Focus on Reproduction ESHRE, ianuarie 2011

Focus on

REPRODUCTIONEuropean Society of Human Reproduction and Embryology // JANUARY 2011 //

l ESHRE newsl Fertility preservation in womenl Charting the progress of IVF in Germany

Robert Edwards honoured as Nobel prize winner

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Focus on Reproduction January 2011 3

This new year issue of Focus on Reproduction reflects arich vein of events related to ESHRE and assistedreproduction but none more so than the award to RobertEdwards, the founder of our Society, of the Nobel prize‘for the development of in vitro fertilization’. Thisprestigious and long-deserved honour, awarded to the manwho inspired our work, takes on even greater significanceas a mark of recognition for reproductive medicine amongthe leading disciplines of medicine.

ESHRE’s scientific activities, the core of the Society, havenow maintained their high standards over many years, and

it was richly deserved that the European IVF Monitoring consortium celebrated itstenth anniversary with a commemorative meeting last September in Munich. Wealso took part with the ASRM in the third consensus workshop on PCOS, thistime on its non-fertility health implications. The report from the first consensus -on the diagnosis of PCOS - has become a citation classic.

From a social perspective, the European legislative framework for ART ispresently going through something of a turmoil. Legislations in several countries(Germany and Malta, for example) are being exposed to the legal test followingjudgements from different national and international courts. I am proud to reportthat in most of these cases ESHRE has been chosen as an authoritative andprivileged interlocutor by the governments dealing with them.

Particularly significant in this same context was the participation of ESHRE inthe European Health Forum held in Gastein, Austria, in October. This meeting wasa unique opportunity to present our view of the current problems in reproductivehealth to an audience of healthcare managers and European policymakers. It seemslikely that 2011 will see many changes as far as these issues are concerned, whichhopefully will prompt greater harmonisation in European legislation, a goal thatESHRE has always pursued.

Several opportunities are now opening up for ESHRE outside its traditionalfields of interest. A collaboration between our Task Force on Management ofFertility Units and a leading insurance group is behind a workshop planned forVenice in February. This will be the first time that professionals in the fields ofART and insurance have collaborated in such a way, but, as the Task Force reportsin this issue, there are clear areas in the management of fertility centres where wecan improve, both for the sake of ourselves the professionals and our patients.

Luca GianaroliESHRE Chairman 2009-2011

EXECUTIVE COMMITTEEChairman

Luca Gianaroli (IT)Chairman Elect

Anna Veiga (ES)Members

Ursula Eichenlaub-Ritter (DE)Jean-François Guerin (FR)

Timur Gürgan (TR)Antonis Makrigiannakis (GR)

Carlos Plancha (PT)Françoise Shenfield (GB)

Miodrag Stojkovic (RS)Anne-Maria Suikkari (FI)

Etienne Van den Abbeel (BE)Heidi Van Ranst (BE)

Veljko Vlaisavljevic (SL)Ex-officio members

Joep Geraedts (Past Chairman)Søren Ziebe (SIG Sub-

committee)

FOCUS ON REPRODUCTIONEDITORIAL COMMITTEE

Paul DevroeyBruno Van den Eede

Hans EversJoep GeraedtsLuca Gianaroli

Hanna HanssenAnna Veiga

Søren ZiebeSimon Brown (Editor)

Focus on Reproductionis published by

The European Society of HumanReproduction and Embryology

Meerstraat 60Grimbergen, Belgium

[email protected] www.eshre.eu

All rights reserved. The opinions expressed in this

magazine are those of theauthors and/or persons interviewedand do not necessarily reflect the

views of ESHRE.

JANUARY 2011Cover picture: Nobelprize.org

CONTENTS NEWS4 Rome 2010 reviewed6 Robert Edwards Nobel laureate10 New data system for PGD Consortium11 ESHRE’s foray into social media12 From Fertility Europe14 Ten year review from the EIM

Consortium17 Third consensus meeting on PCOS18 European Health Forum Gastein20 From the Special Interest Groups27 From the Task Forces

FEATURES32 Fertility preservation in women

Richard Anderson and ClausYding Andersen review progress so far and the realistic options before cancer treatment

35 One million cycles recordedMarkus Kupka on the story of IVF in Germany and how its voluntary registry has recorded every cycle

Focus on

REPRODUCTIONl Chairman’s introduction

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4 Focus on Reproduction January 2011

A face-to-face survey of 500 participants during last year’sannual meeting in Rome found an enthusiastic response toscientific content, but a higher-than-usual level ofdissatisfaction about the congress venue and transportationarrangements. As a result, ESHRE’s Executive Committeehas determined to address these problems specifically andensure they are not encountered again.

The survey was the fourth to be conducted by ESHRE,following similar exercises in Lyon (2007), Barcelona(2008) and Amsterdam (2009). Last year’s questionnairecovered both organisational and scientific content.

As ever, scientific quality - in both the precongresscourses and main programme - proved highly rated; on ascale of 1 (minimum rating) to 5 (maximum), scientificcontent in the invited lectures and oral communicationsessions scored 3.9 and 3.7 respectively, ratings consistentwith those of previous years. Most respondents (75%)thought the balance of science and clinical medicine ‘justright’, and most (71%) actually took time to view thepaper posters (a big increase on 2009). It was thus notsurprising to find that 51% preferred paper posters, though22% gave a preference for both paper and electronicpresentation. This was a big advance in response to posterviewing opportunities.

Local chairman Filippo Ubaldi also notes a veryfavourable response to the congress’s social programme setagainst the backdrop of one of the world’s most attractivecities. The congress party at the spectacular Villa Miani,before a panorama of St Peter’s and Rome below, proved apopular and much enjoyed event.

Many of the logistical problems exposed by the survey,

ANNUAL MEETINGS 2010, 2011

which was based on a ten-minute questionnaire interviewin Rome, are inevitably the growing pains of a congresswhose size and shape are so rapidly increasing. ESHRE’sExecutive Committee now has to plan for a capacity of atleast 10,000 delegates, and that necessarily limits choice.

Complaints of those interviewed in Rome wereconcentrated on three organisational aspects: the congresscentre itself; transportation; and catering. Manyrespondents were unhappy with the congress venue; thecongress centre rated a mean satisfaction score of only 3.This rating compared unfavourably with previous venues inAmsterdam (mean rating 3.8) and Barcelona (mean rating4.3). Venue selection is clearly essential to the success ofany annual meeting, and, says the Executive Committee,must be given the highest priority in future.

Venue selection - and its location - was also at the heartof transportation complaints, which were mainly a lack ofbuses during off-peak hours. Despite the shuttle service,there were many who complained that access to and fromthe congress centre was difficult (and expensive by taxi)outside the shuttle time-table, which, says Ubaldi, wasconcentrated on morning and evening peak times. The localorganisers and ESHRE’s agents in Rome did their best with

Rome retrospectiveSurvey reveals high scientific content scores but some dissatisfaction with logistical arrangements

Deadline for Stockholm abstractsubmission is 1st February

Full details of ESHRE’s abstract submission policy areon the ESHRE website (www.eshre.eu), but pleasenote:l All abstracts must arrive at ESHRE’s Central Officeno later than 23.59 CET on 1st February 2011.l Abstracts should be submitted in English only.l Any investigator submitting an abstract can only bethe first author for one abstract.l The material presented should be unpublished andoriginal material, which has not yet been presented inany other meeting. l All abstracts will be refereed ‘blind’. l Authors are requested to indicate their preferencefor oral and/or poster presentation on the abstractsubmission form. The decisions of the selectioncommittee are final.

ESHRE CHAIRMAN LUCAGIANAROLI: ‘THE

SURVEY HAS EXPOSEDPROBLEMS AND WE

MUST LOOK AT THEM.’

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the shuttle services within a reasonable budget, but clearlyease of travel - preferably by public transport - is apriority for future consideration.

Catering in Rome also scored poorly, with a meansatisfaction score of just 2.4. Complaints were mainlyfocused on lunch queues on the opening Monday, whencatering services proved inadequate for such numbers.Food quality was always high, however, and the logisticsof service had improved dramatically by Tuesday.

‘We were not happy with some of these findings,’ saidESHRE’s Chairman Luca Gianaroli, ‘and it’s clear thatmany participants were disappointed in some of theorganisational arrangements. The survey has exposedproblems and we must look at them. I want to reassureour members that we will do our best - even at the earlieststage of venue selection - to ensure we don’t have suchcomplaints again.’

Gianaroli was also confident that many of the logisticalproblems reported in Rome will not be encountered thisyear in Stockholm. The venue, Stockholmsmässan, isfamiliar with large medical congresses and importantly isjust nine minutes away by commuter train fromStockholm Central Station. Trains are frequent andefficient, and the congress station is just a two-minutewalk from the congress centre. The EC and localorganisers will also be paying particular attention tocatering and meeting-room logistics.

The invited scientific programme and precongresscourses for Stockholm are already in place, and deadlinefor the submission of abstracts is 1st February. Allabstracts will be scored (blind and weighted) by theScientific Committee. Last year’s event prompted anunprecedented number of abstract submissions, and,despite the shortcomings of Rome, a similar response isexpected this year. Almost 70% of those questioned inRome said they expected to be in Stockholm in 2011.q

A big advance in numbers viewing both paper and electronic posters.

The congress party, set against the panorama of St Peter’s and Rome,proved a popular and much enjoyed event.

Scientific content inall parametersmeasured scoredhighly among thesurvey respondents.

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am sure that every member of ESHRE was delighted to hear thenews that Robert Edwards had been awarded the Nobel Prize forMedicine. Bob, who was born in 1925, has had to wait many years

for this richly deserved appreciation of his lifelong and pioneeringwork. The award is also a tribute to the whole sector of reproductivemedicine.

Bob’s original work was in physiology at the University ofCambridge. As early as the 1950s he was studying the physiology of theoocyte and the control of maturation, and by the 1960s had achievedthe in vitro fertilisation of an oocyte in an animal experiment.

It was in the late 1960s that Bob, who by now was Head of theDepartment of Physiology in Cambridge, met the gynaecologist PatrickSteptoe. The latter was head of department in Oldham, UK, and one ofthe pioneers of laparoscopy. Before then the retrieval of oocytes wasperformed via laparotomy - unthinkable to Edwards and Steptoe evenat that time. They thus developed a concept for detecting the time ofoptimal oocyte maturation for the retrieval of oocytes by laparoscopy.And, as might be expected with Bob’s experience in animal models, itdid not take long before the first in vitro fertilisation was achieved.

Embryo survival, however, proved a challenge, as did theencouragement of his peers and financial support. But Bob and Patrick

COVER STORY

Robert Edwards,joint founder ofESHRE, honouredas Nobel laureateKlaus Diedrich, Chairmanof ESHRE from 1993 to1995 and a member ofthe Society’s originaltemporary committee,congratulates BobEdwards on this muchdeserved honour andrecalls his distinguishedplace in ESHRE’s history.

Pictures:Robert G. Edwards - Photo Gallery. Nobelprize.orgESHRE archivesKlaus Diedrich

Bourn Hall days:left, Bob in 2008 at acelebration of 30 years of IVF; below, Lesley Brown withLouise in 1978, and in 2008at Bourn Hall with Louise andher own baby.

I

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never gave up, and in 2008 Bob recalled: ‘Iwill never forget the day when I first saw ahuman blastotocyst under my microscope. Itwas wonderful.’ This happened in 1972, but itwould take six more years before the first IVFbaby, Louise Brown, was born. That world-famous team of Edwards and Steptoecontinued to work together until Steptoe’sdeath in 1988.

* * * *I first met Bob in 1978 at a reproductionmeeting in Japan. At the time societies inreproductive medicine were springing up allover Europe, and the foundation of our ownsociety in Germany took place with the closecollaboration of our colleagues in Britain. Wehad three centres performing IVF: in Erlangenunder the lead of Siegfried Trotnow, Lübeckunder Dieter Krebs, and Kiel under LieselotteMettler. Germany’s first IVF baby was born inErlangen in 1982 (see page 35) and a second

in Lübeck in 1983. The third World Congress of IVF was held

in Helsinki in 1984 and it was here that Boband the French gynaecologist Jean Cohen setabout the creation of a European society inreproductive medicine, which would very soonbecome ESHRE. From then on ESHREcongresses were held every year, and even thefirst, which I organised in Bonn in 1985,began with 650 participants. Even so, it wasstill possible for Bob and Jean Cohen to greeteveryone personally at the door.

Edwards was the founder and for manyyears the editor of ESHRE’s journals HumanReproduction, Human Reproduction Updateand Molecular Human Reproduction. Theseremain among the leading international titlesin O&G and reproductive biology. Bob alsofounded Reproductive Biomedicine Online in2000, following his resignation from theeditorship of Human Reproduction. It was a

ESHRE days:top, welcoming PatrickSteptoe to ESHRE’s firstannual meeting in Bonn,1985, with joint founderJean Cohen and localcongress chairman KlausDiedrich;above left, in 2004 withESHRE’s chairmen thus far(l to r), Pier GiorgioCrosignani, Basil Tarlatzis,Jose Egozcue, Lynn Fraser,Klaus Diedrich, Jean Cohen,Bob Edwards, André VanSteirteghem, (seated) ArneSunde, Hans Evers;above right, acceptinghonorary membership ofESHRE in Thessaloniki1993.

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Bob makes the front cover of a 1993Focus on Reproduction alongsideESHRE’s next four chairmen: VanSteirteghem, Cohen, Crosignani andDiedrich; right, with a note to KlausDiedrich after the first ESHRE congressin Bonn, 1985.

time with him, and I am proud to say that Bob wasawarded honorary membership of the GermanSociety of Obstetrics and Gynecology when DieterKrebs led the society’s congress in Berlin in 1992.

The Nobel prize is a fitting tribute to the influencethat Bob’s work has had on infertility throughoutthe world and for so many years. The members ofESHRE congratulate Bob and send him their kindestregards.

