2002 VOLUME 16 - ISSUE 1

ISSN 1012-8220

Volume 16

Issue 1

July 2002

EFSUMB EUROPEAN FEDERATION OF SOCIETIES FOR ULTRASOUND IN MEDICINE AND BIOLOGY

EXECUTIVE BUREAU President: President Elect: Past-President: Honorary Secretary: Honorary Treasurer:

K Jäger (Switzerland) D H Evans (UK) M Claudon (France) L Greiner (Germany) N Juul (Denmark)

ECMUS - EUROPEAN COMMITTEE FOR MEDICAL ULTRASOUND Chairman: Secretary: Members:

K Salvesen (Norway) T Whittingham (UK) P Arbeille (France) K Marsál (Sweden)

PUBLICATION COMMITTEE Members: J-M de Bray (France) D W Pilling (UK) W Mann (Germany) Ex-officio: M Claudon (France) L Greiner (Germany EFSUMB NEWSLETTER Editor: D W Pilling (UK)

EDUCATION AND PROFESSIONAL STANDARDS COMMITTEE Chairperson: Members:

L Valentin (Sweden) B Cacciatore (Finland) B J Hackelöer (Germany) D Lindsell ( UK)

SECRETARIAT General Secretary: Gianna Stanford, Carpenters Court, 4a Lewes Road, Bromley, Kent BR1 2RN, UK Tel: +44 (0)20 8402 8973 Fax: +44 (0)20 8402 9344 Email:efsumb@compuserve.com Website:http://www.efsumb.org

CONTENTS EFSUMB Officers and Committees

2

Safety Session at Euroson 2002

Contents

2

EFSUMB Safety Tutorial

Report from the Past President

3

Contents of EJU

18

Message from the New President

4

Report from the Publication Committee

19

Report from the Past Honorary Secretary

5

Report from the Newsletter Editor

19

Report from the Honorary Treasurer

6

IBUS Breast Ultrasound Seminar, Warsaw 2002

20

Young Investigator Award 2002

7

Industrial Board

20

7

Letter from WFUMB

21

Diary Dates

22

th

16 Euroson Congress 2004, Zagreb, Croatia Paper from the Education and Professional Standards

8-11

Committee 15th Euroson Congress 2003, Copenhagen, Denmark

12-13

2

14 15-18

REPORT FROM THE PAST PRESIDENT Unfortunately, after a recent discussion with the Publisher, Elsevier, the EJU might cease at the end of the year.

This is my final message, as President of EFSUMB. Three years have passed quickly, and time has now come to make an assessment of our activities.

We have also opened relationships within the industry. This has already been rewarding in the fields of Education and Safety with COCIR, which regroups at the European level, the main companies providing US machines. We are willing to further develop this cooperation with all those involved in ultrasound, including contrast agents and recording media companies and create an industrial board.

EFSUMB membership has increased during the last period, with now approximately 14500 members from 25 national societies.

The European Federation has definitively established itself as the second largest affiliated society within the World Federation, after the Asian group. We suspended the Turkish Society’s membership following no communication over the past two years; however we have established contacts with Yugoslavian and Georgian societies.

Three years ago Luigi Bolondi established three committees within the Federation which have done a great job, and significantly contributed to the life of the Federation. I would like to express my gratitude to all committee members for their work and expertise. I suggest that all our national societies should become increasingly involved in these committees’ activities: the more a National Society does for the Federation, the more it will be recognized and honored.

Holding Euroson Congresses in conjunction with National Society congress is a new formula, established five years ago.

After Tours in 1998 and Berlin in 1999, we had a very successful and a high scientific level congress in Edinburgh in 2001. The present meeting in Warsaw is a unique opportunity to reinforce the contribution to the Federation of previously named Eastern countries. This is a major objective for the coming years, as we together build the European community, step by step. The introduction of the Euro has resulted in a decrease of exchange cost for our budget. However, we have to review our by-laws to better determine the responsibility of both parts, the National Society and EFSUMB in the preparation and management of joint meetings.

The Education and Professional Standards Committee has been brilliantly chaired by Lil Valentin and Henry Irving.

This group has worked hard to prepare a specific session, held during our last meeting in Edinburgh. A very productive discussion involved representatives from the European clinical specialties working in the world of ultrasound, including gynecology and obstetrics, radiology, gastroenterology, urology, angiology, and cardiology. A revised version of the initial draft entitled “Minimum training requirements for the practice of medical ultrasound in Europe” has been completed and will be sent to all these groups. EFSUMB acting as an umbrella organisation is helping to establish commonly accepted guidelines for initial and continuous education in ultrasound.

I would like to take this opportunity to express the sincere thanks of EFSUMB to Prof Wieslaw Jakubowski and his colleagues for organising such a successful and enjoyable congress in Warsaw. A full report of this Congress will appear in the next Newsletter.

A positive point was the success of the Euroson Schools organized during the last years in Germany, Italy, UK and especially in Romania. These Euroson Schools have to be developed, as they also appear to be an effective tool for continuous education.

The ECMUS, Safety committee, previously named the Watchdog Committee, has been effectively managed by Francis Duck with review documents regularly published in the Newsletter. To emphasize the importance of this field for the practice of ultrasound, the decision was made to organize a plenary session on various aspects of safety during the present congress in Warsaw, congregating experts from all around the world, including WFUMB Safety Committee. The key points of this session are to be circulated to the European clinical societies, as suggested in Edinburgh.

The WFUMB, our World Federation, has decided, after many requests from EFSUMB, to improve communication with all the affiliated societies’ members, and to regularly circulate a Newsletter. We are very happy with this decision, which will result in clearer information about their activities, which at the present time include two new development projects, in Africa and Asia (Bangladesh). These demonstrate to our members the value of their indirect financial contribution of 1.5 USD to the World Federation. The next World meeting will be held in Montreal, Canada, 1-4 June 2003. I hope that many European representatives will be present at this important event. Several European lecturers have already been selected. Luigi Bolondi and I have been nominated for the next board election, respectively as President Elect and Vice president.

Hylton Meire has the difficult task of managing the Publication’s Committee. This has been a tough task, because preparing the biennial Newsletter is a challenge. This challenge has been highly successful, and the Newsletter is now a well-established, effective link between all the members. However, a major problem has arisen with the European Journal of Ultrasound. This scientific journal, edited by Johann Thijssen and listed two years ago by Medline, has unfortunately not been accepted by ISI, and therefore did not achieve any impact factor. Despite multiple efforts the newly appointed Editor-in-Chief, Peter Twinning, has had to face a very low flow of manuscripts, thus making the situation critical.

I would like to warmly thank the ExB of EFSUMB, Kurt Jäger, David Evans, Niels Juul, Luigi Bolondi, Ioan Sporea and our General Secretary, Gianna Stanford, for their very positive action, continuous support and friendship. It has been a real pleasure to work hard with all of you, for the benefit of

the European Federation, and progress in Ultrasound.

Michel Claudon Past President EFSUMB

3

MESSAGE FROM THE NEW PRESIDENT the association. We would therefore like to bring the EUROSON Congresses up to an even more professional level. In the future, a EUROSON Committee will thus revise the statutes and bylaws and, in collaboration with the Organizing Committee from the lcal associations, coordinate both the administrative and the scientific interests of the congress. Here it is obvious that representatives of the industry must also be included as important partners.

With the general assembly held in connection with the EUROSON Congress in Warsaw, a new 3-year cycle commenced for the EFSUMB. It is indeed both a pleasure and a privilege to be able to lead the EFSUMB during the next three years as its president, and I sincerely appreciate the trust you have extended to me.

Professor Michel Claudon (Nancy, France) has assumed the office of the Past President and the former Past President, Professor Luigi Bolondi (Bologna, Italy) now retires from the Executive Bureau. I would like to warmly thank these gentlemen, both personally and on behalf of the EFSUMB, for their untiring engagement.

Professor David Evans (Leicester, UK) who, to date, has served as the Honorary Secretary, has been selected as the President Elect, and Professor Lucas Greiner (Wuppertal, Germany) has been chosen as the Honorary Secretary. We are fortunate in being able to continue to rely on the valuable collaboration of the Honorary Treasurer, Niels Juul (Roskilde, Denmark). It is extremely gratifying to have such an outstanding staff at my side and I am convinced that, together, we will experience a very positive and constructive time at the EFSUMB. A friendship that extends beyond professional cooperation and respect combined with a common goal of achieving optimal collaboration in their endeavors has always characterized the Executive Bureau to date, and should continue to be our leitmotif.

In this respect, the EFSUMB Committee for Education and Standardization takes on a special importance. It is expected that the EFSUMB will play a leading role in standardization questions. Here, as an example, one could think of guidelines for contrast media examinations.

National Societies and Member Communication: It was only a few years ago that ultrasound techniques gave the impression of being a method that was somewhat stagnant. This has now fundamentally changed. The technical advances of the past years open new perspectives whose abundant possibility for development can hardly be appreciated at this time. This naturally advances the national associations and the EFSUMB is most pleased about the continually increasing number of members.

Typically, ultrasound societies are multidisciplinary groups. This is, on one hand, a great strength of the EFSUMB and its national associations, however, for some individual national societies, it can simultaneously become a weak link. In many European countries, it has been possible to promote the interdisciplinary character, and

In past years, resourceful and initiative presidents have steered the Executive Bureau on a very dynamic path.

Many good ideas for our continuing course have been initiated and should be followed or indeed, their time is ripe for implementation. The future of the EFSUMB is thus on solid ground and there is no need for a change in our orientation. However, responsibilities, duties and problems have not become smaller and an increasing engagement is required on the part of the Executive Bureau. Active leadership is expected on various fronts in the European Ultrasound arena, and I would like to emphasize a few of these below.

thus to potentiate the political clout of the association.

However, in other countries, the activities have been taken over by the specialized professional societies and not by the Ultrasound Society. From a strictly professional point of view, this may have a certain advantage, it does, however, weaken the matters of ultrasound itself. Furthermore, representation by a common and unified voice vis-à-vis third parties, such as political authorities or insurance companies, is lacking.

EFSUMB is challenged to give these national societies the necessary support.

EUROSON Congress The annual EUROSON Congress, held in cooperation with a national society, boasts an ever-increasing popularity and quality. I need only mention the past congresses in Berlin (together with the Dreiländertreffen), Florence (Italian Society and World Federation), Edinburgh (British Society) and, recently, Warsaw (Polish Ultrasound Society) with 1000 - 2000 participants. Even at this stage, we can foretell that the 2003 EUROSON Congress in Copenhagen (in cooperation with the Scandinavian Ultrasound Societies) will be a success. The organizers have already assembled a program that has been worked out with a fine eye for detail. The list of the invited speakers is impressive, the selected topics are of utmost relevance and, in addition, a broad spectrum of continued education and training courses will be offered.

Based on the experiences made in past years, we would like to strengthen and enhance the communication between the European Federation and the national societies. EFSUMB’s efforts for the society should be communicated to the individual members, who should clearly be made more aware of these endeavors. The Newsletter is probably the best tool to achieve this. Since the European Journal of Ultrasound has not been able to meet expectations, we will have to plan a new orientation for our communication instrument.

Much work awaits us and I eagerly look forward to a productive and gratifying collaboration with all of you, my colleagues. The future is now.

Success encourages and impels us to offer to our members EUROSON Congresses that are constantly improving. The annual congress is, to a certain degree, the central event of any association, but at the same time, it is also a representative beacon that encourages identification with

Kurt Jäger President EFSUMB

4

REPORT FROM THE PAST HONORARY SECRETARY It seems amazing that my term of office as Honorary Secretary has flown by so quickly, but this will be my last secretary’s report. A great deal has been achieved by the Executive Bureau, the Board of Directors, and by our committees during those three years, and it has been a privilege and a pleasure to work with so many committed people, and to begin many new friendships.

Professor Claudon has summarised many of the achievements of the Federation over this period in his report, and so it falls to me simply to provide an update on the many events that occurred at the recent EUROSON meeting in Warsaw. First and foremost I would like to take this opportunity to thank Professor Jakubowski for organising what was without doubt a tremendous meeting, both scientifically and socially, one I am sure will long remain in the memory of all participants. Special mention must also go to the rest of the team involved in the organisation and particularly to Anna Pajk. Many thanks indeed!

infrainguinal arterial disease has a high inter-observer agreement’.

The abstract of this paper appears elsewhere in this newsletter.

As usual our various committees were hard at work during the meeting, and their reports appear elsewhere.

Two things I would particularly like to draw to your attention are the excellent news that a new draft of the ‘Minimum Training Requirements for the Practice of Medical Ultrasound in Europe’ was unanimously agreed by the Education and Professional Standards Committee, and the very sad news that the European Journal of Ultrasound is to cease publication at the end of the year, although the Publications Committee are actively considering ways in which the journal might be relaunched.

During the course of the meeting we were able to talk to the organisers of all the EUROSON meetings currently in the planning phase, and the Board of Directors endorsed a new bid for 2006. The 2003 meeting will of course be held in Copenhagen in April, in conjunction with the Scandinavian Societies, and plans for this meeting are well advanced. The 2004 meeting is to be held in Zagreb in June, and I know that Professor Drinković and his team will be working hard over the next few months to ensure the meeting is a great success. EUROSON 2005 is to be held in Geneva in June in conjunction with the Dreiländertreffen, whilst it was agreed that the 2006 meeting will be held in Bologna in conjunction with the Italian Society, probably in October.

Remaining with EFSUMB committees, the Board of Directors have agreed to set up two new committees, one a small ad-hoc committee to consider ways of strengthening EUROSON meetings, the second an Industrial Board, where representatives of EFSUMB and the manufacturers can discuss matters of mutual interest including forthcoming meetings. Initial exploratory talks in Warsaw with several manufacturers proved very productive and bode well for mutual cooperation in years to come.

I mentioned at the beginning of my report that this would be my last as Honorary Secretary, as three years have

As in Edinburgh last year there was a special EFSUMB session at the meeting, kindly sponsored by COCIR, on this occasion devoted to ultrasound safety, with speakers drawn from the USA, Japan, and Australia in addition to a number of safety experts from European countries. In addition, the EUROSON lecture also addressed the issue of safety, and was given by Professor Francis Duck from Bath in England. Both the session and the lecture were of an extremely high standard and highly entertaining. The Young Investigator session was also of a high standard, with entries from Belgium, Denmark, Norway and Poland.

