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Focus onREPRODUCTIONEuropean Society of Human Reproduction and Embryology // SEPTEMBER 2011 //Embryo selection for IVFIs there a signal in the noise?l ESHRE newsl A record-breaking annual meetingl The embryo as a patient

European Societyof Human Reproduction and Embryology28 th Annual MeetingIstanbul - Turkey1 to 4 July 2012The information in this announcementis subject to change.For updated information consultthe ESHRE web-site at

EXECUTIVE COMMITTEEChairmanAnna Veiga (ES)Chairman ElectJuha Tapanainen (FI)MembersCarlos Calhaz-Jorge (PT)Ursula Eichenlaub-Ritter (DE)Roy Farquharson (GB)Anis Feki (CH)Niels Lambalk (NL)Jolieneke Schoonenberg-Pomper (NL)Antonis Makrigiannakis (GR)Milan Macek Jr. (CZ)Cristina Magli (IT)Jacques De Mouzon (FR)Miodrag Stojkovic (RS)Anne-Maria Suikkari (FI)Etienne Van den Abbeel (BE)Ex-officio membersLuca Gianaroli (IT)(Past Chairman)Françoise Shenfield (GB)(SIG Sub-committee)FOCUS ON REPRODUCTIONEDITORIAL COMMITTEEPaul DevroeyBruno Van den EedeHans EversJoep GeraedtsLuca GianaroliAnna VeigaSøren ZiebeSimon Brown (Editor)Focus on Reproductionis published byThe European Society of HumanReproduction and EmbryologyMeerstraat 60Grimbergen, Belgiuminfo@eshre.euwww.eshre.euAll rights reserved.The opinions expressed in thismagazine are those of theauthors and/or persons interviewedand do not necessarily reflect theviews of ESHRE.SEPTEMBER 2011Cover pictures:CARE Fertility GroupCONTENTSFocus onREPRODUCTIONl Chairman’s introductionWe have a new picture for the chairman’s introduction!The time has now come for me, your new madamchairman and the first since Lynn Fraser in 1999, to takeover the chairmanship of our Society.There’s no need to say how proud I am to hold thisposition and responsibility. You are all aware that oursystem of Chairman Elect, Chairman and Past Chairmanensures continuity of direction and I have been extremelylucky to learn from Luca Gianaroli and Joep Geraedts.Luca has done an enormous amount of work for theSociety and we thank him for this - and especially for being so positive andenthusiastic even in the face of difficult situations. As I have told him, he’s not aneasy act to follow! But I also acknowledge the work done by the ExecutiveCommittee these last two years and especially thank Jean François Guérin, TimurGürgan, Carlos Plancha, Veljko Vlaisavljevic and Søren Ziebe, who are stepping down.We will miss them but I am sure they will continue to serve ESHRE from theirrespective positions and countries.A new Executive Committee is in now place after ratification at the AGM inStockholm and I am looking forward to working with the new members. There areplenty of ongoing tasks and new challenges ahead. As always, ESHRE’s CentralOffice, with Bruno and his very efficient team, will be of paramount importance.After a very successful annual meeting in Stockholm - the best ever in terms ofscientific quality, venue and services - we now look to new locations in Istanbul,London and Munich. We must continue the trend of scientific excellence in all ourmeetings and Campuses, and this represents a real challenge. Attracting youngscientists, especially the ones involved in basic science, is one of our immediategoals, both for the meetings and the ESHRE journals. Special Interest Groups andTask Forces, the core of our Society, can play an active role here.Another important challenge is to continue the development of ESHRE’s role asa reference society in reproduction among the European institutions. We havealready made big efforts in this direction and expect to achieve more results whichpositively affect our day-to-day work - and our patients.As I said at the beginning of this introduction, being Chairman of the world’smost important society in reproductive science and medicine is a real challenge forme and I will do my best to serve the Society and its members. I count on you all!Anna VeigaESHRE Chairman 2011-2013NEWS4 Annual meeting 2012 Istanbul6 Stockholm: a record-breaking congress13 EIM and world data collection15 The ‘best’ of ESHRE and ASRM16 From the PGD Consortium18 ESHRE journals’ record impact factors20 Minutes from the AGM 201122 Fertility Europe23 From the Special Interest Groups32 From the Task ForcesFEATURES34 Embryo selection for IVFSimon Fishel and AlisonCampbell explain the latesttechniques of embryo selectionand say it makes good sensefor patients40 The embryo as a patientNick Macklon reports onhow periconceptionalcare may have an effecton later developmentFocus on Reproduction September 2011 3

ANNUAL MEETING 2012Where East meets WestTimur Gürgan, local chairman of next year’s annual meeting,previews the scientific - and social - programmes in IstanbulWith the success of ESHRE’s 2011 annual meeting nowbehind us, it’s the time to begin again in search of furthersuccess in Istanbul in 2012. So, on behalf of the localTIMUR GURGAN:‘SOMETHING FOREVERYONE INISTANBUL.’organising committee, it gives me a great pleasure to inviteyou to the 28th annual meeting of ESHRE to be held inIstanbul, Turkey, from 1-4th July 2012. Please mark thedate in your diaries!The invited scientific programme is already in place andthe first printed announcement distributed in Stockholm.As ever, the meeting will bring together a distinguishedinternational faculty of clinicians and basic scientists,experts from all over the world with different cultural,historical, ethnic and religious backgrounds, and in fittingreflection of a venue which bridges the border betweenWest and East. For this for ESHRE is as far East as anannual meeting has ever been and we hope it will helpattract more participants from the Middle and Far East,India and Russia.It will also enable us to share with you the joy ofTurkey’s history and culture, but with it the rapid change ofeveryday life as we prepare our candidacy for the European4 Focus on Reproduction September 2011

Abstract submission policyFull details of ESHRE’s abstract submission policy are on theESHRE website (, but please note:l All abstracts must arrive at ESHRE’s Central Office no laterthan 1st February 2012.l Abstracts should be submitted in English only.l Any person submitting an abstract can only be the firstauthor for one abstract.l The material presented should be unpublished and originalmaterial, which has not yet been presented in any othermeeting.l All abstracts will be refereed ‘blind’.l Authors are requested to indicate their preference for oraland/or poster presentation on the abstract submission form.The decisions of the selection committee are final.Union. And hand in hand with this development Turkey isalso increasing its strength in science and medicine. Nolonger is it a dream for Turkey to be a centre of highquality medicine; indeed, we now have 120 IVF centresproviding some 40,000 treatment cycles each year, withsignificant success rates. It’s fair to say that ESHRE itselfhas contributed much to the training which made thiskind of progress possible. Indeed, for the first time nextyear’s precongress programme will feature an exchangecourse with the Middle East Fertility Society on improvingoutcome in IVF.The 2012 annual meeting will take place at the brandnew congress centre located in the heart of the city. It wasbuilt to host the International Monetary Fund summit of2009 and can accommodate more than 12,000participants (and houses an exhibition area of more than9000 square meters). The congress centre is only a shortwalk from most of the city centre hotels.Istanbul has two international airports, AtatürkInternational on the west side of the city and served by themetro, and Sabiha Gökçen on the east side in Asia.Residents of some countries (but not all) will require a visa,and these are conveniently available on entry into Turkey atthe airport; details of all visa requirements can be found onthe website is a unique city - built on two continents andhaving served as the capital of three empires: Roman,Byzantium and Ottoman. Today the city is home tolegendary treasures in the Hagia Sophia museum andTopkapı Palace, but everywhere its history can be felt andappreciated. And Istanbul’s restaurants are similarlylegendary, with kebabs, fish, and so many different dishesprepared with olive oil - and of course the sweet desserts offruits, nuts and pastry in a tempting combination.Everyone coming to ESHRE 2012 can enjoy the famousnight life of Istanbul, especially at the congress party whichwill be held on the famous Suada island on the Bosporus,with panormaic views over Asia and Europe. And of coursewe should not forget the shopping, from modern malls tothe 600-year-old Grand Bazaar covered market with morethan 4000 shops.There will be something for everyone in Istanbul, from asuperb programme organised by the Scientific Committeeto the colourful social activities in the exotic surroundingsof the city. We hope ESHRE 2012 will be a rewardingeducational, social and cultural experience for you all.Timur GürganChairman Local Organising CommitteeIstanbul is a city steeped in history but now making rapid change as it prepares its candidacy for the European Union.Focus on Reproduction September 2011 5

More than8000 through the doors in StockholmAnother record-breaking congress for ESHRELaura Rienzi fromRome delivers thesecond HumanReproductionkeynote lecturebefore an audienceof at least 3000.Rarely - if ever - can so many have attended aninvited session at an ESHRE annual meeting,especially at 8.30 on a Monday morning. But thefact is that more than 3000 found seats for theopening two keynote lectures of this year’s meetingin Stockholm, the first from Terry Hassold ofWashington State University on our currentunderstanding (or lack of) of aneuploidy, and thesecond from Laura Rienzi from the GENERAcentre for reproductive medicine in Rome withresults from several recent studies of oocytevitrification. The latter was the second HumanReproduction lecture, following inauguration of theevent in Rome last year, but, as Bill Ledger notedthe following day, ‘vitrification was all overthis congress’.Packed lecture rooms were a hallmark -yet again - of this year’s meeting. The barestatistics show that 8361 people registered -not quite an attendance record - but enoughto ensure standing room only in somelecture halls and a commercial exhibitionarea like Las Vegas on a Friday night.Developments in the IVF lab once againprovided many of the talking points of themeeting. Indeed, Hassold’s opening keynotelecture underlined the magnitude of thechallenge of aneuploidy in the human, andhow far we are still away from explainingor dealing with it. ‘We’ve been staggered atthe frequency of abnormalities we see,’ said6 Focus on Reproduction September 2011

