epidemiology of human exposure to ultrasound: a critical review

Ultrasound in Med, & BioL Vol. 14, No. 2, pp. 91-96, 1988 0301-5629/88 $3.00 + .00 Printed in the U.S.A. © 1988 Pergamon Journals Ltd.

OReview

E P I D E M I O L O G Y O F H U M A N E X P O S U R E T O U L T R A S O U N D :

A C R I T I C A L R E V I E W

MARVIN C. ZISKIN Department of Diagnostic Imaging, Temple University Medical School, Philadelphia, PA 19140, USA

and

DIANA B. PETITTI Department of Family and Community Medicine, University of California, San Francisco

School of Medicine, San Francisco, CA 94143, USA

Abstract--Epidemiologic studies and surveys and widespread clinical usage over 25 years have yielded no evidence of any adverse effect from diagnostic ultrasound. Nonetheless, the inability to find convincing proof of an effect, either from epidemiology or from physicians' experience, does not preclude the possibility of it happening. Statistical reasoning shows that even with large population studies, it is difficult to identify a small increase in the rate of a commonly occurring event. Subtle effects, long-term delayed effects, and certain genetic effects, could easily escape detection.

Key Words: Epidemioiogy, Ultrasound, Safety, Human exposure, Biological effects.

EPIDEMIOLOGY

The study of the effects of ultrasonic exposure on human populations is the province of epidemiology. No matter how many laboratory experiments show a lack of effect from diagnostic ultrasound, it will always be necessary to study directly its effect in human populations before any definitive statement regarding risk can be made. The simplest and most rudimentary form of epidemiological study is the clinical survey, of which several have been performed. These surveys dealt with routine clinical examinations of patients in which commercial instruments were used; acoustic output data and exposure durations were not specified.

In 1972 an international survey of clinical users of diagnostic ultrasound revealed no adverse effects attributed to examination by ultrasound (Ziskin, 1972). This report included 68 respondents and over 121,000 patient examinations. A national survey of clinical users was conducted in 1980 by the Environ- mental Health Directorate of Canada (1981). From the replies, it was estimated that 340,000 patients were examined with diagnostic ultrasound in 1977 in Canada for a total of 1.2 million examinations. Only one adverse effect on a patient was reported, but its nature was not identified. Statistical considerations

indicate that these large surveys give strong evidence against ultrasound producing obvious abnormalities which are evident soon after the exposure, and which in the absence of any exposure are rare. However, even such large surveys are not well suited for detecting small changes in the rates of more common oc- currences. While it is reassuring that the surveys found no clear example of an adverse effect, it must be pointed out that it is not known how diligently these clinical users were looking for adverse effects, or what kinds of effects they were looking for. Perhaps the fairest statement to be made is that based on 461,000 patient examinations, 179 clinical users overwhelmingly believed that their experience with ultrasound had been safe.

A number of clinical studies have been performed to determine if diagnostic levels of ultrasound would produce adverse effects in children and adults. For the most part, these studies utilized commercially available diagnostic instruments and looked for var- ious biological endpoints such as changes in electro- encephalogram tracings, pathological alterations of the urologic tract, and morphological changes in brain tissue. All of these studies have been negative. However, it must be noted that the acoustic outputs of the instruments used in these studies were, in general, not known and that the sample sizes of the stud-

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92 Ultrasound in Medicine and Biology Volume 14, Number 2, 1988

ies were very small (the largest was less than 300 patients).

Both the National Council on Radiation Protec- tion and Measurements and The National Institute of Health have recently reviewed the literature on the epidemiology of human exposure to ultrasound, and the reader should consult these excellent reports (NCRP, 1983; NIH, 1984) for the further details.

Most of the concern about adverse effects of ultrasound in humans has centered on the possibility that in utero exposure to ultrasound may harm the fetus. Concern about the possibility of effects of ultrasound on the fetus has been intense for at least three reasons. First, fetal exposure to ultrasound often occurs when a pregnancy is progressing nor- mally. In contrast, ultrasound is used in most other situations only when there is suspicion of illness. At any given level of risk, where the probability of illness is high, the risk-benefit ratio of a test will be more favorable than in situations where the probability of illness is low. Second, a very high proportion of all fetuses are exposed to ultrasound in utero. For this reason, the public health implications of even small risks of ultrasound is great. Third, an adverse effect of ultrasound for the fetus has the potential to affect the exposed individual over his or her entire lifespan.

