EFSUMB Newsletter
European Federation of Societies for Ultrasound in Medicine and Biology
Prenatal Ultrasound and Autism: A Prediction Tool, a Risk Factor, Both or Neither? Kimon Chatzistamatiou, Eleni Tsepkentzi, Konstantinos Dinas, Alexandros Sotiriadis Second Department of Obstetrics and Gynecology (KC, KD, AS) and First Department of Pediatrics (ET), Aristotle University of Thessaloniki, Greece E-mail: asotir@gmail.com Ensuring a favorable long-term neurodevelopmental outcome for the offspring has become a major objective in current Maternal – Fetal Medicine. To this end, autism remains a blind spot, and there are many reasons for this, including its clinical heterogeneity (autism spectrum disorders, ASD) and the lack of a single identifiable cause [1 – 3]. Instead, various prenatal, perinatal and postnatal factors, often contradictory to each other, have been reported to statistically increase the risk for autism [4, 5]. Studies on ultrasound and autism are sporadically published, examining their relationship in two contexts, i. e. in the context of fetal ultrasound as a prediction tool for the development of autism in infant life, and in the context of prenatal ultrasound as a risk factor for autism. The rationale for identifying fetuses at risk for ASD is that intervention in early infancy, before the onset of symptoms, may improve their outcomes in a cost-effective way [6, 7]. Therefore, given that atypical postnatal head growth trajectories had been reported in children with ASD [8, 9], fetal growth has been an obvious candidate ultrasound marker for prenatal prediction of autism. A population-based Swedish case-control study comparing fetal growth of more than 4,000 children with ASD to more than 36,000 matched controls identified increased risk for ASD for both children
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with decreased fetal growth (less than two standard deviations below the mean), and children with excessive fetal growth (more than two standard deviations above the mean). Moreover, preterm birth was independently associated with ASD, regardless of fetal growth [10]. Therefore, screening for and prevention of preterm birth at midtrimester scan could theoretically modify one of the risk factors for ASD. Second-trimester fetal growth may not be as an accurate predictor; two small case-control studies reported no difference between ASD cases and controls in fetal growth parameters, i. e. head circumference (HC) at 18 weeks [11] and second trimester biparietal diameter (BPD), abdominal circumference (AC) and femoral length (FL) [12]. Notably, the latter study reported a significant AC decrease in the subgroup of patients with multiplex ASD, i. e. ASD with schizophrenic symptoms [12]. There are several minor physical findings in children with ASD. Some of these (e. g. increased volume of the cerebellum, increased volume of the cerebral ventricles, high steeped or narrow palate and decreased second to fourth digit length ratio) may be assessed prenatally by ultrasound imaging, defining a fetus as potentially at increased risk for autism [13]. However, these findings are not consistent and represent mere associations, as does fetal gender, in that male fetuses could be four to five times more likely to have ASD in childhood than female ones. Quite recently, a registry-based Danish study (unselected cohort of more than 220,000 euploid foetuses; follow-up to the age of 4.4 years) reported that nuchal translucency above the 99th percentile was associated to 2.48 times increased
odds for the development of ASD. The association was stronger (OR2.60) when children with structural malformations were excluded. Still, the absolute risk was very low overall (< 1 %) [14]. However, as strong as a statistical association may be for certain findings, there are three debilitating problems with ultrasound-based markers: (i) they have low specificity, in that they are commonly found in foetuses with normal development, (ii) they do not have an apparent etiological link with autism and (iii) there is no confirmatory test for foetuses identified as at high risk. Regarding the potential role of prenatal ultrasound itself as a causative factor for autism, a statistical concern has arisen by the observation that ASD prevalence increases in parallel with the increase of global antenatal ultrasound use [15]. This issue was extensively discussed in a 2012 review [16]. The first axis for this discussion focused on the fact that ultrasound as a form of energy can have certain effects on live tissue [17]. For example, there are animal data indicating that prolonged ultrasound exposure can affect neuron migration during the development of the central nervous system [18]. No such effects have been demonstrated in humans, and the only effect of antenatal ultrasound possibly associated to a CNS-related phenomenon would be the weak association of nonright-handedness in boys, as it has been reported by the ISUOG-WHO fetal growth study group [19]. However, just being male would increase the risk for ASD by four to five times. The author of the review concludes that there is no evidence of a causal relationship between antenatal ultrasound and autism [16]. A larger cohort