Hassold, adding that the human female appears tohave an ‘exceptionally high level’ among the animalspecies. There are, he explained, multiple sites andstages at which these chromosomal nondisjunctionscan occur, but are especially so at thefirst maternal meiotic division.This was also a pattern similarly (but notexclusively) seen in a spin-off from ESHRE’s ownpolar body screening study started in 2009 andnow completed as a pilot for a stronger randomisedtrial. Array CGH analysis of all 23 chromosomepairs (in 105 zygotes generated from 34 cycles inwomen all over the age of 35) indicated multiplechromosome errors in both meiotic divisions. Thispattern of meiotic aneuploidy, however, was judgedto be different from that observed in naturallyconceived zygotes (where the pattern of errorpredominates in the first meiotic division); inattempting a biological explanation for thediscrepancy, the investigators proposed ‘a role forovarian stimulation in perturbing meiosis in ageingoocytes’. ‘So we need to look further into theincidence and pattern of meiotic errors followingdifferent stimulation regimes,’ said investigatorAlan Handyside, ‘including mild stimulation andnatural cycle IVF. The results should enable us toidentify better clinical strategies to reduce theincidence of chromosome errors in older womenundergoing IVF.’There have been similar safety concerns -expressed for several years - over the effect ofculture media on embryo development, and this tooIn the openingkeynote lectureTerry Hassolddescribed thelevel of aneuploidyin women as‘exceptionallyhigh’.was the subject of awhole session inStockholm. A studyfrom the AcademicHospital of Maastrichtin the Netherlandscompared the effects oftwo commerciallyavailable sequentialmedia on fetal growthafter IVF (in a total of294 singleton pregnancies), with ultrasoundmeasurements at eight, 12 and 20 weeks’ gestation.However, only free-beta hCG levels differedsignificantly between the two media groups at 12weeks, but a ‘larger than expected’ fetal weight wasevident at 20 weeks in one of the two mediagroups.Dr Nelissen, presenting the data from Maastricht,was not yet able to apply any positive or negativeclinical implications to the results, which is thesame conclusion reached by a meta-analysis fromAmsterdam. Trawling the literature to unearth 37applicable studies, the investigators found ‘littleevidence’ to indicate which culture medium seems‘best’ for preimplantation embryos in terms of ARToutcome. Well designed randomised trials are nowurgently needed, they reported.The concerns over culture media underlying thissession are to be taken up by a new working groupratified by ESHRE’s Executive Committee inStockholm with a brief to examine changes inmethylation patterns associated with culture mediaand make recommendations for the improvedregulatory control of commercial formulations.Oocyte vitrificationLaura Rienzi’s Human Reproduction lecture wasbased on a study from her group in Rome whosepublication attracted the most full-text downloadsduring the first six months of publication betweenJanuary 2009 and June 2010. That original study, arandomised non-inferiority outcome trial of freshversus vitrified MII oocytes, was also an indicationof how much the whole concept of oocytecryopreservation has been driven by Italy, where2004 legislation banning embryo freezing madesome alternative option a clinical necessity.Focus on Reproduction September 2011 7

Lap of honour: InStockholm the Swedishgynaecologist LarsHamberger andAustralian IVF pioneerAlan Trounson wereawarded honorarymembership of ESHRE.They are seen herereceiving their awardsfrom outgoing ChairmanLuca Gianaroli.Indeed, it was striking to see inthe first oocyte cryopreservationdata collected by ESHRE’s IVFmonitoring group and presented byJacques De Mouzon two days laterthat - in 2008 at least - Italy wasresponsible for 79% of all cyclesreported (and 70% of all deliveriesderived from cryopreservedoocytes.) And Rienzi herselfreported in her lecture that almostall patients now offered oocytestorage in the routine Rome IVFprogramme accepted the offer.Vitrification, she said, has proved‘the breakthrough’, her data fromthe three studies described showingthat vitrified oocytes perform justas well as fresh in terms offertilisation, pregnancy anddelivery. A prospective follow-upstudy found that overall ongoingpregnancy rates from the fresh, andfirst and second warming cycleswere 37.4, 25.0 and 27.3%,respectively. The cumulative ongoing pregnancy rateper stimulation cycle was 53.3%, with maternal agethe only variable found to influence outcome. Athird study noted in the lecture was a three-centretrial with the University of Milan and IVI Valencia,where more than 2700 oocytes have been warmedfor fertilisation and 147 deliveries already recorded.So far, said Rienzi, results reflect a 5.4% live birthrate per ‘woman-oocyte’, suggesting that eachpatient requires nine oocytes to maximise results. Itwas notable that the results were always presentedwithin the context of either medical or socialfertility preservation, and this, insisted Rienzi, wasreason strong enough to justify thecryopreservation.However, the further potential of vitrification as adevelopment in oocyte banking for egg donationwas highlighted in a presentation from one ofRome’s collaborating groups, IVI Valencia.Reported results from four years of oocyte banking(with oocytes vitrified for at least six months)showed that more than 22,000 stored oocytes weredonated to 1602 recipients (with an average age of41 years). Treatments totalled 1856 donation cycles,with an implantation rate of almost 42% per cycle.Total ongoing pregnancy rate (from ‘fresh’cryopreserved and revitrified oocytes) was 50%when a total of 13 oocytes were available, and 59%with 15. Vitrification, said Ana Cobo Cabalpresenting the data, ‘offers excellent clinicaloutcomes, achieving the advantages of gametestorage without jeopardising success rates’.Oocyte donation is one of several techniqueswhose use is now increasing throughout the world.The same pattern is apparent in the use of ICSI,whose worldwide use is now twice that oftraditional IVF, and in frozen embryo transfer,whose use in Europe now represents almost 25% ofall ART cycles. Karl Nygren, presenting the worlddata on behlf of ICMART, also noted a rapiddecline in the number of triplet pregnancies in thedecade 1998-2007, with rates under 1% nowapparent in Europe, Australia, Asia (from limitedcycles reported) and the Middle East. However, twinpregnancy rates have remained relatively stablethroughout the decade, and in Europe haveremained static (at around 20%) for the past twoThe live surgerysession held onTuesday morningattracted its usualhigh attendance. Thesession, chaired byStephan Gordts andVasilios Tanos, relayedlive pictures from anoperating theatre ofTübingen UniversityHospital, Tübingen,Germany.8 Focus on Reproduction September 2011

A new Chairman and a new Executive CommitteeAfter two years, Luca Gianaroli’s term as Chairman of ESHRE came to an end in Stockholm, where he wassucceeded by Anna Veiga. The new Executive Committee, with a two-year term ahead of them and pictured above,comprises (back row, left to right) Niels Lambalk, Luca Gianaroli (Past Chairman), Anis Feki, Bruno Van Den Eede(Managing Director), Milan Macek Jr., Carlos Calhaz-Jorge, Anne-Maria Suikkari, Roy Farquarson; (front, left to right)Juha Tapanainen (Chairman Elect), Françoise Shenfield, Jacques De Mouzon, Anna Veiga (Chairman), Cristina Magli, andUrsula Eichenlaub-Ritter. Not pictured are Etienne Van den Abbeel, Antonis Makriagiannakis and Moidrag Stojkovic.years of data collection.The world’s lowest rate of multiple pregnancy isnow in Sweden, where 70% of embryo transfers in2007 were single. In a presentation in Stockholm,Jan Holte from Uppsala described the developmentof a mathematical model based on four variables(embryo quality, patient age, IVF history, andresponse to stimulation) designed to predict thechances of pregnancy after the transfer of one ortwo embryos and the risk of twins.Over a four-year period between 2004-2007, theyapplied the model to 3410 embryo transfers. Duringthis period the proportion of single embryotransfers increased to 76.2% (compared to 11.1%in the previous period), and the rate of twindeliveries reduced from 26.1% to 1.9%. Live birthrates per fresh embryo transfer fell from 29.1% to24.6%, but were similar when transfers of frozenthawedembryos were included. Holte found thatthe model correctly predicted pregnancy rates in allwomen, regardless of their chances of becomingpregnant.As ever, many of the presentations selected for thepress programme were widely covered throughoutthe world, with popular stories featuringmiscarriage (prediction, specialist care), reducingmultiple pregnancy rates (with single embryotransfer), and the award-winning presentation ofElpida Fragouli on the chromosomal assessment ofoocytes by cumulus cell analysis.qFocus on Reproduction September 2011 9

ESHRE 2011: award-winning presentationsClinical Science Award for Oral PresentationO-121 A pilot, double blind randomised controlled trialof prednisolone for women with recurrent miscarriage andraised uterine natural killer cell densityAW Tang, Z Alfirevic, MA Turner, J Drury, J Topping, FDawood, R Farquharson, S Quenby; Liverpool andWarwick, UKAi-Wei Tan presentsdetails of hergroup’s study ofprednisolone inrecurrentmiscarriage, whichwon the ClinicalScience Award forOral Presentation.Clinical Science Award for Poster PresentationP-539 An association of IL-18 gene polymorphisms with impaired glucoseregulation in Korean patients with polycystic ovary syndromeJW Kim, TK Yoon, WS Lee, JE Han, SW Lyu, SH Shim; Seoul, South KoreaDr Kim receives the Clinical Science Awardfor Poster Presentation from Chairman ElectJuha Tapanainen and EIM Chairman AnnaPia FerraretttiBasic Science Award for Oral PresentationO-217 Follicle-specific predisposition to aneuploidy as revealed by transcriptomic analysis of cumulus cellsE Fragouli, Z Huang, V Bianchi, A Borini, U Kayisli, P Patrizio, D Wells; Oxford, UK, Bologna, Italy, NewHaven, USAElpida Fragouli with herBasic Science award forOral Presentation.Basic Science Award for Poster PresentationP-240 Human embryo-endometrium interactions at the time of implantationM Peters, S Altmäe, J Reimand, T Laisk, M Saare, O Hovatta, R Kolde, J Vilo, A Stavreus-Evers, A Salumets; Tartu, Estonia,Stockholm, Sweden, Uppsala, SwedenFertility Society of Australia Exchange Award (pictured left)O-180 Influence of 5-HTTLPR variants in the SLC6A4 gene over pregnancy outcomes among recipients ofdonated eggsAR Palomares, AM Lendinez Ramirez, B Pérez-Nevot, F Martinez, A Jimenez, M Ruiz Galdón, A Reyes-Engel;Malaga, SpainArmando Reyes Palomares presentsdetails of his Fertility Society ofAustralia exchange award.Nurses AwardO-146 'Patient-centred infertility care' is a European concept: results from aninternational multi-lingual qualitative studyE Dancet, TM D'Hooghe, WLD Nelen, W Sermeus, JA Garcia-Velasco, LG Nardo,H Strohmer, C Wyns, JAM Kremer; Leuven, Belgium, Nijmegen, The Netherlands,Madrid, Spain, Manchester, UK, Vienna, Austria, Brussels, BelgiumElizabeth Dancet (right) receives the NursesAward from Juha Tapananinen and JolienekeSchoonenberg-Pomper, chairman of theParamedical Board.ART Laboratory AwardO-097 Improved embryo development in a time-lapse incubator system evaluated by randomized comparison of surplus embryodevelopment to the blastocyst stageJ Speksnijder, C van de Werken, SM de Jong, AJAM Dons, JSE Laven, EB Baart; Rotterdam, The Netherlands10 Focus on Reproduction September 2011