The only disappointment was that there were not entries from many more National Societies, and I would like to encourage all eligible young investigators to consider submitting an entry for forthcoming EUROSON meetings. The bylaw concerning the Young Investigator Award can of course be found on our web-site, but can I remind you that the selected candidates are offered free registration by the congress, have their travel and accommodation expenses sponsored by their member society, and stand to win €1,000 if they are selected as winner. Not a bad deal! On this occasion the winner of the award was Dr J Eiberg from Denmark for his presentation entitled ‘Ultrasound imaging of

elapsed since the election of the current Executive Bureau (ExB). Our Past President, Luigi Bolondi, leaves the ExB after nine years, and we must thank him for the vast amount of time and effort that he has put into EFSUMB over that period. Our President, Michel Claudon,

automatically becomes Past President, and our President Elect, Kurt Jäger, automatically becomes President. This leaves three vacancies on the ExB for President Elect, Honorary Secretary, and Honorary Treasurer. Elections for these positions took place at our General Assembly, and were filled by myself, Professor Lucas Greiner from Wuppertal, Germany and Dr Niels Juul from Copenhagen, Denmark (for a second term) respectively. I am of course delighted and flattered that the Board of Directors and General Assembly have seen fit to appoint me as

President Elect.

I would like to finish my report by saying how much I have enjoyed working with the ExB and Board of Directors over the past three years and to thank Mrs Stanford for the tremendous work she has done for the Federation, and the support she has given me in my capacity as Honorary Secretary.

David H Evans Past Honorary Secretary EFSUMB

5

REPORT FROM THE HONORARY TREASURER EFSUMB Trading and profit and loss account Year ended 31 December 2001 in £sterling INCOME Subscriptions 65,055 Newsletter sponsorship 14,942 Euroson School/Congresses 11,139 Deposit account interest 486 Reimbursements 2,176 93,798 EXPENDITURE Subscription WFUMB 15,034 Publishing and mailing costs of Newsletter 27,734 Meeting and Travelling expenses of all committees 17,364 Wages 13,256 Printing, postage and stationery 619 Auditors remuneration 764 Loss on exchange 195 Office services 6,224 Bank charges 486

My mandate period from 1999 to 2002 as Honorary Treasurer is about to terminate. It has been a pleasure for me to work in the Executive Bureau to take care of the finances, with the assistance of the General Secretary.

The EFSUMB economy is now stable and solid.

After a year with a loss, two years with surplus has followed and furthermore, a positive outcome of the years 2002 and 2003 is expected. It is therefore not necessary in the coming years to raise the fee, which still can be kept as low as 8€ per member.

As previously mentioned, the WFUMB congress in Firenze in 2000 was also an economical success, and together with surplus from successful Euroson School events in Romania, Germany and in the UK, a considerable income has been paid to EFSUMB. The Treasurer is very grateful for this contribution from the organizers of the Euroson Schools.

Depreciation: Plant and machinery Fixtures and fitting Computer equipment

On this page I have listed the end of year accounts for 2001, the budget for 2003 and an updated membership status.

91 234 852 82,853

Excess of income over expenditure

10,945

Niels Juul Honorary Treasurer EFSUMB

Country AUSTRIA BELGIUM BULGARIA CROATIA CZECH REP DENMARK FINLAND FRANCE GERMANY GREECE HUNGARY ISRAEL ITALY NETHERLANDS NORWAY POLAND PORTUGAL ROMANIA RUSSIA SLOVAK REP SLOVENIA SPAIN SWEDEN SWITZERLAND UK TOTAL

EFSUMB Budget For The Year 2003 (In £sterling) INCOME Membership fee 14000 members 72,000.00 because of the euro rate against the pound sterling Newsletter sponsorship 6,000.00 Bank deposit interests 1,000.00 European Journal 0.00 EUROSON CONGRESS Warsaw 2002 to be determined 0 Copenhagen to be determined 0 TOTAL INCOME 79,000.00 EXPENDITURE WFUMB 15,000.00 Newsletter 24,000.00 Meetings, Executive Bureau 8,000.00 Meetings, Committees 8,000.00 Prizes etc 1000 Secretary 14,000.00 Printing, postage 2,000.00 Accountants 1,000.00 Loss on exchanges 2,000.00 Office 5,000.00 Bank charges 500 TOTAL EXPENDITURE 80,500.00

Number Of Members In Database 813 211 75 67 45 332 270 361 5007 100 49 101 1850 49 194 800 63 247 68 40 108 168 96 2043 2150 15307

BALANCE

6

-1,500.00

YOUNG INVESTIGATOR AWARD 2002 The following papers were accepted for presentation at the Young Investigator Session during the 14th Euroson Congress in Warsaw on 6 July 2002.

• Dr Roland Devlieger - Department of Obstetrics and Gynaecology, University Hospital “Gasthuisberg”, Leuven, Belgium

Reducing the risks of ultrasound guided endoscopic fetal surgery: experimental models in sheep and rhesus monkey.

• Dr Jonas Eiberg Dept of Vascular Surgery, Rigshospitalet, Copenhagen, Denmark

Ultrasound Imaging of Infrainguinal arterial disease has a high interobserver agreement • Dr. Johan Axel Lunding, Medical department, Haukeland University Hospital of Bergen, Norway

Symptom perception and gastric response to an increasing gastric water load with and without simultaneous duodenal lipid infusion in functional dyspepsia patients using 3D ultrasonography.

• Dr Ewa Bialek Wojewódski Szpital Bródnozski Zaklad Diagnostyki Obrazowejul. Kondratowicza 8, 03-242 Warsaw, Poland New Ultrasound Imaging Methods (tissue Harmonic Imaging, Panoramic Imaging, Three dimensional imaging) in head and neck area.

The winner was Dr Jonas Eiberg, Dept of Vascular Surgery, Rigshospitalet, Copenhagen, Denmark. The abstract of his presentation is printed below: “ULTRASOUND IMAGING OF INFRAINGUINAL ARTERIAL DISEASE HAS A HIGH INTEROBSERVER AGREEMENT” stenosis) or significantly (> 50% stenosis or occlusion) diseased, alternative inconclusive. CA was performed within 24h and was independently described by two radiologists in the same manner. Within 10 months the arteriograms were reassessed.

Results: DUAS interobserver-agreement was good (ic = 0.79 (Cl: 0.72-0.86)) and not significantly different (p>0.7) from the CA interobserver-agreement (rc= 0.80 (0.74-0.87)).

The intraobserver-agreement between the two CA readings was 0.84 (0.79-0.90).

Conclusion: Arterial duplex scanning is as reliable as arteriography when visualizing severe lower limb ischaemia.

Objectives: To evaluate the operator dependency of duplex arterial scanning (DUAS) and contrast arteriography (CA) in chronic lower limb ischaemia.

Design: Prospective and blinded study.

Material: 26 consecutive patients (13 men and 13 female) with severe claudication (n=6, 23%), rest pain (n=7, 27%) and tissue loss (n=13, 50%).

Methods: Two physicians independently performed a DUAS of the entire lower limb, from the groin to the foot.

Arterial segments were diagnosed as insignificantly (< 50%

IF YOU WISH TO SUBMIT A PAPER FOR THE YOUNG INVESTIGATOR AWARD SESSION TO BE HELD DURING THE 15TH EUROSON CONGRESS IN COPENHAGEN 27-30 APRIL 2003 PLEASE CONTACT YOUR NATIONAL SOCIETY (and see Bylaw no.4 on the EFSUMB website: www.efsumb.org)

16th EUROSON CONGRESS – 6-9 JUNE 2004 - ZAGREB – CROATIA Dear Colleagues, On behalf of The Croatian Society for Ultrasound in Medicine and Biology, I have the great pleasure in inviting all involved and interested ultrasound societies to Zagreb, the capital of the republic of Croatia, where we will host the XVIth Congress of the European Federation of Societies for Ultrasound in Medicine and Biology.

Zagreb, your host city, has developed out of the thousand year old medieval market place and ecclesiastical centre of North-western Croatia. Its geographical position at the cross-roads of trade routes and its turbulent past have made Zagreb an important cultural and scientific centre, an economic centre, a traffic cross-roads, and the capital of Croatia.

Come and share with us your recent research achievements, your clinical experiences, and the pleasure of your company. The local organizing committee, the University, and the City of Zagreb will be honoured to be able to provide you with Croatian hospitality and look forward to giving you a warm welcome and a memorable congress.

Kurt Jäger Congress Co-President EFSUMB

Ivo Drinković Congress Co-President CSUMB

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EDUCATION AND PROFESSIONAL STANDARDS COMMITTEE EFSUMB´s Education and Professional Standards Committee are trying to collect evidence for how some common ultrasound guided invasive procedures should be performed. In January 2001 we published a document on amniocentesis. Below you will find a document presenting the evidence with regard to chorionic villus sampling (CVS) in singleton pregnancies. The document has been prepared

by Dr Lil Valentin (Malmö, Sweden) and Dr Steen Smidt Jensen (Hvidovre, Denmark).

We should highly value any comments you might care to make on the document. Are you aware of evidence that is not presented in the document? Have we forgotten to discuss one or more important issues? Do you disagree with one or more statements, and if so, which are your arguments for doing so??

Send your comments to EFSUMB´s general secretary, Ms. Gianna Stanford (efsumb@compuserve.com).

Lil Valentin Committee Chairman

DIAGNOSTIC CHORIONIC VILLUS SAMPLING (CVS) IN SINGLETON PREGNANCIES. Indications: a) Increased risk of chromosomal abnormality b) DNA and biochemical analyses for monogenic hereditary diseases c) Determination of fetal sex d) Paternity testing

Comments Re a) The unintended abortion rate increases extensively if the membranes are entered (Saura et al. 1991; Lilford et al. 1987). To eliminate possible side effects of a collapse of the membranes and of needle lesions, which could seriously damage the first trimester fetus, the membranes must not be entered. In almost all cases the membranes can be avoided even in a posterior placenta. Difficult sampling by the transabdominal approach may be expected when the uterus is retroflexed. Increased transducer pressure and sampling from the lateral side of the uterus may solve the problem (Smidt-Jensen et al. 1988)

Comments Re a) The individual risk of chromosomal abnormality can be calculated on the basis of maternal age, personal and family history, status of inherited structural chromosomal abnormalities, first trimester serum biochemistry, fetal nuchal translucency, and fetal abnormality.

Re b) If the ultrasound investigation shows haematomas, the presence of an intrauterine device (IUD), large fibromas, or other uterine abnormalities, or if there is active bleeding, the risk of spontaneous abortion must be considered to be increased and the woman should be counseled accordingly. Although benefit of postponement in case of active bleeding has not been documented, most operators would postpone prenatal testing until the time of amniocentesis or at least until bleeding has ceased.

Ad b) Trophoblastic tissue constitutes an excellent basis for DNA analysis and biochemical analyses in case of a family history of monogenetic diseases or carrier status.

Re c) The gender of the fetus can be established in the first trimester.

This may be clinically important in case of serious x-linked hereditary disease, e.g. hemophilia.

Re d) Paternity can be established in the first trimester by comparing markers of the chromosomes of the fetus and of those of its possible father.

The diagnostic potential of CVS is similar to that of amniocentesis with regard to chromosomal, DNA and biochemical analyses. A disadvantage of CVS is that screening for neural tube defects and abdominal wall defects by analysis of AFP is not possible.

CVS can be performed transabdominally or transcervically guided by ultrasound. For the transabdominal approach some operators use a free-hand needle technique, others use a needle guide attached to the transducer head and a superimposed electronic needle pathway on the ultrasound monitor. For the transcervical approach a plastic catheter or forceps are used.

The advantages of CVS in the first trimester over standard amniocentesis at 16 gestational weeks is that knowledge of the chromosomal status of the fetus can be obtained much earlier in pregnancy, because sampling can be performed earlier in gestation, and the reporting time is shorter using trophoblastic cells for culture instead of amniocytes. Short term culture of trophoblastic cells reduces reporting time even more but entails poorer chromosome quality (Therkelsen et al. 1988). Screening with fluorescent in situ hybridization (FISH) with probes for the most common aneuploidies can be performed without culture (Quilter et al. 2001). CVS is attractive to the woman because it offers an early solution of her anxiety, and she can avoid a second trimester termination in case of a diseased fetus.

Should a fetal abnormality be detected by ultrasound later in pregnancy, a quick chromosomal result is needed for optimal management of the pregnancy. Short term culture of trophoblastic tissue with chromosomal analysis, or FISH analyses of villi or amniotic fluid cells may clarify the chromosomal status of the fetus within hours/days (Smidt-Jensen et al. 1994; Hitschold et al. 1997; Podobnik et al. 1997).

Re c) Because the spontaneous loss of chromosomally abnormal fetuses is high early in pregnancy, the loss rate of fetuses with of Down´s syndrome at 10 gestational weeks being nearly 50 %, and that of fetuses with other trisomies or Turner´s syndrome being even higher (Snijders and Nicolaides 1996), it seems reasonable not to perform CVS earlier than at 9 completed weeks (crown rump length 23 mm). Since the early 1990´ies it has been discussed, whether CVS is associated with limb reduction defects, in particular CVS carried out before 9 completed gestational weeks. From three CVS centres clusters of limb reductions and high abortion rates were reported after CVS (Firth et al 1991; Burton et al. 1992; Hsieh et al 1995).

In 1992 the World Health Organization, WHO, initiated an international registration of post-CVS limb defects. Reporting to the registry was made on a voluntary basis, but special efforts were also made to find and include clusters of limb defects not directly reported to the registry. It was concluded that limb reduction might occur in clusters, but that there is no indication of an increased risk of limb reduction defects after CVS, irrespective of when in pregnancy CVS is performed. However, there is very limited experience with CVS before 9 completed gestational weeks and insufficient knowledge of the effects of performing CVS before that time. The WHO group recommends no specific sample week as long as CVS is performed after 9 completed gestational weeks (Froster and Jackson 1996; Kuliev et al. 1996).

Re d) Because of feto-maternal bleeding after CVS, the risk of Rhimmunization must be taken into account. Aggravation may occur in a woman already immunized (Brambati et al, 1986), but is perhaps unlikely.

Complications a) Unintended fetal loss b) Feto-maternal bleeding (possibly causing immunization) c) Vaginal bleeding and amniotic fluid leakage d) Maternal cell contamination

Rhesus

iso-

Comments Re a) Several studies compared first trimester CVS, usually performed at 9 - 12 gestational weeks, with ‘standard‘ amniocentesis at around 16 gestational weeks. A Danish randomised controlled trial comparing transcervical CVS in the first trimester, transabdominal CVS in the first trimester, and amniocentesis at 16 weeks, showed no significant difference in fetal loss rate between transabdominal CVS and amniocentesis (SmidtJensen et al.1992). This Danish

Contraindications a) The amniotic membranes cannot be avoided b) Pregnancies with increased risk of miscarriage c) Gestational age < 9 completed weeks d) Rh-immunised woman

8

Re c) Spotting and bleeding occur significantly more often after transcervical CVS than after transabdominal CVS (spotting: 7.3% vs.

3.2%; 19% vs. 4%; bleeding 6% vs. 1.9%; 8.6% vs. 4.7%; 6% vs. 1%; Brambati et al. 1991; Smidt-Jensen et al. 1992; Jackson et al.1991).

