Are Prenatal Ultrasounds Safe for the Developing Brain?

RESEARCH NEWS Are Prenatal Ultrasounds Safe for the Developing Brain?

A review of: Ang ES Jr, Gluncic V, Duque A, Schafer ME, Rakic P 2006 Prenatal exposure to ultrasound waves impacts neuronal migration in mice. Proc Natl Acad SciUSA103:12903–12910

onitoring the fetus throughout ultrasound waves for a total duration of PIERRE GRESSENS M pregnancy has become a major 30 min or more, they observed a sig- task of modern obstetrical care and PETRA S. HUPPI¨ nificant and dose-dependent increase ultrasonography, first applied 30 y ago, in dispersion of neurons (from 9% dis- has revolutionized the possibility of http://www.wombwithaview.com/” persion difference in the group ex- following fetal well-being and of In this success story of fetal ultra- posed to 30 min to 19% in the group screening fetal organ abnormalities sonography, the scientific community exposed to 420 min of ultrasound with congenital malformations (e.g., is alerted by an interesting study con- waves), meaning that more neurons anencephaly, holoprosencephaly, spina ducted by universally-known neurosci- failed to migrate in the superficial neo- bifida, neck and chest malformations entist Pasko Rakic and his team show- cortical layers and remained blocked in such as major congenital heart disease, ing that exposure to ultrasonography the deep cortical layers or even in the abdominal malformations such as mega- during neuronal migration leads to mi- underlying white matter. The magni- bladder or polycystic kidneys, limb de- grational arrest in the young rodent tude of dispersion of labelled neurons fects tumors or structural indications of brain (1). was variable, but increased systemati- chromosomal abnormalities) which help The authors exposed pregnant mice cally with duration of exposure to ul- in counselling parents. The develop- to ultrasound waves produced by an trasound waves. ment of endovaginal probes allowed ultrasound system routinely used in Of note, no pups survived when ex- visualization of early pregnancy as human medical clinics. The exposure posed to 600 min of ultrasound waves early as 10–14 weeks. More recently, started on embryonic day 16 and lasted and several exposed to 420 min were the development of 3D and 4D ultra- for different periods, ranging from 1 ϫ cannibalized by the mothers at birth. sound has allowed the physician to 5 min to 12 ϫ 35 min (witha4to12h This suggests that prolonged exposure assess facial malformations such as periods separating the different ses- to ultrasound waves is a stressful cleft palate, but has also moved the sions of ultrasound in cases of multiple event. The present study did not permit technique into public interest for the exposures). When animals were killed the total elimination of the potential beautiful “picture in the womb” poten- on postnatal day 10, they did not ob- role of stress on migration dispersion tial of the technique. serve any significant effect on brain in the 420-min exposure group. The rat “At Womb with a View, you can size or on gross brain cytoarchitectony. pups of mothers that were exposed to the spend time with your developing baby. In addition, in the same animals, the ultrasound probe for 420 min, but with- See her move, watch him play. There is authors injected once on embryonic out US waves (US machine switched no time more precious and cherished day 16 bromodeoxyuridine (BrdU), a off), showed a dispersion of 12% of during pregnancy than the time that thymidine analogue incorporated into neurons, which again was significantly the mother-to-be gets to spend looking DNA during S phase of the mitotoic higher than the approx. 6% of dis- at her baby through the miracle of cells. This allows labelling of a cohort persed neurons found in normal con- ultrasound. Using state-of-the-art 3D of neuronal precursors which are di- trol pups. No hormonal measurements ultrasound technology, we offer ex- viding at that time and which will mi- were made in the pregnant mice during pectant mothers the time and opportu- grate predominantly to superficial neo- these procedures, so assessment of nity to view the developing baby. This cortical layers. On postnatal day 10, neuroendocrine modification due to is your time! No frightening measure- neurons which had incorporated BrdU stress hormones cannot be evaluated. It ments. No full-bladder. Just you, your were immunolabelled and their distri- is well known that exposure to corti- baby and your guests. Womb with a bution along the different cortical lay- costeroids during critical periods of View provides expectant mothers the ers and underlying white matter was brain development alter neuronal pro- opportunity to spend quality time with defined, allowing determination of dis- genitor cell survival and proliferation the new baby in a mother-centered persion differences between controls and differentiation (2) and might there- environment. We welcome family and and animals exposed in utero to ultra- fore have contributed to the findings of friends to join our celebration. sound waves. In animals exposed to this study. Interestingly, preterm in-

