what the MI was and 80% did not know where to find either displayed index on their machines. Results from European surveys5,11 were similar.
The above animal study1 should be a catalyst for an effort to keep ultrasound exposure times, especially pulsed Doppler, as short as possible. Also, this study might make us re-tool our protocols for first trimester screening for aneuploidy. Doppler examination of the ductus venosus and tricuspid valves do improve the sensitivity of the screening process. But if used only in those who are at highest risk (after standard NT, nasal bone, and biochemistry have been accomplished), the detection rate for trisomy 21 with this selective approach is essentially the same (94-96%) as if all patients had a Doppler examination as part of their first-line screening protocol.12 This would save 85% from having unnecessary pulsed Doppler exposure.