Concern about the possibility of an adverse effect of in utero ultrasound on the fetus has been heightened by recognition that the documented adverse effects of some fetal exposures were discovered many years after exposure became widespread (e.g. effects of x-ray pelvimetry in increasing the risk of childhood leukemia; effect of DES exposure on the risk of vaginal clear cell adenocarcinoma). The fact that these fetal exposures were widely hailed as safe based on anecdotal experience has made skeptics, cynics, and intellectual conservatives justifiably con- cerned about the adequacy of the information upon which some claims for the safety of diagnostic ultrasound are made.

Most concern about ultrasound and the fetus has centered on the possibility of effects on birthweight, structural fetal anomalies, neurological development of the infant and child, cancer, and hearing.

EFFECTS OF I N U T E R O ULTRASOUND ON BIRTHWEIGHT IN HUMANS

In utero exposure to ultrasound at diagnostic levels has been shown to cause a decrease in birthweight in mice (O'Brien, 1983). This observation has caused concern about similar effects on birthweight in humans.

The most important information about the effect of ultrasound on birthweight in humans comes

from studies by Wladimiroff and Laar (1980) and by Bakketeig et al. (1984), in which subjects were exposed to ultrasound based on random assignment. In both of these studies, there was no difference in the percentage of low birthweight infants between preg- nancies assigned to have ultrasound and those assigned not to have ultrasound. In the study of Bakketeig et aL (1984), the mean birthweight of infants assigned to have ultrasound was also not different from the mean birthweight of infants assigned not to have ultrasound. Scheidt, Stanley, and Bryla (1978), in a retrospective cohort study, also found no association between birthweight and exposure to diagnostic ultrasound done for the purposes of locat- ing the placenta during an amniocentesis.

Two groups of investigators analyzing data from a large-scale retrospective follow-up study done in Denver drew different conclusions about the association of ultrasound exposure with birthweight (Moore et aL, 1982; Stark et al., 1984). Moore, Barrick, and Hamilton (1982) reported a statistically significant association of ultrasound with low birthweight after controlling by multivariate statistical techniques for differences in the rates of pregnancy complications between children who were and who were not exposed to ultrasound. In contrast, Stark et al. (1984) reported that there was no association of ultrasound exposure with birthweight among subjects in the study. The reason why the conclusions of these two groups of investigators might have been different was discussed in the report of the Consensus Develop- ment Task Force on Diagnostic Ultrasound in Preg- nancy (NIH, 1984), and this discussion will not be repeated here. Suffice it to say that the study design made it impossible to draw valid conclusions about the association of ultrasound with birthweight in the face of evidence to indicate that the infants who were exposed to ultrasound were probably at higher risk of being intrauterine growth retarded, independent of their exposure to ultrasound.

ULTRASOUND AND STRUCTURAL FETAL ANOMALIES

In the human fetus, organogenesis is complete by about the 10th week of gestation, which is before the period when exposure to ultrasound is most likely to occur, except when ultrasound is being used as an adjunct to in vitro fertilization. Because fetal ultrasound exposure generally occurs after organogenesis is complete, the fact that ultrasound has not been observed anecdotally to be associated with an increased risk of fetal structural anomalies is not sur- prising.

The absence of an association of ultrasound with

Epidemiology of human exposure to ultrasound • M. C. ZISKIN and D. B. PETITTI 93

increased risk of fetal structural anomalies has been confirmed by Hel lman et al. (1970) in a study designed specifically to examine this possibility. Sup- porting data come from studies of Bernstine (1969); Scheidt, Stanley, and Bryla (1978); Bakketeig et al. (1984); and Stark et al. (1984).