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study in Sweden also failed to connect ASD to prenatal ultrasound examination at 12 or 18 weeks of gestation. The authors noted that, at the time of their study (1999 – 2003), prenatal ultrasound exposure used to be less frequent and utilized lower intensities than in later time, underlining the need for more research on higher prenatal ultrasound exposure [20]. This question was addressed by Stoch et al., who studied pregnancies with intensive prenatal ultrasound exposure (five examinations throughout pregnancy) compared to regular exposure (one single examination at 18 weeks of gestation and further scans as medically indicated). During their 20-yearfollow up, no significant link was found between the timing and frequency of ultrasound examination and ASD [21]. So far, the only effect prenatal ultrasound exposure seems to have on human fetuses is a weak link to non-right-handedness. The biological effects shown on mice were not documented in studies on human fetuses and this might have happened because (a) the dosage and duration of in utero exposure was larger in animals compared to humans, (b) human tissues may be more resistant to ultrasound than those of mice, (c) the duration of intrauterine exposure was longer in animals compared to the shorter exposure throughout a 40 week gestation in humans and (d) it is not possible to have a direct comparison of ASD between humans and animals, as we can only discuss the possibility of autistic-like behaviour in the latter [22]. Based on current data, there is no evidence of association between prenatal exposure to ultrasound and ASD. Apart from finding a causative pathway, a potential link between prenatal ultrasound and ASD would require adjusting for technical parameters (e. g. frequency, time of exposure, probes used, thickness of abdominal wall – BMI, number of examinations, B-mode, Doppler etc) and also for significant confounders (e. g. conditions that have themselves been associated to autism, requiring more intensive ultrasound follow-up). Regarding the
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potential use of ultrasound for autism screening, technical limitations in imaging the fine structures of the fetal brain, together with evidence of later-onset postnatal changes, severely limits its sensitivity and specificity and, collectively, its feasibility as a screening tool.
References [1] Newschaffer CJ, Curran LK. Autism: an emerging public health problem. Public Health Rep 2003; 118: 393 – 399 [published Online First: Epub Date] [2] Kuehn BM. Data on autism prevalence, trajectories illuminate socioeconomic disparities. JAMA 2012; 307: 2137 – 2138 [published Online First: Epub Date] [3] Blaxill MF. What's going on? The question of time trends in autism. Public Health Rep 2004; 119: 536 – 551 [published Online First: Epub Date] [4] Gardener H, Spiegelman D, Buka SL. Perinatal and neonatal risk factors for autism: a comprehensive meta-analysis. Pediatrics 2011; 128: 344 – 355 [published Online First: Epub Date] [5] Wang C, Geng H, Liu W et al. Prenatal, perinatal, and postnatal factors associated with autism: A meta-analysis. Medicine (Baltimore) 2017; 96: e6696 [published Online First: Epub Date] [6] Penner M, Rayar M, Bashir N et al. Cost-Effectiveness Analysis Comparing Pre-diagnosis Autism Spectrum Disorder (ASD)-Targeted Intervention with Ontario's Autism Intervention Program. J Autism Dev Disord 2015; 45: 2833 – 2247 [published Online First: Epub Date] [7] McPheeters ML, Weitlauf A, Vehorn A et al. Screening for Autism Spectrum Disorder in Young Children: A Systematic Evidence Review for the US Preventive Services Task Force. Rockville (MD), 2016 [8] Fukumoto A, Hashimoto T, Ito H et al. Growth of head circumference in autistic infants during the first year of life. J Autism Dev Disord 2008; 38: 411 – 418 [published Online First: Epub Date] [9] Elder LM, Dawson G, Toth K et al. Head circumference as an early predictor of autism symptoms in younger siblings of children with autism spectrum disorder. J Autism Dev Disord 2008; 38: 1104 – 1111 [published Online First: Epub Date]
[10] Abel KM, Dalman C, Svensson AC et al. Deviance in fetal growth and risk of autism spectrum disorder. Am J Psychiatry 2013; 170 (4): 391 – 8 [published Online First: Epub Date] [11] Whitehouse AJ, Hickey M, Stanley FJ et al. Brief report: a preliminary study of fetal head circumference growth in autism spectrum disorder. J Autism Dev Disord 2011; 41: 122 – 129 [published Online First: Epub Date] [12] Hobbs K, Kennedy A, Dubray M et al. A retrospective fetal ultrasound study of brain size in autism. Biol Psychiatry 2007; 62: 1048 – 1055 [published Online First: Epub Date] [13] Gamliel M, Ebstein R, Yirmiya N et al. Minor fetal sonographic findings in autism spectrum disorder. Obstet Gynecol Surv 2012; 67: 176 – 186 [published Online First: Epub Date] [14] Hellmuth SG, Pedersen