Stockholm gets highest ever satisfaction ratingResults from the annual meeting satisfaction surveyconducted each year by ESHRE show that the 2011event in Stockholm achieved the highest rating ever.On a scale of 1-5 this year’s event scored a recordaverage of 4.1, just higher than previous ratings inBarcelona in 2008 and Amsterdam in 2009. Thesurvey was conducted among 500 participants whoeach answered questions from a 10-minutequestionnaire. The interviews were conducted face-toonsite on Wednesday 6th July, with comparisonsmade to the previous four annual meetings.Also rising sharply were ratings for the scientificquality of the invited lectures, while the quality of theoral communications and debates remained high andsimilar to previous years.There was also a perceived improvement in theposter discussion sessions, which in previous eventshad attracted only a moderate response. Almost halfthe participants questioned took time to view theposters, with many viewing both the paper andelectronic versions. However, interest in the paperposters remained strong, with delegate preference stillapparently tending towards the traditional posterboards. However, the e-poster system was highly ratedfor ease of use (a score of 4.1).The congress centre in Stockholm scored highly forits efficiency and provision of venue-related services,although satisfaction with the catering was onlymoderate (3.2). Similarly, the city-related services -notably transportation and hotel booking - were ratedvery highly, and higher than at previous events.This year’s meeting continued the trend of fewerdelegates now supported to attend by industry, andmore by their own employers. Registrations werefunded in roughly equal measure by industry,employers and the delegates themselves.Overall satisfaction scores in Stockholm were higher thanat the previous four annual meetings.Interest in thepaper postersremained strong,with delegatesstill apparentlypreferring thetraditionalposter boards.Congress venue: rotating locations or a different city each year?With the challenge of finding a Europeancongress venue able to accommodate 10,000delegates becoming more and more difficulteach year, the prospect of rotating the locationthrough three or four suitable cities with asuccessful track record seems an attractiveoption. Huge congresses with 20,000 or moredelegates have to do this anyway of necessity,but it seems that ESHRE’s attendees stilloverwhelmingly favour the idea of a differentlocation each year. Only 7% preferred a limitedlocation roster.Focus on Reproduction September 2011 11

ESHRE NEWS// UPDATES FROM STOCKHOLM //ESHRE’s polar body array CGHtrial now good to goESHRE’s polar body array CGH study, arandomised trial of 23 chromosome analysis forpreimplantation genetic screening, is ready tobegin, with funding in place and most of thestudy centres contractually engaged. A pilotstudy completed last year showed that analysisof both polar bodies can be completed within atime period consistent with fresh transfer, withreliable chromosome identification in about 90% of attempts.Joep Geraedts (pictured above), chairman of the PGS Task Forcedirecting the trial, reported in Stockholm that the protocol is nowagreed and that the total study would require a population of 600couples. Randomisation will take place with the administration of hCG,and the analysis when at least four normally fertilised oocytes (2PN) areavailable. The target population, said Geraedts, is women planning IVFor ICSI who are at high risk of having aneuploid embryos because oftheir age. Inclusion criteria are infertility as an indication for ART, agebetween 36 and 41, BMI 20-30 kg/m 2 , and a willingness to accept thetransfer of two embryos. The trial has two primary aims, said Geraedts:to estimate the likelihood of having no euploid embryos in future ARTcycles, and to improve live birth rates.The study is being undertaken with the support of BlueGnome ofCambridge, who will supply the technology (and some training)sufficient to run 5000 samples. Other training will be undertaken by thetrial’s two lead training centres in Bologna and Bonn/Heidelberg. Thefive other centres chosen to take part are the Centre for MedicalGenetics, Brussels, the University Women’ s Hospital, Kiel, Departmentof Medical Genetics, Athens, Shaare Zedek Medical Center, Jerusalem,and the Institut Universitari Dexeus, Barcelona.EU guidance on reportingadverse events in ARTnow at draft stageThe EU’s SOHO V&S (Vigilance andSurveillance of Substances of HumanOrigin) project in ART, in which ESHREhas collaborated with a committee ofcompetent authorities, has now reachedthe stage of draft guidance for a systemof reporting (and investigating) seriousadverse reactions and events.Edgar Mocanu, chairman of ESHRE’sEUTCD Task Force, reported that thedraft guidance covers:l suspected adverse events linked toculture media and equipmentl mix-ups in the identification ofgametes and embryosl lost traceability (because of lostinformation or misrecording)l adverse events in the context of crossbordercarel adverse reactions and events related toprocurementl the diagnosis of genetic disease in thecontext of non-partner donationOnce fully developed, the guidancedocument will be be proposed to theEuropean Commission for applicationacross the EU.Hysteroscopy study on schedule for completion next yearAs of June this year 268 patients had been randomised in the Trophy (Trial of OutpatientHysteroscopy) study, a multicentre trial conducted at eight European centres with thesupport of ESHRE’s SIG Reproductive Surgery. The study, reported investigator StephanGordts from the University of Leuven, Belgium, aims to assess the effects of outpatienthysteroscopy on subsequent IVF outcome after repeated IVF failure in a total populationof 800 subjects. The primary endpoint of the trial is live birth rate per IVF cycle, withsecondary endpoints of embryo implantation rate,pregnancy rate per IVF cycle, and miscarriage rateper pregnancy achieved. The study hopes to confirmearlier single-centre studies (with live birth data)that hysteroscopy (with immediate correction oroperative hysteroscopy) can improve the prospectsof pregnancy in poor prognosis patients (with twoto four failed cycles). With 268 patients alreadyrandomised, Gordts said that completion onschedule next year looked likely.TROPHY study investigatorStephan Gordts: on schedule.12 Focus on Reproduction September 2011

ART DATA COLLECTION //ART success rates have ‘reached a plateau’EIM monitoring data show that both pregnancy - and multiplepregnancy - rates have not changed from the previous yearBoth the pregnancy and multiplepregnancy rate recorded in thepreliminary results of ESHRE’sEuropean IVF monitoring for 2008appear to have levelled off. Overallpregnancy rate per transferfollowing IVF was put at 32.5%,and following ICSI at 31.9%; boththese rates were slightly lower thanthose recorded for 2007.Similarly, pregnancy ratesachieved after egg donation and infrozen embryo cycles - aftershowing substantial gains from1997 - appear also to have peaked,with no gains shown on theprevious year. ‘It seems evident thatwe've reached a plateau,’ said EIMChairman Jacques De Mouzon.And Europe’s twin rate, in 2007rising once again to 21.3% afterIVF and ICSI, remained stubbornlylevel at 20.6% in 2008.Yet, as De Mouzon warned in hispresentation, ‘Europe’ is not a homogeneous region, andsuch generalised results as those of the EIM mask hugenational disparities. Nowhere is this now more starkly seenthan in the pattern of single embryo transfer and multiplepregnancy rate. Among the major IVF countries, forexample, only 13% of IVF/ICSI cycles in the UK were SETin 2008; the majority (almost 80%) were double embryotransfers. This contrasts vividly with patterns in the Nordiccountries where the SET rate in Sweden and Finland - evenin 2008 - was approaching 70%.As a result of this disparity of policy, as reflected in anEIM calculation described by De Mouzon as the ‘optimalend-points’ of IVF, Finland and Sweden achievedcumulative delivery rates of 30.5 and 29.4% in 2008, with29.7% similarly recorded in the UK. But the counterbalanceto these excellent results was a multiple deliveryrate of 9.7% in Finland and 6.6% in Sweden, but of23.5% in the UK.Such results from the UK made another presentation inthe Stockholm programme - from the UK regulator, theHFEA - on UK ‘policy’ to reduce multiple pregnanciesThe EIM Consortium’s chairman Jacques De Mouzon presents the latest data in Stockholm.‘It seems evident that we’ve reached a plateau,’ he said.appear little more than smoke and mirrors. While talk of‘strategy’ and ‘stakeholders’ seemed worthy enough, therewas little hard evidence from the HFEA that ‘we’re slowlygetting there’, especially when one slide from thepresentation showed a current UK twin rate of 44%following the transfer of two blastocysts. ‘We’ll be writingto the clinics in October,’ said the representative of thebeleaguered HFEA.Yet despite such glaring disparities with Finland andSweden (which now has the world’s lowest multiplepregnancy rate) the UK is not alone. Around 50% of cyclesin Hungary, Russia and Ukraine were double transfers in2008, and around 30% triple. More than 5% of deliveriesin Turkey and Lithuania were triplet, and more than 4% inMacedonia and Albania. And more than 50% of transfersin Greece, Turkey, Bulgaria and Romania were of threeembryos or more.The result of these excesses is that the proportion ofsingleton deliveries in the EIM dataset was less in 2008(78.3%) than in 2003 (79.2%), and the proportion of twindeliveries higher than in 2006 (20.6% vs 19.9%). [Focus on Reproduction September 2011 13