U L T R A S O U N D E X P O S U R E A N D N E U R O L O G I C D E V E L O P M E N T OF T H E

I N F A N T AND C H I L D

Concern abou t the possibi l i ty of an effect o f diagnostic ultrasound on neurological development of the infant and child arises from the knowledge that critical events in the migration of neurons within the developing brain occur during the period when exposure to diagnostic ultrasound is most l ike ly-- the 14th to the 22nd weeks of gestation.

Two epidemiologic studies, by Stark et al. (1984) and by Scheidt, Stanley, and Bryla (1978), have fo- cused in particular on the possibility of an association of ultrasound with a number of indicators of neurologic development in the infant and child. Some details about the design of these two studies is presented in Table 1, which also summarizes the findings of the two studies. In both studies, ultrasound was found to be not associated with a large number of develop- mental outcomes, including IQ. Scheidt, Stanley, and Bryla (1978) found a significantly higher rate of abnormal grasp and tonic neck reflexes among new- borns exposed to ultrasound. The importance of this finding is difficult to interpret, especially given the large number of statistical tests done in the analysis of data from this study. Stark et al. (1984) found that children exposed in utero to ultrasound were significantly more likely than unexposed children to have dyslexia, as measured by a special test created for purposes of the study. The higher risk of dyslexia in children exposed to ultrasound was observed in all three hospitals at which subjects were recruited. The fact that ultrasound-exposed children in this study were more likely to have had low birthweights makes

this finding difficult to interpret. It is, however, impossible to dismiss it. Only further research, prefera- bly with children whose ultrasound exposure is determined by selection at random, will permit concern about a possible association of in utero ultrasound exposure with subtle changes in neurologic function that may lead to learning disorders in childhood to be laid firmly to rest.

U L T R A S O U N D AND CANCER

Concern about the possibility of an increase in the risk of cancer in children exposed in utero to ultrasound almost certainly arises from drawing anal- ogies between ultrasound and high energy radiation. Exposure to diagnostic x-rays causes about a two- to three-fold increase in the risk of childhood leukemia (Stewart et al., 1956).

Two large and carefully designed epidemiologic studies of the possible association of in utero ultrasound exposure and ch i ldhood cancer have been done (Cartwright et al., 1984; Kinnier Wilson and Waterhouse, 1984). Neither study found evidence of any association of in utero exposure to ultrasound with an increase in the risk of childhood cancer.

U L T R A S O U N D A N D H E A R I N G

Concern about the possibility of an effect of ul- t rasound on hearing appears widespread, but the ori- gin of this concern is difficult to trace. Stark et al. (1984) specifically tested hearing in children who were and were not exposed to ultrasound and found no association.

L I M I T A T I O N S OF S T U D I E S

No studies of the effect of in utero ultrasound in humans have quantified the dose of ultrasound exposure or the exact period during gestation that exposure occurred. In general acoustic outputs of the in- s truments used were not known, the reasons for examinat ions were not clearly stated, and the number

Table 1. Summary of the design and findings of studies that have examined the possible effects of in utero ultrasound on neurological development of the infant and child.

Study Design Number of subjects Findings

Scheidt, Stanley and Retrospective 303 ultrasound and Bryla ( 1978) follow-up amniocentesis

679 amniocentesis 931 neither

Stark et al. (1984) Retrospective 425 ultrasound exposed follow-up 381 not exposed

Abnormal grasp and tonic neck reflexes; no difference for 122 other outcomes

Increased risk of dyslexia; no difference for many other neurological outcomes


of examinations and the gestational age at each examination were not usually reported. Most of the studies are of pulsed ultrasound and not of Doppler.

Virtually all human teratogens have effects that are dependent on both dose and gestational age at exposure. Existing data on the effects of ultrasound on the human fetus cannot be interpreted to mean that in utero ultrasound exposure is without effect at all combinations of dose and period of exposure, and for all types of exposure.

STATI STICAL C O N S I D E R A T I O N AND S A M P L E SIZE

Adverse effects, if any at all, are certainly not obvious and statistical methods will be required for their detection. The smaller and less obvious the effect, the more difficult it is to be detected, and therefore the larger the sample size must be in order for a study to prove or disprove its existence. Table 2 shows the min imum number of subjects required in a study in order to conclude that an observed increase in incidence is statistically significant at the 0.05 level.