Because spotting and bleeding occur more often after transcervical CVS than after transabdominal CVS, at least some of the bleeding episodes after transcervical CVS are likely to be caused by the procedure itself, because if they were not, one would expect the same incidence of spotting and bleeding episodes after both procedures.

In one randomised trial, transabdominal and transcervical CVS were associated with a similar rate of amniotic fluid leakage (0.6% vs.

0.5%, non-significant difference; Smidt-Jensen et al 1992), whereas in another randomised trial amniotic fluid leakage was significantly more common after transcervical CVS (2% vs. < 1%; p < 0.01; Jackson et al. 1992). The significantly higher rate of leakage after transcervical CVS suggests that at least some of the leakages after transcervical CVS are caused by the procedure, because if not, one would expect the same rate of leakage after both procedures.

Because there is no randomized trial comparing transabdominal CVS with a non-invasive procedure, it is impossible to know whether the spotting, bleeding and amniotic fluid leakage seen after transabdominal CVS are caused by the procedure, or whether they occur with a rate similar to that in the background population. In the randomised trial of Tabor and colleagues (1986a) comparing amniocentesis at 16 weeks with a non-invasive procedure, there was a significantly higher rate of amniotic fluid leakage in women who had undergone amniocentesis at 16 weeks (1.7%) than in controls (0.4%) during 6 weeks of follow-up, whereas bleeding occurred equally often in the two groups (2.4% vs. 2.6%).

trial is the only one comparing transabdominal CVS in the first trimester with ‘standard‘ amniocentesis. Although the Danish trial did not present absolute risk estimations for each procedure, the results suggest that the absolute risk of transabdominal CVS in the first trimester may be similar to the 1% (CI 0.3 – 1.5%) absolute risk associated with amniocentesis at 16 weeks (Tabor et al. 1986a).

In a 7-centre non-randomised study comparing transcervical CVS with amniocentesis, the excess fetal loss rate after CVS was about 0.8% (95% confidence interval; CI; -1.3 – 2.9), a statistically nonsignificant difference (Rhoads et al. 1989). A similar (0.6%) statistically non-significant excess rate of fetal loss after transcervical CVS was found in the Canadian 11-centre randomised controlled trial (Canadian Coll. 1989). Thirty-one centres in Europe participated in the MRC randomized controlled trial (MRC Working Party on CVS 1991). Each centre chose their own favoured CVS method, 72% of the CVS procedures being performed transcervically. The fetal loss rate was significantly higher after CVS than after amniocentesis, the excess loss rate being 4.6% (95% CI 1.6 – 7.5%; p<0.01).

There are also randomised trials comparing transabdominal CVS with transcervical CVS. In the Danish randomised controlled trial mentioned above, the post-procedure spontaneous loss rate was significantly higher after transcervical CVS than after transabdominal CVS, 4% more losses (95% CI 2.3 – 5.8%) occurring in the transcervical group (Smidt-Jensen et al. 1992). One American and one Italian randomised trial compared the two approaches without finding any statistically significant difference in fetal loss rate (Brambati et al.

1991; Jackson et al. 1992), even though the loss rate was slightly higher after transcervical CVS. There were major methodological differences between the three studies, the American and Italian studies being characterised by a high rate of cross-overs, lack of follow-up, and a high degree of patient selection. Differences in the experience of the operators may also have contributed to the differences in results.

Transcervical CVS was the prevailing method in the US and in Italy at the time of the studies. Thus, many American and Italian operators probably had greater experience with the transcervical approach, whereas the reverse was the case in Denmark. An excess risk associated with transcervical CVS was found in a German observational study including more than 16,000 transabdominal and transcervical procedures (Stengel-Rutkowski 1993).

The abortion mechanism associated with CVS is not known.

Theoretically, it may be related to feto-maternal bleeding, disturbance of the feto-maternal barrier, bleeding or haematomas in the placenta, infection, leakage of amniotic fluid, or decompression of the uterus.

A "true" picture the fetal loss rate after CVS can only be obtained in randomised controlled trials performed after some years of routine use of CVS, after the learning curve of the procedure has been passed.

However, a randomised trial conducted after a treatment/diagnostic procedure has become standard practice may provoke controversy (Pocock 1987). The randomised trial on amniocentesis was conducted after several years of routine use of amniocentesis (Tabor et al.

1986a).

Re d) Contamination with maternal decidua was seen in about 1% of cultures after transabdominal CVS vs. in 4% after transcervical CVS (Ledbetter et al. 1992; Smidt-Jensen et al.1993). The cytogenetic results may be compromised by contamination of maternal tissue.

Therefore, maternal tissue must be removed before analysis. Maternal tissue contamination would be negligible if cultures were supported by non-cultured analyses, or if the cultures were screened for convoluted cells (Hertz et al. 1987).

Precautions to be taken a) The transabdominal route is probably preferable b) No sampling before 9 completed weeks c) Use real-time ultrasound guidance d) Use needle guide e) The membranes must be avoided f) Experienced operator g) Sterile conditions h) Remove no more tissue than needed for diagnosis i) Not more than two needle insertions j) Rhesus prophylaxis? k) 12 to 24 hours of restricted activity after CVS? l) Pre-CVS coagulation status?

Re b) Feto-maternal bleeding occurs during invasive prenatal procedures. A rise in maternal alpha-feto-protein (AFP) after an invasive procedure is a result of feto-maternal bleeding (Warren et al.

1985; Brambati et al. 1986; Mariona et al. 1986; Knott et al. 1988). At 9 weeks the total amount of fetal blood is 5 ml (Brambati et al. 1986).

In 18% of women undergoing transabdominal CVS and in 5% of those undergoing transcervical CVS, the maternal serum AFP rose by more than 34 kU/l, which corresponds to 0.1 ml or more of fetal blood transfused into the maternal circulation (Smidt-Jensen et al. 1994).

There is a positive correlation between the amount of aspirated villi and the increase in maternal serum-AFP after first-trimester CVS (Brambati et al. 1986; Schulman et al. 1990; Smidt-Jensen et al.

1994).

The clinical importance of the feto-maternal bleeding caused by CVS in the first trimester or by amniocentesis in the second trimester is uncertain. Brambati and coworkers found no association between a post-CVS increase in maternal serum-AFP and fetal loss after transcervical CVS performed at 8 - 12 gestational weeks (Brambati et al. 1986). In a Danish study (Smidt-Jensen et al. 1994) the fetal loss rate increased with increasing maternal serum AFP levels after transabdominal first-trimester CVS but not after transcervical firsttrimester CVS. The risk of Rhesus immunization after amniocentesis at 16 weeks and after first trimester CVS is probably small (Tabor et al. 1986b, Smidt-Jensen et al. 1994). The increase in maternal serumAFP caused by CVS does not compromise second trimester maternal serum-AFP screening for neural tube defects or abdominal wall defects (Brambati et al. 1986, Smidt-Jensen et al. 1994).

Comments Re a) The transabdominal route is probably safer, it is easier and more successful in sampling than the transcervical route (Brambati et al.

1991; Smidt-Jensen et al. 1992; Jackson et al. 1992). One person operates both the ultrasound transducer and the needles. Moreover, the transabdominal route might be more acceptable to the woman and to any accompanying persons.

Re b) The optimal time for sampling of villi seems to be between 9 and 11 weeks. The ‘placenta‘ is sufficiently large by this time. The villi may loosen more easily the earlier in pregnancy the aspiration is performed. For cultures in the second and third trimesters more villi are needed, laboratory work is more laborious, and the chromosome quality of direct and short term cultures is poorer (Pijpers et al. 1988; Saura et al. 1990; Holzgreve et al. 1990; Cameron et al. 1990; Evans et al 1990; Smidt-Jensen et al. 1993). For these reasons and for those mentioned above (i.e., high background spontaneous loss rate early in pregnancy, and possibly increased risk of limb reduction defects if CVS is performed very early in pregnancy), it is reasonable to perform routine CVS late in the first trimester but not before 9 completed weeks.

Re c) and d) There are no randomized controlled trials comparing transabdominal CVS sampling techniques. However, ultrasonic real time guidance with a needle guide and the needle pathway superimposed on the

9

and the inner aspiration needle usually has an outer diameter of 0.7-â&#x20AC;&#x201C; 0.8 mm (20 â&#x20AC;&#x201C; 21 Gauge) (Smidt-Jensen et al 1984; Lilford et al 1987; Mackenzie et al. 1988; Bovicelli et al. 1988; Copeland et al. 1989; Hibbard et al. 1994). A 19 â&#x20AC;&#x201C; 20 Gauge single needle is usually used (Brambati et al. 1991; Jackson et al. 1992).

monitor may have advantages over the free hand technique, because the needle can be introduced through the skin into the uterus with one quick insertion (Smidt-Jensen et al. 1988; Rodeck 1991). This is probably associated with less discomfort to the woman than the slower freehand needle insertion, which may make the woman move and distort the needle pathway. Moreover, increased sampling time might be associated with increased risk of chorio-amnionitis, and the more freely movable needle might increase the risk of feto-maternal bleeding (Weiner et al. 1991)

Preferred Technique of ultrasound guidance a) Transabdominal approach b) Needle guide c) Double needle

Re e) CVS should be performed as atraumatically as possible. The membranes should not be punctured. Studies of first trimester amniocentesis have shown increased abortion risk and a higher risk of talipes equinovarus after amniotic fluid leakage (Sundberg et al. 1997; CEMAT group 1998; Nicolaides et al. 1994). CVS performed through the amniotic cavity increases the risk of miscarriage (Saura et al.

1991).

Comments Re a) See above under complications. Three randomized trials compared transabdominal and transcervical CVS. Complication rates were similar in two of these (Brambati et al. 1991; Jackson et al.

1992), but in the third study a significantly higher fetal loss rate was found in the transcervical group (Smidt-Jensen et al. 1992). The three studies are methodologically different, see above. An excess risk associated with transcervical CVS was also found in a German observational study including more than 16,000 transabdominal and transcervical procedures (Stengel-Rutkowski 1993).

Re f) The individual transabdominal CVS learning curve depends on previous experience with amniocentesis (Wijnberger et al. 2000).

Transabdominal CVS is easier to learn than transcervical CVS. Peak technical performance was achieved after the first series of 100 cases of transabdominal aspirations vs. after the first series of 300 cases of transcervical aspirations (Brambati et al. 1990; Silver et al. 1990; Saura et al. 1991; Chueh et al. 1995; Stranc et al. 1997). Training on volunteers undergoing abortion or training on an in vitro training model (Ville et al 1995; Nizard et al. 2002) is recommended before performing diagnostic CVS.

Re b) No study compared freehand transabdominal prenatal invasive procedures with transabdominal prenatal invasive procedures performed using a needle guide. In two of the three randomised trials comparing transcervical and transabdominal CVS a single needle freehand technique was used (Brambati et al. 1991; Jackson et al.

1992), whereas in the third trial the double needle technique with a needle guide was used (Smidt-Jensen et al. 1992). The use of a needle guide might be preferable, because when the freehand technique is used, the more freely movable needle might increase the risk of fetomaternal bleeding and chorio-amnionitis (Weiner et al. 1991). For quick needle insertion a needle guide is mandatory. See also above under Precautions (c and d).

Re g) There are no randomised controlled trials comparing CVS performed under clean but not sterile conditions with CVS performed under sterile conditions. Despite lack of scientific evidence, it is probably safest to perform transabdominal CVS under sterile conditions: sterile washing of the skin (chlorhexedine or iodine), ultrasound scanning through a sterile medium, sterile gloves and sterilization of the transducer and needle guide for at least 5 minutes between the procedures (unless a sterile cover is used), and sterile needle. Needle insertions through the intestines and urinary bladder are almost certainly best avoided.

Re c) No trials/studies compared transabdominal CVS performed with different kinds of needles (double vs. single; needles of different sizes). Aspiration through an outer guide needle using a double needle is likely to cause minimal trauma, because the necessary amount of villi can be obtained through one single needle insertion, and vigorous movement of the inner needle is not necessary. The single needle technique is probably more traumatic, because the needle is moved vigorously to-and-fro through the abdominal wall and uterus, and if an inadequate amount of villi is obtained, the needle must be inserted again to obtain more material.

Re h) More villi are usually required for DNA analyses and biochemical analyses than for chromosome analysis. Most laboratories require 10-15 mg of villi for chromosome analysis and 30-50 mg of villi for DNA analysis. There is no evidence of any correlation between fetal loss and the amount of villi aspirated within these limits (Smidt-Jensen et al. 1992; Smidt-Jensen et al. 1994).

Concluding remarks There is evidence from randomized controlled trials that the fetal loss rate after transabdominal CVS is similar to that after amniocentesis at 16 weeks (Smidt-Jensen et al.1992), but that the loss rate is higher after transcervical CVS (Can Coll 1989; MRC Working Party on CVS 1991, Smidt Jensen et al. 1992). However, success, ease and safety may be maximized if operators are experienced in both transabdominal and transcervical CVS (Jackson et al. 1992).

Many of the recommendations above are based on weak evidence, i.e. on results of case-control studies (Rhoads et al. 1989; StengelRutkowski 1993), descriptive studies (Copeland et al. 1989; Bovicelli et al. 1988; Mackenzie et al. 1988), or case reports (Firth et al. 1994; Burton et al. 1992), or on inference from results of studies on amniocentesis or other invasive procedures, or on clinical experience.

It goes without saying that because of the relatively low complication rate after CVS, a huge number of patients would need to be included in randomized trials evaluating different CVS techniques (e.g., different types of needles, or freehand technique vs. use of a needle guide) and post-CVS management strategies (e.g., rest vs. no restriction of activities) to obtain reliable and generalizable results.

Moreover, certain questions would not be suitable for answering in a randomized trial, e.g., whether the number of needle insertions affects the outcome.

Re i) Using the double needle CVS technique as many insertions with the aspiration needle as needed can be done through the introduction needle. If two needle insertions are unsuccessful most operators postpone the procedure for one week. This is not evidence based. For transcervical CVS multiple insertions increase the complication rate (Wapner et al. 1988; Roads et al. 1989; Wade and Young 1989).

Re j) There is insufficient evidence to recommend or discourage routine administration of anti-D immunoglobulin after CVS. Thus, in an unpublished randomized controlled trial comprising 370 women (Smidt-Jensen et al.) benefits of administering 50 micrograms of antiD-immuno-globulin after CVS were not demonstrated. In theory, anti-D immune-globulin could cross the placenta and destroy blood cells of Rhesus positive fetuses. On the other hand, a very small volume of fetal blood may sensitize or immunize a pregnant woman (Brambati et al 1986).

Re k) There are no studies evaluating the effects of post-CVS regimes.