Klaus DiedrichUniversity of Lübeck, Germany

move typical of hischaracter, alwayssearching for newthings to discover,realising newvisions. Indeed, inreproduction he

was the first tocryopreserve surplus embryos and performpreimplantation diagnosis on animal embryos,confident that both techniques would be developedfor human application. Remarkably, he hadexperimented with in vitro maturation andfertilisation in animal models as early as 1965.

Bob and I organised many conferences andworkshops together, and he was the scientific fatherof many German endocrinologists - as well as thedriver of infertility treatment in Europe. It wasalways a special and inspiring experience to spend

Ruth Edwards accepts the prize on his behalfToo unwell to be in Stockholm for the Nobel prize ceremony in December, Bob was represented by his wife Ruth(who as Ruth Fowler had collaborated with him on several papers on the induction of ovulation in mice in the 1950s).

His absence meant that the traditional lecture given by each Nobel laureate was replaced by asymposium in Bobʼs honour. The principal speaker was one of Bobʼs former students inCambridge, Professor Martin Johnson, who in a detailed and finely illustrated lecturedescribed the many years of research which lay behind the triumph of Louise Brownʼs birth.Professor Johnson closed his lecture with two moving film clips of Bob describing his first

association with Patrick Steptoe andforecasting that ʻnext yearʼ (this was shortlyafter the opening of Bourn Hall in 1981) ʻ1500IVF babies would be born worldwideʼ. Twofollow-up lectures - on the development of IVFand its future directions - were given by LarsHamberger, whose group achieved Swedenʼsfirst IVF success in 1982, and Outi Hovatta ofthe Karolinska Institute. The Nobel Prize inPhysiology or Medicine is awarded by theNobel Assembly at the Karolinska Institute.Martin Johnson delivers the symposium’s firstlecture, with Ruth Edwards (inset) also present.

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Six handshakes of separation between the‘Bob picture’ and the rest of the world

Did you ever shake hands with Barack Obama?Does Lady Gaga recognise your e-mail address? Doyou know a Nobel laureate on a first-name basis?According to the ‘small world’ hypothesis proposedby Stanley Milgram, each of us is no more than sixhandshakes away from every other human being onthis planet. In 1967 Milgram developed anexperiment to test his hypothesis that members ofa large social network, in this case the entirepopulation of the USA, would be connectedthrough a relatively short chain of in-betweencontacts. He sent a message to 400 randomlyselected people in Wichita, Kansas, and Omaha,Nebraska, (the starting points) and invited them toforward it to a colleague or friend whom theythought more likely to know a given target personin Boston, Massachusetts (the endpoint), whosename was completely unfamiliar to them. Thereason for selecting Wichita and Omaha at one endand Boston at the other was that according toMilgram they represented as long a geographicaland social distance in the USA as possible.

His experiment turned out to confirm the theory;it took on average six persons to reach the hithertounknown target person - a phenomenon

which later became known as the ‘sixdegrees of separation’. The mostsuccessful chains were composed ofprofessional rather than social links.Social networks are usually moreclosely knit, all members know allother members and the community offriends does not usually extend farbeyond its original nucleus.Professional networks are lesscompact but they reach farther.

ESHRE is a global network ofprofessional links. At its first annualmeeting, in Bonn in 1985, itsfounding father, the 2010 Nobellaureate Professor Robert G.Edwards, personally welcomed everyindividual participant (all 650 ofthem!) at the entrance to the openingreception in the 'Redoute' in BadGodesberg.

On hand was a photographer torecord the moment, and we all stilltreasure our ‘Bob picture’ from thatoccasion - as the many resurrectedphotos suggest.

And Bob was our introduction tothe world at large. He went on to winthe Lasker award, the King Faisalaward, and the Nobel prize. Aftershaking hands with us (handshake 1)in Bad Godesberg he received theKing Faisal award from the hands ofthe late King Fahad of Saudi Arabia(handshake 2), who later shookhands with George Bush senior(handshake 3), the father of GeorgeW. (handshake/spanking 4), whoshook hands with Barack Obama(handshake 5) at the latter'sinauguration. So, if next time wemeet you shake hands with the proud

owner of a ‘Bob picture’ . . . jackpot!The Nobel prize has been awarded

to Bob Edwards. Finally! The Swedesare a brave and independent bunch.Against all odds (ie, the Vatican) theyhonoured Bob, and they honouredAlfred Nobel, who died childless andthus had to find a destination for hisaccrued capital. What would be moreappropriate than a Nobel prize forfighting childlessness? And whatwould be more appropriate forESHRE than to have its annualmeeting in Stockholm this year?

And finally, what would be moreappropriate than for our presentchairman, Luca Gianaroli, topersonally greet all participants inStockholm, the city where AlfredNobel was born, with a welcominghandshake?q

Former ESHRE ChairmanHans Evers with his owntribute to Bob Edwards

Two ‘Bob pictures’ from ESHRE’s first annual meeting in 1985. Bobgreets two future chairmen of ESHRE (the first who insists on remaining

anonymous, and the second whom we cannot even identify).

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clinical PGD analysis and embryo follow-up results, andgive a more complete evaluation of the potential rate ofmisdiagnosis. Additionally, it should identify likelyreasons of discordance (which could include protocol-related parameters, embryo quality, embryo biology)highlighting important criteria for optimising clinicalPGD results. Data analysis is on-going for both studies,with completion aimed for Spring 2011 and resultspublished as multicentre studies.l The Database working group has updated theFileMaker Pro database (see box below); the mainmodification is the use of OMIM numbers forindications. In addition, the group has contactedPatrick Haentjens for statistical analysis of the largeamount of data collected since 1997. We are mergingall databases to allow this analysis.The aim of theanalysis is to assess reproductive outcome of PGD, andto evaluate the evolution of this activity with successrates in relation to various confounding factors. Thegroup is also working on new ways to collect and assessdata on frozen embryo cycles, including from groupsa

Gary Harton took over from Joyce Harper as Chair ofthe Steering Committee in June during last year'sannual meeting in Rome. Shortly after, a ballot washeld to ratify the revised Statutes governing therunning of the Consortium. With the Statutes ratified,a vote was held to re-elect current members of theSteering Committee and elect two new members tobegin their term of office immediately.

Another round of data collection and analysis iswell under way and will be published sometime thisyear. Our Working Group on Guidelines recentlypublished a set of four documents as a Best PracticeGuideline for PGD and PGS. The documents coverOrganization of a PGD Center, Polar Body and EmbryoBiopsy as it relates to PGD, Amplification-based PGDand FISH-based PGD and PGS. The guidelines werepublished online by Human Reproduction in October.

We have now formed a new working group toconsider array-based testing in PGD, which includesmembers of the Consortium as well as non-membersinterested in array-based technology in single cell andembryo testing. The Array Working Group will bechaired by Dagan Wells and Leeanda Wilton and willhold its first meeting in London in March. l The Diagnosis Monitoring and Audit group hasprogressed with two follow-up studies for thereanalysis of untransferred and supernumeraryembryos. One study is for PCR-based PGD cycles (co-coordinated by Joanne Traeger-Synodinos, with JosDreesen as deputy) and the other for FISH-based PGDcycles (co-coordinated by Tugce Pehlivan, with EdithCoonen and Gary Harton as deputies). Data analysisshould identify the rate of discordance between

// PGD CONSORTIUM //

An update from the working groups

The current Steering Committee comprises:Gary Harton (US, Chair)Joanne Traeger-Synodinos (GR, Deputy Chair)Joyce Harper (GB, Past Chair)Céline Moutou (FR), Katerina Vesela (CZ),Sioban Sengupta (GB), Georgia Kokkali (GR),Leeanda Wilton (AU), Martine De Rycke (BE),Tugce Pehlivan (TR), Pamela Renwick (GB),Edith Coonen (NL), Francesco Fiorentino (IT)

Steering committee members

The new method of data collection will be launchedlater this year. Submission of data via the currentFileMaker Pro system has been problematic andtime-consuming, both for centres entering data andthe Consortium steering committee trying to analyseit. The new on-line system will be an intelligent andeasy-to-use method of entering, storing, analysingand submitting PGD data. This new system will nowallow PGD centres to easily analyse their own data.Once data is entered, it will be simple to producetables which include your key quality indicators (orkey performance indicators), such as number of eggscollected, number of embryos biopsied, andefficiency of the biopsy, diagnosis, pregnancy rates,delivery rates, and so on.

The data can be entered in real time so that anaccurate and up-to-date record can be logged foreach PGD cycle. There will be an option to enterreferral data for tracking patient history and thedatabase will incorporate options for embryo freezingat any stage of the process.

This is an exciting new venture from which we aresure many PGD centres will benefit. All Consortiummembers should wait for the e-mail announcing howto register your centre. Anyone who is not already amember and wishes to join the Consortium, pleasevisit the PGD Consortium web page athttp://www.eshre.eu/ESHRE/English/Specialty-Groups/SIG/Reproductive-Genetics/PGD-Consortium

Joyce Harper

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using embryo freezing or vitrification in all IVF cycles.l The Accreditation working group continues to spreadthe word about improvements in the laboratoryfollowing accreditation and continues to perform ayearly survey of the status of accredited centres forpresentation at the ESHRE annual meeting. Thenumber of centres accredited to ISO 15189 or otherlocal standards is growing, although at a very slowpace. It is hoped that an increase will be seen duringthis year, as several centres are just in the process ofaccreditation. A Campus workshop on QualityManagement Towards the Accreditation Process isbeing planned for Athens in the autumn and will beorganised in co-operation with Eurogentest.

l The main focus of the Molecular Methods group hasbeen the primer database, which is available to fullConsortium members only. The main aim of thedatabase is to share molecular PGD protocols amongfull Consortium members. It is hoped that thedatabase will benefit PGD groups and allow them tosave time for optimisation, reduce cost, improvestandardisation, find consensus on specific protocols,and be used as a reference. PGD Consortium membersare invited to submit their protocols in order topopulate the database. Any suggestion to Francesco [email protected] .

Gary HartonChair, PGD Consortium

NEWS// COMMUNICATIONS //

ESHRE tweets to a newcommunity of friendsand fans in the onlineworld of social mediaIt’s now more than a year since ESHRE began its forayinto the social media of Facebook, Twitter and YouTube,and first results - as expected - reflect a relatively high andgrowing level of involvement. We now have more than1300 Facebook fans, with the majority of users apparentlyaged between 25 and 34, and female. Facebook posts havebeen used for press releases, workshop announcements,ESHRE statements and ESHRE news. A click on theFacebook icon on the ESHRE website will take visitorsstraight to their Facebook page and links to all ESHREpostings (which so far total almost 50).

Similarly, a click on the Twitter icon will take visitors toTwitter where they can follow ESHRE from their ownaccount, or open a new account. Twitter now lists morethan 180 ESHRE followers - with instant reaction andinter-reaction to ESHRE’s own tweets - which includepatient groups, exhibitors, clinics, journalists andgovernment bodies. ESHRE itself follows 25 tweeters, suchas the BMJ, NatureHealth, New Scientist, and Bionews.Other sites - like Flickr or YouTube - have also been usedby ESHRE to make audio and visual material available,particularly from last year’s annual meeting in Rome.

Currently, around ten names are signing up each week toany of the ESHRE social networks, and all of them can be

incorporated into one platform for those subscribing toESHRE’s RSS feed.

A copy of ESHRE’s guidelines on the use of social mediacan be found on the ESHRE website (under ‘ESHREcommunity’). The guidelines make clear that these newnetworking technologies are to encourage open dialogueand exchange of ideas.

Top, clips from a selection of ESHRE videos can be found on YouTube;below, the age range of ESHRE’s 1300 Facebook fans.

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Fertility Europe’s mission is to bring fertility organisationstogether with opportunities for networking and sharingbest practice and information. Well, we certainly did thatat our annual meeting in Rome last year. We welcomed 31participants representing 19 organisations from 17countries.

We unanimously voted in nine organisations as EffectiveMembers; these were ‘Iskam bebe’ of Bulgaria, ‘SdruzhenieZachatie’ of Bulgaria, ‘Association Maia’ of France,‘Kiveli’ of Greece, ‘Országos Lombikbébi TámogatóAlapitvány’ of Hungary, ‘Nasz Bocian’ of Poland,‘Associacão Portuguesa de Fertilidade’ of Portugal, ‘SOSInfertilitatea’ of Romania, and ‘Barnlängtan’ (formerlyIRIS) of Sweden.

We were delighted towelcome Anna Veiga,Chairman Elect ofESHRE, to themeeting. Anna spokeon ‘The latestchallenges in ART’,which again generatedmuch discussion andmany questions. We

would like to thank Anna for taking time outfrom what I know was a busy schedule for her inRome.

We also agreed in Rome to form a sub-groupfor developing Fertility Europe policy statements,which includes Sweden, France, Belgium, CzechRepublic and the UK. The first two policystatements will be on reimbursement for fertilitytreatment and single embryo transfer; the draftswill be discussed and hopefully ratified bymembers in Stockholm. We do recognise thatFertility Europe is not there to force any oneview on members; however, we hope that this

initial work will form a template for future policystatements on, for example, surrogacy and donoranonymity.

Special Families projectOne of our most visible activities is the SpecialFamilies project, which was successfully pilotedahead of last year’s annual meeting. At the time of

writing, we are waiting news of sponsorship but are veryconfident that the project will continue successfully.

The idea behind the project is that people send ‘messagesof hope’ - in pictures and words - as an explanation ofwhy a family which had met problems in having a childnow sees itself as ‘special’ in achieving its dreams. Thepictures and stories, in the native language, are then madeinto postcards.

Some of the stories sent in for the pilot were verypowerful and show enormous courage and determination -as well as the multitude of ways for becoming a specialfamily. The project has several aims: to raise awareness offertility problems and their impact on those affected; toshow how successful treatment can be and the joy it bringsto people; and to raise awareness of how you can protectyour fertility. Our aim is for hundreds of thousands ofpostcards to be presented in Stockholm later this year.

So what are our other plans for 2011? l We will consolidate the results achieved in 2010 fromenlarging our network of associations as a ‘reliable voice’at the lobby level. a

Template postcard for the SpecialFamilies project.Fertility Europehopes to receivemany thousands ofpostcardsreflecting theimpact which thetreatment ofinfertility canhave on families.