For example, suppose that a study has been performed to determine whether ultrasound if applied during pregnancy causes congenital abnormalities. The investigators report that 6% of the infants exposed in utero had congenital abnormalities as compared to a 5% natural (unexposed) incidence rate. The one-percentage-point increase could have come about in one of two ways: (1) ultrasound has no effect and the increase occurred by pure chance, or (2) the ultrasound did, in fact, cause an increase in the number of congenital abnormalities. Reference to Table 2 shows that for an observed one-percentage-point in-

Table 2. Minimum sample size required to detect adverse effect of ultrasound.

Observed increase in incidence following

ultrasound (in percent-point

difference)

Naturally occurring incidence of event

5% 10% 20% 50%

10 13 25 69 69 5 52 99 174 273 2 324 613 1,089 1,702 1 1,294 2,451 4,356 6,807 0.5 5,200 9,801 17,400 27,225 0.1 129,400 245,100 435,600 680,700

The values in this table are based on the commonly accepted 5% significance level. The statistical power is 0.5.

Taken from: Ziskin M. C. (1985) Epidemiology and human exposure. In Biological Effects of Ultrasound (Edited by W. L. Nyborg and M. C. Ziskin), p. 111-120. Churchill Livingstone, New York.

crease above 5% to be statistically significant, the minimum sample size would have to be 1,294.

If the hypothesized increase in incidence had been 0.5% instead of 1% (that is, the observed incidence was 5.5% instead of 6%), the sample size would have had to be quadrupled in order to establish the presence of a true effect of this magnitude. In this case, the sample size would have had to be at least 5,20O.

The above considerations were based on a number of assumptions, which if not correct would re- quire even larger sample sizes. For example, it was assumed that the naturally occurring incidence was known. If this is not true, then an equally large con- trol group would also be required.

It is also possible to determine for a given sample size, how large a detected increase in incidence must be in order to be statistically significant. For example, in a study of obstetrical complications following exposure to ultrasound, Bernstein (1969) reported that the prematurity rate was not increased. For compari- son, he had used the U.S. Navy-wide incidence of prematurity, which was 7.9%. For an observed increase to be statistically significant (at the 0.05 level), the observed incidence would have had to exceed 9.5% (a relative increase of over 20%). This points out that even what might appear as a reasonably large study is quite limited in its ability to detect small changes in incidence, if the naturally occurring fre- quency is appreciable in the general population.

In planning a new study, one must also be con- cerned about the probability that the proposed study will actually be able to prove or disprove the existence of a true effect of a given magnitude. This is referred to as the statistical power of the study. In the preced- ing example, even with the large sample sizes men- tioned, a true increase in the congenital abnormality rate would not be found 50% of the time. In order to obtain an 80% probability of detecting a true effect, the sample size would have needed to be more than twice as much as that previously determined.

The purpose of the above discussion is to dem- onstrate (1) the importance of considering the statistical power of a study, and (2) the very large sample sizes required to achieve any reasonable likelihood of detecting a small increase in incidence of an event that occurs frequently in the general population.

THE STATISTICAL LEVEL OF S I G N I F I C A N C E

The use of the 5% significance level for deciding which of two alternative hypotheses is correct is cus- tomary and reasonable. If ultrasound has no effect and experimental ly observed differences are due

Epidemiology of human exposure to ultrasound • M. C. ZISKIN and D. B. PETITTI 95

solely to random chance, then the use of this significance level will permit us to make the fight decision in rejecting the null hypothesis 95% of the time. How- ever, we must not forget that we will be wrong 5% of the time; and in these cases, we will conclude incor- rectly that ultrasound caused the effect. This is one of the reasons why different studies addressing the same question will sometimes produce contradictory results. However, in epidemiologic studies, other fac- tors such as differing patient populations, differing treatments, and differing measurements are much more likely to be the source of contradictory results.

Especial concern has to be given to situations in which a multitude of end points are evaluated in the same study. The probability of finding one or more significant deviations increases with the number of end points measured, unless the statistical analysis is adjusted to compensate for concurrent multiple com- parisons. If this is not done, and enough statistical tests are performed, the investigator is virtually as- sured of declaring one or more differences statistically significant, even when there is in reality no difference between the groups being compared.