Many centers recommend that hard work be avoided until the next day, and some recommend bed rest. Others recommend the woman to rest only in case of pain, spotting, or fluid leakage, and to contact the center if the symptoms continue the following day. None of these recommendations are based on scientific evidence.

References Bovicelli L, Rizzo N, Montacuti V, Morandi R, Vullo C, Toffoli C, Venturoli A. Transabdominal chorionic villus sampling: analysis of 350 consecutive cases. Prenat Diagn 1988 Sep;8(7):495-500.

Brambati, B, Guercilena, S, Boacchi, I, Oldrini, A, Lanzani, A, Piceni, L. Feto-maternal transfusion after chorionic villus sampling: clinical implications. Hum Reprod 1986;1:37-34.

Brambati B, Lanzani A, Tului L. Transabdominal and transcervical chorionic villus sampling: efficiency and risk evaluation of 2,411 cases. Am J Med Genet 1990;35(2):160-4.

Re l) To the best of our knowledge, there are no reports evaluating the need for routine testing of maternal coagulation status before CVS and clinical experience suggests that this is unnecessary. Women with known coagulation defects should be managed in consultation with a coagulation specialist.

The needles There are no randomized controlled trials comparing transabdominal CVS performed with different types of needles. The outer trocar of the double needle usually has an outer diameter of 1.2 mm (18 Gauge),

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Rhoads GG, Jackson LG, Schlesselman SE, de la Cruz FF, Desnick RJ, Golbus MS, Ledbetter DH, Lubs HA, Mahoney MJ, Pergament E, et al.

The safety and efficacy of chorionic villus sampling for early prenatal diagnosis of cytogenetic abnormalities. N Engl J Med 1989; 9;320(10):609-17.

Rodeck CH, Sheldrake A, Beattie B, Whittle MJ. Maternal serum alphafetoprotein after placental damage in chorionic villus sampling.

Lancet 1993;20;341(8843):500 Saura R, Longy M, Horovitz J, Grison O, Vergnaud A, Taine L, Maugey B. Risks of transabdominal chorionic villus sampling before the 12th week of amenorrhea. Prenat Diagn 1990;10(7):461-7.

Saura R, Horovitz J, Grison O, Longy M, Maugey B, Lesesve JF, Vergnaud A, Roux D. Evaluation of the risks of transabdominal chorionic villus sampling. 600 cases. J Gynecol Obstet Biol Reprod 1991;20(4):496.

Schulman, LP, Meyers, CM, Simpson, JL, Andersen, RN, Tolley, EA, Elias, S. Fetomaternal transfusion depends on the amount of villi aspirated but not on method of chorionic villus sampling. Am J Obstet Gynecol 1990;162:1185-1188.

Silver RK, MacGregor SN, Sholl JS, Hobart ED, Waldee JK. An evaluation of the chorionic villus sampling learning curve. Am J Obstet Gynecol 1990;163(3):917-22.

Silver RK, MacGregor SN, Hobart ED. Factors associated with multiplepass procedures during chorionic villus sampling: a video analysis. Prenat Diagn 1992;12(3):183-8.

Smidt-Jensen S, Hahnemann N. Transabdominal fine needle biopsy from chorionic villi in the first trimester. Prenat Diagn 1984;4(3):163.

Smidt-Jensen, S, Hahnemann, N. Transabdominal chorionic villi sampling for fetal diagnosis Technical and obstetrical evaluation of 100 cases. Prenat Diagn 1988;8:7-17.

Smidt-Jensen, S, Permin, M, Philip, J, et al. Randomised comparison of amniocentesis and transabdominal and transcervical chorionic villus sampling. Lancet 1992;340:1237-1244.

Smidt-Jensen, S, Lind, A-M, Permin, M, Zachary, JM, Lundsteen, C, Philip, J. Cytogenetic analysis of 2928 CVS and 1075 amniocenteses from randomised studies. Prenat Diagn 1993;13:723-740.

Smidt-Jensen, S, Lundsteen, C, Lind, A-M, Dinesen, K, Philip, J. Transabdominal chorionic villus sampling in the second and third trimesters of pregnancy: Chromosome quality, reporting time and feto-maternal bleeding. Prenat Diagn 1993;13:957-969.

Smidt-Jensen, S, Philip, J, Zachary, JM, Fowler, SE, Nørgaard-Pedersen, B. Implications of maternal serum alpha-fetoprotein elevation caused by transabdominal and transcervical CVS. Prenat Diagn 1994;14:35-45.

Smidt-Jensen S. Transabdominal chorionic villus sampling Method, safety and accuracy. Dan Med Bull 1998;45(4):402-11.

Snijders RJM, Nicolaides KH. Ultrasound markers for fetal chromosomal defects. The Parthenon Publishing Group, New York, London, 1996.

Stengel-Rutkowski, S. Prenatal diagnostic on chorionic villi. Final report on the documentation of the investigation within the collaborative study in the Federal Republic of Germany 1985-1991, München: Kinderzentrum München, 1993.

Stranc LC, Evans JA, Hamerton JL. Chorionic villus sampling and amniocentesis for prenatal diagnosis. Lancet 1997;8;349(9053):711-4.

Sundberg K, Bang J, Smidt-Jensen S, Brocks V, Lundsteen C, Parner J, Keiding N, Philip. Randomised study of risk of fetal loss related to early amniocentesis versus chorionic villus sampling. Lancet 1997;350:697-703.

Tabor, A, Philip, J, Madsen, M, Bang, J, Obel, EB, Nørgaard-Pedersen, B. Randomised controlled trial of genetic amniocentesis in 4606 low-risk women. Lancet 1986a;7:1287-1293.

Tabor A, Jerne D, Bock J. Incidence of rhesus immunization after genetic amniocentesis. BMJ (Clin Res Ed) 1986b;293:533-536.

Therkelsen, AJ, Jensen, PKA, Hertz, JM, Smidt-Jensen, S, Hahnemann, N. Prenatal diagnosis after transabdominal chorionic villus sampling in the first trimester. Prenat Diagn 1988;8:19-31.

Wade RV, Young SR. Analysis of fetal loss after transcervical chorionic villus sampling-a review of 719 patients. Am J Obstet Gynecol 1989;161(3):513-8; discussion 518.

Wapner RJ, Jackson L. Chorionic villus sampling. Clin Obstet Gynecol 1988;31(2):328-44.

Warren RC, Butler J, Morsman JM, McKenzie C, Rodeck CH. Does chorionic villus sampling cause fetomaternal haemorrhage? Lancet 1985;23;1(8430):691.

Weiner S. Indications, complications, safety, reliability and assessment of quality of fetal blood. Ultrasound Obstet Gynecol 1991;1(suppl):17.

Wijnberger LD, van der Schouw YT, Christiaens GC. Learning in medicine: chorionic villus sampling. Prenat Diagn 2000;20(3):241-6.

Ville Y, Cooper M, Revel A, Frydman R, Nicolaides KH. Development of a training model for ultrasound-guided invasive procedures in fetal medicine. Ultrasound Obstet Gynecol. 1995;5(3):180-3.

Brambati, B, Terzian, E, Tognoni, G. Randomised clinical trial of transabdominal versus transcervical chorionic villus sampling methods.

Prenat Diagn 1991;11:285-293.

Burton, B, Schulz, CJ and Burd, LI. Limb abnormalities associated with chorionic villus sampling. Obstet Gynecol 1992;79:726-730.

Cameron AD, Mathers AM, Wisdom S, Johnstone J, MacKenzie JR, Walker JJ, Imrie SJ, Lowther GW, Connor JM. Second-trimester placental biopsy for rapid fetal karyotyping. Am J Obstet Gynecol 1990;163(3):931.

Canadian Collaborative CVS-Amniocentesis Clinical Trial Group.

Multicentre randomised clinical trial of chorionic villus sampling and amniocentesis Lancet 1989;1:1-6.

Chueh JT, Goldberg JD, Wohlferd MM, Golbus MS. Comparison of transcervical and transabdominal chorionic villus sampling loss rates in nine thousand cases from a single center.

Am J Obstet Gynecol. 1995;173(4):1277-82.

Copeland KL, Carpenter RJ Jr, Fenolio KR, Ledbetter DH Integration of the transabdominal technique into an ongoing chorionic villus sampling program. Am J Obstet Gynecol 1989;161(5):1289-94.

Farrell SA, Summers AM, Dallaire L, Singer J, Johnson JA, Wilson RD. Club foot, an adverse outcome of early amniocentesis: disruption or deformation? CEMAT Canadian Early and Mid-Trimester Amniocentesis Trial. J Med Genet 1999;36(11):843-6.

Firth, HV, Boyd, PA, Chamberlain, P, Mackenzie, IZ, Lindenbaum, RH, Huson, SM. Severe limb abnormalities after chorion villus sampling at 56-66 days' gestation. Lancet 1991;337:762-763.

Froster, UG, Jackson, L. Limb defects and chorionic villus sampling: results from an international registry, 1992-94. Lancet 1996;347:489.

Hertz JM, Jensen PK, Therkelsen AJ. Convoluted cells as a marker for maternal cell contamination in CVS cultures. Clin Genet 1987;31(6):410-2.

Hibbard JU, Loy GL, Hibbard MC. Does chorionic villus sampling compromise fetal umbilical blood flow? Prenat Diagn 1994;14(12):1107.

Hitschold T, Berle P. [Transabdominal chorionic villi and placental biopsy: rapid karyotyping in the 1st-3rd trimester of pregnancy] Ultraschall Med 1997;18(3):134-8.

Hsieh FJ, Shyu MK, Sheu BC, Lin SP, Chen CP, Huang FY. Limb defects after chorionic villus sampling. Obstet Gynecol 1995;85:84-8 Holzgreve, W, Miny, P, Schloo, R. "Late CVS" international registry compilation of data from 24 centres. Prenat Diagn 1990;10:159-167.

Jackson, LG, Zachary, JM, Fowler, SE, et al. A randomised comparison of transcervical and transabdominal chorionic villus sampling. N Eng J Med 1992;327:594-598.

Knott PD, Chan B, Ward RH, Chard T, Grudzinskas JG, Petrou M, Modell B.Changes in circulating alphafetoprotein and human chorionic gonadotrophin following chorionic villus sampling. Eur J Obstet Gynecol Reprod Biol 1988;27(4):277-81.

Kuliev, A, Jackson, L, Froster, U, Brambati, B, Simpson, JL, Verlinsky, Y, Ginsberg, N, Smidt-Jensen, S, Zakut, H. Chorionic villus sampling safety Report of World Health Organization/EURO meeting in association with the Seventh International Conference on Early Prenatal Diagnosis of Genetic Diseases, Tel, Aviv, Israel, May 21, 1994. Am J Obstet Gynecol 1996;174:807-811.

Ledbetter, DH, Zachary, JM, Simpson, JL, et al. Cytogenetic results from the US collaborative study on CVS. Prenat Diagn 1992;12:317-345.

Lilford RJ, Linton G, Irving HC, Mason MK. Transabdominal chorion villus biopsy: 100 consecutive cases. Lancet 1987;20;1(8547):1415-7.

Mackenzie WE, Holmes DS, Newton JR. A study comparing transcervical with transabdominal chorionic villus sampling (CVS). Br J Obstet Gynaecol 1988;95(1):75-8.

Mariona FG, Bhatia R, Syner FN, Koppitch F. Chorionic villi sampling changes maternal serum alpha-fetoprotein. Diagn 1986;6(1):69-73.

MRC working party on the evaluation of chorionic villus sampling Medical Research Council European trial of chorion villus sampling.

Lancet 1991;337:1491-1499.

Nicolaides KH, Brizot ML, Patel F, Snjders R. Comparison of chorion villus sampling and early amniocentesis for karyotyping in 1,492 singleton pregnancies. Fetal Diagn Ther 1996;11(1):9-15.

Nizard J, Duyme M, Ville Y.Teaching ultrasound-guided invasive procedures in fetal medicine: learning curves with and without an electronic guidance system. Ultrasound Obstet Gynecol 2002;19(3):274-7.

Pijpers L, Jahoda MG, Reuss A, Wladimiroff JW, Sachs ES. Transabdominal chorionic villus biopsy in second and third trimesters of pregnancy to determine fetal karyotype. BMJ 1988;1;297(6652):822-3.

Pocock, SJ. Clinical trials. Wiley, S & Sons 1987.

Podobnik M, Ciglar S, Singer Z, Podobnik-Sarkanji S, Duic Z, Skalak D. Transabdominal chorionic villus sampling in the second and third trimesters of high-risk pregnancies. Prenat Diagn 1997;17(2):125-33.

Quilter CR, Holman S, AL-Hammadi RM, Theodorides D, Hastings RJ, Delhanty JD. Aneuploidy screening in direct chorionic villus samples by fluorescence in situ hybridisation: the use of commercial probes in a clinical setting. BJOG 2001;108(2):215-8.

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2002-186_ICS Nanna Bang

15/07/02

EUROPEAN CONGRESS

OF

U LT R A S O U N D

F I R S T J O I N T S C A N D I N AV I A N M E E T I N G

Hosted by EFSUMB and the Scandinavian Ultrasound Societies

WELCOME TO COPENHAGEN

GENERAL INFORMATION

DEAR COLLEAGUES AND FRIENDS

CALL FOR PAPERS

PRE-CONGRESS COURSES AND WORKSHOPS

We are delighted to invite you to participate in EUROSON 2003, the 15th Congress of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) and the 1st joint Scandinavian Meeting. The Congress will be held in Copenhagen, Denmark, from 27 - 30 April 2003.

As a participant to the EUROSON 2003 you may take active part in the courses and workshops planned the first day of the Congress, Sunday April 27. The courses and workshops will be held at the Congress Center or at University Hospitals nearby. We also want to set focus on a series of plenary lectures in honour of professor Hans Henrik Holm´s contribution to diagnostic and interventional ultrasound. These lectures will take place immediately after the opening on Sunday April 27. We have invited 4 internationally well-known experts who will present the latest within US technology, interventional procedures and fetal medicine. The following 3 days - Monday April 28 to Wednesday April 30 - are dedicated to a broad scientific programme, which also include sonographers sessions and symposia. In addition to a scientific programme comprising well-known topics such as urogenital US, gastrointestinal US, breast US, head and neck US and paediatric US we also want to set focus on topics such as surgical and interventional US, musculoskeletal US, vascular US as well as US in gynaecology and obstetrics.

The scientific programme will be held as three parallel sessions. Leading experts will provide invited lectures. However, to ensure a high scientific standard an active contribution from participants is needed. We therefore invite you to submit an abstract for an oral communication or a poster presentation.

We hope that you find the time and the means to come to Wonderful Copenhagen 27-30 April 2003. We will do our best to offer you an unforgettable stay, both from a scientific and a cultural point of view. Please visit our homepage www.euroson2003.com for updates, registration, abstract submission, scientific programme, and pre-congress courses etc.