Anna Veiga,Chairman Elect ofESHRE and seenhere with samplecards from theSpecial Familiesproject, spoke atFertility Europe’sannual meetingabout thechallenges nowfacing ART.

‘Special Families’ projectlooks for postcards tellingmany thousands of stories

D OUTER

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l We will also continue to work closely with ESHREin terms of communications and patient representation. l We will continue to actively reach out to increase ourmembership so that we can all share our activities withmore patient organisations and in turn help them intheir work in their own respective countriesl We will continue to review and add content to ourwebsite, increase and diversify our income, develop ourFE policy programme, agree our business and processesplan, begin planning for ESHRE 2011 in Stockholm

and continue to collect information about ART andnational regulation and reimbursement.

Do visit our website at www.fertilityeurope.eu to findout more. And when you do, if you notice that wedon’t have a European patient organisation listed foryour country and you know of one, please get in touchwith us.

Finally, but very importantly, we thank ESHRE fortheir continued support.

Clare Lewis-Jones, Chair Fertility Europe

NEWS// LEGISLATION IN EUROPE //

Austria granted right toappeal after European court

finds ART law ‘discriminatory’In April last year the European Court of Human Rightsin Strasbourg upheld the complaint of two Austriancouples that Austria’s legal ban on (heterogeneous)oocyte and sperm donation was discriminatory and inviolation of the couples’ rights under article 14 of theEuropean Convention on Human Rights on ‘prohibitionof discrimination’, and article 8 on their ‘right torespect for family life’.

Now, in November, a five-judge panel of the Court hasgranted Austria the right to appeal the ruling before theCourt’s Grand Chamber.

The original case involved two couples seekingtreatment for infertility, one of whom required IVF withdonor sperm and the other male and female gametedonation.

In its April judgement the Court said that the ‘wishfor a child’ is protected by the European Convention,and that its fulfilment through ART should not beprevented by ‘unjustified discriminations’. ‘Moralconsiderations’, the Court added, or concerns aboutsocial acceptability, ‘are not in themselves sufficientreasons for a complete ban on a specific artificialprocreation technique such as ova donation’.

The April decision created a storm among pro-lifeorgansiations, one warning that ‘If this decision isupheld by the Grand Chamber, the flood gates will openfor the recognition of a protected right for same sexcouples to access artificial procreation with egg orsperm donors exactly like a couple composed of a manand a woman’.

ESHRE itself is seeking advice whether it (and otherinterested groups) has the right to submit expert opinion(‘ad adjuvandum’) to the Grand Chamber court.

Despite protests, Danishgovernment abandons itspolicy of state-funded ART Denmark has formally abandoned its policy of fully state-funded ART after the Danish government, supported bythe Dansk Folkeparti, approved new legislation in mid-December introducing patient co-payment for ART.

The move, which became operative on 1st January, wasstrongly opposed by professional organisations inDenmark, including the Danish Fertility Society, whichunanimously but unsuccessfully advised against theintroduction of patient co-payment.

Denmark’s former system allowed free-of-charge fertilitytreatment in public clinics up to a maximum a threecompleted ART cycles for childless couples. Those whodid conceive a first child in a public centre were referredto a private clinic for subsequent treatments; however, allmedication costs were reimbursed for all patients, whetherfor public or private treatments.

Now, all patients having fertility treatment must pay fortheir medication (up to a maximum of DKK 15,000[~2000 euro] per year). In addition, in the public clinics afee of DKK 5000 (~670 euro) is now charged for a freshcycle of IVF or ICSI, DKK 3000 (~400 euro) for a frozencycle, and DKK 1271 (~170 euro) for a cycle of IUI.Patients are also charged for any donor sperm used. Thenew regulations thus cover all types of treatments -except(possibly) PDG, which may be free of charge.

Rates of access to ART in Denmark have consistentlybeen among the highest in Europe, with registriesrecording ART birth rates as high as 8-10% of all babiesborn. Now, says Søren Ziebe, IVF laboratory director atthe Rigshospitalet fertility clinic in Copenhagen, there arefears that the uptake of IVF will decline (as happened inGermany when patient co-payment was introduced in2004), treatments will become more aggressive, and theopportunities for research will shrink.

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EIM CONSORTIUM// TEN YEARS OF IVF MONITORING REPORTS //

More than 600,000 ART and IUI cyclesnow monitored by ESHRE each yearHigh quality measurement is a prerequisite of confidence

The Campus event held in September last year tocelebrate ten years of ESHRE’s European IVFMonitoring (EIM) consortium was not just aboutreminiscing, nor even about celebrating. This wasalso a meeting about the EIM’s future and howmany of the problems faced in building acomprehensive database of ART activity in Europecan be resolved.

According to the EIM’s present chairman Jacquesde Mouzon, the latest round of data collection - for2007 - gathered registry data from 32 Europeancountries (including Turkey) representing 88% ofclinics in these countries. And, while this is morethan enough to provide a realistic picture of ARTlife in Europe, there are still major omissions.Spain, for example, which is ranked as Europe’s

third most active ART country (behind France andGermany), can provide registry data on only 60% ofits activity. Moreover, although amendments toSpain’s legislation in 2006 required the country's 17administrative regions to collect audited data on acycle-by-cycle basis, only one - Catalonia - is fullycompliant. As a result, said Jose Antonio Castillafrom the University Hospital of Granada, theresponsibility for a registry of nationwide ARTperformance is left to the Spanish Fertility Society(SEF) and a voluntary system of summary reports(clinic-by-clinic, not cycle-by-cycle) which areneither audited nor official. Castilla, who is co-ordinator of the SEF registry, said that in 2008 nomore than 60% of Spain’s ART cycles were reportedto the registry - and from only 50% of its clinics.Moreover, the number of centres participating in thescheme in 2008 actually fell by 14% on the previousyear.

Spain, along with Cyprus, Greece, Switzerlandand several countries of eastern Europe, is one of 13countries to supply only partial information to theEIM. Nevertheless, there was strong representationat this meeting from eastern European registries,including presentations from Russia and Slovenia,and most countries (with the exception of Albania,Croatia, Romania and Slovakia, which did notsupply data in 2007) seem keen to be involved.

Indeed, Tomaz Tomazevic from the UniversityClinical Center in Ljubljana, reported that the EIM’sown data reporting system is now the formalmandatory data collection system for the SlovenianMinistry of Health. This official registry, he added,is able to provide ‘optimal endpoint’ data (deliveryrate per started cycle) with real demographic impact,for it was on the basis of the annual EIM reportsthat Slovenia’s public health insurance schemesupported the use of elective single embryo transferin the first two cycles of treatment by extendingcoverage from four to six cycles.

Such complete systematic reporting - alongsideSlovenia’s progressive legislation on ART - is anillustration of how comprehensive data collectioncan have an effect on national (and Europe-wide)

Most of the 32countries nowsupplying registrydata to the EIMwere represented atthe celebrationreview in Munich.

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Putting the show on the road

demographic initiatives, and this was one of theEIM’s achievements singled out by its co-founderAnders Nyboe Andersen. ‘Indeed,’ said Andersen,‘demographic impact is perhaps our finestachievement, and trends identified by our annualreports are now recognised outside the professionalcommunity.’

Not only has EIM data confirmed substantialinequalities in access to treatments, but have alsounderlined the ever increasing age of ART patientsand the link between infertility and deferredpregnancy. Such links are now well recognised bythe EU, and the European Parliament’s 2008 reporton ‘the demographic future of Europe’ called on theEuropean Commission to address infertility as ademographic issue; such urging, said Andersen,could not be possible without the strength of theEIM database.

The database has also identified a marked butsteady increase in pregnancy rate per transferthroughout the past decade, which has risen from26% for both IVF and ICSI in 1997 to 33% in2007. Similar increases have been seen in pregnancyrates from frozen embryo transfers (from 15% to22%) and in oocyte donation (from 27% to 46%).

Andersen further noted that ‘without the EIMreports no-one would be aware of the positivetrends’ in the number of embryos transferred. In1997 more than one-third of transfers were withthree embryos, but this rate had more than halvedby 2007. Current data suggest that transfer trendsare now relatively stable; two embryos weretransferred in 57% of cycles in both 2006 and2007, and one embryo in 22% of cycles.

However, as Jacques de Mouzon has also insisted,the EIM reports highlight the variability, not thehomogeneity, of European ART, and the collection

of such detailed data has allowed benchmarking fornational comparison of efficacy, efficiency,availability and - to some extent - safety. Certainly,with multiple pregnancy the acknowledged majorrisk of ART, multiple pregnancy rates and trends asdetermined by the EIM have reflected ART’s safetypotential as well as its risks. The data, however, havenot allowed the monitoring of emerging safetyparameters, especially in relation to such newlyintroduced techniques as vitrification or oocytecryopreservation.

Similarly, the long-term effects of assistedconception remain beyond the scope of EIM data,and even, in some countries at least, the obstetricoutcome of pregnancy. Indeed, the standardisation ofall inputs to the database remains a theoreticalobjective, said Andersen, although many countries -such as Germany and France - with newly upgradeddata systems have the ability to provide detailed cycledata with linkage to delivery outcome.

Taraneh Shojaei reported that responsibility for a

ESHRE's Executive Committee had already heard one or twosuggestions for surveillance data collection before Karl Nygren andAnders Nyboe Andersen, pictured above, submitted a formal proposalin March 1998 for the establishment of a European IVF monitoring(EIM) committee. The two Scandinavians spoke of data 'monitoring'and not data 'collection', although in their proposal collecting andauditing data (from national registries) were essential activities.European monitoring, they said, was needed to prevent IVF activitiesin any country from 'derailing' as a result of negative publicity.

The EIM consortium was formally established at the 1999 annualmeeting in Tours, and attracted to its first meeting representativesfrom 19 European countries, who each provided an overview ofnational data collection registries.

The EIM's first report - on ART activity in 1997 - was published in2000, and its 11th report - on activity in 2007 - presented in Romeprior to publication. Annual citations of EIM reports now total morethan 100.

EIM data then and now

CountriesClinicsProportionComplete reportsART cyclesIUI cyclesPR per ET IVFPR per ET ICSIPR per FETPR egg donationSETDETSingle deliveryTwin

199718482

?10

203,893None

26.1%26.4%15.2%27.1%11.5%35/7%70.4%25.8%

200732

101688%19

479,288168,17832.9%33.3%22.5%46.3%22.8%57.5%78.2%20.5%

E INNER

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registry data in France has now passed fromFIVNAT to the government’s Agence de laBiomedecine (of which she is the evaluationdepartment manager), with a legal requirement thatall clinics must participate in the scheme and submitat least summary data, and by 2012 individual cycledata. The system, said Shojaei, combines registry,licensing and monitoring requirements in ART withthose of the EU’s Tissue and Cell Directives.

Similarly, the meeting’s local organiser, MarkusKupka from Munich University Hospital, reportedthat the German IVF register, whose cumulativedata collection is now approaching 1 million cyclessince its inception in 1982, allows the submission ofindividual cycle data through various softwarepackages to a centralised linkage library.

A recent analysis performed by the Germanregistry (of almost a half million cycles) suggeststhat prospective data input is a mark of quality andassociated with higher pregnancy rates. ‘Ourexperience of prospectivity,’ said Kupka, ‘ispositive.’ The German data also show that thenumber of treatment cycles is beginning to rise onceagain (by around 10% per year) followingrestrictive changes to reimbursement policy in 2004.

Comprehensive cycle-based systems such as thosein Germany, France or the UK provide what theEIM’s other co-founder Karl Nygren called those‘high-quality measures which are a pre-requisite forbuilding confidence in ART’, and this, he readilyacknowledged, was the mission of the EIM’sfoundation more than a decade ago. The challenges,Nygren added, remain in the definition of ‘key data’and ‘key outcomes’, but would ideally concentrateon benefit indicators (access, efficacy, safety andcost) according to specific interventions. However,there still remains huge variability in definition,tension in the submission of cycle and/or summarydata, and a reliance on extrapolation forcomprehensive coverage. Moreover, said Nygren,there are still deficiencies in reporting, with manypregnancies lost to follow-up and inadequatecoverage for full risk assessment.

The future, added Nygren, may apply a morerelevant and comprehensive way of reportingefficacy (pregnancies, deliveries, singletons, healthysingletons . . . ) and a more appropriate definitionof intervention (started cycles, fresh and frozen,cumulative . . . ), but for the moment he urgedongoing surveillance and continuing commitment tothe project. There is, he noted, no other comparabledatabase in the world, and continuing confidence inthe treatments monitored depends on theavailability - and transparency - of such data.

Simon Brown Focus on Reproduction

MART safety monitoringproject is now ‘making

real progress’

Following a feasibility report in 2006 and withfunding in place from ESHRE, the Universityof Copenhagen and the Danish Agency ofScience, Technology and Innovation, work onthe MART (Morbidity in ART) project began in2008 and has now assembled a provisionaldatabase of almost a 100,000 IVF children -21,398 IVF children born between 1984 and2007 in Norway, 35,017 in Sweden, 19,065in Finland, and 23,477 in Denmark, allmatched with around 400,000 controls.

The plan now, said Anna-Karina AarisHenningsen, pictured above, who is co-ordinating the project from the UniversityHospital in Copenhagen, is to pool the ARTdata and cross-link with national health systemregisters in the four countries. The sheer sizeof the cohort, said Henningesen, should reflectthe prevalence of even rare epigeneticdisorders or the effects of newly introducedtechniques. Similarly, the database may wellover time reflect the perinatal anddevelopmental health benefits derived from thetransfer of fewer embryos.

Danish data are ready, and Finnish, Swedishand Norwegian data almost available forpooling. Once completed, the project shouldnot only provide an unequivocal assessment ofthe perinatal outcome of 98,957 IVF births inthese countries, but a clear picture ofmorbidity trends over time associated withassisted conceptions.