ART DATA COLLECTION //The ‘optimal endpoints’ of ART. Cumulative delivery rates after freshand frozen embryo transfer. Deliveries per initiated cycle 2008.InitiatedcyclesIVF/ICSIDeliveriesex freshIVF/ICSIcyclesFERcycles(thawings)DeliveriesFERMultipledeliveriesFERDeliveriesfresh (%)Cumulativedeliveryrate - fresh+ FER (%)AllmultiplesFinland4952980Mulitpledeliveriesex freshcycles111(3790)5285519.8%30.5%9.7%Sweden11,010238616947338544521.7%29.4%6.6%UK39,47610,07825118957163024525.5%29.7%23.5%However, De Mouzon didnote that in women under 40having IUI the twinpregnancy rates (8.3%) wereless than half those followingIVF or ICSI.And De Mouzon addedthat, over the 11 years of IVFdata monitoring in Europe,overall multiple delivery rateshad indeed declined, from29.5% in 1997 to 21.7% in2007, with a four-foldreduction in triplet deliveriesfrom 3.7% to 1.1%.On other safety issues, DeMouzon noted 2947 cases ofOHSS among the 535,000cycles reported, an incidence rate of 0.8%, derived fromthe data of 30 contributing countries (from a total of 36).Nine of those 36 countries also reported for the firsttime data on 3359 transfer cycles from cryopreservedoocytes, with 358 deliveries (8.6% per cycle and 10.7%per transfer).Also new were data from 12 countries on IVM cycles,which produced 172 pregnanciesat a rate of 18.3 per cycle and22.4% per transfer. In bothtreatments more than 50% ofcycles reported were performedin Italy.With Europe now representing52% of world ART activity, itwas no surprise to see many ofthe trends of the EIM data alsoevident in ICMART's worldreport (for 2007).ART activity in Europe is nowwell over 500,000 cycles a yearKarl Nygren presents preliminary ICMART data for 2007.Estimates put current global activity at 1.5 million cycles per year.ICMART’s global snapshot of ARTl An estimated 1.5 million cycles worldwideper yearl An estimated minimum of 340,000 ARTbabies born per yearl An estimated 4.6 million babies since 1978l 66.6% of all cycles are ICSIl 19.9% in women over 40 yearsl Mean number of transferred embryos = 2.14l Delivery rate per aspiration = 21.7%l Cumulative delivery rate = 27%and continues to rise -although the world's twobiggest centres of actionremain Japan (159,761cycles) and the USA(130,287). France performsthe most IVF in Europe(73,085 cycles), followed byGermany (63,787) and Spain(52,905).EIM data also show thatSpain is now responsible for30% of all Europe’s eggdonation treatment (followedby the Czech Republic (15%)and Russia (12%).Karl Nygren, presentingthe ICMART report, said itssubmitted data are thought to cover up to 70% of globalactivity, with many cycles missing from Africa, Middle Eastand Asia. Nevertheless, almost 1 million cycles werereported for 2007, prompting an estimate that around 1.5million cycles will take place in the world this year, with atleast 340,000 babies born.Cumulatively, the total of IVF babies since Louise Brownis now put at 4.6 million, with alandmark 5 million expected tobe reached next year. The meannumber of embryos transferredglobally was 2.14 and theaggregate delivery rate peraspiration 21.7%. The USA - asever - had the highestcumulative delivery rate of40.7% per started cycle, albeitwith a twin delivery rate ofaround 30%.Simon BrownFocus on Reproduction14 Focus on Reproduction September 2011

THE BEST OF ESHRE AND THE ASRM //A further step in ESHRE’scollaboration with the ASRMProgramme for joint winter meetingnow finalised, with emphasis oncontroversies in reproductive medicineThe first ‘best practice’ meeting to beorganised jointly by ESHRE andASRM in Italy next March is,according to ASRM chairmanRogerio Lobo, ‘an experiment’, butone which both societies have graspedwith enthusiasm as a further way ofworking more closely together. ‘Ofcourse,’ says Lobo, ‘we’ve each gotour respective roles in the USA andEurope, but we still have sharedinterest in many areas, and this is oneway where we can encourage thoseshared interests.’The meeting will take place from 1-3rd March 2012 in the ski resort ofCortina d'Ampezzo in the ItalianDolomites, a well established wintersports centre. Both ESHRE andASRM have stressed the importanceof the location for off-programmeand off-piste exchanges betweensociety members. ‘It’s not a skimeeting,’ insists Lobo, ‘but we dowant to make time for an informal aswell as formal programme.’The three-day scientific programme- which will leave mornings free forleisure activities - has been builtaround established and emergingASRM CHAIRMANROGERIO LOBO: ‘APROGRAMMEWHICH REVIEWSTHE BEST OFSCIENCE BUTWITHOUT ANYSELF-INTEREST.’controversies in reproductivemedicine, with presentations oneach topic reflecting a US andEuropean perspective. Oocytecryopreservation, for example, nowmoving into the mainstream ofEuropean treatment for both medicaland social indications (as well as foroocyte banking for egg donation),remains an ‘experimental’ techniquein the US. There are also wellrehearsed differences in the diagnosisof PCOS (and the relative role ofhyperandrogenism), the application ofsingle embryo transfer policies, andday 3 or day 5 embryo transfers, allof which will be explored in Cortina.Lobo additionally sees ESHRE andASRM taking a stand against themany small meetings now popping uplike mushrooms which he describes as‘self-promoting and purelycommercial’. ‘So we’re not planning afly-by-night meeting or running atravel club,’ he says. ‘The idea is toput our best foot forward in aprogramme which reviews the best ofscience but without any self-interest.’The ‘best practice’ initiative alsorepresents a continuation of the everstrong and cordialrelationship between ESHREand the ASRM, which for thepast 20 or more years hasbeen most evident inreciprocal exchange sessionsat the respective annualmeetings - in both thescientific programme andprecongress courses. ESHREhas traditionally been waryof close relationships withThe Italian ski resort of Cortina d’Ampezzo,chosen as the venue for the first ESHRE-ASRMbest practice meeting for its off-piste and offprogrammeopportunities.other societies, forging itscollaborative links most usually at theSIG level for training and logisticalreasons. ASRM, however, has alwayshad a more conceptual overlap withESHRE, despite the enormousdifferences between the two societies.Both describe themselves as‘international’ societies, which theirmembership readily reflects, and it’snoteworthy - as if further proof wereneeded - the ASRM has recentlyappointed a European, AntonioPellicer, to the co-editor’s chair ofFertility and Sterility. The ASRM,inasmuch as it is nominally anAmerican society, also represents anhomogenous professional group, witha strong core of practice guidelines athis heart, often applied at the clinicallevel in the absence of regulation.‘So there are big differencesbetween ESHRE and ASRM,’ saysLobo, ‘but I don’t think they drive usfurther apart or bring us any closertogether. The US is more homogeneousthan ESHRE’s representationof Europe, and ASRM has a broaderrange of clinical interests. But there’sstill a lot we have in common,especially at the scientific and clinicallevels. And this is what we’re lookingto develop in Cortina.’l More information and registrationdetails on the ESHRE website, under‘Annual meeting’.Focus on Reproduction September 2011 15

PGD CONSORTIUM// DATA COLLECTION XII //PGD for aneuploidy screening still dominatesworld activity in preliminary results for 2009Around 3000 cycles of array CGH reported to new working groupDespite the negative results of clinical trialsand a less than enthusiastic response by thePractice Committee of the ASRM in 2008,preliminary results from the ESHRE PGDConsortium for 2009 - its 12th round ofdata collection - show that PGD foraneuploidy screening still accounted formore than all other PGD procedurescombined (which included sexing for x-linked disease, chromosomal abnormalities,social sexing and monogenic diseases). Datawere collected on more than 6000 cycles in2009, with PGS representing well over3000 cycles. ‘PGS is still dominating,’ saidGary Harton, chairman of the Consortium,‘but screening for monogenic diseasecontinues to grow each year.’The cumulative picture of theConsortium's activity - accounting for 12rounds of data collection beginning in1997 - reflected the same pattern. Over the14 years, 30,250 embryos were transferredfollowing aneuploidy screening, with 10,888 embryostransferred following PGD for monogenic disease, and6458 for chromosomal screening. This was derived from atotal of 46,522 embryos biopsied for monogenic disease,36,787 biopsied for chromosomal abnormality, and131,539 for PGS. Cumulatively, there have now been morethan 6000 babies born following PGD, 74.5% of them asHighlights from data collections I-XIIl 39,507 total cyclesl 23,853 PGS (60.4%)l 14,960 PGD (37.9%)l 694 social sexing (1.7%)l 227,823 embryos biopsiedl Monogenics increasing each yearl PGS still dominates PGD worldwidel 7550 clinical pregnancies reviewed (74.5%singletons)l Miscarriage rate 'unremarkable'l Birth weights comparable to other datasetsPGD Consortium chairman Gary Harton presents preliminary resuts from theConsortium’s data collection for 2009: PGS is still dominating, he said.singletons and 48% by Cesarean section.The most common monogenic disorders diagnosed overthe 13-year period were beta-thalassaemia, sickle celldisease, cystic fibrosis and spinal muscular dystrophyamong the recessive disorders, Huntington’s disease amongthe dominant, and fragile-X, Duchenne musculardystrophy and haemophilia among the sex-linked.Harton also reported that 164 centres are now supplyingdata, with three of these centres performing more than 500cycles a year; 60 centres supplied full data for 2009. Spain(14 centres), Germany (11 centres), and the USA (ninecentres) had the greatest national memberships.Membership, Harton explained, is of three types, toreflect the way in which PGD is now performed: fullmembers are those centres supplying complete data fromoocyte collection through to pregnancy; transport membersare those who perform the genetic testing but withoutaccess to full IVF data; and associate members are thosenew labs just embarking on PGD.The Consortium now has five active working groups:l Misdiagnosis monitoring and audit (chair Jan Traeger-Synodinos)16 Focus on Reproduction September 2011