You are kindly invited to submit an abstract describing an original research work that you wish to present at the Congress, either orally or as a poster. All abstracts will be evaluated. Abstracts will be published in the Final Programme & Abstract Book. Deadline for abstract submission is 16 January 2003. For further details please check the webpage or the second announcement available in September.

Sunday 27 April 2003 “IBUS - International Breast Ultrasound Seminar” “Advanced “hands-on” in surgical and interventional ultrasound, including RF tissue ablation” “Workshop in Ultrasonography of Joints” “Workshop in Vascular Ultrasound” “US Technology Update” “The 11 to 14-week scan - Fetal Medicine Foundation (FMF) Course” “Fetal echocardiography” “The role of ultrasound in early pregnancy complications”

REGISTRATION Early registration is before 16 January 2003. There will be a reduced fee for presenting authors, residents 35 years, sonographers, nurses and midwives. Presenting authors must register. We will try to keep the registration fees as low as possible, please check second announcement and the homepage for details.

CONGRESS VENUE The Bella Center, which will be the Congress Venue, is a modern Congress and Exhibition facility, less than 10 minutes from downtown Copenhagen and the airport.

IMPORTANT DATES

Hope to see you in Copenhagen Michael Bachmann Nielsen Congress President Chairman of Local Organising Committee

Kurt A. Jäger Congress President President of EFSUMB

Steen Karstrup Chairman of Scientific Committee

ORGANISATION Odd Helge Gilja (NO), Vicepresident

Nanna Bang (DK), Chairman of Publications & PR

Lil Valentin (SE), Vicepresident

Anders Nilsson (SE), Chairman of Social Committee

Bruno Cacciatore (FI), Vicepresident

Niels Juul (DK)

Christian Nolsøe (DK), Vicepresident

Torben Larsen (DK)

Torben Lorentzen (DK), Treasurer

Thomas Axelsen (DK), Webmaster

Peter Myschetzky (DK), Secretary

Congress Secretariat, ICS A/S, Copenhagen Tel: +45 3946 0500 • Fax: +45 3946 0515 E-mail: euroson2003@ics.dk

Bjørn Skjoldbye (DK), Chairman of Exhibition & Sponsorships

DEADLINE

FOR

ABSTRACT SUBMISSION:

CONGRESS DATES:

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W W W. E U R O S O N 2 0 0 3 . C O M

E UROSON 2003

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Side 2

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E UROSON 2003

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EUROSON 2002 SAFETY SESSION: 6 JULY 2002: WARSAW Much more emphasis will be required during training before it may be assumed that these indices are the sole means of managing safety.

During the second session, six speakers gave detailed reviews of particular aspects of safety.

Tissue heating in vivo, caused by clinical scanners, is being investigated by a team in the UK, funded by the Department of Health. Some results were presented by Adam Shaw (NPL), who showed quite good

Euroson 2002, held in Warsaw during the first week of July, gave this year a particular emphasis to the safety of diagnostic ultrasound. Thanks to the generous financial support of COCIR an international group of speakers were able to come together in Warsaw to share with the Congress delegates their knowledge and experience. In addition to European experts, speakers from Australia, USA and Japan also contributed to the sessions. It was possibly the first time that the chairs of the Japanese, European, Australian, American and WFUMB ultrasound safety committees all spoke during a safety session of a medical ultrasound congress.

The papers on safety were grouped into two sessions. In the first, appropriate ways of managing ultrasound safety were discussed. Prof Marvin Ziskin, Chairman of the WFUMB Safety Committee, described the activities of WFUMB in creating recommendations on safety of diagnostic ultrasound. He reviewed the many issues needing consideration to ensure that the clinical benefits of using ultrasound are weighed against any small risks. He informed the audience that the WFUMB Safety Committee is currently compiling information on any risks that may be associated with the use of gas-body contrast agents. Six international experts meet immediately after EUROSON 2002 to discuss a detailed draft report. This report, with conclusions and recommendations, will be circulated to a wider group for comment in the next few months, and it is intended to complete the report in time for the next WFUMB meeting in Montreal in June 2003.

The responsibility of industry to design safe ultrasound systems was reviewed by Dr Peter Linders (Philips Medical). He made it clear that manufacturers were bound by international safety standards of manufacture, but that the safe use of ultrasound scanners, and risk/benefit judgements, were in the hands of clinical users.

Classification of equipment was presented by Dr Roy Preston (National Physical Laboratory, UK) as a possible means to assist users to make safety judgements.

Publications in Germany and in the UK describe a classification scheme, within which the lowest class could be used with minimal concern for patient safety. This approach has been rejected, at present, by the International Electrotechnical Commission (IEC). It was interesting, nevertheless, to hear from the chairman of the Japanese Ultrasound Society Safety Committee, Dr Natori, who described the difficulties experienced in Japan in creating complete links between the national medical ultrasound society and the national standards committees.

Safe management is becoming increasingly important, with the rapid development of wide range of new techniques.

The safety implications of these new techniques were reviewed by Dr Tony Whittingham, secretary of ECMUS.

agreement between predicted and measured heating, at least for soft tissues. Temperature rises of a few degrees have been observed, with greatest heating close to the transducer, caused by probe self-heating. Professor Lesek Filipczynski (Warsaw) has also been studying tissue heating, but at higher frequencies in a 33MHz ultrasonic microscope. He reported focal temperature increases of 3.3 K for 2.25W pulses. Contrast agents present completely concerns for ultrasound safety, and this rapidly-developing field was presented with great clarity

by Prof Diane Dalecki, from Rochester, New York. Drawing on her own experimental results and those of other leading laboratories, she identified two major safety issues for contrast use. These are the potential to cause capillary rupture, and the generation of premature ventricular contractions. Further studies are essential to create further understanding of the

mechanisms and thresholds.

The chair of ECMUS, Dr Kjell Salvesen, discussed in some detail new evidence for an association between ultrasound exposure in utero and a subsequent tendency to be left-handed. There is consistency between the four epidemiological studies into this topic. Nevertheless, he advised that causation has yet to be proved, and that the evidence does not alter ECMUS advice allowing ultrasound examination during pregnancy for all patients.

Dr Stan Barnett, (Sydney, Australia) chair of the ASUM safety committee, reviewed policies used around the world on the use of live models at scientific conferences. He contrasted the ASUM position, banning all use of live models, with that of EFSUMB where the ban extends only to exposure of pregnant women, juveniles and the use of contrast agents. WFUMB has no policy at present. He pointed out that some countries and disciplines place no bar on live scanning at commercial exhibits, and expressed the view that such practices should not be supported by responsible societies of ultrasound in medicine. The Safety Session was concluded with an entertaining overview by Dr Jacques Abramovich (Chicago), who drew many of the themes together in presenting a practical approach to safety management in the clinic. MI and TI give a practical means to monitor exposure from which to make risk-benefit judgements. For all their deficiencies safety indices give, at present, the best means available for users to ensure the continued safety of their patients.

He reminded us that some new techniques may result in reduced exposure, in 3D scanning for instance. Other techniques may require no net alteration in exposure, whilst yet others may be expected to require higher levels to work successfully. Users should ensure that they are informed about the exposure implications of the introduction of new methods.

At the end of the first safety session, the speakers debated briefly the question of whether acoustic output should be limited: only the FDA in the USA applies output limits at present. Of particular interest from this discussion was the view that the Safety Indices (TI and MI) are, to a large extent, ignored by users as a means for safety management.

The EUROSON 2002 Safety Session enabled a wide-ranging debate of safety issues at the highest level of knowledge and understanding. It demonstrated the intimate links between clinical users, basic scientists, industry and regulators who, working in co-operation, will ensure that diagnostic ultrasound remains the safest of imaging modalities.

Francis Duck Past Chairman ECMUS â&#x20AC;&#x201C; Safety Committee

14

EPIDEMIOLOGY OF DIAGNOSTIC ULTRASOUND EXPOSURE DURING PREGNANCY EFSUMB SAFETY TUTORIAL Childhood malignancies

Despite many laboratory experiments, which show a lack of adverse effects from diagnostic ultrasound, it will always be necessary to study directly its effect in human populations before any definitive statements regarding risk can be made. With an increasing number of epidemiological studies of diagnostic ultrasound, the need to review and interpret the results from these studies is evident.

When the outcome under study is rare, such as childhood malignancies, any approach other than the case-control design is unsuitable. Four published studies regarding ultrasound and childhood malignancies have been well conducted and are of adequate size[14-17]. Results from these studies are presented in Table 1. No association between in utero ultrasound exposure and childhood leukemia or solid tumours was found.

Epidemiological studies may be divided into observational and experimental studies (see figure 1). The observational studies are subdivided into descriptive and analytical studies. Descriptive studies are suitable for generating new hypotheses about associations between exposure and disease, whereas analytical studies are designed to test such hypotheses. The simplest descriptive study is the cross-sectional study, in which patients are examined only once. In a longitudinal study, the patients are followed over time, but the study is still classified as hypothesis generating. Analytical studies, on the other hand, have a prior hypothesis of a possible association between exposure and disease. They are subdivided into cohort and casecontrol studies depending on whether the scientist starts out with the exposure or the disease. In the simplest case-control design, patients are examined only once, whereas it is necessary to follow patients over time in a cohort study. The randomised controlled trial is regarded to be the best way to examine possible cause-effect relationships in human populations. There are, however, many problems in medicine that would be impossible or unethical to test in a randomised controlled trial.

Neurological development and dyslexia In a cohort study, Stark and co-workers (1984) examined 425 ultrasound exposed and 381 unexposed children when they were 7 to 12 years old[3].

They studied a possible association between ultrasound exposure and 17 outcomes that included hearing, vision, cognitive function, behaviour, and neurological examination. They found a significantly greater proportion of exposed children to be dyslexic, but no association with other outcomes.

The difference between groups was possibly a chance finding due to multiple hypotheses testing, or the result of the general problem with bias and confounding factors in cohort studies. The consensus was, however,

that further research was needed, and this is why a follow-up of two Norwegian randomised controlled trials on routine ultrasound in pregnancy was performed in 1988-90.

The follow-up of the Norwegian trials was designed to look for possible adverse effects of ultrasound on the fetal brain. The study tested six hypotheses of a possible association between ultrasound and dyslexia, school performance, non-right handedness, deficits in attention, motor control and perception, hearing ability, visual acuity and neurological development. Handedness was assessed because lefthandedness is linked to dyslexia and deficits in attention, motor control and perception. Data were collected from a questionnaire to the parents and records from maternal and child health centers. In the second year of primary school, 2 011 children were evaluated by their teachers with regards to reading aptitude, spelling, arithmetic and overall performance. A subset of 603 children was tested with specific tests for dyslexia (tests measuring intelligence, reading and spelling).

There were no associations between ultrasound and dyslexia, poor school performance, delayed neurological development, poor vision or hearing[18-20]. In fact, there was a trend towards improvement of all these outcomes in the ultrasound group, although this was not statistically significant. The results suggested that it is unlikely that routine ultrasound examinations can “cause harm to the developing fetal brain”.

This tutorial summarises some of the epidemiological evidence from studies on in utero ultrasound and subsequent childhood development.

Emphasis is placed on birth weight, childhood malignancies, neurological development, handedness and speech development.

Birth weight The question of whether ultrasound exposure in utero leads to reduced birth weight has probably been given more attention than any other end point. This may be due to the existence of such an effect in some animal models or possibly because it is relatively quick and easy to measure.

Human birth weight data have been reported in many epidemiological studies[1-12], but there is only one study[12], which has created some concern. Newnham and co-workers did a randomised controlled trial with 2 834 pregnant women from Western Australia[12]. They offered half of the women continuous wave Doppler ultrasound examinations five times in the 3rd trimester. These were compared with controls that received one diagnostic imaging ultrasound scan at 18 weeks and otherwise had standard antenatal care. The authors reported a statistically significant increase in the number of babies in the Doppler group with a birth weight below the 10th percentile (relative risk 1.35, 95% confidence interval 1.09 to 1.67), but the difference in mean birth weight between the groups was only 25 g (not significant). It must be emphasised that this randomised trial tested a formal hypothesis that frequent Doppler ultrasound examinations might improve pregnancy outcome. Additional data analyses performed in the study do not have the advantages built into a randomised controlled trial. They may, however, be used to generate a new hypothesis, which must then be tested in another independent study.

Handedness There was, however, a statistically significant association between two routine ultrasound examinations at 18 and 32 pregnancy weeks and subsequent non-right handedness among 8-9 year old children[20]. The finding was of borderline statistical significance (odds ratio 1.32, 95% confidence interval 1.02 to 1.71), but the hypothesis was stated in advance and thus it was unlikely to result from multiple hypotheses testing. The association was restricted to boys[21], and it was strengthened when an exploratory analysis on ultrasound exposure was performed[20]. The authors emphasised “the need to replicate the association between ultrasound and non-right handedness before it is interpreted as more than a chance finding”[20].

In a similar follow-up study from Sweden, 3 265 children (71% of all eligible children from a randomised controlled trial) were followed up through a questionnaire sent to their mothers. There were no differences between ultrasound exposed and unexposed children with regards to hearing, vision, growth or behavioural disorders[22, 23].

Furthermore, there was no statistically significant association between one routine ultrasound scanning at 15 weeks and non-right handedness among all the children at age 8-9 years[24]. However, there was a statistical significant association between ultrasound exposure in utero and non-right handedness in a separate analysis of the boys (odds ratio 1.33, 95% confidence interval 1.02 to 1.74)[24].

Results from the Australian trial are inconsistent with the available data on birth weight from other randomised trials of diagnostic imaging ultrasound[1, 2, 7, 8, 10, 11]. Those studies have been summarised in a Cochrane review [13] which concludes that there is no statistically significant difference in the proportion of low birth weight children (< 2.5 kg) between ultrasound-screened children and controls (odds ratio 0.96, 95% confidence interval 0.82 to 1.12). Since Doppler ultrasound studies usually imply higher levels of exposure than diagnostic imaging, the differences between the Australian trial and the other trials may reflect a dose-response relationship. However, the results from the Australian trial should be repeated by a new independent study before the reported effect of Doppler ultrasound on birth weight should be regarded as anything more than a chance finding.

The results from the Norwegian and Swedish follow-up studies have been analysed together in two review papers[25, 26]. A meta-analysis is also available in a Cochrane review[13]. The metaview from Cochrane is presented as figure 2. Figure 2 demonstrates that almost all the odds ratios (except for handedness) lie to the left of the vertical line.