LH, Miltoft CB et al. Increased nuchal translucency thickness and risk of neurodevelopmental disorders. Ultrasound Obstet Gynecol 2016. doi:10.1002/ uog.15961 [published Online First: Epub Date] [15] Rodgers C. Questions about prenatal ultrasound and the alarming increase in autism. Midwifery Today Int Midwife 2006; 80: 16-19, 66-67 [16] Abramowicz JS. Ultrasound and autism: association, link, or coincidence? J Ultrasound Med 2012; 31 (8): 1261 – 1269 [17] Abramowicz JS. Prenatal exposure to ultrasound waves: is there a risk? Ultrasound Obstet Gynecol 2007; 29: 363 – 367 [published Online First: Epub Date] [18] Ang ES Jr, Gluncic V, Duque A et al. Prenatal exposure to ultrasound waves impacts neuronal migration in mice. Proc Natl Acad Sci U S A 2006; 103: 12903 – 12910 [published Online First: Epub Date] [19] Torloni MR, Vedmedovska N, Merialdi M et al. Safety of ultrasonography in pregnancy: WHO systematic review of the literature and metaanalysis. Ultrasound Obstet Gynecol 2009; 33: 599 – 608 [published Online First: Epub Date] [20] Hoglund Carlsson L, Saltvedt S, Anderlid BM et al. Prenatal ultrasound and childhood autism: long-term follow-up after a randomized controlled trial of first- vs second-trimester ultrasound. Ultrasound Obstet Gynecol 2016; 48: 285 – 288 [published Online First: Epub Date] [21] Stoch YK, Williams CJ, Granich J et al. Are prenatal ultrasound scans associated with the autism phenotype? Follow-up of a randomised controlled trial. J Autism Dev Disord 2012; 42: 2693 – 2701 [published Online First: Epub Date] [22] McClintic AM, King BH, Webb SJ et al. Mice exposed to diagnostic ultrasound in utero are less social and more active in social situations relative to controls. Autism Res 2014; 7: 295 – 304 [published Online First: Epub Date]
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Upcoming EUROSON Schools
EFSUMB Recommendations and Guidelines for Gastrointestinal ultrasound in IBD Gastrointestinal ultrasound (GIUS) has gained an important role in the last decades as the first diagnostic tool for assessing patients with suspected inflammatory bowel disease and for the management and follow up of those with Crohn’s disease or ulcerative colitis. Thanks to its accuracy, repeatability and lack of invasiveness, GIUS is nowadays one of the preferred diagnostic tools in several IBD units both by doctors and their patients. Despite these well-recognized advantages by international guidelines and increasing worldwide interest in GIUS for IBD, its use in real life has still some limitations. This is mainly due to the need of standardization and general agreement in the definition of the luminal and extra-intestinal features of the disease which has a great impact on training and in spreading its use, in particular among those physicians and specialist who regard ultrasound with skepticism due to its infamous operator-dependence. For this reason our international team of experts in GIUS, under the umbrella of the
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European Federation of Societies for Ultrasound in Medicine and Biology, developed GIUS recommendations for assessing IBD, which will be shortly published as “EFSUMB Recommendations and Guidelines for Gastrointestinal ultrasound in IBD” in Ultraschall in der Medizin/European Journal of Ultrasound Starting from the analysis of the literature, which has been assessed according to the level of scientific evidence, and taking into account the authors’ great experience in intestinal ultrasound, the members of the task force group developed 34 recommendations with correspondent level of evidence, showing for the first time the sonographic criteria for defining and assessing Crohn's disease and ulcerative colitis. It has to be underlined that these guidelines, which are part of a guideline-series on GIUS that also covered examination of normal gastroinestinal tract and will cover transrectal / perineal ultrasound, acute inflammatory disorders, functional disorders and miscellaneous pathologies, present
Abscess in Crohn’s disease
the consensus on current data on sonographic features of IBD, and summarise the accuracy of different sonographic modalities for the management of IBD patients to be used in the clinical setting, as well as in scientific studies. We hope you will find these guidelines and recommendations helpful in your clinical work and an inspiration for future research. Prof. Giovanni Maconi, Milan, Italy on behalf of the GIUS Task Force Group,
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Join us at EUROSON 2017 Ljubljana, Slovenia