Evolution of PGDConsortium data over time,showing the continuingdominance of PGS foraneuploidyl Accreditation (chair Katerina Vesela)l Database (chair Celine Moutou)l Molecular methods (chair Francesco Fiorentino)l Arrays (chairs Leeanda Wilton and Dagan Wells).Presently, the misdiagnosis monitoring group iscompleting two re-analysis studies on PCR and FISHcycles using untransferred supernumerary embryos. Theaim, said Harton, is to determine how accurate the PGDanalysis is, and if there is any discordancy between theinitial PGD results and the re-analysis. Accuracy, he added,may be affected by the analysis method used, the numberof cells biopsied, mode of disease inheritance, embryoquality, and whether the analysis was performed on day 3or day 5 of embryo development. Presently, the full dataon the PCR cycles have been submitted within the deadlinefrom eight centres, have been analysed, and are now readyfor review; data from the FISH cycles have been cleaned,but not yet analysed. ‘The FISH-based study is lookingdifficult,’ said Harton, ‘because of mosaicism, so we’rehaving to discuss its viability.’A report from the array working group suggests thatmost clinical cases are currently being performed with theBlueGnome array technology (as used in ESHRE’s arrayCGH trial); however, there are some clinical cases alsobeing performed with SNP array. Around 3000 cycles havealready been performed by the members of the workinggroup, but the moment of biopsy varies throughout theworld. For example, most US centres analyse at thecleavage stage (although analysis at the blastocyst stage isgrowing quickly, with around 15% of cases in onelaboratory), most cycles in the UK are polar body analysis(with some blastocysts), while all cases in Germany areperformed at the polar body stage (no doubt because ofembryo protection laws - but see below).Among the Consortium’s future projects outlined byHarton are continued yearly data collection with new webbaseddata entry and deeper analysis of data, new learningtools for labs, guidelines and an external qualityassessment (EQA) scheme for array-based PGD, andcompletion of the misdiagnosis monitoring workinggroup's follow-up studies on amplification-based and(possibly) FISH-based analysis. In addition, theaccreditation working group will continue to assess andhelp PGD labs towards accreditation, and has two newworkshops on accreditation planned for 2011 (Athens)and 2012 (Istanbul) in conjunction with EuroGentest.After heated debate, German parliament votes to lift ban on PGDIn July Germany’s parliament voted by a majority of 326to 260 to overturn the country’s ban on PGD. Thecontroversial move followed a heated national debate (inwhich Chancellor Angela Merkel voiced her opposition toPGD) and a Federal Court ruling last year that PGD wasnot in violation of the country’s embryo protection laws.The Bundestag move will now allow PGD, but only oncondition that there is a strong likelihood of passing on agenetic defect, or when the chances of miscarriage orstillbirth are (genetically) high. All applications for PGDmust be approved by an ethics committee and couples arerequired to undergo counselling. According to newsreports, the bill thus provides an exception to the currentEmbryo Protection Act of 1990, which originally outlawedPGD but otherwise now remains intact.After a tense three-hour debate, the results of the freevote in the lower house of the Bundestag showed a clearsupport for the highly controversial bill.Focus on Reproduction September 2011 17

ESHRE NEWS// ESHRE JOURNALS //Onwards and upwardsImpact factors of all ESHREjournals make record gainsWhile impact factors may still be controversialin some corners of science and clinicalresearch, in academic publishing they remainthe clearest statement yet of journal quality.Which is why ESHRE - and its journalpublishers Oxford University Press - had suchhuge cause for celebration in June when theISI Web of Knowledge announced its impactfactors for 2010.All three ESHRE journals - HumanReproduction, Human Reproduction Updateand Molecular Human Reproduction - maderecord gains in their impact factors and nowdominate the two categories of ‘Obstetrics andGynaecology’ and ‘Reproductive Biology’.l HRU increased its impact factor to 8.755and now leads - by a very wide margin - bothcategories of O&G and Reproductive Biology.l HR, which is now second in the category ofReproductive Biology and third in O&G,increased its impact factor to 4.357.l And MHR, whose future was less thansecure as recently as five years ago, has madeenormous strides to now sit fourth in thecategory of Reproductive Biology with animpact factor of 3.506. This is a remarkablegain on last year’s figure of 3.005.Notable among the results is the decline ofFertility and Sterility, which fell from a 2009impact factor of 3.970 to 3.122 in 2010.Outgoing editor Alan DeCherney blamed theslump on a backlog of accepted manuscripts inneed of publication and on the inclusion ofshort reports (case studies, correspondence) inthe calculations. Reproductive BiomedicineOnline also fell back from last year - from2.380 in 2009 to 2.285 in 2010.‘We had an idea from the publishers thatour impact factor would increase,’ saysUpdate editor John Collins, ‘but the finalfigure was considerably higher than the“slightly over 8” prediction.’ Collins explainsthe record impact factor as ‘almost entirelydue to the quality of the manuscripts’, whichin turn reflects the confidence of authors in thejournal itself. ‘This is somewhat self-fulfilling -The three ESHRE journals now occupy three of the top four impact factor positions inthe category of ‘Reproductive Biology’, and two of the first three positions in‘Obstetrics and Gynaecology’. The impact factors of both Fertility and Sterility andReproductive Biomedicine Online fell from the previous year.Reproductive biologyTitleHuman Reproduction UpdateHuman ReproductionBiol ReprodMolecular Hum ReprodSemin Reprod MedReprod ToxicolFertil SterilReproductionPlacentaSex Plant ReprodObstetrics and gynaecologyTitleHuman Reproduction UpdateObstet GynecolHuman ReproductionGynecol OncolSemin Reprod MedBJOG - Int J Obstet GynMenopauseAm J Obstet GynecolUltrasound Obst GynFertil SterilTotal cites4791254682168345251156324325664570349581001Total cites47912403025468153871156110973161316406829256645-yr Imp Factor9.5994.2583.9793.1703.3993.3173.4753.4093.0602.2315-yr Imp Factor9.5994.6654.2583.0683.3993.3433.4743.4603.0933.475Impact Factor8.7554.3573.8703.5063.3693.1373.1223.0492.9852.680Impact Factor8.7554.3924.3573.7603.3693.3493.3183.3133.1633.12218 Focus on Reproduction September 2011

ecause the higher impact factors bringin more articles from good authors,which in turn gives the editors morechoice. It’s also true, of course, thatreview journals generally tend to havehigher impact factors. But it’s also fair tosay that the ESHRE journals excel onother indicators of a successful medicaljournal, such as a rising number ofsubmitted manuscripts, profitability,short time-lag to publication, readerinvolvement, readability, the adoption oftechnological advances, integrity of theliterature, editorial independence andfairness to authors and reviewers.’Outgoing ESHRE Chairman LucaGianaroli, in his comments on thejournals at the Annual GeneralAssembly, noted a mean time of 4.9weeks between acceptance and onlinepublication for Human Reproduction, amean time of 5.1 weeks for Update, anda mean time of just 1.1 weeks for MHR.André Van Steirteghem, editor ofHuman Reproduction, agrees thatmanuscript quality is the essence of ahigh impact factor. ‘I’ve never believed inmanipulating the impact factor with selfcitationsor other artefacts,’ says VanSteirteghem. ‘In fact, I am now moreconvinced than ever that the best thingESHRE journal editors, from the top,Steve Hillier (MHR),André Van Steirteghem (HR)and John Collins (HRU).you can do is accept only thosemanuscripts which meet the qualitystandards of the reviewers and of myown opinion as editor. So over the yearsI have tried to make HR moreprofessional, have had more contactwith the associate editors and havedeveloped a closer editorial team ofmanaging and deputy editors. Regularmeetings and teleconferences have allbeen very useful - and for sure an addedvalue.’For Steve Hillier, editor-in-chief ofMHR, the key to the impact factor hikelies in several factors, but notably in theintroduction of the ‘New ResearchHorizons’ section, which, he says, hasattracted some interesting and well citedsubmissions. But this, adds Hillier, ‘isonly one step on the way to establishingMHR as the journal of choice in itsdomain’. Future plans include eventighter editorial control and ‘a drive toensure that MHR leaves the rest of thepack in its wake’.New chairman for Committeeof National RepresentativesNo change in subscription feesto ESHRE journals for membersThe Annual General Assembly of ESHRE in Stockholm(see following page) agreed to Executive Committeeproposals to freeze members’ subscription fees to theESHRE journals for 2012. This means that subscriptionprices for both the online and print editions of HumanReproduction, Human Reproduction Update and MHRwill remain as in 2011 for all ESHRE members. However,subscriptions for non-members will rise by 5% in 2012.Non-members include academic and corporate institutions,as well as personal subscribers.Following the resignation last year of Peter Braudefrom the chairmanship of ESHRE’s Committee ofNational Representatives (CNR), and in a bid tostrengthen the working relationship between the CNRand Executive Committee, the ExCo and CNR haveagreed that the chairman of the CNR should be thePast Chairman of the Society - and thus Luca Gianaroliwas duly appointed to the chairmanship until the endof his term in 2013.It is hoped that a permanent ExCo member willfacilitate communication and exchange between thetwo committees. With members of the CNR elected bytheir national colleagues, the CNR provides all ESHREmembers with sounding-board access to the ExCo andthe opportunity for involvement in congress planning,abstract refereeing, and - most importantly - localrepresentation.Elections to the CNR were completed last year, andmembership of the present committee remains in placeuntil next year.Focus on Reproduction September 2011 19