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// PCOS CONSENSUS WORKSHOP //

Attention now turns to the health risks of PCOSThe report from the first jointESHRE/ASRM consensus conferenceon the diagnostic criteria forpolycystic ovary syndrome has, injust seven years since publication,become a citation classic. The'Rotterdam criteria' developed at thatmeeting recognised that women withPCOS represent a heterogeneouspopulation which cannot be definedby strict definitions. Thus,Rotterdam concluded that PCOSmight be confidently diagnosed inwomen with any two of threefeatures: polycystic ovaries seen onultrasound, hyperandrogenism andoligo/amenorrhoea. The NIH criteria of1990 which the Rotterdam consensussuperseded had required only twodiagnostic features: hyperandrogenism andchronic anovulation.

As of November last year, the Rotterdam consensusreport - published jointly by Human Reproductionand Fertility & Sterility - was HR's most frequentlycited publication, and F&S's second.

The second consensus statement, like the first,considered PCOS from the perspective of infertility,and developed consensus on treatment. After lifestyleadvice, first-line management was defined asovulation induction (with clomiphene citrate) followedby gonadotrophin therapy or laparoscopic ovariansurgery and IVF.

Now, a third consensus conference, held inAmsterdam in November last year, has shifted thefocus from infertility to the health implications ofPCOS in early and later reproductive life. 'So it's verydifferent from the two previous statements,' said BartFauser, chairman of the writing committee, with theperspective now moving from reproductive disordersto a population deemed at risk of type 2 diabetes andother cardiovascular diseases.

In the adolescent, however, even the definition ofPCOS is 'confusing', according to Leeds gynaecologistAdam Balen, a member of the six-man writingcommittee. Many of the normal features ofadolescence are similar to those of PCOS, he said,such as ovarian morphology and cycle regularity.However, Balen confirmed that oligomenorrhoeapersisting two years after menarche in the adolescentis an early sign of PCOS - and a better predictor thanLH or androgen concentrations.

Somewhat later in the reproductivelifespan, Felice Petraglia, Universityof Siena, reported that the presenceof PCOS had been associated with ahigher incidence of miscarriage andan adverse pregnancy outcome. Therewas some discussion from the floorabout the former, with Londonendocrinologist Steve Franksdoubting the strength of themiscarriage data, and Rick Legrofrom Penn State College of Medicinenoting that in the US randomisedtrials on the use of metformin therewas no difference found inmiscarriage rates among the different

patient groups. However, Petragliaemphasised the adverse effects of PCOS onpregnancy outcome through the mediatorsof gestational diabetes, pregnancy-inducedhypertension, pre-eclampsia and fetal

growth retardation. He also noted that this adverseeffect was not just a matter of obesity, citing datashowing far higher rates of gestational diabetes inPCOS subjects than in those who were only obese.

However, in later life the overriding risks of PCOSlie with type 2 diabetes and cardiovascular health,risks which are amplified anyway in obese women.Steve Franks cited the observational Nurses HealthStudy to show that the risk of type 2 diabetes wasmore than doubled in women with a history ofirregular cycles. Obesity, he added, would increasethat risk. However, Franks emphasised that PCOS is a'prediabetic' state which invariably presents at ayounger age; thus, diet and lifestyle advice are themost important ways for reducing the diabetes risk inlater life.

And it is, of course, the presence of type 2diabetes which increases the risk of CVD. Thelandmark Interheart case-control study found thatdiabetes was associated with a 4.2 relative risk formyocardial infarction. Advice from this meeting,therefore, was to take a multifactorial approach, withthe usual recommendations of weight loss, exercise,smoking cessation, and medication.

Fauser expects that this broad-scope consensusstatement will be published later in 2011. Itsdevelopment is now in the hands of a writingcommittee composed of three ESHRE and threeASRM representatives, and publication will onceagain be a joint exercise by both groups’ journals.q

Bart Fauser, chairman ofthe writing committee

for this third PCOSconsensus statement.

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ESHRE took part in Europe’s leading conference on healthpolicy in October last year, hosting a workshop on‘Individual choice in reproductive health’. The workshop,which took place at the European Health Forum inGastein, Austria, considered infertility and its treatmentfrom the perspective of the patient, the drug industry, thepolitician and society.

However, all four presentations ultimately pointed in theone direction of cross-border reproductive care and themultiplicity of regulation and practice now present inEurope. It is this very multiplicity - as the panel discussionmade clear - which is now driving cross-border movementin European fertility treatment.

In particular, Clare Lewis-Jones, chair of Fertility Europeand speaking on behalf of the patient, described apatchwork of legislation and reimbursement policies whichmade, for example, anonymous donor inseminationallowed in France and Belgium, but outlawed in theNetherlands, Germany and UK.

A survey performed by Infertility Network UK on ‘theattraction of overseas clinics’ for UK patients found short

ESHRE NEWS// EUROPEAN HEALTH FORUM //

The legislative inconsistency behindcross-border reproductive careESHRE’s perspective at Europe’s leading forum for health policymakers

waiting times for treatment, cost, success rates andavailability of donor gametes as the leading reasons fortravel. ‘Perhaps it’s because their fertility declines as eachmonth goes by which makes waiting time so sensitive,’ saidClare. Almost all patients (88%) made travel and clinicarrangements themselves, and most were happy with theoutcome.

The increasing attraction of clinics in eastern Europe,said Clare, is cost and limited regulation, with prices inRomania, Ukraine and Russia reportedly a quarter that ofprivate treatment in western Europe. However, herunderlying theme was the inconsistency of treatmentregulation throughout Europe. Her recommendations onbehalf of the patient were:l Consistent regulation and recommendations across thewhole of Europe, with the same rules appliedl Standardised health information (in a range oflanguages) from health professionals/governments/EU andpatient organisationsl A common minimum standard of care across Europel Consistent counselling support

Similarly, from the social perspective ESHRE ChairmanLuca Gianaroli defined the controversies in ART assurrogacy, anonymous and non-anonymous gametedonation, embryo freezing and PGD, which were eachreflected in inconsistent national legislation. However, thelegislative anomalies, he said, are increasingly subject to

The workshop was chaired by ESHRE’s Past Chairman Joep Geraedts, with presentations by (left to right) Luca Gianaroli,Clare Lewis-Jones, Joan-Carles Arce, and Isabel de la Mata Barranco.

jan11_nwpFri:46355 17-12-2010 15:12 Page 18


legal challenge. Gianaroli not only cited the successfulchallenges to Italy’s Law 40 requirements (to transfer allfertilised oocytes), but a 2010 judgement from theEuropean Court of Human Rights that Austria’s ArtificialProcreation Act - which disallows gamete donation - was inviolation of the Convention because the claimants couldnot conceive by any other means than gamete donation.

The European overview presented by Gianaroli - as alsofound on the ESHRE website under ‘Guidelines and Legal’- proved salutary to the audience of health policymakers,who appeared astonished at the disparities. ‘There can beno other areas of medicine with such diversity oflegislation,’ said one bemused guest from the floor.

EU cross-border directiveWhile ESHRE’s own Task Force on cross-borderreproductive health is moving ahead with its ownguidelines, Isabel de la Mata Barranco, a Principal Adviserto the European Commission (DG SANCO) with a specialinterest in public health, reported that the draft directive oncross-border healthcare (which was approved by theCouncil of EU ministers in June 2010, backed by theParliament’s public health committee in October, and isnow in its second reading in Parliament) will only allowreimbursement of costs up to the amount that would havebeen paid had they received that treatment at home.Procedures not allowed (or not reimbursible) in the homecountry will not be reimbursed.

The directive, said Ms de la Mata, is intended to smoothcross-border healthcare and ensure free citizen movementamong member states (in compliance with Article 25 of theoriginal treaty of Europe) while ensuring each country’srights to run its own health systems.

The directive has been bogged down in financial

concerns and amendments over the outward flow ofpatients (and whether prior authorisation is necessary forhospital procedures) and over the quality and safety ofcare. Many member states had insisted that priorauthorisation should be necessary, while the Commissionitself insisted that any prior authorisation would be anobstacle to the free movement of citizens - which the Courtof Justice would not allow.

Now, in its final draft the Council has not only agreedthat patients are to be reimbursed up to the level theywould have received in their home country (ie, what wouldhave been paid for by its own social security system) buthas also added a new provision that member states maydecide to cover other related costs, such as accommodationand travel expenses (which may still need priorauthorisation). The latest draft thus lists reasons whymember states may refuse authorisation, which seem toinvolve entitlement to treatment, standards and safety.

The draft also suggests that each member state mustensure, via ‘national contact points’, that patients fromother EU countries can receive information on safety andquality standards to make an informed choice.

It now seems that the draft proposal has broad supportin the EU Parliament and is likely to be accepted at itssecond reading this year. Should that happen, the directivecould be adopted as ‘soft’ law by June.

Speaking to the press in October last year, French MEPFrançoise Grossetête, who has been the Parliament’srapporteur on the directive, said: ‘This directive is designedto allow patient mobility. We already have mobility ofworkers and students. It’s part of the fundamental rights ofEuropean citizens. This does not however encouragemedical tourism. We simply want to allow a wider range ofpublic health for patients.’q

Despite a background of great social and medical need and an ART success storywhich boasts delivery rates comparable to spontaneous conception, industry researchinto fertility now commands only a minute proportion of an annual R&D expenditure of$34 billion. Based on data from 22 pharma companies and bundled into the categoryof 'GU/sex hormones', fertility (alongside contraception, menopause, BPH and erectiledysfunction) represents no more than 3% of industry's total R&D budget, with littleprospect of any advance, according to Joan-Carles Arce, Vice President of ClinicalResearch & Development at Ferring Pharmaceuticals.

He described the development pipeline of the three 'big players' in fertility as'stagnating', with only two new entities in phase II, and just one in phase III. Past developments, he added, havenot realised aims to improve efficacy or safety, but have improved convenience (in new presentations, deliveryroutes, and longer action). Dr Arce described biomarkers for diagnostics and treatment, drug delivery technology,and embryo selection processes as new areas with potential for progress.

However, he said, any pharma developments in fertility today are constrained by complex targets (notablyconfined to sub-groups of patients), increasing regulatory requirements (for documenting efficacy and safety),heterogeneous legislations, a necessity to duplicate clinical trials, and cost.

There is, he added, a need for joint efforts between industry, governments and organisations to allocateresources and establish structures to ease the burden of infertility, and for realistic drug development objectivesand reward to stimulate further development activities in fertility.

‘Heterogeneous legislation’ also blocks industry’s‘stagnating’ fertility development pipeline

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The SIG RE ended 2010 withcontinuing activity in jointmeetings, the latest in Septemberin Dubrovnic, Croatia, on ‘Ahealthy start - The determinants ofa successful pregnancy’. This was ajoint Campus event with the SIGsEarly Pregnancy and ReproductiveSurgery but unfortunately there were fewer delegates thanspeakers - a great shame, as the quality of thepresentations and the high level of discussion were verystimulating. We do need to ensure that our meetings arewell attended, especially as they are now held in variedlocations and our speakers take a lot of time out of busyschedules to share their knowledge and participate in ouracademic sessions.

The third joint ESHRE/ASRM PCOS consensus meetingon medical problems associated with PCOS took place inNovember hosted by Bart Fauser and Basil Tarlatsis, bothformer co-ordinators of the SIG RE. The programmestarted with a one-day open meeting and continued with atwo-day, closed consensus workshop along the lines of theearlier Rotterdam and Thessaloniki meetings. As our shortreport on page 17 indicates, the aim was to develop aconsensus on the impact of PCOS on early and laterreproductive life, and those aspects not necessarily seenfrom a fertility perspective (as in the two previous reports).Thus, on the agenda were quality of life, obesity, hyper-androgenism, pregnancy and, in later reproductive life,type 2 diabetes, the menopause and cardiovascular health.

Training programme in 2011For 2011 we encourage you to register for the firstCampus in Kempten, Bavaria, on 4th February on ART

and the oncological impact, hosted by RicardoFelberbaum. The programme includes presentations on:Sexual steroids and their oncogenic potency; Estrogens,endometriosis and ovarian cancer: is there a missing link;Cancer incidence in infertile women after COH; Incidenceof malignancies in children born after IVF - results ofepidemiological studies; Ovarian protection duringchemotherapy by GnRH agonists.

Nick Macklon will be hosting The embryo as patient on13-14th May in Winchester, UK. It is now clear that thepericonceptional period determines not only perinataloutcomes but has an impact on the long-term health ofmother and child. This one-day course will cover theevidence base supporting the developmental origins ofhealth and disease (formerly referred to as the ‘Barkerhypothesis’), and how this relates to the periconceptional

period. Examples of hownutrition, environmental factorsand fertility interventions mayaffect developmentalendocrinology, long-term healthand fertility in the offspring willbe reviewed, and interventionstrategies discussed.

We agreed at our AGM in Stockholm that this year’sprecongress course will be titled Ovarian ageing and willcover the formation of oocytes in the ovary anddeterminants of their rate of loss. The causes andmanagement of premature ovarian failure will also bedescribed, as will ways to preserve fertility by oocyte orovarian tissue cryopreservation. The day will concludewith a socio-ethical talk on the effect on society ofpostponing pregnancy.

We shall be holding a further training workshop withour colleagues in the Paramedical Group and SIGEmbryology in St Petersburg, Russia, from 7-8thSeptember. The first of these courses in Kiev last May wasvery popular and so we encourgae you to register early!We are also considering a meeting on PCOS for Bulgarialater in the year.

. . . and into 2012The precongress course in Istanbul in 2012 will beOptimising the IVF protocol and the use of adjunctive

therapies, covering such controversial issues as aspirin,DHEA, growth hormone, steroids, heparin, acupuncture,homeopathy etc, etc...

Also in 2012 we plan an update on the use and role ofGnRH antagonists to be hosted by Georg Griesinger inLuebeck, Germany. And in the Spring in Lille, hosted byDideir Dewailly, an update on AMH. We also have aproposal for a meeting in Montenegro to be hosted byTatjana Motrenko Simic, the programme for which is stillto be finalised.