T H E VALUE OF NEGATIVE SURVEYS

A number of clinical surveys described in the previous section have reported an absence of any adverse effect due to ultrasound. Although described as negative, these surveys do provide information relative to risk.

Statistical theory permits us to quantify the significance of nonobservance of adverse effects, pro- vided that these effects would be detected if they occur. That is, based on the number of patient examination studies, we can state that the probability of such an effect is less than some amount (with 95% confidence). The exact relationship is given by

p < 1 - ( 0 . 0 5 ) I /N ,

where p is the true probability of the effect under consideration and N is the number of patient examinations studied.

For example, suppose that there have been no cases of a missing fight thumb in 10,000 live births of infants who received ultrasound in utero. In this case,

p _< 1 - (0.05) 1/1°'°°°° = 0.0003.

Thus, we can be 95% confident that the true occurrence of this effect is less than 0.030%. If we had wished to be more conservative and had demanded to be 99% confident, 0.01 would have been substituted for 0.05 in the above equation, and we would have obtained a maximum occurrence rate of 0.046%.

Consider the survey by Ziskin (1972) of 121,000 patient examinat ions in which no adverse effects were reported. One can utilize the above equation to provide an upper limit to the probability of occurrence for any gross effect which practically never occurs in the absence of ultrasound and hence would have been seen and reported had it occurred:

p ~ 1 - ( 0 . 0 5 ) 1 /121 '000 = 0.000025.

Thus, if the unusual event under consideration occurs at all, its rate of occurrence must be very low, specifically less than 25 in one million examinations. Analysis of findings from the survey carried out by the Canadian Envi ronmenta l Heal th Directorate ( 1981) leads to similar conclusions. It is clear that the absence of positive findings in such a survey provides useful information on rare events. However, the un- derlying theory is valid if and only if the effects would have been detected had they occurred. Obviously, effects with a long latency, such as cancer, would not be detected by the person doing the ultrasound examination. Nor would effects occurring frequently under normal conditions be likely to be attributed to the exposure.

The theory also provides insight into the limita- tion imposed on interpretation and meaningfulness of studies with small sample sizes. For example, consider the study by Kohorn et al. (1967), who found no EEG tracing alterations in 20 infants. Applying the above equation, we see that the true incidence of EEG alterations could have been as high as 14% of all infants and still not have been detected. Conse- quently, we do not learn much concerning the true incidence of the effect from this small a study.

C O N C L U S I O N

There have been relatively few studies of the effects of in utero ultrasound exposure on the human fetus. Almost all fetuses may soon be exposed to ultrasound, if this is not already the case. For this reason, the effect of even a small risk of ultrasound for the fetus will have profound implications for public health. Historically, some fetal exposures with important risks were deemed safe on the basis of the anecdotal observations. In this context, it is important that concerns about the possibility of adverse effects of in utero ultrasound exposure on the fetus be taken seriously.

As is true with the administration of any drug or agent, the safety of diagnostic ultrasound is of para- mount importance to the physician. In the physician's experience, even when all laboratory tests have been free of adverse effects, unexpected untoward re- actions will frequently be seen when any given agent


is administered to a large number of patients. It is, therefore, most reassuring that epidemiological studies and surveys of clinical experience have yielded no firm evidence of any adverse effects from diagnostic ultrasound, in spite of large clinical usage.

Nontheless, the inability to find convincing proof of an effect, either from epidemiology or from the physician's experience, does not preclude the possibility of it happening. Statistical reasoning shows that even with large population studies, it is diflScult to identify a small increase in rate of a commonly occurring event, even if each event is easily seen. Also subtle effects (such as minor chemical changes and minor behavioral changes), long-term delayed effects, and certain genetic effects could easily escape detection.

Randomized clinical trials evaluating the effec- tiveness of routine ultrasound are on-going in several countries. A long-term follow-up of subjects in one or more of these studies should be undertaken in order to address remaining concerns about the possibility of risks of ultrasound for the fetus. Such follow-up studies should examine the possibility that in utero ultrasound has an effect on learning disorders. Every attempt should be made to quantify the dose of ultrasound exposure.