GENERAL ASSEMBLY OF MEMBERS// ANNUAL MEETING 2011 //ESHRE’s General Assembly of Members took place at the Stockholmsmässan, Stockholm,on 5th July 2011 at 18.00. The minutes of the meeting are recorded below. Mattersarising and their approval will take place at next year’s Assembly in Istanbul.1. Minutes of the last meeting held in Rome- The minutes of the 2010 Annual Assembly of Members(AGM), having been circulated to all members in Focus onReproduction (September 2010), were approved. There wereno matters arising.2. Membership of the Society- Membership of the Society now stands at 5477, a slightdecrease on last year's number, with almost 71% of membersnow coming from Europe. The top membership countries areUSA (355 members), UK (340), Italy (306), Netherlands (290),Germany (290), and Spain (270). Growth in membershipcontinues from India (159 members), Japan (100) and China(51).- Disciplines most prominently represented are embryology(1670 members) and reproductive endocrinology (1516), butthere is strong membership growth in andrology andreproductive genetics. 'ESHRE is not a society of clinicians,'said the Chairman, noting that around 50% of themembership is now drawn from basic science, laboratorydisciplines and nursing. 'This is what ESHRE has alwaysaimed for,' added the Chairman.3. Society activitiesTrainingCampus events and precongress courses continue to dominatethe training programme, with a 2011 level of activity slightlyreduced from 2010's peak (of almost 40 total events). TheChairman explained that the 2011 Campus programme hadbeen slightly scaled back to 2009 levels, but, he said, 'there isstill much going on', with already more than 20 planned for2012 (including precongress courses). Sixteen precongresscourses were run in Stockholm, with seven of them fullybooked; 13 precongress courses have been scheduled for 2012in Istanbul.Future annual meetingsThe Society's 28th annual meeting will take place in Istanbulfrom 1-4th July 2012 at the Istanbul Congress Center; the29th annual meeting in 2013 will be held in London and the30th in 2014 in Munich.Embryology certification- While the number of applications for senior certificationcontinues to fall (following introduction of the scheme forseniors in 2008), applications received and accepted forcertification in clinical embryology remains buoyant, withmore than 140 accepted in 2011. Almost 100 passed theirexams and received clinical certification in 2010.- Two innovations in the certification programme wereEmbryology certification results achieved since the scheme waslaunched in 2008.introduced in Stockholm:* The Continuous Embryology Education Credit System bywhich embryologists can collect education credits, and therebyrenew their certificate. Senior clinical embryologists will needten credits and clinical embryologists six credits, obtainedover a three-year period, in order to apply for renewal.Attendance at scientific meetings, publications, contributionsto meetings and courses will all be taken into considerationfor the award of credits.* The ESHRE certification scheme will also be extended tooutside the borders of Europe. Appropriately, this will beginwith the 2012 examination to be held before the annualmeeting in Istanbul.Collaborations- In 2011 ESHRE became a member of the Alliance forBiomedical Research in Europe, an organisation of variousassociations which aims to promote research across allmedical disciplines.4. ESHRE journals- 2010 impact factors for all three ESHRE journals werereleased in June and show remarkable increases: HumanReproduction Update from 7.042 in 2009 to 8.755 in 2010;Human Reproduction from 3.859 to 4.357, and MHR from3.005 to 3.506. The results, said the Chairman, were‘astonishingly high’, and ‘a great achievement’. HumanReproduction Update now leads the category of obstetricsand gynaecology, with Human Reproduction in third place,while all three ESHRE journals occupy the first four positionsin the category of reproductive biology. The Chairman singled20 Focus on Reproduction September 2011

Campus events 2005-2011, with those already planned for 2012. With Campusand precongress courses a reaffirmed priority, SIG and Task Force expenditure isexpected to reach almost 1 million euro in 2011.out the achievement of MHR in raising its impact factor somuch in just 12 months - ‘an incredible jump, and we are veryproud of this,’ he said. The Chairman congratulated theeditors and the editorial office.- Circulation of all three journals continues to rise,particularly among academic consortia, which suggests aneven wider readership than indicated by circulation alone(which for Human Reproduction now stands at 7000).Circulation of MHR reached almost 5000 in 2010, a fineachievement, said the Chairman, given the journal'spredicament only five years ago.- Time from acceptance to online publication has been cutdramatically by all three journals, Human Reproduction to amean of 4.9 weeks, Update to a mean of 5.1 weeks, andMHR to a median of just 1.1 weeks.- 2012 subscription prices for the journals (online and print)will remain as in 2011 for all ESHRE members, but for nonmembers(including academic and corporate institutions, aswell as personal subscribers) the price will rise by 5%.5. Paramedical group- Jolieneke Schoonenberg-Pomper, chairman of theParamedical Board, reported that 11% of the total ESHREmemberships (604) were from the Paramedical Group; thisrepresented an increase of 0.6% from 2010. Paramedicalmembers comprise nurses, midwives, lab technicians,counsellors and psychologists, and ESHRE-certified clinicalembryologists.- Among the training events previewed was a first workshopfor paramedics, junior doctors and embryologists to be held ineastern Europe (in St Petersburg in September). In March2012 the Paramedical Group will host a training course forthose new to the theory and practice of medical research inAmsterdam.6. Financial report- The Chairman presented the report of the Finance Subcommitteeshowing the balance sheet (incomeand expenditure) for 2010 and the budget for2011. Both income in 2010 (5,909,026 euro) andexpenditure (5,759,414 euro) were slightly lessthan budget, and showed a small favourablebalance of 149,611 euro. The budget for 2011sets a higher negative balance of -190,038 euro,much accounted for by continuing investment inthe SIGs and Task Forces; SIG expenditure hasbeen budgeted at 699,000 euro for 2011 (12% oftotal expenditure), with Task Forces accountingfor a further 4%. The annual meeting continuesto provide the Society's greatest source of income(66%) and expenditure (57%).- The financial state of the Society was describedas 'good', and the report was approved by themembers.7. New Executive Committee- Five members of the Executive Committeestood down having served two two-year terms:Jean François Guérin (FR), Timur Gürgan (TR),Carlos Plancha (PT), Veljko Vlaisavljevic (SL), and FrançoiseShenfield (GB), who will remain an ex officio member of theExCo as Co-ordinator of the Special Interest Group & TaskForce Sub-committee following the completion of Søren Ziebe’stwo-year term of office.- The nomination of five current ExCo members to continuetheir membership for a second two-year term was approved bythe membership: Ursula Eichenlaub-Ritter (DE), AntoniosMakrigiannakis (GR), Miodrag Stojkovic (RS), Anne-MariaSuikkari (FI), and Etienne Van den Abbeel (BE) were reappointedfor a second term of two years.- The nomination of seven new members of the ExCo wasapproved by the membership, and Carlos Calhaz-Jorge (PT),Jacques De Mouzon (FR), Roy Farquharson (GB), Anis Feki(CH), Niels Lambalk (NL), Milan Macek Jr. (CZ), and CristinaMagli (IT) were appointed as new members of the ExCo.- The nomination of the Finnish gynaecologist JuhaTapanainen as Chairman Elect was approved by themembership. Juha will take over as ESHRE Chairman at the2013 General Assembly in London, after Anna Veiga completesher two-year term as Chairman.- Luca Gianaroli stood down as ESHRE Chairman, to beformally replaced by Anna Veiga. Luca received warmappreciation from the membership for his tireless and inspiringwork.8. Election of honorary members for 2011- The two nominees proposed by the Executive Committee forhonorary membership in 2012 were Sir Ian Wilmut(international) and Victor Gomel (national). Both nominationswere ratified by the AGM.7. Any other business- There was no other business.l The next Annual Assembly will be on 3rd July 2012 inIstanbul at 18.00 pm.Focus on Reproduction September 2011 21

Special Families campaignbuilds Wall of Hope forinfertile couples in EuropeFertility Europe in StockholmTwenty-nine patient representatives from 17 Europeanpatient organisations/countries from across Europeattended our Annual Members Meeting in Stockholm. Wehad a full agenda and one of the liveliest sessions was onour policy work and taking forward the work of ourpolicy sub-group, which was formed the previous year inRome. The group, led by Isabelle Chandler, had met onseveral occasions during the year via Skype in order todraft our first policy paper on Equity of access toMedically Assisted Reproduction, which had beendiscussed at our previous members meeting in Prague inMarch 2011. The many useful comments and suggestionsfrom that meeting were then incorporated into the draftpresented in Stockholm. An excellent discussion withfurther suggestions for amendments and refinements weremade - which the sub-group will work on over the nextfew months with the aim of circulating a final draft soon.The plan is to use this policy paper as a briefing documentto give to policymakers and the press, and as a platform toshare ideas with ESHRE. Our members come from all overEurope with different laws and different cultures - so it isimportant that the policy is something that all patientorganisations can support. We agreed that our next policypaper should be about prevention.Our members had expressed a desire to know moreabout the work of ESHRE and how it functions. We weretherefore delighted to once again welcome Anna Veiga, theincoming Chairman of ESHRE, to the meeting to speak toexplain the Society's history and its work in advocacy,education and data collection.Finally, our Executive Committee member and Vice-Chair Denisa Priadkova from Bocian/Slovakia, brought usall up to date with our Special Families project. The Wallof Hope, with postcards from patients from all overEurope, came from an idea 18 months before and had nowbecome a reality in the main entrance hall of the congresscentre in Stockholm. The project will run until the end of2011 and is aimed at raising awareness right acrossEurope.Finally, but very importantly, can we thank ESHRE onceagain for their generosity in allowing our delegates entry tothe congress, providing the room for our meeting and ofcourse our booth in the exhibition. We are truly grateful.Clare Lewis-Jones MBEChair Fertility EuropeOur Special Families campaignCouples with fertility problems need hope and reliableinformation. In June 2011, in order to provide themwith both, Fertility Europe introduced in 19 Europeancountries its first Special Families Campaign campaign sends a multiplied message of hopefor fertility in the form of postcards with stories,messages and notes on prevention and treatment.Thousands of postcards with moving stories areexpected to cross Europe before October 2011.The goals of the Special Families campaign are toraise awareness of fertility and give a voice and a faceto those concerned. Those who successfully travelledthe bumpy road to a family life are a source of hopefor millions. Sharing their dramatic and emotionalstories with others is a great way to share hope.The Special Families campaign is a collection ofpostcards made from pictures and stories of specialfamilies and sent from Fertility Europe membercountries. The postcards will be created and sentby e-mail to family planning couples facing difficultiesin conceiving and collected in the National Gallerieson the internet.l For more information on the Special FamiliesCampaign please contact Denisa Priadková,Vice Chair of Fertility Europe at info@fertilityeurope.eu22 Focus on Reproduction September 2011