15

a general problem with all cohort studies. One can control for known confounding factors, but there is always the possibility that some other unknown bias or confounding factor can invalidate the study. Thus, a cohort design will always give weaker epidemiological evidence of an association between exposure and outcome than a randomised controlled trial.

the odds ratios (except for handedness) lie to the left of the vertical line. This means that ultrasound screened children are doing better than the controls for all outcomes other than handedness. This is not statistically significant, however, because the 95% confidence intervals include the value of 1. However, it should be noted that both spelling at school (odds ratio 0.73, 95% confidence interval 0.53 to 1.00) and visual acuity (odds ratio 0.82, 95% confidence interval 0.66 to 1.01) were improved among the screened children with “borderline” statistical significance[13]. The metaview from Cochrane also demonstrates that there are no statistically significant differences between screened children and controls with regards to non-right handedness, left-handedness or ambidexterity (figure 2).

A final conclusion of a possible association between prenatal ultrasound and left-handedness among males can not yet be drawn. If we rely on the data presented in the Cochrane review[13], there is no statistically significant association between prenatal ultrasound and left-handedness (figure 2). The Cochrane review has decided not to present any data from a gender-specific subgroup analysis of the trials.

If we accept subgroup analyses from randomised controlled trials[26], we find a statistically significant association between prenatal ultrasound and left-handedness among males. If we also accept the results from cohort studies, such as the Swedish one[27], the conclusion must be that three epidemiological studies report a 30% increase in the likelihood of sinistrality among males, and so far no other epidemiological evidence contradicts this association.

There is a debate in epidemiological literature whether to allow for subgroup analyses in randomised controlled trials. A gender-specific analysis of handedness is a subgroup analysis. Subgroup analyses must always be interpreted with caution, and exploratory analyses will always be influenced by possible biases and confounding factors. The Cochrane review has chosen not to present any data from a genderspecific subgroup analysis of the trials[13].

The discussion on prenatal ultrasound and left-handedness is complex and is explored in greater detail elsewhere[28]. A statistical association between ultrasound and left-handedness should not lead to the conclusion that ultrasound causes harm to the developing brain.

One of the experts in the field of laterality research has stated: ”Laterality research is unfortunately prone to misapplying complex statistics and producing wrong or uninterpretable findings”[29].

Studies on adverse effects on the brain must be based on multiple outcomes, not on a single parameter like handedness. The Scandinavian randomised controlled trials were based on multiple outcomes, and the results were reassuring.

In a meta-analysis with a less conservative statistical approach, a gender-specific subgroup analysis was done[26]. When boys were analysed separately and according to the “intention-to-treat” principle, there was a statistically significant increase of non-right handedness among the screened boys (odds ratio 1.26, 95% confidence interval 1.03 to 1.54)[26]. In an exploratory analysis according to ultrasound exposure before 19 or 22 weeks of pregnancy, there was a statistically significant increased prevalence of non-right handedness among the exposed children (odds ratio 1.19, 95% confidence interval 1.02 to 1.38). When the analysis of exposure was confined to boys only, the difference between the groups increased (odds ratio 1.34, 95% confidence interval 1.10 to 1.65)[26]. All meta-analyses can give ”numbers needed to treat” (NNT). This relationship between treatment (or exposure) and outcome is calculated from the observed risk differences. The risk difference (RD) between exposed and nonexposed boys was 0.05 (95% confidence interval 0.01 to 0.08). Since NNT = 1/RD, it may be estimated that 20 male fetuses need to be exposed to give one non-right handed boy. This corresponds to five extra non-right handed boys among one hundred male births[26].

Speech development In a case-control study[30], Campbell and co-workers compared 72 children with delayed speech of unknown origin with 144 matched controls. The study reported that the odds of suffering from delayed speech were 2.8 (p = 0.001) times higher among children who were exposed to ultrasound at least once during pregnancy. In this rather small study, the information on ultrasound exposure was not assessed blind, and there is the possibility of misclassification of exposure.

Also, the study design of a case-control study makes it impossible to rule out other biases, especially related to selection of subjects and misclassification of information between cases and controls. Thus, the results from the study should be viewed cautiously.

The University Hospital in Malmö was the first medical center in Sweden to use ultrasound scans as part of standard antenatal care. In a further study, males born in Malmö in 1973-78 were compared with males born during the same time period at other Swedish medical centers that had not yet introduced ultrasound[27]. Handedness was determined as part of eligibility testing for military service. Preferred hand was determined by handing a replica rifle to the enrolee, who was then asked to take up alert position. Only enrolees who shot lefthanded were registered as such. Those not registered were either right handed or not tested. During the introduction phase of routine screening with ultrasound (1973-75) there was no difference in lefthandedness between ultrasound exposed and unexposed (odds ratio 1.03, 95% confidence interval 0.91 to 1.17). When ultrasound was offered more widely (1976-78), the association with left-handedness was higher among those exposed to ultrasound compared with those unexposed (odds ratio 1.32, 95% confidence interval 1.16 to 1.51).

The estimated effect corresponds to three extra left-handers among one hundred male births[27].

In the Norwegian randomised follow-up study, assessment of speech development was done through a parental questionnaire and also from records from maternal and child health centers[31]. According to health center records, screened children were not referred to a speech therapist as often as control children were (odds ratio 0.51, 95% confidence interval 0.31 to 0.85). However, the association between ultrasound exposure in pregnancy and speech development was not among the six prior hypotheses in the Norwegian study. Thus, the statistically significant protective effect of ultrasound exposure may have been due to chance. On the other hand, unlike the Canadian casecontrol study[30], misclassification bias was not likely to be responsible for this result.

The Swedish follow-up study has also reported on speech development[22]. In a questionnaire with 52 questions, parents were asked four questions regarding the speech development of their children. Delayed speech development was reported by 2.9% in the screened group compared with 2.4% in the control group (odds ratio 1.21, 95% confidence interval 0.79 to 1.88).

Since the study is a cohort study, there might be bias or confounding factors involved in explaining the reported association between ultrasound and left-handedness. There is no doubt that the rough method of assigning ultrasound exposure has misclassified some of the people in the study. Misclassification of handedness is also possible. However, the authors argue that the misclassification bias would be of non-differential nature. This means that misclassification of exposure and outcome are unrelated (enrolees at different centres throughout Sweden had equal chance of being misclassified as lefthanded according to the replica rifle test). This implies that if the association between ultrasound and handedness is distorted, it would be larger than what is reported, not smaller.

Conclusions Epidemiological studies have indicated no association between diagnostic ultrasound exposure during pregnancy and childhood malignancies. Diagnostic ultrasound imaging does not seem to influence birth weight, whereas frequent Doppler ultrasound was associated with reduced birth weight in one study. This association between Doppler ultrasound and low birth weight is probably a chance finding. The possible associations between ultrasound and dyslexia, and ultrasound and delayed speech development, reported in two studies, have not been confirmed in two later randomised controlled trials. However, the two randomised controlled trials and a recent cohort study have been unable to rule out a possible association

The authors have controlled for the influence of possible confounding factors. The statistical analyses are appropriate and support the reported association between ultrasound and left-handedness.

However, there are indications of differences between the populations of Malmö and the rest of Sweden. Such differences (e.g. race, social conditions, and sinistrality in the family) can distort the results. This is

16

Acknowledgment The figure from the Cochrane Review is reproduced with the kind permission of Update Software Limited. Cochrane Reviews are regularly updated as new information becomes available and in response to comments and criticisms. The reader should consult The Cochrane Library for the latest version of a Cochrane Review.

Information on the Cochrane Library can be found at www.updatesoftware.com.

between ultrasound and left-handedness among males. Thus, there is still a need for more research.

Based on scientific evidence of ultrasonically induced biological effects to date, there is no reason to withhold scanning for any clinical application, including the routine clinical scanning of every woman during pregnancy. Competent personnel who are trained in safety matters should continue their prudent use of ultrasound.

Table 1. Case-control studies of ultrasound exposure during pregnancy and childhood malignancies.

Year of Cases Exposed Controls Exposed Study Cancer type death/diagn.

N % N % OR Leukemia 1972-81 665 6 665 6 1 Wilson and Solid Waterhouse1984 tumours 1972-81 1066 6 1066 6 0.98 Leukemia 1980-83 149 23 298 22 1.12 Cartwright et al.

Other 1984 tumours 1980-83 406 27 812 29 0.86 Leukemia 1986-91 166 36 166 38 0.9 Shu et al. 1994 Other tumours 1981-91 476 23 476 27 0.8 RES Sorahan neoplasms 1982-84 212 25 212 25 1.03 et al. 1995 Solid tumours 1982-84 308 28 308 29 0.94

p-value ns ns ns ns ns ns ns ns

Figure 2. Metaview from the Cochrane Review of ultrasound for fetal assessment in early pregnancy. The Peto odds ratios are displayed with 95% confidence intervals.

Figure 1. Classification of epidemiological studies

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Bakketeig, L., et al., Randomised controlled trial of ultrasonographic screening in pregnancy. Lancet, 1984. 2: p. 207-211.

Eik-Nes, S., et al., Ultrasound screening in pregnancy: a randomised controlled trial. Lancet, 1984. 2: p. 1347.

Stark, C., et al., Short and long term risks after exposure to diagnostic ultrasound in utero. Obstet Gynecol, 1984. 63: p. 194-200.

Scheidt, P., F. Stanley, and D. Bryla, One-year follow-up of infants exposed to ultrasound in utero. Am J Obstet Gynecol, 1978. 131: p.

743-748.

Moore, R., E. Diamond, and R. Cavalieri, The relationship of birth weight and intrauterine diagnostic ultrasound exposure. Obstet Gynecol, 1988. 71: p. 513-517.

Lyons, E., et al., In utreo exposure to diagnostic ultrasound: A 6-year follow-up. Radiology, 1988. 166: p. 687-690.

Waldenström, U., et al., Effects of routine one-stage ultrasound screening in pregnancy: a randomised controlled trial. Lancet, 1988.

2: p. 585-588.

Saari-Kemppainen, A., et al., Ultrasound screening and perinatal mortality: controlled trial of systematic one-stage screening in pregnancy. Lancet, 1990. 336: p. 387-391.

Davies, J., S. Gallivan, and J. Spencer, Randomised control trial of Doppler ultrasound screening of placental perfusion during pregnancy. Lancet, 1992. 340: p. 1299-1303.

Ewigman, B., et al., Effect of prenatal ultrasound screening on perinatal outcome. N Engl J Med, 1993. 329: p. 821-827.

Geerts, L., E. Brand, and G. Theron, Routine ultrasound examinations in South Africa: cost and effect on perinatal outcome a prospective randomised controlled trial. Br J Obstet Gynecol, 1996.

103: p. 501-507.

Newnham, J., et al., Effects of frequent ultrasound during pregnancy: a randomised controlled trial. Lancet, 1993. 342: p. 887-891. .Neilson, J., Ultrasound for fetal assessment in early pregnancy (Cochrane Review). 2001, The Cochrane Library: Oxford.

Wilson, L.K. and J. Waterhouse, Obstetric ultrasound and childhood malignancies. Lancet, 1984. 2: p. 997-999.

Sorahan, T., et al., Pregnancy ultrasound and childhood cancer: a second report from the Oxford Survey of Childhood Cancers. Br J Obstet Gynaecol, 1995. 102: p. 831-832.

Cartwright, R., et al., Ultrasound examination in pregnancy and childhood cancer. Lancet, 1984. 2: p. 999-1000.

Shu, X., et al., Diagnostic x-ray and ultrasound exposure and risk of childhood cancer. Br J Cancer, 1994. 70: p. 531-536.

Salvesen, K., et al., Routine ultrasonography in utero and subsequent vision and hearing at primary school age. Ultrasound Obstet Gynecol, 1992. 2: p. 243-247.

Salvesen, K., et al., Routine ultrasonography in utero and school performance at age 8-9 years. Lancet, 1992. 339: p. 85-89.

Salvesen, K., et al., Routine ultrasonography in utero and subsequent handedness and neurological development. Br Med J, 1993. 307: p.

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Salvesen, K., et al., Routine ultrasound scanning in pregnancy Authors' reply. Br Med J, 1993. 307: p. 1562.

Kieler, H., et al., Routine ultrasound screening in pregnancy and aspects of the children's subsequent neurologic development. Obstet Gynecol, 1998. 91: p. 750-756.

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CONTENTS OF EJU VOLUME 15 - ISSUE 3 2002

Combined carotid and transcranial color coded sonography in acute ischemic stroke.

Wada et al.

Bronchioloalveolar carcinoma: Sonographic pattern of pneumonia.

Gorg et al.

Improved detection of liver metastases with contrast enhanced wideband harmonic imaging :comparison with CT findings.

Esteban et al The efficacy of liver biopsy under ultrasonographic guidance on an outpatient basis.

Spezia et al.

GPs skills to perform limited goal orientated abdominal ultrasound examinations after one month of intensive training.

Suramo et al.

Grading of Pars Planitis by ultrasound biomicroscopyechographic and clinical study.

Greiner at al.

Observer variation in the sonographic measurement of optic nerve sheath diameter in normal adults.

Ballantyne et al.

Performance testing of medical echo/Doppler equipment .

Thijssen and Cuypers.

NEUROSONOLOGY SPECIAL ISSUE Transcranial Doppler Assessment of Cerebral Vasospasm Rune Aaslid Microembolus Detection by Transcranial Doppler Sonography Ralf Dittrich Clinical Impact of PFO Diagnostics with TCD G.P. Anzola Clinical Applications of a Non-invasive ICP Monitoring Method Bernhard Schmidt NAIS – Design of a Multicenter Study on Neurosonology in Acute Ischemic Stroke Michael Goertler Sonographic Imaging of the Brain Parenchyma Stefanie Behnke Impact of Contrast Agents in Cerebrovascular Diagnostics Günter Seidel Impact of the Contrast Agents in Cerebrovascular Diagnostics: Brain Perfusion and Ultrasonic Imaging Techniques Jens Eyding Ultrasound Enhanced Thrombolysis for Stroke: Clinical Significance Andrei Alexandrov Clinical Impact of IMT measurements Touboul Axial plane – the main domain of the transcranial duplex ultrasonography?

E Bartels Cerebral autoregulation studies in clinical practice Diehl Ultrasound enhanced thrombolysis Daffertshofer Transcranial duplex sonography of the venous system Valdueza / Stolz

18

REPORT FROM THE PUBLICATIONS COMMITTEE

REPORT FROM THE NEWSLETTER EDITOR

The Committee met during the Warsaw EUROSON Congress in July.

This will be my final issue of the Newsletter. I have had the privilege of compiling and editing the Newsletter for the past nine years and I would like to welcome Dr David Pilling as the new editor. His first issue will be the January 2003 issue.

The main item on the agenda was the position of the European Journal of Ultrasound. Unfortunately manuscript flow has remained below the level necessary to ensure the viability of the Journal and the number of subscriptions remains insufficient to make the Journal financially viable.

It is my sincere hope that at least some of you have found the contents of the Newsletter interesting and helpful. It is the prime means by which the decisions and activities of the committees of EFSUMB are notified to its members.

