Ultrasound Affects Development of Murine Brains

NEW HAVEN, Conn., Aug. 8 -- Prolonged exposure to ultrasound in the womb causes brain abnormalities in fetal mice, according to researchers here.

The finding sounds a cautionary note about the frivolous use of ultrasound for such things as keepsake sonograms, even though the study is not directly applicable to humans, reported Pasko Rakic, M.D., of Yale, and colleagues, in the online issue of the Proceedings of the National Academy of Sciences.

"Our study in mice does not mean that use of ultrasound on human fetuses for appropriate diagnostic and medical purposes should be abandoned," Dr. Rakic said. "Instead, our study warns against its non-medical use."

The FDA and the American Institute of Ultrasound Medicine have formally opposed such uses, warning that the effects of repeated ultrasound exposures on human fetuses are not known.

The development of the cerebral cortex both in mice and in humans requires neurons to migrate from their place of origin to their final position, Dr. Rakic and colleagues noted, and a range of environmental influences -- including alcohol -- can disrupt that migration, with sometimes devastating effects.

The researchers exposed fetal mice to ultrasound for various lengths of time -- up to 420 minutes -- over three days starting at the 16^th day of gestation, when most of the neuronal migrations take place. The pregnant mice were injected with a thymine analog that allowed researchers to track newly developed neurons in the fetuses.

Compared with controls, mice exposed to ultrasound had no differences in brain size or neocortical cytoarchitecture, the researchers said, and there was no evidence of tissue injury. On the other hand, Dr. Rakic and colleagues said there was clear evidence that a proportion of neurons destined for the cerebral cortex had failed to migrate to the appropriate position and were stuck in the lower layers of the brain.

For example, they said, doubling exposure time from 15 to 30 minutes increased the proportion of misplaced cells in the lower layers from 5% to 9%. Doubling the exposure time again -- to 60 minutes -- increased the proportion of misplaced cells to 11%, which was a statistically significant difference compared with control mice, at P<0.0001.

"The magnitude of dispersion of labeled neurons was highly variable but increased with duration of exposure to ultrasound waves," Dr. Rakic said, although there was no consistent dose-response curve: mice exposed to 210 minutes of ultrasound had fewer misplaced neurons than those exposed to 60 minutes.

The effect was relatively small, Dr. Rakic said, and even some of the control mice showed misplaced neurons in the lower layers of their brains. Moreover, the researchers said they have no evidence of any behavioral effects caused by the ultrasound exposure.

Nonetheless, he concluded, the finding suggests "the desirability of further work in this area." Dr. Rakic said he is planning a similar study on non-human primates, which may shed more light on the possible effects on humans.

One reason for not being overly worried about the finding is that the mouse brain is both much smaller than a human brain and develops over a much shorter time, according to Verne Caviness, M.D., D.Phil., of Boston's Massachusetts General Hospital and Ellen Grant, M.D., of Harvard Medical School.

Writing an accompanying commentary, they concluded that the study is not directly applicable to the medical use of ultrasound in human pregnancies, since, proportionately, a human fetus will get a much lower exposure to the brain than did the mice in the Yale study.

"The weight of the fetal mouse brain at day 16 is at most a few milligrams, whereas that of the human fetus in the sixth month is of the order of 100 g, a difference of orders of magnitude," they pointed out. "This extreme difference in brain size results in a significant difference in the volume of brain exposed to an ultrasound beam."

"Moreover, for these experiments, the probe was held stationary for up to 35 minutes, meaning that essentially the entire fetal mouse brain would have been continually exposed to the ultrasound for 35 minutes. The continuous exposure of the entire brain in the experimental condition is in sharp contrast to the duration and volume of the human fetal brain exposed by ultrasound which will typically not linger on a given tissue volume for greater than one minute."

They added, "We view as highly unlikely the possibility that the present findings speak directly to risks of fetal ultrasound as currently practiced in competent and responsible centers."

Nevertheless, they argued, the study is a "sober reminder" that ultrasound exposure -- as with all medical imaging -- should be as low as possible and that unregulated uses, such as videos, should be avoided.