Panel ASPECIAL INTEREST GROUPS// STEM CELLS //A dapper little SIG, but more hands are welcomeThe year has been a good one forthe SIG Stem Cells: two successfulhands-on workshops in Valenciaand Barcelona were followed by awell attended and scientificallystimulating precongress course.Indeed, the hands-on workshopswere such a success, also attracting participants fromoutside ESHRE, that we have now decided to make this arecurrent activity, with the next workshop probably takingplace in early 2012 in Stockholm.Precongress coursesThe precongress course organised jointly with the SIGEmbryology covered everything - or at least those parts ofeverything that we know of - between the embryonic stemcell and the blastocyst. It was interesting to see howquestions such as what really determines toti- andpluripotency can be answered when looked at from theviewpoint of the embryo, or from that of the stem cell.Very often, the answers are the same, which strengthensour conviction that embryonic stem cells can act as a modelfor embryos, and as such have a place in the scientificcommunity of ESHRE.We plan to have our next PCC in Istanbul on pluripotentstem cells, cancer disease and fertility preservation, a fieldin full ebullition that will interest many ESHRE members,both clinicians and scientists. Along with an interest instem cells as models in developmental biology, and theiruse for fertility specialists as potential sources of gametesafter differentiation, this is a further aspect of stem cellswhere reproductive scientists (in the broadest sense of theword) and stem cell biologists meet.Panel BSteering committeeKaren Sermon (BE), Co-ordinatorRita Vassena (ES), DeputyAnis Fekis (CH), DeputyCarlos Simon (ES), Past Co-ordinatorMembershipOur past success is in no smallway thanks to our Past CoordinatorAnna Veiga (nowchairman of ESHRE) and CoordinatorCarlos Simon, helpedand assisted by deputies Anis Feki(now a member of the Executive Committee of ESHRE)and myself, with Rita Vassena as Junior Deputy (who iscertainly a future coordinator in the making!). However,because of his increasing duties elsewhere, Carlos Simonhas delegated his role as Co-ordinator to myself one yearearlier than planned. This means that Rita Vassena hasbeen promoted to Deputy, and that there is now a seatavailable as Junior Deputy. So I take this opportunity tocall upon interested members of the SIG Stem Cells tocome forward and participate in the running andorganisation of the SIG. Once elections for (junior)deputies are scheduled, we will then have valuablecandidates to ensure the continuation and expansion ofthe SIG.Indeed, the SIG Stem Cells is a relatively small SIG,nominated by many ESHRE members as their second fieldof interest. We in the steering committee, however, believethat there is a tremendous potential for many memberswho could join - so please, the next time you fill in yourESHRE membership renewal form, consider the SIG StemCells as your first choice special interst. Moreover, as arelatively young SIG working in a constantly moving andscientifically challenging field, we would specifically wishto encourage all those young PhDs and post-docs workingin IVF and research labs to join the SIG Stem Cells, and toultimately become a significant factor in its future success.I hope to prove a worthy successor to Carlos Simon,and, with the help of an enthusiastic membership, to makethe SIG stem cells an ever-expanding success.Karen SermonCo-ordinator SIG Stem CellsPanel CIllustration of a novel concept presented during a long day’s work atthis year’s precongress course: Waddington's epigenetic landscapedescribed in 1940 holds the dogma that, once cells have rolled downfrom their undifferentiated peak into a differentiated valley, theycannot go back (panel A). Current experiments with inducedpluripotent stem cells challenge that dogma (panel B). In the future, itis probable that we will be able to manipulate cells from one level ofpluripotency to another, and from one differentiated state to another,as illustrated by the ‘new epigenetic landscape’ in panel C.Focus on Reproduction September 2011 23

SPECIAL INTEREST GROUPS// REPRODUCTIVE SURGERY //RCOG meeting a highlight of the year so farOne of the highlights of the year forthe SIG Reproductive Surgery was atwo-day meeting in London jointlyorganised by the Royal College ofObstetricians and Gynaecologists,ESHRE and European Society forGynaecological Endoscopy. It was avery successful and well attendedevent, with very positive feedback. Course organisersLuciano Nardo (GB), Stephan Gordts (BE) and MarcoGergolet (IT) aimed to provide those with an interest inreproductive surgery with reviews of current evidence-basedcare and up-to-date recommendations for good clinicalpractice. A strong scientific programme and internationalpanel of speakers guaranteed some excellent lectures withlively discussion and debate over the two days.The opening day began with a session on basics,covering set-up and safety measures for laparoscopy andthe implementation of training and accreditation inreproductive surgery. The session moved on to tubalsurgery - with discussion on why the fallopian tube fails -salpingectomy versus salpingostomy, reversal of sterilisationand peri-adnexal adhesions. A session on endometriosisfollowed, which covered the rationale of treating early stageendometriosis, endometriosis and IVF, and rectovaginalendometriosis. Ovarian surgery concluded the first day’sprogramme, with discussion on management ofendometrioma, adnexal torsions and borderline ovariantumours.Day two concentrated on uterine surgery and fertilitypreservation. Beginning with indications and theclassification of myoma, the programme covered the prosSteering committeeVasilios Tanos (CY), Co-ordinatorTC Li (GB), DeputyGregoris Grimbizis (GR), DeputyNatasa Kenda Suster (SI), Junior DeputyMarco Gergolet (IT), Past Co-ordinatorSpeakers at this year’s precongress course: left to right, Marco Gergolet, MariaMercedes Binda, Vasilios Tanos, Stephan Gordts, Rudi Campo and Antoine Watrelot.and cons of hysteroscopic andlaparoscopic myomectomy, therisks and benefits of surgicaltreatment for adenomyosis, thetreatment and prevention ofintrauterine adhesions and treatmentof congenital uterine anomalies. Thefinal session of the event was onfertility preservation, beginning with techniques andefficacy before cancer treatment. Ovarian stem cells andorthotopic versus heterotopic ovarian transplantation werediscussed before the final thought-provoking lecture on‘Uterine transplantation: reality or fiction?’.Feedback from the meeting indicated that it was anenjoyable and educationally worthwhile event, withwidespread appreciation of the expertise shared and theopportunity for interactive discussion on some interestingand sometimes controversial topics.In May we organised a Campus course in Grado, Italy,on how surgery can increase the success rate of ART. Theevent was well attended, with stimulating discussion aftereach presentation - a sign of the good quality of thelectures and preparation of the participants. The goal ofthe organisers was not ex cathedra lectures but a peer-topeerexchange of experience. The first day was focused ondiagnostic tools, followed by congenital and acquireduterine anomalies. The second morning considered ovarianand fallopian tube pathology. The final lectures addresseda need for the standardised training of young surgeons andfor an integrated reproductive medicine and surgeryservice across Europe.Events in StockholmOnce again, our precongress course this yearproved of high quality. The course addressedthe problem of gynaecological adhesions andtheir reproductive implications. The lecturescovered the theoretical explanation ofadhesion formation and the clinicalimplications of leaving or treating them. Thefirst part of the course covered intraabdominaland particularly tubal adhesions,and the second uterine synechiae.The business meeting reviewed plans forthe coming year, and welcomed the reformedsteering committee.Marco GergoletPast Co-ordinatorSIG Reproductive Surgery24 Focus on Reproduction September 2011

EMBRYOLOGY //A working group to investigate culture mediaThe SIG Embryology has hadanother active year in which we triedto develop a fruitful mix of basic,clinical and practical interest.We are happy to announce that ourmembership has increased since lastyear, now, with 1670 members, thelargest of ESHRE’s SIGs (closelyfollowed by the SIG Reproductive Endocrinology).This year also sees a change in the steering committee,with myself, Kersti Lundin, taking over as Co-ordinatorfrom Cristina Magli, who will now be the Past Coordinator.Etienne van den Abbeel who has been a veryactive and appreciated committee member has steppeddown from his position as Past Co-ordinator. Deputy boardmembers are Maria José de los Santos and JosephineLemmen. We also have a new Junior Deputy member thisyear, Ana Sousa Lopes from Belgium. Carlos Plancha willhelp our close collaboration with the Task Force BasicScience in Reproduction.Courses and workshopsOur courses and workshops are always very well attended,usually with a number of participants ranging between 100and 200. In the spring we ran a very successful updateworkshop in a beautiful and sunny Salzburg, organised incollaboration with the Austrian Reproductive MedicineSociety. The course - Practical aspects of non invasiveselection of gametes, embryos and blastocysts in a modernIVF laboratory - was covered by a number of excellentlectures, working our way from sperm DNA fragmentationand IMSI/ICSI through oocyte and embryo qualityassessment to the newest proposals of embryo selection.We were also invited to a fantastic party at the old castle.Looking at it from below, it was amazing that we couldwalk there at all, but we did, and were rewarded withfood, drinks and games.Because embryology is such a core issue in assistedreproduction, we often collaborate with other SIGs andTask Forces. Thus, at the annual meeting in Stockholm thisyear, our precongress course was jointly organised with theSIG Stem Cells, and was again very well attended with justover 300 registered participants. The course focused onThe blastocyst: perpetuating life, and covered both basics,such as mitochondria and microRNAs during embryodevelopment, as well as more practical aspects such ascryopreservation. Webcasts from the course can befollowed on the ESHRE website.Forthcoming eventsNext year, on 19-21st April, we are organising a workshopSteering committeeKersti Lundin (SE), Co-ordinatorMaria José de los Santos (ES), DeputyJosephine Lemmen (DK), DeputyCristina Magli (IT), Past Co-orindatorAna Sousa Lopes (BE), Junior Deputyin Stresa, Italy, in collaboration withthe SIG Reproductive Genetics andTask Force Basic Science inReproduction, the seventh workshopon Mammalian folliculogenesis andoogenesis; oocyte legacy forembryology development. Thesecourses have a basic and researchorientation, aiming for highly interactive sessions and havebeen very successful.Please read more on theESHRE website.Our other great news,of which many of youwill be aware, is that wehave now published aconsensus document onembryo assessment incollaboration with AlphaScientists. The paper ispublished in both HumanReproduction and RBMOnline, with free access.The consensus onWe see this first document as a great step embryo assessmenttowards a worldwide common assessment developed by thesystem for oocytes and embryos.Alpha Scientists inReproductiveWe will also now be focusing on the launchMedicine and theof the planned Atlas of Embryology, which SIG Embryology iswill build upon the assessment system of the now published.consensus paper. A lot of images have alreadybeen collected from many contributors, but, aswith most projects, things take longer andinvolve more work and more problems than originallyexpected. The IT section at ESHRE’s Central Office havebeen working very hard to put a media platform in place,where all pictures can be downloaded and stored in a waythat provides easy access for the users. Hopefully, this willbe completed by early autumn. As soon as we have a trialversion, it will be announced on our website.Finally, we are pleased to announce that ESHRE’sExecutive Committee has agreed to the formation of a newworking group within SIG Embryology to look into themany issues related to culture media, such as composition,requirements, research models,child and placental correlates. Weall realise that these are extremelyimportant subjects, and it will alsobe the topic for our precongresscourse in Istanbul 2012.Kersti LundinCo-ordinator SIG EmbryologyFocus on Reproduction September 2011 25