The combination of these two factors has lead the publishers, Elsevier, to decide to cease publication of the EJU at the end of 2002. In addition our Editor-inChief, Dr Peter Twining, has decided that he can no longer continue to dedicate his time to a rather unsuccessful journal.

The publication and distribution of the Newsletter has become the single most expensive item in the EFSUMB budget. My only real regret about my time as editor is that I have not managed to solicit more support from industry. However, we did receive great support from both ACUSON and ESAOTE during the early years and subsequently BRACCO have been fantastically generous in their support for the Newsletter. I would like to thank all three of these companies most sincerely for their generosity, the Newsletter could not have survived without them.

There will be a special issue of the Journal later this year on Neurosonology. This has been prepared under the editorship of Dr Eva Bartels and promises to be extremely good. We hope that there will be sufficient papers to fill the remaining issues to complete 2002.

At the end of the year ownership of the journal will be passed from Elsevier to EFSUMB in order to allow EFSUMB to consider relaunching the journal at some time in the future. There are three possible forms in which the EJU could be relaunched; these are, as a similar paper journal, as an electronic journal, or incorporated with an existing ultrasound journal. Each of these is under active consideration. However, whichever route is chosen we will need an enthusiastic and dedicated Editor-in-Chief. Any volunteers?

As you will see elsewhere in the Newsletter EFSUMB has established an Industrial Board to establish and improve communication between industry and EFSUMB. The first meeting was held in Warsaw and it was very reassuring to perceive the enthusiasm of the industrial representatives present for various forms of support for, and collaboration with, EFSUMB. I am sure that this new liaison will be very fruitful for both industry and EFSUMB and I hope that it may lead to increasing and more diverse support from industry for the Newsletter.

There were major changes to the membership of the committee.

The new committee is: Michel Claudon, Past President of EFSUMB, ex officio member Lucas Greiner the new Honorary Secretary of EFSUMB, ex officio member Jean-Michel de Bray, continuing member David Pilling, continuing member W Mann, new member

Finally I would like to thank Gianna Stanford, General Secretary of EFSUMB, for her unerring support and assistance with the production of the Newsletter. Ever since her appointment she has progressively improved and refined the ways in which the Newsletter is produced and has repeatedly searched out new printers and alternative means of distribution in order to try to contain the cost. Both EFSUMB and I owe her a great debt of gratitude.

Dr David Pilling has agreed to take over editorship of the EFSUMB Newsletter, starting with the January 2003 issue.

It has not yet been possible to publish the collected tutorial articles of ECMUS but the editing of these is almost complete and we hope to send them for publication before the end of the year.

I wish EFSUMB and all its members success in the future.

Hylton B Meire Past Chairman Publication Committee

Hylton B Meire Past Editor EFSUMB Newsletter

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IBUS BREAST ULTRASOUND SEMINAR - WARSAW 2002 (Dr Dominique Amy, France); ultrasound guided biopsy (Prof. Enzo Durante, Italy); 3D and 4D ultrasound of the breast (Prof. Christian Weismann, Austria), and new ultrasound techniques (Dr Kazimierz Szopinski, Poland).

A one-day "Breast Ultrasound Seminar" was held on July 4th, 2002 in Warsaw, Poland under the auspices of the 6th Scientific Congress of the Polish Ultrasound Society and the 14th Congress of the European Federation of Societies for Ultrasound in Medicine and Biology - Euroson 2002. The programme was complimentary for all participants registered at the Euroson 2002 congress, and three hundred fifty six physicians from 31 countries participated.

The last session in the afternoon took the form of demonstrating scanning techniques on a series of patients to find breast pathology, and the use of ultrasound guidance to perform a biopsy on a breast phantom. Ultrasonic imaging equipment was provided

by B-K Medical, Hitachi Medical Systems and Siemens Medical Systems, and these companies also sponsored the production of the lecture notes.

The seminar was arranged by the International Breast Ultrasound School (IBUS) as part of a series of teaching programmes designed to improve the quality of breast ultrasound examinations. Dr Dominique Amy of France was the programme director for the Warsaw seminar, and Dr Kazimierz Szopinski the local co-ordinator. A comprehensive set of lecture notes edited by Dr Jack Jellins, the Founding President of IBUS, was distributed to all registrants, and consisted of texts covering the lecture topics as well as other teaching materials supplied by IBUS faculty members.

The majority of the participants were from Poland (245), followed by Lithuania (25), Russia (18), Croatia (6), Latvia (6), Switzerland (5), Ukraine (5), Finland (4), Romania (4), Spain (4), Germany (3), Austria (2), Byelorussia (2), Denmark (2), Estonia (2), France (2), Ireland (2), Italy (2), Norway (2), Sweden (2), Turkey (2), USA (2), Australia (1), Azerbaijan (1), Belgium (1), China (1), Greece (1), Israel (1), Portugal (1), South Africa (1), and United Kingdom (1).

The seminar consisted of nine presentations covering a wide range of subjects including a special emphasis on the thorough understanding of breast anatomy and pathology, and defining the role of breast ultrasound in recognizing benign changes and early breast cancers.

The International Breast Ultrasound School would like to gratefully acknowledge Drs Malgorzata Szopinska, Katarzyna Wojtowicz, Javier Amoros, Camilo Fuster, and Mr Robert Cichecki who were instrumental with the organization of the IBUS seminar, and in particular Professor Wieslaw Jakubowski (President of the Polish Ultrasound Society) for inviting IBUS to Warsaw so that Euroson 2002 participants could benefit from experts in breast ultrasound.

Topics included: high resolution ultrasonic imaging principles (Dr Jack Jellins, Australia); ultrasonic anatomy and examination techniques (Dr Dominique Amy, France); ultrasonic differentiation of benign and malignant lesions (Prof. B Joachim HackelĂśer, Germany); mammographic â&#x20AC;&#x201C; ultrasonic correlation (Dr Michel Teboul, France); assessment of vascularity by ultrasound (Prof. Ivan Drinkovic, Croatia); the ultrasonic examination of cancers less than one cm

Kazimierz Szopinska Local Organizing Committee.

INDUSTRIAL BOARD The first meeting of this group was held during the Warsaw Congress in July.

Although no firm decisions were made during this first exploratory meeting many matters were discussed, including the establishment of an 'Industrial Member' category of EFSUMB and the formation of formal links between EFSUMB and the EC administration in Brussels.

If was agreed that the group would remain informal and that up to 2 members could attend from any Company with a bona fide interest in any aspect of ultrasound.

The Board will meet again during the Copenhagen Congress in April 2003. There was general agreement that the Board was an excellent idea and should lead to benefits for both EFSUMB and the individual companies.

The industrial members present at the first meeting expressed great enthusiasm for the concept of an Industrial Board and were keen to co-operate with EFSUMB on a wide range of subjects. These included; standardisation, safety, education, Congresses, Euroson Schools and the establishment of guidelines for various ultrasound related procedures.

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LETTER FROM WFUMB HARALD LUTZ – CHAIRMAN COMMITTEE AFRICAN PARTNERSHIP partnerships, identify and support centers of excellence in Africa in cooperation with WHO, organize and support regional courses and meetings, care for teaching material and establish a system of certification for teachers and students.

The purpose of my letter is to inform the members of the European Federation about the activities of WFUMB concerning the project, “African Partnership”.

This committee was created following initial discussions a few years before the board meeting in Florence 2000. The idea is to support the development of ultrasound in Africa in cooperation with the Mediterranean and African Society for Ultrasound (MASU) and World Health Organization (WHO).

As a first step, the group visited Kenya and Uganda in autumn last year. In Kenya, the group took part in a meeting in the WHO recognized center of excellence in education and training in diagnostic imaging in the Kenyatta National Hospital, chaired by Dr. Wambugu.

We held discussions there and at other Hospitals about the situation in Kenya, especially the ultrasound examination facilities.

WHO has formed a global steering group for education and training in diagnostic imaging.

Dr. Harald Østensen, Med. Officer of WHO as Chairman.

WFUMB, MASU and the Asian Federation (AFSUMB) are permanent members of this steering group. The common vision of this steering group is to make safe and reliable diagnostic imaging services accessible to as many as possible. The idea is to support especially diagnostic imaging service in less developed regions of the world. One of these areas is, as you know, the Sub-saharian part of Africa.

The present members of the African partnership cooperation group of WFUMB are Søren Hancke from Denmark, Hassen Gharbi from Tunisia and Elisabetta Buscarini from Italy, the present secretary of the MASU and me as chairman.

In Uganda, the members of the group participated in the annual meeting of the Uganda Society for the Advancement of Radiology and Imaging. The exclusive theme of the meeting was medical ultrasound. I was sponsored by MASU. The members of the group presented as teachers a number of lectures at this occasion and had a very interesting discussion with around 80 engaged participants. At this occasion the situation in Uganda was discussed again with local authorities, the chairman of the University and interested doctors and medical officers.

The next event supported by the WFUMB group will be an ultrasound course in Tanzania.

The group coordinates the activities of WFUMB in Africa in cooperation with MASU. The purpose is to promote and facilitate collaboration on education between societies, institutes and individuals in Africa and in well developed countries.

With this information I would like to invite everybody who has special contacts in this area and is interested to cooperate with us to support or to participate in our efforts for the development of ultrasound in Africa.

Please contact myself or other members of the group and give your proposals and comments for this project.

The idea is to establish so called, “twin partnerships”, according to a proposal of WHO.

Prof Dr Med H Lutz email:herald.th.lutz@t-online.de

The group will work out roles for these twin

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DIARY DATES August 4 - 6, 2002 World Class Breast Imaging: You Can Provide It, Vancouver, BC, Canada. Contact: Timothy Blackwelder, Loma Linda University School of Medicine, Loma Linda, CA 92350. Tel: 888-207-9105; Fax: 909-5580330; E-mail: blackt@hscis.net;

October 25 - 27, 2002 2nd Annual Meeting and Postgraduate Course of the Society of Radiologists in Ultrasound (SRU), San Francisco, CA. Contact: SRU, 44211 Slatestone Court, Leesburg, VA 20176-5109. Tel: 703-858-9210; Fax: 703-729-4839; E-mail: info@sru.org; Website: http://www.sru.org.

October 30, 2002

Website: http://www.worldclassrad.com

IBUS - Breast Ultrasound Seminar, A lecture programme in conjunction with the Lynn Sage, Breast Imaging Symposium, Chicago, USA. E-mail: info@ibus.org, Website: www.ibus.org

August 5 - 7, 2002 Introduction to Carotid Duplex/Color Flow Imaging; August 8-9, Introduction to Peripheral Vascular Duplex/Color Flow Imaging. St. Pete Beach, FL. Contact: Gulfcoast Ultrasound Institute, Inc, 4615 Gulf Blvd, Suite 205, St. Pete Beach, FL 33706. Tel: 727-363-4500; Fax: 727-363-0811; E-mail: learn@gcus.com; Website: http://www.gcus.com.

November 1-5, 2002 12th World Congress on Ultrasound in Obstetrics and Gynecology. New York,USA. Tel: +44 20 8725 2505, Fax: +44 20 8725 0212

December 1 – 6, 2002

August 7 - 10, 2002

88th Annual Meeting of the Radiological Society of North America, (RSNA) at Chicago, USA. Contact: Steven T Drew, Executive Director, 820 Jorie Boulevard, Oak Brook, IL 60523-2251, USA.Tel: +1 630 571 2670,

Vascular Imaging and Doppler Ultrasound, Philadelphia, PA. Contact: Ultrasound Institute, Thomas Jefferson University, 7th Floor-Main Building, 132 South 10th Street, Philadelphia, PA 19107-5244 Tel: 215-955-8533 or 888-390-5051; Fax: 215-923-9452; E-mail: JUREI@mail.tju.edu;

Fax: +1 630 571 7837 December 11 -13, 2002

Website: http://jeffline.tju.edu/ultrasound.

August 10 - 11, 2002 Current Trends in Breast Ultrasound and August 11, AIUM Accreditation Getting Started Workshop, New York, NY. Contact: Brenda Kinney, AIUM, 14750 Sweitzer Lane, Suite 100, Laurel, MD 20707-5907. Tel: 301-498-4100 or 800-638-5352; Fax: 301-498-4450; E-mail: conv_edu@aium.org; Website: http://www.aium.org August 31 - September 4, 2002 12th Annual Musculoskeletal Ultrasound Society Conference, Brussels, Belgium. Contact: AIMS International Belgium, Park Hill, Mommaertslaan 18B, B-1831 Diegem, Belgium. Tel:+ 32 2 722 82 30; Fax: + 32 2 722 8240; E-mail: dflament@aimsbru.be; Website: http://www.musoc.com/index.htm September 6 - 8, 2002 Fetal and Women's Ob/Gyn Imaging Course 2002, Seattle, WA. Contact: David Nyberg, MD, (Sponsored by Fetal and Women's Center and Swedish Medical Center). Tel: 206-386-6300, ext. 40438; Fax: 206-3866316; E-mail:nyberg@u.washington.edu; Website: http://www.fetalcenter.org.

September 11 - 14, 2002 15th Congress of the International Perinatal Doppler Society at Prague, Czech Republic. Contact: Congress Secretariat, Guarant Ltd /IPDS, Opletalova 22, 111 00 Praha 1, Czech Republic, Tel: +420-2-84 001 444, Fax: +420-2-84 001 448, E-mail: IPDS@guarant.cz,, website: www.guarant.cz/IPDS2002 September 19 - 22, 2002 32nd Annual Scientific Meeting of the Australasian Society for Ultrasound in Medicine (ASUM). Queensland, Australia. Contact: ASUM, 2/181 High Street, Willoughby NSW 2068. Tel: 61 2 9958 7655; Fax: 61 2 9958 8002; E-mail: asum@asum.com.au; Website: http://www.asum.com.

September 20 - 22, 2002 31st t Annual Diagnostic Ultrasound in Gynecology and Obstetrics and

34th BMUS Annual Scientific Meeting at the Manchester International Conference Centre. Contact:BMUS office, 36 Portland Place, London W1BLS. Tel:+44 (0)20 7636 3714, Fax: +44 (0)20 7323 7323, E-mail:secretariat@bmus.org

March 20 - 23, 2003 Ob/Gyn Ultrasound and Radiology Conference, Paradise Island, Bahamas.

Contact: Ulla Buchner-Howard, UBH International, 501 Fifth Avenue, Suite 1701, New York, NY 10017. Tel: 646-227-1850; Fax: 646-227-1849; E-mail: ubuchner@ubhinternational.com.

