Ultrasound-induced Fetal Bioeffects

When diagnostic ultrasound started being used more routinely for fetal imaging in the 1970’s, it motivated an interest in the question of whether diagnostic ultrasound might induce biological effects in the fetus. As a result a great number of studies, primarily in animal models, have been performed over the last 30+ years to investigate the possible effects of in utero ultrasound exposure. These studies demonstrated that ultrasound could induce biological effects via both thermal and mechanical processes. However, most experts have concluded that the threshold for adverse effects was above the exposure conditions presented by diagnostic ultrasound devices. Epidemiological studies of fetal exposure to diagnostic ultrasound have renewed a scientific interest in potential effects induced by exposure to diagnostic ultrasound, particularly since the subjects studied were exposed to acoustic output levels several times lower than current diagnostic devices are capable of producing. The experimental and epidemiological evidence for potential effects of fetal exposure to diagnostic ultrasound are discussed. Introduction The potential effects of ultrasound on pregnant animals were extensively investigated during the 1970’s and 1980’s due to the increased use of obstetrical ultrasound and the recognized susceptibility of the embryo or fetus undergoing active development to chemical and physical insults. These investigational studies used many different ultrasound outputs and exposure conditions which contributed to contradictory results and complicated extrapolation of the animal data to the potential human effects [1]. Experimental Studies The mechanisms of action by which ultrasound interacts with tissues and induces biological effects include both thermal and mechanical processes [2-7]. Many of the early studies used average ultrasound intensities that probably resulted in significant fetal heating. Because hyperthermia was a recognized cause of developmental defects, we designed our studies to focus on developmental effects induced by mechanical processes. Hyperthermia was controlled in our early experiments by reducing the body temperature of pregnant ICR mice by anesthesia and performing the exposures in a 30o C water bath. Body weight and survival were used as endpoints in a large screening study (> 13,000 mice and > 1,100 pregnancies) because they were easily obtainable and indicative of a variety of dysfunctions. Animals were exposed to spatial average temporal average intensity levels of 0 mW/cm (sham), 75 mW/cm and 750 mW/cm, 1 MHz continuous wave ultrasound, for 2 minutes. Animals were exposed on day 4, 10 or 14 post coitus (pc). For the first six experiments, subjects were exposed at each stage of gestation and euthanized on either day 18 pc or day 200 pc. A seventh experiment was conducted in which animals were exposed on day 10 pc and euthanized on day 21 pc (early postpartum period). In utero survival was not affected by these exposure conditions. A few statistical differences were observed in body weight, however the magnitude of the changes was small and no discernable pattern was observed. We did observe an increase in early deaths (days 21-35 postpartum) in the 75 mW/cm exposure groups, but not in the 750 mW/cm exposure groups exposed in early or midgestation. This finding did prompt us to investigate whether more subtle early effects might be induced by ultrasound exposure during pregnancy [1]. A teratology study was conducted to evaluate the effects of exposure of pregnant mice on gestational day (gd) 8, a highly susceptible developmental stage. Animals were exposed to 0 mW/cm, 50 mW/cm , 500 mW/cm and 1000 mW/cm, 1 MHz continuous wave ultrasound, for 2 minutes in a 30o C water bath. Animals were euthanized on gd 17 and the fetuses were weighed and examined for external, visceral and skeletal defects. Slight, but statistically nonsignificant, increases in the general incidence of malformations were observed [8]. To confirm that the results of this study were indeed nonsignificant and to increase the possibility of inducing effects by a non-thermal mechanism of action, a study was conducted using 1 MHz pulsed ultrasound with a 6.5 μsec pulse duration and a 90 W/cm spatia l peak, pulse average intensity at the surface of the abdomen. Animals were exposed to 0 mW/cm, 50 mW/cm , 500 mW/cm and 1000 mW/cm spatial average, temporal average intensities by varying the pulse repetition frequency. The corresponding spatial peak, temporal average intensities were 0 W/cm, 0.12 W/cm, 1.2 W/cm and 2.4 W/cm. The number of animals in each exposure group was doubled from 30 to approximately 60 and the exposure time was increased to 20 minutes. Animals were exposed in a 30o C water bath on gd 8 and were euthanized on gd 17. The fetuses were weighed and examined for WCU 2003, Paris, september 7-10, 2003