I stand down as Co-ordinator of the SIG RE in 2011and would like to thank the committee for their hardwork, help and suggestions. Georg Griesinger takes over asCo-ordinator at Stockholm. We have just held our firstfully open election to the committee and we are pleased toannounce that joining as Deputy Co-ordinators are FrankBroekmans and Stratis Kolibianakis, with DanielaRomualdias the new Junior Deputy. I wish Georg and hisnew team all the very best for the coming years.

Adam BalenCo-ordinator SIG Reproductive Endocrinology

[email protected].

New elected officers in place after Stockholm

OfficersAdam Balen (GB), Co-ordinatorRichard Anderson (GB), Deputy Co-ordinatorJuan Garcia-Velasco (ES), Deputy Co-ordinatorGeorg Griesinger (DE), Junior DeputyNick Macklon (NL), Past Co-ordinator

SPECIAL INTEREST GROUPS// REPRODUCTIVE ENDOCRINOLOGY //

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// SAFETY & QUALITY IN ART //

Central Office research support for guidelinesIt is now three years since aninvitational meeting was convenedby the SIG Safety & Quality inART (SQUART) - represented byPast Co-ordinators Christina Berghand Jan Kremer - in Nijmegen toconsider the future of ESHRE’sclinical guidelines. After two days of discussion,representatives of ESHRE’s SIGs, journals and ExecutiveCommittee (as well as the Cochrane Collaboration)concluded that ESHRE, as an authority in reproductivescience and medicine in Europe, does have a responsibilityto set guideline standards for high-quality clinical practice.Thus, at the end of this meeting the ESHRE guidelineprogramme was born - at least in name - and the rules ofthe game determined.

The overall aim of the guideline programme is todecrease practice inconsistency and increase the overallquality of patient care in reproductive medicine in Europe.Thus, it was agreed that the guidelines emerging from theESHRE programme would be authoritative, based on thebest available evidence (most relevant and highest level),reliable and consistent in style and approach. It was clearthat such guidelines would be aimed at professionals(doctors, scientists, paramedics, etc), with patientsinvolved as stakeholders in a consultation process.Production would be according to up-to-date process andquality indicators.

The development of clinical guidelines has generallybecome a formalised process in recent years. Instrumentssuch as that of the Appraisal of Guidelines for Researchand Evaluation in Europe (AGREE) collaboration (seewww.agreecollaboration.org) provide structures for the

design, preparation, review,dissemination and evaluation ofguidelines. And it was according tothese internationally acceptedcriteria that the SIG SQUARTdeveloped an ESHRE manual forguideline development; the

guideline programme has now become one of the coreactivities of the SIG SQUART, with Willianne Nelen asprogramme co-ordinator.

Publication of the ESHRE manual for guidelinedevelopment has in the meantime also sharpened the rulesfor publication of other ESHRE documents. Thus, anyESHRE document (eg, position statements, specialityreviews, notice of intention and clinical guidelines) mustnow either be commissioned by the Executive Committeeitself or its subject approved in advance. In addition,manuscripts must be posted on the ESHRE website forreview by members (fixed as one month) before theirpublication. The rules, said past ESHRE Chairman JoepGeraedts, were introduced to bring some consistency - aswell as authority - to the increasing output of ESHREdocuments, and an accepted and uniform methodology forcomposition and approval will inevitably raise the value ofthe documents.

However, the principal aim of the manual is to provide astepwise practice tool for members of ESHRE’s guidelinedevelopment groups and is available for consultation onthe ESHRE website. Each chapter of the manualcorresponds with one of the interdependent activities ofguideline development (eg, scoping, search and selection of evidence, dissemination) and consists of a description,an overview in flow chart form and some practical a

OfficersPetra De Sutter (BE), Co-ordinatorKarl Nygren (SE), Deputy Co-ordinatorWillianne Nelen (NL) , Deputy Co-ordinatorJan Kremer (NL), Past Co-ordinator

ESHRE’s new research specialist for guideline developmentThe missing link in full-speed ESHRE guideline development has been the absence ofa research specialist, but now, with the addition of a full-time researcher in CentralOffice from October last year, that gap has ben filled. Nathalie Vermeulen, 27, hasbeen appointed as a research specialist on behalf of the ESHRE guideline programme.She graduated in biochemistry from Leuven in 2005 and obtained her PhD onserological markers in inflammatory bowel disease in January 2010. Before starting atESHRE, she was employed as a pharmaceutical company product manager.

As a research specialist Nathalie will assist the SIGs in the development ofguidelines, and in that capacity will document existing guidelines, conduct stepwiseliterature search and summarise evidence, formulate and classify recommendations,record evidence gaps and update the literature search every two years for everyguideline. Nathalie can be contacted at [email protected]

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The SIG Stem Cells organised its firsttwo ESHRE Campus meetings in2010, in February in Barcelona and inNovember in Valencia; both combineda basic update course on pluripotentstem cells and a hands-on workshop.The meetings were organised with theSpanish Stem Cell Bank (Instituto deSalud Carlos III) and involved a number of speakers fromdifferent areas of stem cell biology, from academia tocommercial companies, and covered biological, technicaland ethical aspects of stem cell research. The basic coursewas followed by a four-day intensive workshop on thederivation and culture of pluripotent stem cells. Bothworkshops were fully booked, and were attended bystudents coming from Europe (Bulgaria, UK, Latvia, Italy,Germany), Asia (Russia, Turkey, India), Africa (Gambia),and Latin America (Brazil).

Participants had the chance to learn how to derive mouseembryonic stem cell lines, to culture, expand and freezehuman embryonic stem cells, to test pluripotency of humanES cells by making embryoid bodies and teratomas, toreprogramme human fibroblasts, and to manipulateembryos during their preimplantation development. Thestudents were followed by tutors on almost a one-to-onebasis with a highly personalised teaching system thatcovered most of the techniques actually in use in hES cellsand induced pluripotent stem cell research.

We now plan to continue this teaching initiative every sixmonths at the labs of SIG members, with Anis Feki at the

SPECIAL INTEREST GROUPS// STEM CELLS //

SIG Stem Cells agrees endorsement ofISSCR research and clinical guidelines

University of Geneva and JoseInzunza at the Karolinska Institutein Stockholm joining the initiative.

Stockholm 2011We are pleased to announce that theprecongress course in Stockholm,The blastocyst: perpetuating life, is

already prepared and announced. The course is acollaboration between our SIG and the SIG Embryologyand will be chaired by Karen Sermon and Cristina Magli.The course will cover the common ground betweenembryology (embryo polarity, pluripotency) and stem cells(epigenetic regulation, micro RNAs and pluripotency). Fulldetails can be found on the ESHRE website. We will bedelighted to receive any suggestions or contributions forthe preparation of future events.

Research guidelinesThe field of regenerative medicine is rapidly expandingthanks to the discovery of human embryonic and inducedpluripotent stem cells.1,2,3 In addition, current preliminary,proof-of-principle studies in model systems indicate a realtherapeutic value of pluripotent or progenitors cells.4,5,6

Regenerative medicine through pluripotent cells promisesto tackle some of the most devastating and life alteringdiseases, such as Parkinson's disease, diabetes, spinal cordinjury derived paralysis, and many more.

In the last few years, basic research into the derivationand the biology of human embryonic stem (hES) cells has

OfficersCarlos Simon (ES), Co-ordinatorKaren Sermon (BE), Deputy Co-ordinatorAnis Feki (CH), Deputy Co-ordinatorRita Vassena (ES), Junior DeputyAnna Veiga (ES), Past Co-ordinator

suggestions. The manual also recommends that all ESHREguidelines are kept to a reasonable size to ensure theirdevelopment within an 18-24 month period. And now, tohelp in meeting tighter deadlines, each guidelinedevelopment group will be supported by the ESHREresearch specialist to provide technical support andfacilitate evidence search and selection.

Several SIGs, including Endometriosis & Endometrium,Early Pregnancy and Psychology & Counselling, havealready announced that their (updated) guidelines will bedeveloped in accordance with the new manual. In April2009 a training course was organised to inform all SIGs

about the new guideline development methodology, andthis will be repeated for all future development groups to

help them follow the manualand to guarantee a consistentlevel of methodological quality.

Willianne NelenDeputy Co-ordinator SIG

SQUART and co-ordinator of the ESHRE

guideline programme

SIG Safety & Quality continued

jan11_nwpFri:46355 17-12-2010 15:12 Page 22


increased considerably. There are now hundreds of hES celllines banked across the world, and more are being derived.This situation naturally leads to transnational research, andthe need of a sound scientific and ethical framework isstrongly felt. It is for this reason that the SIG Stem Cellsendorses the Guidelines for the Conduct of HumanEmbryonic Stem Cell Research, prepared by theInternational Society for Stem Cell Research(http://www.isscr.org/guidelines/ISSCRhESCguidelines-2006.pdf). The ISSCR is the leading international scientificassociation for pluripotent cell scientists and clinicians, andits guidelines set the standard of practice and the ethicalframework for the use of hES cells in research. Theguidelines also offer guidance to researchers and clinicianscollaborating across national (and often legislative)borders, address important ethical issues (such asprocurement of embryonic material for hES cell derivation),and help in defining the scope of acceptable researchprojects (for instance, by taking a clear stance againstreproductive cloning).

A stand against unproven treatmentsThe great promise of regenerative therapies, although so farunproved in clinical trials, has prompted a keen interestamong professionals and patients alike. As research intothe clinical potential of pluripotent and progenitor cellsadvances, so does the hope of patients and families in theirsearch for solutions to severe health problems. Sadly, inparallel to the rigorous testing and initial clinical trials nowunder way with pluripotent cells, there also flourishes amarket of unproven, and often dangerous, treatments.Numerous clinics, mostly in countries with lax legislativeframeworks, market their ‘treatments’ directly to thepatients, often without disclosing the source of the cellsinfused (among them embryo and fetal derivedpreparations), the details of the protocol, and, mostimportantly, without rigorous efficacy and safety data.

Two dramatic cases stand out from the recent literature,one involving the development of a donor cell-derivedbrain tumor in a 13-year-old boy undergoing fetal neuralstem cell treatment to treat ataxia teleangiectasia,7 and oneinvolving a 46-year-old woman with systemic lupuserythematosus who had her own hematopoietic stem cells

mobilised and injected percutaneously in the kidney region;the patient developed angioproliferative tumors neverdescribed before, and likely of stem cell origin.8

In the wake of these events, the SIG Stem Cells hasagreed to take a clear stance on the issue of cell therapies,in order to protect the interests of patients and familiesseeking a cure for highly invalidating diseases. The SIGStem Cells has therefore also endorsed the Guidelines forthe Clinical Translation of Stem Cells, again prepared bythe ISSCR (http://www.isscr.org/clinical_trans/pdfs/-ISSCRGLClinicalTrans.pdf). The document details, forinstance, the conduct to be taken when faced with issuessuch as patient information, disclosure of source of cells,disclosure of safety and efficacy trials, and advice topatients on unproven procedures. We warmly invite allESHRE members to adopt these two sets of guidelineswhen planning hES-based research activities and discussingthe potential of cell therapy approaches with their patients.

Carlos SimonCo-ordinator SIG Stem Cells

1. Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embryonicstem cell lines derived from human blastocysts. Science 1998; 282:1145-1147.2. Takahashi K, Yamanaka S. Induction of pluripotent stem cellsfrom mouse embryonic and adult fibroblast cultures by definedfactors. Cell 2006; 126: 663-676.3. Takahashi K, Tanabe K, Ohnuki M, et al. Induction ofpluripotent stem cells from adult human fibroblasts by definedfactors. Cell 2007; 131: 861-872.4. Raya A, Rodriguez-Piza I, Guenechea G, et al. Disease-correctedhaematopoietic progenitors from Fanconi anaemia inducedpluripotent stem cells. Nature 2009; 460: 53-59.5. Hanna J, Wernig M, Markoulaki S, et al. Treatment of sicklecell anemia mouse model with iPS cells generated from autologousskin. Science 2007; 318: 1920-1923.6. Wernig M, Zhao JP, Pruszak J, et al. Neurons derived fromreprogrammed fibroblasts functionally integrate into the fetal brainand improve symptoms of rats with Parkinson’s disease. Proc NatAcad Sci USA 2008; 105: 5856-5861.7. Amariglio N, Hirshberg A, Scheithauer B, et al. Donor-derivedbrain tumor following neural stem cell transplantation in an ataxiatelangiectasia patient. PLoS Med 2009; 6(2): e1000029.8. Thirabanjasak D, Tantiwongse K, Thorner PS.Angiomyeloproliferative lesions following autologous stem celltherapy. J Am Soc Nephrol 2010; 21: 1218-1222.

Participants in the fully booked 2010 update andhands-on courses in Valencia (left) and Barcelona.

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In earlier issues of Focus onReproduction I have noted thatthat SIG-A - and indeed the wholefield of andrology - is not justabout the laboratory and semenanalyses. Andrology is the studyof all facets of reproductive healthin the man, and therefore includes clinical andrology,laboratory andrology and basic andrology.l Clinical andrology will mainly include those subjectsrelated to male (in)fertility - its diagnosis and treatment,HIV, immunological aspects, environmental influences, age,ejaculation (spinal injuries), contraception, surgery, spermretrieval (MESA, TESA, TESE), varicocelectomy and spermdonation.l Laboratory andrology will include such topics as basicsemen analysis, diagnostic tests, sperm functional tests,semen preparation, semen preservation and sperm DNAtests.l Basic andrology will include spermatogenesis, anunderstanding of the entire process of ejaculation, spermfunction and roles of spermatozoa and sperm DNA up toand including the whole process of fertilisation and embryodevelopment.With these definitions in mind it is clear that clinicians andscientists working in andrology are equal partners in thefield - and thus in all aspects and functions of SIGAndrology.

New committee membersA little later in this year we will need to elect two newmembers for the SIG-A committee; Jose Castilla will step

SPECIAL INTEREST GROUPS// ANDROLOGY //

Defining the broad boundaries of andrologydown as committee member andI will take over as Past Co-ordinator from Lars Björndahl.As mentioned in the last editionof Focus on ReproductionSheena Lewis will take over asCo-ordinator at the next SIG-A

members business meeting scheduled to take place afterour precongress course in Stockholm. We will also have toelect a new Junior Deputy in the place of Jessica Tu,whose term also ends in Stockholm. Candidates for thejunior position must be clinicians or scientists youngerthan 35 years of age. The newly elected members willserve a term of two years. After one year, one of the twonew committee members will be appointed by the Co-ordinator and Past Co-ordinator as the Co-ordinator electto take over from Sheena at the annual meeting in 2013.All SIG-A members, clinical and scientists, can nominatenew members.