March 26 - 29, 2003 Ultrasound/Women's Imaging, Boston, MA. Contact: Danielle Pokorski Klette, Director of Continuing Medical Education, Brigham and Women's Hospital, Department of Radiology, PO Box 470617, Boston, MA 02447-0617. Tel: 617-5253310; Fax: 617-525-3320; E-mail: dpokorski@partners.org; Website: http://www.radcme.harvard.edu

April 27 – 30, 2003 EUROSON 2003, 15th Congress of the European Federation of Societies for Ultrasound in Medicine and Biology, First Joint Scandinavian Meeting, Copenhagen, Denmark. Contact: Congress Secretariat :ICS, P O Box 41, Strandvejen 171, DK-2900 Hellerup, Denmark.

Tel: +45 3946 0500, Fax: +45 3946 0515, E-mail:euroson2003@ics.dk.

Website:www.euroson2003.com

April 27, 2003 IBUS - International Breast Ultrasound Seminar, A lecture and workshop programme in conjunction with EUROSON 2003, Copenhagen, Denmark. E-mail: info@ibus.org, website: www.ibus.org June 1 - 4, 2003 AIUM hosting World Federation for Ultrasound in Medicine and Biology (WFUMB), Montreal, Canada. Contact: The American Institute of Ultrasound in Medicine (AIUM), 14750 Sweitzer Lane, Suite 100, Laurel, MD 20707-5906. Tel: 301-498-4100 or 800-638-5352; Fax: 301498-4450; E-mail: conv_edu@aium.org; Website: http://www.aium.org.

June 5 - 7, 2003 IBUS - International Breast Imaging Update. A lecture and workshop programme in conjunction with the Radiological Society of Finland, Naantali Spa, Finland. E-mail: finland@ibus.org, website: www.ibus.org September 4 - 7, 2003 33rd Annual Scientific Meeting of the Australasian Society for Ultrasound in Medicine (ASUM). Perth, Western Australia. Contact: ASUM, 2/181 High Street, Willoughby NSW 2068. Tel: 61 2 9958 7655; Fax: 61 2 9958 8002; E-mail: asum@asum.com.au; Website: http://www.asum.com.

November 30 – December 5, 2003 89th Annual Meeting of the Radiological Society of North America (RSNA) at Chicago, USA. Contact: Steven T Drew, Executive Director, 820 Jorie Boulevard, Oak Brook, IL 60523-2251, USA. Tel: +1 630 571 2670, Fax: +1 630 571 7837 June 6 - 9, 2004 EUROSON 2004, 16th EFSUMB Congress, Zagreb, Croatia in conjunction with CSUMB. Contact EFSUMB Secretariat: Carpenters

Abdomen, Baltimore, MD. Contact: Johns Hopkins Medical Institutions, Office of Continuing Medical Education, Turner 20 / 720 Rutland Avenue, Baltimore, MD 21205; Tel: 410-955-5880; Fax: 410-955-0807; E-mail: cmenet@jhmi.edu; Website: http://www.med.jhu.edu/cme.

September 24 - 25, 2002 Gynaecological Ultrasound Course, London, United Kingdom. Contact: Royal College of Obstetricians and Gynaecologists, 27 Sussex Place, Regent's Park, London NW1 4RG. Tel: +44 (0)20 7772 6200; Fax: +44 (0)20 7723 0575; Website: http://www.rcog.org.uk.

September 27 – 29, 2002 3rd Annual Obstetric Ultrasound in the High Risk Patient, Las Vegas, NV. Contact: Institute for Advanced Medical Education, 14 Elm Place, Rye, NY 10580. Tel: 914-921-5700; Fax: 914-921-6048; E-mail: info@iame.com; Website: http://www.iame.com.

October 3, 2002 IBUS - International Breast Ultrasound Seminar A lecture programme in conjunction with the Gemeinsame Jahrestagung der Österreichischen Gesellschaft und der Schweizerischen Gesellschaft für Senologie, Bregenz,

Court, 4a Lewes Road, Bromley, Kent BR1 2RN, UK. Tel: +44 (0)20 8402 8973, Fax: +44 (0)20 8402 9344, E-mail:efsumb@compuserve.com Website:http://www.efsumb.org

Austria. E-mail: info@ibus.org, website: www.ibus.org October 4 - 6, 2002 Advanced Sonography Symposium in Ob/Gyn, Boston, MA. Contact: Harvard MED-CME, PO Box 825, Boston, MA 02117-0825. Tel: 617-384-8600; Fax: 617-384-8686; E-mail:hms-cme@hms.harvard.edu; Website: http://www.cme.hms.harvard.edu.

June 26 - 29, 2005 EUROSON 2005, 17th EFSUMB Congress: Geneva, Switzerland, in conjunction with the Dreiländertreffen at the Palexpo Geneva Contact: Dr S Tercanli, Delegate SGUM, Universitäts-Frauenklinik/, Kantonsspital, CH 4031 BASEL SWITZERLAND, Tel: +61 325 90 46, Fax: +61 3259241, E-mail:stercanl@uhbs.ch

October 23, 2002 IBUS - International Breast Ultrasound Seminar, A lecture and workshop programme in conjunction with the 26. Dreiländertreffen SGUM - DEGUM ÖGUM,Basel, Switzerland.E-mail: info@ibus.org, website: www.ibus.org

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1.1) Name of the medicinal product during SonoVue®-enhanced echocardiography with a SonoVue®, 8 microlitres / ml, powder and solvent for pharmacological stress (e.g. with dobutamine). ECG dispersion for injection monitoring should be performed in high-risk patients as clinically indicated.

1.2) Qualitative and quantitative composition Caution is advised when SonoVue® is administered to Sulphur hexafluoride microbubbles 8µl per ml patients with severe heart failure (NYHA class IV) or to On reconstitution as directed, 1 ml of the resulting patients with clinically significant pulmonary disease, dispersion contains 8 µl sulphur hexafluoride in the including severe chronic obstructive pulmonary disease. microbubbles, equivalent to 45 µg.

Numbers of patients with the following conditions who For excipients, see 4.1.6.1 were exposed to SonoVue® in the clinical trials were limited, and therefore, caution is advisable when 1.3) Pharmaceutical form administering the product to patients with: serious Powder and solvent for dispersion for injection arrhythmias, recent myocardial infarction, with ongoing and/or unstable angina, acute endocarditis, prostetic 1.4) Clinical particulars valves, acute systemic inflammation and/or sepsis, hyperactive coagulation states and/or recent 1.4.1) Therapeutic indications thromboembolism, and end-stage renal or hepatic This medicinal product is for diagnostic use only. disease.

SonoVue® is not suitable for use in ventilated patients, SonoVue® is for use with ultrasound imaging to enhance and those with unstable neurological diseases. the echogenicity of the blood, which results in an improved signal to noise ratio.

1.4.5) Interaction with other medicinal products and other SonoVue® should only be used in patients where study forms of interaction without contrast enhancement is inconclusive.

No specific interaction studies have been performed.

Echocardiography There was no apparent relationship with respect to ® SonoVue is a transpulmonary echocardiographic contrast occurrence of adverse events in the clinical studies for agent for use in patients with suspected or established patients receiving various categories of the most common cardiovascular disease to provide opacification of cardiac concomitant medications. chambers and enhance left ventricular endocardial border delineation.

1.4.6) Pregnancy and lactation Doppler of macrovasculature No clinical data on exposed pregnancies are available. ® SonoVue increases the accuracy in detection or exclusion Animal studies do not indicate harmful effects with respect of abnormalities in cerebral arteries and extracranial to pregnancy, embryonal/foetal development, parturition carotid or peripheral arteries by improving the Doppler or postnatal development (see section 4.1.5.3 Preclinical signal to noise ratio. safety data). Caution should be exercised when SonoVue® increases the quality of the Doppler flow image prescribing to pregnant women. It is not known if sulphur and the duration of clinically-useful signal enhancement hexafluoride is excreted in human milk. Therefore, caution in portal vein assessment. should be exercised when SonoVue® is administered to Doppler of microvasculature breast-feeding women. ® SonoVue improves display of the vascularity of liver and breast lesions during Doppler sonography, leading to 1.4.7) Effects on ability to drive and use machines On the basis of the phar macokinetic and more specific lesion characterisation. pharmacodynamic profiles, no or negligibile influence is expected with the use of SonoVue® on the ability to drive 1.4.2) Posology and method of administration This product should only be used by physicians or use machines. experienced in diagnostic ultrasound imaging.

The microbubble dispersion is prepared before use by 1.4.8) Undesirable effects injecting through the septum 5 ml of sodium chloride The undesirable effects reported with SonoVue® were, in 0.9%w/v solution for injection to the contents of the vial. general, non-serious, transient and resolved spontaneously The vial is then shaken vigorously for a few seconds until without residual effects. the lyophilisate is completely dissolved. The desired volume The most commonly reported adverse reactions are of the dispersion can be drawn into a syringe any time headache and altered sensation at the injection site, up to six hours after reconstitution. Just before drawing both occurring in approximately 2% of patients. into the syringe, the vial should be agitated to re-suspend The adverse reactions observed in more than 1400 adult the microbubbles. SonoVue® should be administered patients in clinical trials are: immediately after drawing into the syringe by injection Common Reactions (>1%) into a peripheral vein. Every injection should be followed Body as a whole: by a flush with 5 ml of sodium chloride 0.9%w/v solution headache, altered sensation at the injection site, for injection.

Digestive system: nausea The recommended doses of SonoVue® are: Nervous System: flushing, paraesthesia B-mode imaging of cardiac chambers, at rest or with Special Senses: taste perversion. stress: 2 ml.

Less Common Reactions (<1%) Vascular Doppler imaging: 2.4 ml.

Body as a whole:chest pain, asthenia, abdominal pain, During a single examination, a second injection of the back pain, non-specific pain recommended dose can be made when deemed Respiratory system: respiratory disorder, pharyngitis, sinusitis necessary by the physician.

Skin and appendages: pruritus, rash Elderly Patients Special senses: abnormal vision The dosage recommendations also apply to elderly Nervous system: dry mouth, dizziness, personality disorder, patients. insomnia, nervousness Paediatric Patients Metabolic and nutritional: hyperglycaemia, peripheral ® The safety and effectiveness of SonoVue in patients oedema under 18 years old has not been established and the Haemic and Lymphatic organ system: ecchymosis product should not be used in these patients.

One case of sensory-motor paresis was reported.

There were isolated changes reported in ECG 1.4.3) Contraindications components, blood pressure and in some laboratory SonoVue® should not be administered to patients with parameters measured, but these were not deemed to known hypersensitivity to sulphur hexafluoride or to any be of clinical significance. of the components of SonoVue®.

SonoVue® is contraindicated for use in patients known to 1.4.9) Overdose have right-to-left shunts, severe pulmonary hypertension Since there have been no cases of overdose reported (Pulmonary artery pressure >90 mmHg), uncontrolled to date, neither signs nor symptoms of overdosage have systemic hypertension, and in patients with adult respiratory been identified. In a Phase I study doses up to 56 ml of distress syndrome.

SonoVue® were administered to normal volunteers without The safety and efficacy of SonoVue® have not been serious adverse events being reported. In the event of established in pregnant and lactating women therefore, overdosage occurring, the patient should be observed SonoVue® should not be administered during pregnancy and treated symptomatically. and lactation (see Section 4.1.4.6) 1.5) Pharmacological properties 1.5.1) Pharmacodynamic properties 1.4.4) Special warnings and special precautions for use Pharmacotherapeutic group: ECG and blood pressure monitoring should be performed Ultrasound contrast media ATC code VO8DA.

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Changing the Role of Ultrasound The addition of sodium chloride 0.9%w/v solution for injection to the lyophilised powder followed by vigorous shaking results in the production of the microbubbles of sulphur hexafluoride. The microbubbles have a mean diameter of about 2.5µm, with 90% having a diameter less than 6µm and 99% having a diameter less than 11µm.

Each millilitre of SonoVue® contains 8µl of the microbubbles.

The interface between the sulphur hexafluoride bubble and the aqueous medium acts as a reflector of the ultrasound beam thus enhancing blood echogenicity and increasing contrast between the blood and the surrounding tissues.

The intensity of the reflected signal is dependent on concentration of the microbubbles and frequency of the ultrasound beam. At the proposed clinical doses, SonoVue® has been shown to provide marked increase in signal intensity of more than 2 minutes for B-mode imaging in echocardiography and of 3 to 8 minutes for Doppler imaging of the macrovasculature and microvasculature.

Sulphur hexafluoride is an inert, innocuous gas, poorly soluble in aqueous solutions. There are literature reports of the use of the gas in the study of respiratory physiology and in pneumatic retinopexy.

1.5.2) Pharmacokinetic properties The total amount of sulphur hexafluoride administered in a clinical dose is extremely small, (in a 2 ml dose the microbubbles contain 16 µl of gas). The sulphur hexafluoride dissolves in the blood and is subsequently exhaled.

After a single intravenous injection of 0.03 or 0.3 ml of SonoVue®/kg (approximately 1 and 10 times the maximum clinical dose) to human volunteers, the sulphur hexafluoride was cleared rapidly. The mean terminal halflife was 12 minutes (range 2 to 33 minutes). More than 80% of the administered sulphur hexafluoride was recovered in exhaled air within 2 minutes after injection and almost 100% after 15 minutes.

In patients with diffuse interstitial pulmonary fibrosis, the percent of dose recovered in expired air averaged 100% and the terminal half-life was similar to that measured in healthy volunteers.

1.5.3) Preclinical safety data Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and toxicity to reproduction. Caecal lesions observed in some repeat- dose studies with rats, but not in monkeys, are not relevant for humans under normal conditions of administration.

1.6) Pharmaceutical particulars 1.6.1) List of excipients Powder: Macrogol 4000 Distearoylphosphatidylcholine Dipalmitoylphosphatidylglycerol Sodium Palmitic acid Solvent: Sodium chloride 0.9% w/v solution for injection 1.6.2) Incompatibilities SonoVue® should not be admixed with any other medicinal product except the solvent provided.

1.6.3) Shelf life 2 years Once reconstituted, chemical and physical stability has been demonstrated for 6 hours. From a microbiological point of view, the product should be used immediately.

If not used immediately, in use storage times and conditions prior to use are the responsibility of the user.

1.6.4) Special precautions for storage No special precautions for storage.

1.6.5) Nature and contents of container Presentation 01(with integral Bio-Set transfer system) -25 mg of dry, lyophilised powder in an atmosphere of sulphur hexafluoride in a colourless Type I glass vial, with elastomeric closure and integral transfer system.

Type I glass pre-filled syringe containing 5 ml sodium chloride 0.9%w/v solution for injection.

Presentation 02 (with separate MiniSpike transfer system): -25 mg of dry, lyophilised powder in an atmosphere of sulphur hexafluoride in a colourless Type I glass vial, with elastomeric closure.

Separate transfer system.

Type I glass pre-filled syringe containing 5 ml sodium chloride 0.9%w/v solution for injection.

Please consult full locally approved information before using Marketing auhorisation holder: Bracco International B.V. Strawinskylaan 3051, 1077ZX Amsterdam, The Netherlands.

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