David Cosgrove Obituary David Owen Cosgrove, “Doc” to his friends, of Wimbledon, London, UK, lost his battle with cancer on Tuesday the 16 th of May 2017, at St. Raphael’s Hospice, North Cheam, London. Professor Cosgrove died two days short of his 79th birthday. He was born on the 18 th of May 1938 in Nairobi, Kenya, the son of Alfred Owen Cosgrove (born 1901 South Africa, BSc Electrical Engineering, Cape Town University, died Nairobi 1962) and Kathleen Mary Cosgrove (nee Carlisle, born South Africa 1908, secretary, died Nairobi 1967). He is survived by his brother John Philip Carlisle Cosgrove (born Nairobi 1945), financial accountant and retired United Nations Official, and by his partner Zhen Li (Jason). David went to a number of good schools in Kenya, culminating in his secondary education at the Duke of York High School, where he was Head Boy. This is now known as Lenana School (https://en.wikipedia.org/wiki/ Lenana_School), situated outside Nairobi at the foot of the Ngong Hills near the village of Karen, named after Karen Blixen author of “Out of Africa” (details: http://www. mccrow.org.uk/eastafrica/duke%20of% 20york%20school/Duke%20of%20York% 20School.htm and http://www.oldyorkist.
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com/). The 1985 film of the same name gives a good impression of the surrounding countryside that formulated David’s early years. When David was at home in Nairobi for school holidays, he and his brother John would go on various trips to game parks and the coast. John recalls that this was where he learnt of David’s strong interest in, and great deal of knowledge of, almost everything, but in particular nature: “David had a major positive influence on my life in the appreciation of flora and fauna. He also taught me about classical music, a great love of his.” David graduated from high school in 1955 with “A levels”, ready for university entrance. His parents had the foresight to understand that David was exceptionally gifted and they supported his wish to apply to Oxford University, with his mother working to pay for his fees, which were then as now considerable for an “overseas” student. At age 17 David left Kenya, passed the Oxford University entrance examination and went on to obtain a BA in Physiology from Oxford (1961) and subsequently a BM BCh (Bachelor of Medicine, Bachelor of
David (circa 1983), holding the probe of a radically new real-time phased array abdominal ultrasound scanner (code named at EMI CRL as the “Falcon”), a prototype being evaluated in comparison with the home-built ceiling-mounted static B-scan system “Icarus” (probe out of view, control console on the right of the picture).
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Surgery – Medicinae Baccalaureus, Baccalaureus Chirurgiae) at St. George’s Hospital Medical School in Tooting, London (1963). After working at several hospitals in London he returned to Kenya and practiced medicine at the Jomo Kenyatta Hospital in Nairobi (1971). He soon understood that he would be happier and could make a more significant contribution to Medicine in England, the country to which he returned and in which he subsequently remained for the rest of his life, working in medical ultrasound to achieve world renowned standing and advancing his speciality in an unprecedented manner. The ensuing list of honours and accomplishments in David’s astonishingly successful career are extensive, suffice to say that David’s contributions were immense. The main areas where he substantially advanced the clinical role of “radiological” (i. e. non-obstetric) ultrasound, included improved understanding of the basic mechanisms of the ultrasound image-forming process and of Doppler ultrasound, developed and evaluated ultrasound “tissue characterisation” methods, developed and greatly advanced many clinical applications of microbubble (contrast) enhanced ultrasound, and demonstrated how to apply ultrasound elastography to clinical diagnosis. He became a Member of the Royal College of Physicians in 1967 and a Fellow in 1990. He obtained an MSc in Nuclear Medicine, University of London, in 1975. A key moment in David’s career, and the career of many others, was when he started as a Research Fellow in the Department of Nuclear Medicine at the Royal Marsden Hospital under V.R. (Ralph) McCready, in collaboration with C.R. (Kit) Hill in the Institute of Cancer Research, who together had a Medical Research Council programme grant to develop and evaluate investigative ultrasound methods. At that time in the Royal Marsden Hospital, patients were scanned with ultrasound in the Nuclear Medicine Department as interest in ultrasound started there, prior to any radiology interest, whilst still an emerging diagnostic modality in cancer medicine. David moved this work forward in his characteristically professional way. He stayed in this area of medicine and research for the remainder