Training activitiesRecent activities have included a combined meeting withthe SIG Reproductive Surgery, which took place inTreviso, Italy, in October last year. Although we presenteda very interesting and well balanced programme of femaleand male surgery, the meeting was very poorly attended,which was of course a big disappointment.

Future activities will include the presentation of ourprecongress course in Stockholm (on 3rd July), which thisyear will be on a more basic science theme of Lifestyle and

male reproduction. We also plan a SIG-A Campus meetingin Seville, Spain, on 22-23rd September titled The whole

man. This will focus on the impact of infertility on men’swell-being, sexuality and social relationships, as well asour care of the man and his sperm in the clinic.

SIG-A members are invited to send in suggestions fortopic for campus meetings with possible venues and dates

and any other suggestionsregarding SIG-A matters to me atthe address below.

Roelof MenkveldCo-ordinator SIG-Andrology

[email protected]

OfficersRoelof Menkveld (ZA), Co-ordinatorJose Antonio Castilla (ES), Deputy Co-ordinatorSheena Lewis (GB), Deputy Co-ordinatorJessica Tu (SE), Junior Deputy

Despite an attractive programme, our combined meeting with theSIG Reproductive Surgery in Treviso was poorly attended.

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A mantra for the SIG EarlyPregnancy is joint meetings withother SIGs or non-ESHRE societies.For a relatively small SIG like ours itis advantageous that joint meetingscan attract speakers and participantsfrom both societies; this improvesthe scientific quality of the meetingsand results in a better economic balance.We have good experience from organising joint meetings inthe past and we hope 2011 continues the trend.

Our precongress course (3rd July) in Stockholm will be ajoint meeting with SIG Reproductive Genetics titled From

genes to gestation. We think that we have produced a veryexciting programme with up-to-date overviews of the mostimportant discoveries relating to the genes of importance inimplantation and early pregnancy.

From 24-26th August we have organised a joint meetingwith the European Society for Reproductive Immunology inCopenhagen. The aim of the meeting is mainly to presentresearch which integrates the clinical, immunological andepidemiological aspects of early pregnancy disorders. Wehope the meeting will attract both clinicians and

immunologists and be of benefit tothe work of both.

In October, as a precongress eventbefore the ASRM meeting inOrlando, there will be an ASRM-ESHRE postgraduate exchangecourse on early pregnancy. Courseorganisers are Mary D. Stephenson

for the ASRM and Ole B. Christiansen for the SIG EP.Our annual winter symposium, to be held this year in

Birmingham, UK, on 17-18th November is titledComparing management of pregnancy loss in different

settings and will give participants the opportunity toexchange best practice. The symposium has been organisedas a joint meeting with the British Association of EarlyPregnancy Units by Siobhan Quenby. The presentationsgiven by both physicians and nurses at this meeting areinformative for doctors, psychologists and paramedicalstaff (nurses, midwives, etc) working with couples withearly pregnancy disorders.

Ole B. ChristiansenCo-ordinator SIG Early Pregnancy

[email protected]

// EARLY PREGNANCY //

Enjoying the benefits of joint meetingsOfficersOle Christiansen (DK), Co-ordinatorMariette Goddijn (NL), Deputy Co-ordinatorSiobhan Quenby (GB), Deputy Co-ordinatorMarcin Rajewski (PL), Junior DeputyRoy Farquharson (GB), Past Co-ordinator

// ENDOMETRIOSIS & ENDOMETRIUM //

Let me first remind allSIG members about theabstract deadline (1stFebruary) for this year’sannual meeting inStockholm. We hope tobuild on last year'simpressive number of abstracts in the areas ofendometriosis, endometrium, implantation and fallopiantube, and that the programme once again reflects thegrowing interest in these areas of women's health andfemale reproductive tract biology.

On that note I should add that abstract submission isnow open for the 11th World Congress on Endometriosisto be held in Montpellier, France, on 4-7th September.This is an abstract-driven congress, with very fewinvited speakers; clinicians and scientists have theopportunity to present their work in a plenary sessioncovering one of 19 topics. You can submit yourabstracts at www.wce2011.com – deadline is 31st

March. All abstractssubmitted will be peerreviewed, and the fivetop submissions in eachcategory will be selectedfor plenary presentation.The remainder will be

judged for the free communications and posters.l Our precongress course this year in Stockholmfocuses on the female tract environment. Theprogramme is now on the ESHRE website and we lookforward to another full-house attendance. l A Campus event planned for Rome on 28-29thOctober aims to highlight the impact of endometriosison fertility status. Importantly, the meeting will addressour current knowledge of the interface between IVF andendometriosis and provide an opportunity for discussionabout current views on management.

Hilary CritchleyCo-ordinator SIG Endometriosis & Endometrium

Call for abstracts for Stockholm . . . and Montpellier

OfficersHilary Critchley (GB), Co-ordinatorAnneli Stavreus-Evers (SE), Deputy Co-ordinator EndometriumGerard Dunselman (NL), Deputy Co-ordinator EndometriosisAnnemiek Nap (NL), Junior Deputy

jan11_nwpFri:46355 17-12-2010 15:13 Page 25


of how important the selectionof culture medium is for theirlaboratories.

Events in 2011Our next course Practical

aspects of non invasive selection

of gametes, embryos and

blastocysts in a modern IVF laboratory will be in Salzburgon 1-2nd April. The programme is very attractive and canbe found on our web page. The course will provide clinicalembryologists with the latest information on the rathernew technologies for gamete, embryo and blastocystselection. The course is organised in collaboration with theAustrian Reproductive Medicine Society.

The Atlas of EmbryologyThe working groups involved in the revised Atlas ofEmbryology are now very active. Many images have beencollected for allocation to four main chapters: oocytes,pronuclear stage, embryos and blastocysts, all of whichinclude cryopreservation. Our idea is to prepare anelectronic document where many images are presented,including those which also focus on those deviating fromwhat is commonly considered the gold standard. Thesedeviations from the norm will be characterised in terms offrequency and implantation potential. It is planned to havean initial sample of the final document ready forpresentation at the annual meeting in Stockholm.

Elections for Junior DeputyThe present steering committee of the SIG Embryology willchange in Stockholm. The new committee will consist of aKersti Lundin as Co-ordinator, Cristina Magli as PastCordinator, and Maria José de los Santos and JosephineLemmen as the two Deputies. There is vacancy for theJunior Deputy for which we ask nominations before 15thFebruary. To be eligible, the candidates must be under theage of 35 and be member of ESHRE with embryology astheir primary field of interest. Nominations will beevaluated by the steering committee and candidatesmeeting the requirements will be proposed to stand forelection - for which all SIG Embryology members will beasked by e-mail to cast their vote. Please see moreinformation on the ESHRE website.

Cristina MagliCo-ordinator SIG Embryology

The second half of 2010 provedvery active, with two coursesand the kick-off for the Atlas ofEmbryology.

The first course took place inLisbon in October on Forgotten

knowledge about gamete

physiology and its impact on

embryo quality with 136 participants. The course wasorganised in collaboration with the Portuguese Society of

Reproductive Medicine and refreshed ourbasic knowledge of biology, includinggametogenesis, fertilisation andembryogenesis. It was a great opportunityto review those basic mechanismsregulating cell growth. Evaluation formsfilled in by participants indicated a veryhigh degree of satisfaction. Our host,Carlos Plancha, delighted participantswith his warm hospitality, whichincluded a small exhibition of artefactsfrom Africa related to the promotion offertility and campaigns againstinfertility.

Our second course was a full-daypostgraduate course held at this year’sASRM meeting in Denver on The

enrichment of culture media: towards

the best environment for IVF

embryos? All speakers gave excellentpresentations illustrating how, in manyaspects, culture conditions are set up withoutfull knowledge of human requirements (forexample, osmolarity). There was concern inmany discussions that, in order to promoteembryo growth in vitro, media are nowsupplemented with growth factors, anti-oxidants, cytokines and vitamins atconcentrations which are often far from

physiological. Several formulations are now commerciallyavailable, but their composition is usually not disclosed. Itwas quite clear from our discussions in Denver that there isnow an urgent need to know whether promoting embryogrowth so intensively might have an effect on laterdevelopment. A very lively debate co-ordinated by LucaGianaroli followed the presentations, and there is no doubtthat participants left the room with a renewed awareness

SPECIAL INTEREST GROUPS// EMBRYOLOGY //

First draft of the new Atlas of Embryologyplanned for presentation in Stockholm

OfficersCristina Magli (IT), Co-ordinatorMaria José de los Santos (ES), Deputy Co-ordinatorKersti Lundin (SE), Co-ordinator ElectJosephine Lemmen (DK), Junior DeputyEtienne Van den Abbeel (BE), Past Co-ordinator

Our Octobermeeting in Lisbon

on ‘forgottenknowledge’ of

gamete physiologyincluded anexhibtion of

African artefactsrelated to fertility.

jan11_nwpFri:46355 17-12-2010 15:13 Page 26


TASK FORCES// MANAGEMENT OF FERTILITY UNITS //

Fertility centres list‘human resources’ astop management priority

proportion had no such system inplace. The same proportions wereevident with respect to datamanagement for monitoringoutcome and treatment statitsics.

There were similar levels ofvariability found in financialmanagement, with only a relativelysmall number of clinics (37/207)negotiating an annual budget withrespect to personnel, investments,IT and operations. However, mostclinics (92/207) periodicallyevaluate financial performance andare interested in developing modelsfor the evaluation of financialperformance.

Less variable is the favouredmeans of external communication -the website. Indeed, many centresemployed an in-housecommunications manager

(111/200), or used an externalagent, but their favouredcommunications tool was by farthe website. Internally, almost allcommunication was conducted byintranet and e-mail. The phone andletter are rapidly becomingredundant.

On the question of insurance,164 of 207 centres responding didhave liability cover - but 43 didnot. The majority of those withcover (82) had a limit to theirindemnity of 1 million euros orless. Only 30 centres had coverageabove 5 million euros. Coveragewas also concentrated on theclinicians, with embryologists andparamedics only rarely covered.Very few centres hadsupplementary cover (over andabove legal requirements) for the

cryostorage of gametes andembryos, or for the reimbursementof costs to the patient.

As a follow-up to the survey theTask Force is organising a meetingin February at the Fondazione Ciniin Venice on Insurance models for

reproductive medicine. The two-day meeting, which has beenfacilitated by an unrestricted grantfrom the insurance companyGenerali, will consider insurancefor medical malpractice, the legalimplications of ART, and lossprevention - within a context ofdemographic dynamics, cross-border care, outcome and cryo-preservation. Full details are on theESHRE website under ‘Calendar’.

Luca GianaroliCo-ordinator Task Force

Management of Fertility Units

A survey of 207 fertility centres performed by theTask Force has found that ‘human resources’ rankshighest among their business priorities. The survey,which was conducted last year, sought informationon human resources, data management andplanning, financial planning, communication,insurance cover, and business management. Theclinics surveyed were mainly from Europe (146),but North America (24 units), Africa (eight units),Asia (24 units) and Australia (eight units) were alsorepresented.

With respect to human resources, only aroundone-third of centres had established trainingsystems in place for medical staff, nurses andlaboratory staff (though most said they wouldwelcome some active involvement by ESHRE). Themajority of centres (147/207) have a fullydedicated manager on site.

The level of data management in clinics wasfound to be varied, with around one-fifth reportinga fully implemented system of documentmanagement (treatment information, informedconsents, cycle details), but a similar

Among six areas of management identified by the Task Force, human resourcesproved the number one priority among the clinics surveyed.

In terms of external communications, thewebsite is now the favoured means of

communication for nearly all fertility clinics.

jan11_nwpFri:46355 17-12-2010 15:13 Page 27


patients, and we hope that patient support groups likeFertility Europe will continue to lobby in this directionand at all levels.2 Meanwhile, back in the real world manypatients continue to travel, and, economic crisis or not,this trend will continue; indeed, many ART treatmentsoverseas are now cheaper abroad than in London, evenwhen the cost of travel is included.

This first paper from the Task Force sets out guidancefor fertility clinics and physicians treating foreign patients,but may also help regulators and policymakers create aframework by which centres can follow the rules.Although in principle the care of foreign and local patientsshould be the same and meet the best possible standards,there is evidence that this is not always the case.

We focus on several principles - equity, safety, efficiency,effectiveness (including evidence-based care), timelinessand patient centeredness - as applied to patients, gametesdonors, surrogates and professionals. In our view, theseprinciples are all of equal importance and have no fixedorder of priority.

The messages of this guidance1. Patients l Any differences between local and foreign patientsshould be justified, as, for instance, the extra cost for

l Cross border reproductive care refers to a widespreadphenomenon in which infertile patients or collaborators(such as egg donors or potential surrogates) cross nationalboundaries in order to obtain or provide reproductivetreatment outside their home country. l The reasons for travelling vary between countries, butthe most common is to circumvent a law which forbids aparticular technique or a particular group from treatment.There may be other access limitations, such as longwaiting-lists at home, or a perceived better quality of careabroad, or cheaper treatment.1,2

Our guidance report reiterates the fact that the idealscenario is fair access at home to all treatments for all

TASK FORCES// CROSS-BORDER REPRODUCTIVE CARE //

ESHRE ‘guidance’on cross-borderreproductive carenow approved byExecutive CommitteeWhile cross-border reproductive care continues to make internationalheadlines, the Task Force’s Good Practice Guidance to Cross BorderReproductive Care has now been approved by ESHRE’s ExecutiveCommittee. The guide is applicable to centres and individualpractitioners, and will shortly be published in full.