Acknowledgement--Supported in part by N.I.H. Grants 1 RO1 HD22460 and 1 ROI HD21676.

Some of the material in this manuscript was originally pre- pared for NCRP Report No. 74 (3) while Dr. Ziskin was a member of NCRP Scientific Committee 66. Permission by the National Council on Radiation Protection and Measurements to use this material is hereby acknowledged. The above committee was chaired by Wesley L. Nyborg, Ph.D., whose invaluable guidance and encouragement was greatly appreciated.

REFERENCES

Bakketeig L. S., Eik-Nes S. H., Jacobsen G., Ulstein M. K., Brodt- korb C. J., Balstad P., Eriksen B. C. and Jorgensen N. P. (1984) A randomized controlled trial of ultrasonographic screening in pregnancy. Lancet 2, 207-210.

Bernstine R. L. (1969) Safety studies with ultrasonic Doppler tech- nique: A clinical follow-up of patients and tissue culture study. Obstet. Gynecol. 34, 707-709.

Cartwright R. A., McKinney P. A., Hopton P. A. et aL (1984) Ultrasound examination in pregnancy and childhood cancer. Lancet 2, 999-1000.

Environmental Health Directorate ( 1981 ) Safety Code 23 Guide- lines for the Safe Use of Ultrasound Part I. Medical and Para- medical Applications, Report 8-EHD-59. Environmental Health Directorate, Health Protection Branch, Ottawa, Can- ada.

Hellman L. M., Duffus G. M., Donald I. and Sunden B. (1970) Safety of diagnostic ul t rasound in obstetrics. Lancet 1, 1133-1135.

Kinnier Wilson L. M. and Waterhouse J. A. (1984) Obstetric ultrasound and childhood malignancies. Lancet 2, 997-999.

Kohorn E. T., Pritchard J. W. and Hobbins J. C. (1967) The safety of clinical ultrasonic examination. Obstet. Gynecol. 29, 272.

Moore R. M., Barrick M. K. and Hamilton P. M. (1982) Ultra- sound exposure during gestation and birthweight. Paper presented at the meeting of the Society for Epidemiologic Re- search.

National Council on Radiation Protection and Measurements (NCRP) (1983) Biological Effects of Ultrasound: Mechanisms and Clinical Applications, NCRP Report NO. 74 NCRP Publi- cations, Bethesda, MD.

National Institute of Health (1984) Diagnostic Ultrasound Imaging in Pregnancy. Report of a Consensus Development Conference. Feb 6-8, 1984. DHHS, NIH Publication No. 84-667.

O'Brien W. C., Jr. (1983) Dose-dependent effect of ultrasound on fetal weight in mice. J. Ultrasound Med 2, 1-8.

Scheidt P. D., Stanley F. and Bryla D. A. (1978) One-year follow- up of infants exposed to ultrasound in utero. Am. J. Obstet. Gynecol. 121,742-748.

Stark C. R., Orleans M., Haverkamp A. D. and Murphy J. (1984) Short- and long-term risks after exposure to diagnostic ultrasound in utero. Obstet. Gynecol. 63, 194-200.

Stewart A., Webb J., Giles D. and Hewitt D. (1956) Malignant disease in childhood and diagnostic irradiation in utero. Lancet 2, 447-448.

WladimiroffJ. W. and Laar J. (1980) Ultrasound Measurement of fetal body size: a randomized controlled trial. Acta Obstet. Gynecol. Scand. 59, 177-179.

Ziskin M. C. (1972) Survey of patient exposure to diagnostic ultrasound. In Interaction of Ultrasound and Biological Tissues (Edited by J. M. Reid and M. R. Sikov), p. 203. Department of Health, Education and Welfare Publication (FDA) 78-8008. Government Printing Offace, Washington, DC.

Ziskin M.C. (1985) Epidemiology and human exposure. In Biologi- cal Effects of Ultrasound (Edited by W. L. Nyborg and M. C. Ziskin), pp. 111-120. Churchill Livingstone, New York.

epidemiology of human exposure to ultrasound: a critical review

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