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fants with intrauterine growth retarda- waves (6). As suggested by the authors itor cells in the adult hippocampus. Neuroscience 137:83–92 tion due to placental insufficiency, often themselves, similar studies in nonhu- 3. Tolsa CB, Zimine S, Warfield SK, Freschi M, followed up with frequent US measure- man primates will be necessary to ad- Sancho RA, Lazeyras F, Hanquinet S, Pfizenmaier M, Hu¨ppi PS 2004 Early alteration of structural and ments between 20 and 30 weeks gesta- dress these key questions. functional brain development in premature infants tion, have been shown to have a 20– In terms of the underlying mecha- born with intrauterine growth restriction. Pediatr Res 56:132–138 30% reduction in overall cortical volume nisms, ultrasound waves might affect 4. Murphy BP, Inder TE, Hu¨ppi PS, Warfield S, at birth and at follow-up in the newborn cell motility through radiation forces Zientara GP, Kikinis R, Jolesz FA, Volpe JJ 2001 Impaired cerebral cortical gray matter growth fol- period (3). Preterm infants treated with and microstreaming of low-viscosity lowing treatment with dexamethasone for neona- corticosteroids showed a 35% reduc- fluids of the extracellular space, lead- tal chronic lung disease. Pediatrics 107:217–221 5. Gressens P, Huppi PS 2006 Normal and abnormal tion of cortical volume compared with ing to disturbances of membrane- brain development. In: Martin RJ, Fanaroff AA, nontreated preterm infants (4). No cor- mediated cell-to-cell attachments and Walsh MC (eds) Neonatal-Perinatal Medicine. Mosby, Philadelphia, pp 883–909. relative studies exist that would link nuclear translocation. 6. Gressens P 2000 Mechanisms and disturbances of these observations in human infants to With regard to exposure to US neuronal migration. Pediatr Res 48:725–730 7. Saari-Kemppainen A, Karjalainen O, Ylostalo P, increased neuronal dispersion as ob- waves, the prenatal US assessments in Heinonen OP 1990 Ultrasound screening and peri- served in the animal model. As men- a normal pregnancy are indeed made natal mortality: controlled trial of systematic one- stage screening in pregnancy. The Helsinki Ultra- tioned above, pups were killed at post- with 5MHz probes and do not last sound Trial. Lancet 336:387–391 natal day 10. Although this is at some much longer than 30 min and are made 8. Bricker L, Neilson JP 2000 Routine ultrasound in late pregnancy (after 24 weeks gestation). Cochrane distance from the end of normal migra- for the first time between 16 and 20 Database Syst Rev CD001451. tion, in animals exposed to ultrasound weeks. This procedure has been shown 9. Bricker L, Neilson JP 2000 Routine Doppler ultrasound in pregnancy. Cochrane Database Syst Rev waves this time point does not allow in a large trial to reduce perinatal mor- CD001450. clear discrimination between a defini- tality, increase malformation detection tive arrest of migration of neurons and rate and decrease healthcare costs (7). Pierre Gressens Both routine and repeated ultrasound Inserm, U676, F-75019 Paris, France an important delay in migration. Faculte´deMe´decine Denis Diderot Translation from small rodents to in later pregnancy (after 24 weeks) and Universite´ Paris 7, F-75019 Paris, France the human situation is always a chal- routine Doppler ultrasound measure- Service de Neurologie Pe´diatrique lenge as, beyond the conservation of ments in unselected and low-risk preg- Hoˆpital Robert Debre´, F-75019 Paris, France basic mechanisms of brain develop- nancies do not confer benefit for Petra S. Hu¨ppi ment, several differences are obvious. mother or baby (8,9). In view of the Department of Pediatrics As far as neuronal migration for the above, one can conclude that fetal ul- Division of Child Development & Growth neocortex is concerned, it occurs in trasound assessment should be per- University of Geneva formed upon clear clinical indication 1211 Geneva, Switzerland mice mostly between embryonic days Department of Neurology 11 and 19 while it extends over several following evidence-based medical de- Harvard Medical School weeks (roughly between 6 to 24 gesta- cisions and the advertised view into the Children’s Hospital tional weeks) in humans (5). In this womb might be more stressful and po- Boston, MA 02115 tentially harmful for the fetus than the context, a 420-min exposure to ultra- Received December 11, 2006; accepted sound waves represents more than 3% desired quality time with your baby. December 13, 2006. of the total period of neuronal migra- Correspondence: Petra S. Huppi, M.D., tion. In humans, 3% of the migration REFERENCES University Children’s Hospital Geneva, Division of Child Development & Growth, period would correspond roughly to Department of Pediatrics, 6 rue Willy Donze´, 90 h. On the other hand, the migration 1. Ang ES Jr, Gluncic V, Duque A, Schafer ME, Rakic P 2006 Prenatal exposure to ultrasound waves im- 1211 Geneva, Switzerland, Te´l.412238243 path in humans is much longer than in pacts neuronal migration in mice. Proc Natl Acad 52, FAX 41 22 382 43 15; email: Sci USA 103:12903–12910 [email protected] mice, which might make migrating 2. Wong EY, Herbert J 2006 Raised circulating corti- neurons more susceptible to ultrasound costerone inhibits neuronal differentiation of progen- DOI: 10.1203/pdr.0b013e318032252f