Members of the Task Force are aware that this is only a first step,and aware too that ‘guidance’ is not a top-heavy system ofcertification or accreditation. So this must be seen as a first step on aEuropean scene which more and more demands control of standardsto ensure the safety of patients, gamete donors and surrogates, as wellas the children born. Our guidance also provides an inter-professionalcommunication

We already know the facts:

TASK FORCECO-ORDINATOR

FRANÇOISE SHENFIELD:‘THE FIRST STEP ON A

EUROPEAN SCENEWHICH MORE AND MORE

DEMANDS CONTROL OFSTANDARDS.’

jan11_nwpFri:46355 17-12-2010 15:13 Page 28


interpreters. l Patients should receive clear information aboutinvestigations and their cost, waiting-lists and the expectedtime they will have to spend outside their home country. l The provision of accurate success rate of the centre isimportant to help patients agree on a treatment plan. l Communication and collaboration between the homeand foreign teams is an essential aspect of patient safety.l Understanding is the key to proper consent, and it maybe difficult to ensure that patients understand enough togive appropriate consent when there is no commonlanguage. Counselling and psychological support should beavailable in a language understood by the patients. l There should always be the possibility of redress for thepatients, including the name of the foreign clinic’sombudsman or the person to whom complaints should beaddressed.

2. Gamete donation l The requirements of the EU Tissue & Cells Directivesshould always be followed, with special regard to screeningprocesses and non-commercialisation. l Donors should receive the same degree of care aspatients.l The question of donor safety has been less investigatedthan patient safety, and will be the focus of our efforts thisyear. This indeed forms the core of the Task Force plansfor new research, with the collaboration already engagedof Belgian, Spanish, Czech and Dutch colleagues. The factsare that reliable data regarding risks are scarce, especiallyin the case of repeated donation. We thus feel it isessential to establish national registers of gametes donors,and for centres to participate in the collection of nationalor international data. We plan to introduce such adatabase via ESHRE, with the help of our colleagues in theEIM consortium.

We recommend that all treatments should comply withthe rules of ESHRE’s ‘good clinical treatment in ART’,which stress the avoidance of multiple pregnancy.3

Legal problemsWhat about the wellpublicised legal problemswhich have happened insome cases of cross-borderreproductive care, albeitrarely? We stress that theprovision of legal adviceabout local rules isessential. There is alreadyone law firm in the UKspecialising in such advice,but such advice should alsobe provided by the localpractitioner, or, if notpossible, through referral to

appropriate legal advisors. There have been headlines fromsome cases of surrogacy from the Ukraine for UK-intendedparents, or from India for Japanese-intended parents, andpossible conflicts with the law in the home country shouldbe explained to the patients.

We also discuss the degree of collaboration andresponsibility between doctors of different countries.Indeed, this may be a legal concern for our Germancolleagues, who are technically forbidden to even mention‘illegal’ treatments abroad - although the picture inGermany seems rapidly changing following a failedprosecution brought under the 1990 embryo protectionlaws. We are also seeing some German patients travellingto neighbouring Czech Republic for PGD, where Germanpractitioners are said to be looking after them.

Where to in 2011?Our first aim will be to enroll as many signatures aspossible to the guidance, from regulatory bodies tonational fertility societies. We already have a principledagreement from the IFFS on this matter.

Second, our research will consider the unknown aspectsof gamete donation, and especially oocyte donation acrossborders. This will not only mean donors in those countrieswhere our patients choose to go, but also ‘travelling’oocytes from the banks which are beginning to proliferatesince introduction of vitrification.

As usual, Focus on Reproduction readers will be the firstto be informed.

Françoise Shenfield, Co-ordinator Task Force Cross-border Reproductive Care

1. Shenfield F, de Mouzon J, Pennings G, et al. Cross borderreproductive care in six European countries. Hum Reprod 2010;25: 1361-1368.2. ESHRE Task Force on Ethics and Law 14. Equity of access toART. Hum Reprod 2008: 23; 772-774.3. Good Clinical Treatment in Assisted Reproduction,www.eshre.eu.

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he preservation of female fertility inthe face of significant disease andits treatment is a rapidly growingclinical field. It is the subject of a

dedicated ESHRE Task Force as well as aninternational society yet it remains in manyways a subject in its infancy, with no morethan 14 babies born worldwide through thereplacement of frozen/thawed ovariantissue over the six years since the firstreport of success.1

This surge in activity is based largely onthe improved survival of women and girlsfrom malignant disease. This has beenparticularly so in paediatric oncology, witha transformation from very low successrates for many conditions to the currentsituation where 80-90% of children withcancer can expect to survive long term.

The loss of fertility is a commonconsequence of the use of many therapeuticagents for non-malignant as well asmalignant conditions, including systemiclupus erythematosis and otherrheumatological diseases. Bone marrowstem cell transplantation withchemotherapy conditioning is now beingused in sickle cell disease and tried in otherconditions.

There is also the remarkable series ofovarian transplants in monozygotic twinsdiscordant for premature ovarian failure,with several successful pregnancies nowreported from both fresh and frozenovarian tissue.2 Moreover, the growingpublic awareness of the age-related declinein female fertility may well bring manymore requests for fertility preservation forsocial reasons in the years to come.

Effects of chemotherapy and radiotherapyThe adverse affects of chemotherapy andradiotherapy on female reproductive

It is now six years since the world's first baby was born following thecryopreservation of ovarian tissue. Yet this and other techniques offertility preservation remain in their infancy. Richard Anderson and

Claus Yding Andersen review progress so far and the realistic fertilityoptions for women facing cancer treatment.

FEATURE

T Fertilitypreservationin women

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understanding is based on a premise that women have afinite population of oocytes. This axiom, of course, hasbeen the subject of vigorous debate in recent years and,while many of us will have seen pregnancies in womenwith established post-cancer ovarian failure, clinicalevidence for recovery of the follicle population is stilllacking.

Options for fertility preservationAs illustrated below, there is a range of clinical scenarios inwhich different fertility preservation techniques areappropriate. These can be discussed with the patient or, inthe case of a child, with the patient and her parents. Themost established technique is of embryo cryopreservation,which is available in all IVF units. IVF protocols are welldefined, although it may be helpful under somecircumstances to induce luteolysis with a GnRH antagonistto allow FSH injections to start sooner.3 GnRHantagonists also allow for a shorter duration of treatment.

One area of recent development here is the morewidespread use of embryo vitrification, which - as withoocyte vitrification - is becoming much more common. Itis unclear, however, whether the embryos obtained from

function have been extensively reviewed, although there arefew data on the precise effects of chemotherapy on theovary. It is clear that alkylating agents have highgonadotoxicity compared with other drugs but manyregimes use combinations, thereby complicating assessment.In addition, oncology is a rapidly advancing speciality andgood quality data on, for example, the prevalence of acuteovarian failure with modern regimes are lacking. There arealso international variations, so the need for fertilitypreservation for a given diagnosis will also differ betweencountries.

Women who have had radiotherapy to the uterus are atan increased risk of miscarriage and premature labour,although there are no data on whether current tests toassess uterine function - such as uterine artery blood flowanalysis - are predictive of pregnancy outcome in thesecircumstances. There are therefore substantial opportunitiesto improve our data on the effects of cancer therapies onreproductive function in women, and thus our advice topatients.

While it is well recognised that some women withapparent acute ovarian failure during and immediately afterchemotherapy do show some recovery, our current

Pathways for fertility preservation in women. Adapted from Lobo RA. Potential Options for Preservation of Fertility in Women. N Engl J Med 2005; 353: 64-73.

RICHARD ANDERSON (left) andCLAUS YDING ANDERSEN:‘PATIENT SELECTION REMAINSA CHALLENGE, TO BECONFIDENT IN OFFERINGTREATMENT TO THOSE WHONEED IT, AND REASSURING TOTHOSE WHO DO NOT.’

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women having emergency IVF under thesecircumstances are of normal quality. Thewomen involved are of course unwell and thismay have an adverse impact onoocyte/embryo quality, just as semen qualitycan be markedly impaired in men with cancer.There are no published data on this but ourown limited experience in Edinburgh andCopenhagen suggests that the pregnanciesfollowing embryo replacement in cancerpatients are fewer than expected. Clearly, thisis an important question to be addressed as itwill affect the efficacy of fertility preservationand potentially the technique that a womanmay choose to have.

The provision of IVF varies hugely betweencountries and in these times of economicausterity state funding may well become morerestricted. Women with a newly diagnosedcancer cannot go on a waiting-list but, if resources arefinite, treating one woman may delay the treatment ofanother. One could argue that treatment of a couple whoseaetiology is, for example, of unexplained infertility is abetter use of resources than treatment of a couple wherethe woman has a serious disease associated with significantshort and long-term morbidity and mortality. On the otherhand, many patients find that the mere fact of receivingfertility preservation is of substantial psychological benefit.

There are also theoretical concerns over the highconcentrations of estradiol generated during IVF cycles,particularly in such estrogen-responsive conditions as somebreast cancers. Ovarian stimulation regimes whichminimise this effect with aromatase inhibitors have beendescribed.4 However, it remains unclear how much of areal risk an IVF cycle is to a woman with breast cancergiven that the tumour would have been growing for manymonths before becoming clinically apparent; there are alsono data on the pregnancy outcome from embryosgenerated from these protocols. However, many womenand their physicians will choose not to expose an estrogen-responsive cancer to more estrogenic stimulation than isstrictly necessary.

Avoiding the need for fertilisationEmbryo cryopreservation also requires a male involvement.The woman’s male partner may find himself in a positionof significant emotional pressure to take part in an embryocryopreservation procedure. There have been wellpublicised cases where the man has subsequentlywithdrawn his consent for the transfer of embryos, sorequiring them to be destroyed. This difficult situation canbe avoided by the use of oocyte cryopreservation, which isnow being more widely used. Success rates are improvingand approaching those of fresh IVF. Both embryo andoocyte cryopreservation will, however, leave a woman witha limited number of chances to become pregnant, withonly one cycle of stimulation likely in this time-limited

situation. The efficacy of this approach also needsthorough evaluation.

Ovarian tissueAn alternative option therefore is to store ovarian tissue,which may contain many more oocytes. In contrast tomany fertility-related treatments, ovarian tissue storagehas been introduced into clinical practice followingdevelopment in a large mammalian species, the sheep.5

Advantages include the fact that no other treatment isrequired and it can be carried out at short notice. Itrequires no male involvement, but does require a surgicalprocedure both to recover the tissue and replace it at alater date. Replacement provides the option ofspontaneous rather than assisted conception as well as thechance of more than one pregnancy; this has now beendemonstrated.6,7 Importantly, ovarian tissuecryopreservation also offers a potential option for childrenand adolescents for whom ovarian stimulation isinappropriate. This, however, may be better described as atheoretical option; as yet no adolescent girl has gone on tohave a child following this procedure.

One important consideration is that a significantamount of ovarian tissue must be removed from thepatient and will not therefore be available for spontaneousfertility should she not be sterilised by her cancertreatment.

At present there is debate over whether unilateraloophorectomy or ovarian biopsy is the more appropriatesurgical technique - and there are both clinical andorganisational considerations here. It is clear thatfollowing cryopreservation and reimplantation some 70%of follicles are lost. This needs to be balanced against thenumber likely to be lost as a result of the cancer treatmentitself. And accurate data on how to assess this are lacking.

Our practice in Edinburgh is generally to carry outovarian biopsy, taking strips of ovarian cortex from oneovary and leaving the contralateral ovary intact. The

Histomicrograph of plentiful primordial follicles in a prepubertal girl. Courtesy of Dr M McLaughlin, University of Edinburgh.

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rationale behind this is to do the minimum amount ofharm and it’s been our experience that a surprisingly largeproportion of patients referred for fertility preservation goon to retain spontaneous fertility.8 And this is despite aclear statement required from the treating oncologist thatthe patient faces a greater than 50% risk of ovarian failurefollowing the anticipated treatment. This may well reflectbiological variability and age of the patient, plus a lack ofprecise knowledge of the gonadotoxic effect.

The alternative approach is taken in Denmark, wheremost patients will have a unilateral oophorectomy. Thisallows the surgery to be performed at a hospitalconvenient for the patient, with the ovary subsequentlytransported to the central lab for preparation andcryopreservation. Although only a small fraction of thefollicles may survive the procedure, they will be usedsequentially and only after the endogenous store has beenexhausted. This hub and spoke model has advantages butis not possible in the UK because of the tight regulatoryenvironment imposed by the Human Tissue Authority andHFEA.

At present a total of 14 children have been born towomen who have had ovarian tissue cryopreserved andreimplanted. Both spontaneous and assisted conceptionshave been demonstrated, but interestingly no successfulpregnancies have yet been described following heterotopictransplantation of the ovary.9 Sites where follicular growthhas been observed include the anterior abdominal wall andthe arm, although successful non-human primatepregnancies have been reported following freshtransplantation to a subcutaneous site. These approaches

do, however, offer the opportunity for our improvedunderstanding of the extra-ovarian requirements for normalfollicular and oocyte development.

The malignant contamination of the ovarian tissue mustalso be considered. So far, a total of some 30 women havereceived transplantation of ovarian tissue without anyreports of relapse caused by the transplantation. Two largeseries of ovarian biopsies in breast cancer patients haverecently revealed no evidence of malignant cellcontamination,10,11 but the availability of specificmolecular tumour markers in some conditions has revealedthe potential for contamination. This is a particular issuefor haematological malignancies;12 importantly,chemotherapy prior to ovarian cryopreservation did notpreclude contamination.

In vitro follicle growthOne option in cases where the ovary might becontaminated is in vitro follicle maturation. Thedevelopment of IVM has been a challenge, even in smalllaboratory animals, and it remains in its infancy in humans.Significant developments in culture techniques have,however, been reported using a multi-step process. Clearly,there’s a long way to go to show that this technique is botheffective and safe.

Protection strategiesAlternatively, an agent which protects the oocyte in situwould be attractive. Prominent among these approaches isthe use of GnRH analogues. Their use has been promotedfor many years but remains a heated topic for discussion.

Preparation ofovarian tissue forcryopreservation.

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Isolated human preantral follicles for in vitro growth.