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of his career, making such an important and sustained contribution to investigative radiology that most people assumed he was a radiologist. In 1998 the Royal College of Radiologists recognised this by inviting him to become an Honorary Fellow. The team at the Institute of Cancer Research and Royal Marsden Hospital at this time built its own ultrasound scanners for clinical use (with the new “grey scale” imaging method), and had a collaboration with EMI Central Research Laboratories. At the time, EMI was the world’s largest producer of vinyl records, but had also pioneered airborne radar, commercialised television and developed the x-ray CT scanner from the Nobel Prize winning invention that Godfrey Hounsfield had made while working there. During the late ‘70 s and early ‘80 s EMI were also a leader in medical ultrasound. They had built, in part with David’s advice, one of the early commercial phased array abdominal ultrasound scanners. He had a deeply intellectual approach, and a tremendous curiosity, particularly about the ultrasound physics related to his many observations of imaging phenomena in clinical ultrasound practice, and how best to explain them. At joint clinical-physics meetings he would bring (initially) Polaroid photographs and (subsequently) video tapes of recent cases which he used to challenge physicists, to find an explanation of some observed phenomenon. In 1993, after a tremendously successful period at the Royal Marsden Hospital (Consultant in Nuclear Medicine and Ultrasound from 1977), David moved to the Royal Postgraduate Medical School at the Hammersmith Hospital. This later became a part of the Imperial College School of Medicine, where he was awarded a personal chair as Professor of Clinical Ultrasound. He may have been happier with the moniker ‘Professor of Bubbles’; during this time he was at the forefront of developments in the use of microbubble contrast agents in ultrasound imaging. He co-founded the International Contrast Ultrasound Society (ICUS) in 2008. He was an active and highly valued contributor to weekly Engineering and Physics ultrasound meetings until very recently.
The Board of Delegates honoured David as an EFSUMB Fellow in March this year.
After David ‘retired’ in 2004, becoming Emeritus Professor at Imperial College, he took a new role as a Senior Research Investigator at King’s College Hospital, and generously continued weekly clinical sessions at the Hammersmith and Charing Cross Hospitals. At King’s, he immersed himself into paediatric use of microbubble contrast to establish once again in his career a new direction for ultrasound. He was actively publishing new reports in this field at the time of his death. At Imperial he also remained an active senior investigator, bringing together physicists, engineers, radiologists and clinical teams with his insight for studies of clinical applications of new ultrasound technologies. Although David published more than 200 peer reviewed research articles and 30 teaching books/book chapters over his career, teaching is something for which David will be particularly remembered, much conducted at a very personal level. His talent for clarity, when summarising or explaining anything, combined with his gentleness and patience, made him a magnet for trainees from around the world. Over the decades he inspired a small army of individuals, both clinical and technical, many of whom have gone on to have successful careers and take up leadership roles in clinical, academic and commercial institutions. This built him a world-wide network of friends who held him in great esteem and with considerable affection, in Europe, Japan, North America, South America, India, China, Russia, the Middle Eastern and many other countries. He held visiting professorships in Philadelphia USA, Wenzhou China and Hangzhou China, was one of the world’s most sought-after invi-
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ted speakers at international conferences and held honorary memberships in many national and regional ultrasound societies. David’s knowledge, experience and clear thinking meant that he was often asked to take advisory and consultative positions, even in fields outside of his own such as high intensity focussed ultrasound. He was Director, Secretary and Vice President of the International Contrast Ultrasound Society, advisor to NICE and various grant giving authorities, and a member of many editorial boards of journals and expert working groups. A particularly important
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contribution, which continued throughout his retirement, was his role in advising companies. His advice for product improvement was invaluable, and in return he would be able to work with the very latest and novel products for evaluation and research study. Through his diplomacy and visibly open integrity he was able to engage simultaneously in this way with many companies. David possessed a deep intellect and was driven by an insatiable curiosity. He also exhibited an intellectual generosity that helped many people, and this was one of the attributes that won him so many
friends. He was the “go to” person for objective and thoughtful advice on a great many topics. A modest, kind and gentle person, he valued quietly continuing his work, listening to music, studying the arts and nature (including diving), cooking and spending time with his friends. A giant of the medical ultrasound world has passed away, unique in so many ways and an inspiration to generations of ultrasound practitioners across the world. Jeff Bamber, Robert Eckersley, Chris Harvey, Adrian Lim, Paul Sidhu, Meng Xing Tang
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