References1. Donnez J, Dolmans MM, Demylle D, et al. Livebirth afterorthotopic transplantation of cryopreserved ovarian tissue. Lancet2004; 364: 1405-1410.2. Silber SJ, Lenahan KM, Levine DJ, et al. Ovariantransplantation between monozygotic twins discordant forpremature ovarian failure. N Engl J Med 2005; 353: 58-63.3. Anderson RA, Kinniburgh D, Baird DT. Preliminary evidence ofthe use of a gonadotrophin releasing-hormone antagonist insuperovulation/IVF prior to cancer treatment. Hum Reprod 1999;14: 2665-2668.4. Oktay K, Hourvitz A, Sahin G, et al. Letrozole reduces estrogenand gonadotropin exposure in women with breast cancerundergoing ovarian stimulation before chemotherapy. J ClinEndocrinol Metab 2006; 91: 3885-3890.5. Gosden RG, Baird DT, Wade JC, Webb R. Restoration offertility to oophorectomized sheep by ovarian autografts stored at-196oC. Hum Reprod 1994; 9: 597-603.6. Ernst E, Bergholdt S, Jorgensen JS, Andersen CY. The firstwoman to give birth to two children following transplantation offrozen/thawed ovarian tissue. Hum Reprod 2010; 25: 1280-1281.7. Demeestere I, Simon P, Moffa F, et al. Birth of a second healthygirl more than 3 years after cryopreserved ovarian graft. HumReprod 2010; 25: 1590-1591.8. Anderson RA, Wallace WH, Baird DT. Ovariancryopreservation for fertility preservation: indications andoutcomes. Reproduction 2008; 136: 681-689.9. Rosendahl M, Loft A, Byskov AG, et al. Biochemical pregnancyafter fertilization of an oocyte aspirated from a heterotopicautotransplant of cryopreserved ovarian tissue: case report. HumReprod 2006; 21: 2006-2009.10. Sanchez-Serrano M, Novella-Maestre E, Rosello-Sastre E, etal. Malignant cells are not found in ovarian cortex from breastcancer patients undergoing ovarian cortex cryopreservation. HumReprod 2009; 24: 2238-2243.11. Rosendahl M, Timmermans V, Nedergaard L, et al.Cryopreservation of ovarian tissue for fertility preservation: noevidence of malignant cell contamination in ovarian tissue frompatients with breast cancer. Fertil Steril 2010; in press.12. Dolmans MM, Marinescu C, Saussoy P, et al. Reimplantationof cryopreserved ovarian tissue from patients with acutelymphoblastic leukemia is potentially unsafe. Blood 2010; 116:2908-2914.13. Anderson RA, Cameron DA. Prediction of ovarian functionafter chemotherapy for breast cancer. Hum Reprod 2010; 25(suppl 1): O-100.

At present, the data are unconvincing, with most findingsderived from non-randomly controlled studies. There are,however, large studies under way which may yielddefinitive answers.

So it’s fair to say that there have been substantial advancesin fertility preservation in the last decade, but there stillremain very significant gaps in our knowledge as to howbest to proceed. Patient selection remains a challenge, to beconfident in offering treatment to those who need it andreassuring to those who do not. In this respect we haverecently shown that serum AMH predicts long-termovarian function following chemotherapy in women withbreast cancer. Indeed, in a multivariate analysis only AMH- but not age or FSH - remained a significant predictor.13

This result, if confirmed, may allow a more individualisedrisk assessment based on the proposed treatment regimeand a measure of the patient's ovarian reserve.

Richard A Anderson is Professor of Clinical Reproductive Scienceat the Centre for Reproductive Biology, University of Edinburgh,Scotland, and Deputy Co-ordinator of ESHRE's SIG ReproductiveEndocrinology.Claus Yding Andersen is Professor of Human ReproductivePhysiology, Laboratory of Reproductive Biology, University ofCopenhagen, Denmark

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Germany’s first IVF baby was born on 16th April 1982 in the careof the late Professor Siegfried Trotnow (pictured below, right, in1983) and Safaa Al-Hasani at the University Hospital of Erlangen,still one of Germany’s leading centres in reproductive medicine.

The German IVFRegistry (DeutschesIVF Register, D.I.R)was founded in1982, the year that(West) Germany’s

first IVF birth was announced, a babyboy born in April at the UniversityHospital of Erlangen. Two years laterthe Lübeck group reported thatbetween July 1982 and March 1983they had treated 130 patients with

IVF, with 585 follicles punctured and404 egg cells obtained; embryotransfer was achieved in 95 patients,and pregnancy in 14 cases. Since then,and reflecting the remarkable advanceof ART in Germany, data submittedto the D.I.R for 2010 are likely toreach a cumulative total of 1 millioncycles reported.

And just as Germany’s IVFprogrammes moved so rapidlyforward, so did the country’s data

collection requirements. By 2009,when the registry adopted a new legalform and created articles ofincorporation, 120 IVF centres wereproviding data, reporting a totalperformance of 49,602 IVF and ICSIcycles that year.

The registry itself remains aninitiative based on the involvement ofall physicians engaged in the field ofreproductive medicine in the Germanhealthcare system - that is, it is not

FEATURE// IVF IN GERMANY //

One million cyclesand still counting

Markus Kupka tells the story of IVF in Germany and howits successful history has been recorded cycle by cycle

in a non-governmental registry system.

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supported by the government. So,financial support is provided by theIVF units themselves and is not partof any government funding scheme.

As can be seen in Table 1 above,the percentage of ICSI cyclesincreased rapidly in Germany from1993 onwards - as it did throughoutEurope - and today ICSI accounts foralmost three times the ART activity ofIVF. The other major trend, clearlyevident in the table, is that until 2004government reimbursement covered100% of the cost of four treatmentcycles. But that year the reimburse-ment system was changed to provideonly 50% payment for three cycles.This change prompted a dramatic

decrease in cycle numbers, which isonly now creeping back towardsformer levels.

D.I.R participates in data collectionfor the European IVF Monitoringconsortium (EIM) of ESHRE, andalso sends data to the InternationalCommittee Monitoring AssistedReproductive Technologies(ICMART), which operates on aworldwide scale. Germany now ranksas Europe’s second most active ARTcountry (after France) according todata submitted to the EIM.

In comparison to otherinternational and European registries,D.I.R employs a large dataset whichalso collects follow-up information on

the babies born.However, the German healthcare

system, unlike that of Denmark or theUK, has no social security number orother unique registration system foreach individual. Thus, D.I.R is nowpreparing a dedicated ID based on theso-called ‘DDR code’, which creates aunique case number out of the familyname, first name, date of birth andsex. This code can only be read in onedirection, which means thatindividual identity cannot be decodedfrom the eight-digit number, but case,treatment and outcome can betracked, as well as couples changingtheir treatment centre.

Unfortunately, the code is notsufficient to analyse cross-borderactivities, which appear to play animportant role throughout Germanybut especially in the southern regions,where overseas clinics with moreliberal laws are highly promoted.

Legal restrictions in Germany - theprincipal reason for cross-bordertreatment - are currently among themost restrictive in Europe. TheEmbryo Protection Law, passed 20years ago in 1991, allows the freezingof fertilised oocytes only at thepronuclear stage, outlaws embryo

MARKUS KUPKA: ‘THEFRAMEWORK FOR ART IN

GERMANY IS MUCHDIFFERENT FROM THAT

OF MOST OTHEREUROPEAN COUNTRIES.’

Table 1. The number of IVF

and ICSI cyclesperformed in

Germany between1982 and 2009

IVF

ICSI

Total*

1982

742

742

1986

3806

3806

1990

7343

7343

1994

16175

5856

22031

1996

14344

16108

30452

1998

14024

22420

37933

1999

21880

21244

44086

2000

28945

15752

45487

2001

28506

24897

54098

2002

23936

37692

62306

2003

28058

51389

80434

2004

11848

25339

37633

2005

11410

26370

38382

2006

11062

28015

39769

2007

11362

31452

43612

2008

11048

33591

45461

2009

11715

37006

49602

* The value of combined IVF/ICSI cycles is included in the total - eg, 881 cycles in 2009

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selection, and requires that no morethan three embryos can betransferred. The legislation isunequivocal: ‘Anyone will bepunished with up to three yearsimprisonment or fine who attempts,within one treatment cycle, totransfer more than three embryosinto an woman and attempts tofertilise more egg cells from a womanthan may be transferred to her withinone treatment cycle.’ Egg donationand research on embryos or PGD arealso illegal.

The framework for ART inGermany, therefore, is much differentfrom that of most other Europeancountries. Nevertheless, over theyears our success rates have beencomparable, as demonstrated in theannual reports of D.I.R, which werefirst made available in 1991. Averagepregnancy rate for IVF cyclesreported for 2009 was 30%, and28.9% for ICSI. As explained inTable 1, a single cycle combination ofIVF and ICSI was performed in 881instances in 2009, while frozentransfers (embryos derived fromoocytes cryopreserved at the 2PNstage) were performed in 17,646cases and achieved a pregnancy rate

of 18.2%. A twin rate of 20.8% (andhigher multiple births of 0.8%) wasdocumented from pregnancies.

Since 1996, the annual report hasbeen published as a single booklet(www.deutsches-ivf-register.de/Jahresberichte). But now, starting in2010, the report is also published inEnglish in the Journal of Reproduct-ive Medicine and Endocrinology(www.kup.at/journals/reproduktions-medizin).

Nearly all German IVF units arecurrently using a standard, computer-based dataset description, but employdifferent software tools to submittheir data to the registry. These toolshave undergone numerousdevelopments, but, from its inception,the registry has been collecting dataon a cycle-by-cycle basis. The reportthus represents a summary of allreported cycles, but, because ofGerman legal requirements andinternal procedural rules, no datarelated to specific centres can bereleased.

The report is broken down intothree sections. The first is a patient-based section comprising responses tocommon questions or offeringcomments on different therapeutic

options. The second section is auniform analysis of all reportedcycles and contains detailed chartsand tables. The third section focuseson those special statistics which varyfrom year to year and considerlifestyle aspects or regionaldifferences. An epilogue, a commenton aspects related to the statistics anddata processing together with a list ofall participating centres, is alsoincluded.

Since 1997, more than 80% of allART cycles reported to the systemhave been entered prospectively(within seven days of the start ofovarian stimulation). This is intendedto prevent cycle selection, and is oneof the most powerful quality tools inthe system. A dynamic link library(DLL) maintained by the registryallows data plausibility to bemonitored either online or shortlyafter data input. Participation in theregistry became mandatory in 1999.

In 2009, a total of 75,662 cycleswere reported, 84% prospectively. Incontrast to the IVF registries of othercountries, the D.I.R containsinformation about reproductivehistory and pre-existing conditionsfor both partners.

Table 2.Clinical pregnancyand miscarriagerates by age groupfrom IVF treatmentsin 2009. The right-hand column belowprovides estimatedresults for ‘ideal’patients.

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Each centre provides informationtwice a year (on average) and thepublished data not only report aclinic’s own results but also acomparison with all otherparticipating centres.

Since the registry requests data forboth the current year as well as pastyears, our loss to follow-up - 13%after a year - is generally low.However, as in other Europeancountries, many foreign couples arealso treated in Germany, making itsomewhat difficult to obtaincomplete information on the outcomeof pregnancy.

The pale blue column in Table 2describes the ‘ideal’ couple. Toovercome geographical differences inreimbursement or availability ofservices the registry has generated amodel pregnancy rate when twoembryos are transferred with at leasttwo more at the 2PN stage(cryopreserved or destroyed). Overall,this ‘ideal’ pregnancy rate wascalculated to be 37.5% per embryotransfer.

Our data have also confirmed thatthe age of female partner representsthe most confounding factor foroutcome, and the D.I.R providesdetailed statistics on this. Table 3, forexample, shows success rates as afunction of the number and quality ofembryos transferred in each of fourage groups. This table is frequently

used during patient counselling toexplain the effect of age. As can beseen, treatment of women over theage of 34 shows a significant decreasein the likelihood of pregnancy -especially with ‘non-ideal’ embryos.

Each year the annual report alsoincludes ‘special’ statistics which varyfrom year to year. In 2009 weincluded data on pregnancy rates inpatients with an ideal prognosis (andother patients too) as a function ofcentre size over ten years (2000-2009). We defined ideal prognosis asage under 35 years and having a firststimulation cycle for ART. Wedemonstrated that for both idealpatients and others the larger centres(more than 500 cycles per year)offered a trend of higher pregnancyrates than the smaller centres.

Consumer demands forinformation and clarity in this highlysensitive area of human reproductivemedicine are more than justified. Thesuccess of these treatments will onlybe socially acceptable andmisunderstandings can only beprevented once a reliable assessmentand an open discussion of theattainable results have been carriedout. And this is why nationalregistries in nearly every Europeancountry have collected and areanalysing their data. In Germany, thishas been our aim since 1982. Overthe years, the number of participating

centres and registered treatments hasgreatly increased, but furtherimprovement is still required. Ourintroduction of 'ideal' patientmodelling has gone some way toremoving variations inreimbursement or availability, andour registry data cannot be combinedwith prenatal medical data or cancerregistries. The creation of follow-upID statistics on infant births isextremely difficult.

And now, as its cumulative totalheads towards 1 million cycles, ourD.I.R report will for the first time bepublished in English and we are nowable to research specific angles suchas lifestyle factors (smoking, weight)or reproductive history (formerpregnancies, miscarriages). However,from our perspective the greatestadvance of the German registry lies inthe decision of nearly every IVF unitto support its work throughprospective data collection andpayments made to maintain suchcomprehensive files.

Markus S Kupka is Reader inReproductive Medicine & Endocrinologyat the Ludwig-Maximilians-Universität,Munich, a director of the Deutsches IVFRegister, and member of the EIMConsortium steering committee.

Table 3. 2009 results for IVF, ICSI and IVF/ICSI as a function of embryo quality and number transferred.’

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The European Society of Human Reproduction and EmbryologyMeerstraat 60

Grimbergen, [email protected] www.eshre.eu

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Documents

Focus on Reproduction ESHRE, ianuarie 2011