SPECIAL INTEREST GROUPS// ENDOMETRIOSIS & ENDOMETRIUM //More published data on endometriosisTopics of interest to theSIGEE were again wellrepresented at this year’sannual meeting inStockholm - there wassomething for everyone inthe programme.Our precongress course,on the The impact of thereproductive tract environment on implantation success,was well supported with over 100 members at all sessions.Huge thanks go to our contributors and the eagerdiscussants, which ensured a very successful, inspiring andinformative start to the meeting.Our SIG business meeting also had a healthy attendance,with the following key points discussed:l Lone Hummelshoj updated us on three important WERFstudies. Data from the Global Study of Women’s Health(GSWH) are now published ( Krina Zondervan will deliver akeynote lecture at this year’s World Congress onEndometriosis based on data from the GSWH and Women’sHealth Symptoms Study (WHSS). The EndoCost studyprotocol was published last year ( and extracts of data werepresented in Stockholm, with more being presented atWCE2011.l A major achievement this past year has been thedevelopment of an informational five-minute film aboutendometriosis, which to date has had more than 15,600plays. It aims to help women recognise the symptoms ofendometriosis and explain the treatment options. It will bemade available in French, German, Italian and Spanish.WES president Hans Evers and the vice-president of theEuropean Parliament, Diana Wallis MEP, produced filmedstatements at the time of the film’s launch urging womenwith symptoms to seek early help. All three films may beviewed at members who wish to be kept up to date withnews in endometriosis may follow Lone on Twitter committeeHilary Critchley (GB), Co-ordinatorAnneli Stavreus-Evers (SE), Deputy Co-ordinator EndometriumGerard Dunselman (NL), Deputy Co-ordinator EndometriosisAnnemiek Nap (NL), Junior DeputyPaola Vigano (I) Basic Science representativeThomas D’Hooghe (BE), Past Co-ordinatorFuture activitiesWe now look forward toour SIG agenda for thenext 12 months andbeyond.By the time you readthis many SIG memberswill have attended the11th World Congress onEndometriosis meeting in Montpellier - I am sure this willbe an outstanding success and further strengthen theglobal endometriosis network.The day after the congress WES has arranged aconsensus workshop on the management of endometriosis,where 32 international professional and patientorganisations will participate; Gerard Dunselman andThomas D’Hooghe will be representing ESHRE.Next on our SIG calendar is the ESHRE Campusmeeting on Endometriosis and IVF in Rome on 28-29thOctober ( Themeeting promises to be comprehensive and featuressessions on the impact of endometriosis on the IVFprocedure and the impact of IVF on endometriosis,treatments pre- and post-IVF from the surgeon’sperspective and the effect of endometriosis on IVF-derivedpregnanciesLooking further ahead we have an exciting precongresscourse prepared for Istanbul on 1st July 2012: this will bea joint course with the ASRM on the theme of Pain andendometriosis. Please put this event in your diaries now.The course will consider clinical issues as well asmechanistic insights and the best available evidence forclinical management. It should appeal to all those with aninterest in endometriosis and pain mechanisms.And please come forward now with your suggestions forour SIG’s precongress course in London in 2013. We needyour suggestions. We hope to see many of you again soonin Montpellier and Rome - and please let us know whatyou would like to see your SIG deliver for youHilary CritchleyCo-ordinator SIG Endometriosis & Endometrium26 Focus on Reproduction September 2011

Ai-Wei Tang withher ClinicalScience Award forOral Presentation,flanked (left) byESHRE’s ChairmanElect JuhaTapanainen andthe SIG EP PastCo-ordinator RoyFarquharson.// EARLY PREGNANCY //Long-term prognosis after recurrent miscarriageThe annual meeting in Stockholmmust be deemed a big success in ourefforts to enhance interest in earlypregnancy complications withinESHRE. The lectures in theprecongress course organised incollaboration with the SIGReproductive Genetics were of highscientific standard and most of them were very useful forboth geneticists and clinicians.Firsts in StockholmFor the first time there were four early pregnancy sessionsat the main meeting. The sessions on Monday and Tuesdaymorning were especially well attended and discussions weregood. Two presentations from one of the selected oralcommunication sessions were chosen for discussion at thepress conference, and received widespread press coverage.These two studies looked at the long-term prognosis forpregnancy and live birth in patients with recurrentmiscarriage, and the data presented will be very useful incounselling patients in clinical practice. The study by Lundet al showed that 67% of patients with recurrentmiscarriage referred to a Danish miscarriage clinic wouldexperience a live birth within five years, whereas a study byKaandorp et al showed that 86% of Dutch patients wouldachieve a pregnancy after 24 months, with a median timeto subsequent pregnancy and live birth of 41 weeks.Also for the first time ever, the Clinical Science Awardwinner at an ESHRE annual meeting came from the SIGEarly Pregnancy. Dr Ai-Wei Tang from the LiverpoolWomen’s Hospital won the prize for her presentation of arandomised trial of prednisolone for women with recurrentmiscarriage and high uterine natural killer cells.At the business meeting, which was also attended byProfessor Mary Stephenson from Chicago, who isSteering committeeOle B Christiansen (DK), Co-ordinatorMariette Goddijn (NL), Deputy Co-ordinatorSiobhan Quenby (GB), Deputy Co-ordinatorMarcin Rajewski (PL), Junior DeputyRoy Farquharson (GB), Past Co-ordinatororganising an early pregnancyspecial interest group in the USA, itwas agreed to write a SIG EarlyPregnancy report for HumanReproduction with guidelines for theevaluation of biochemicalpregnancies and their treatmentamong patients with recurrentmiscarriage. Repeatedbiochemical pregnanciesare an increasingproblem and attitudeson how to deal withthem varyconsiderably.During the latterpart of this year wewill be asking all ourSIG members tonominatecandidates forthe election of anew JuniorDeputy andDeputy Coordinatortotake over fromthe summer2012.Early pregnancyreports featuredin two of theESHRE pressconferences, withOle B Christiansen(left), and KaltumAdam (below) with amodel for predictingthe risk of miscarriageFuture activitiesOur future activities are running as scheduled: the jointESHRE SIG Early Pregnancy and European Society ofReproductive Immunology meeting about early pregnancycomplications in Copenhagen in August looks set to havebeen a success, with more than 130 registered in advance.Preparations for the postgraduate ESHRE exchangecourse on early pregnancy at the ASRM meeting inOrlando in October are almost completed. And althoughour planned precongress course in Istanbul 2012 Gametequality and ovarian reserve as markers for early pregnancyloss was omitted by error in the printed announcementdistributed in Stockholm, the course is indeed inpreparation and will be announced later.Our winter symposium in November/December 2012 willbe held in Amsterdam and organised by our next CoordinatorMariette Goddijn.Ole B. ChristiansenCo-ordinator SIG Early Pregnancyolbc@rn.dkFocus on Reproduction September 2011 27

SPECIAL INTEREST GROUPS// REPRODUCTIVE ENDOCRINOLOGY //A new guideline for premature ovarian insufficiencySteering committee changesA new committee took over theSIG RE in Stockholm and gavewarm thanks to Past Co-ordinatorAdam Balen and his committee fortheir hard work and for setting thescene with so many fine workshopsand precongress symposia. Thenew committee consists of Frank Broekmans (NL),Efstratios Kolibianakis (GR), and a new juniorrepresentative Daniela Romualdi (IT). The committee isnow looking forward to serving the SIG and representingreproductive endocrinology within ESHRE for the nexttwo years.Steering committeeGeorg Griesinger (DE), Co-ordinatorFrank Broekmans (NL), DeputyEfstratios Kolibianakis (GR), DeputyAdam Balen (GB), Past Co-ordinatorDaniela Romualdi (IT), Junior DeputyPrecongress course on ovarian ageingThis year’s precongress course attracted more than 200participants who followed an impressive array of speakerscovering all the important scientific and clinical detail ofthe life cycle of the ovary. Claus Yding Andersen set thescene on the question of whether or not ovarian stem cellsstill exist in postnatal life. Richard Anderson reviewed thedeterminants of ovarian ageing, and Helen Picton andUrsula Eichenlaub-Ritter went deeply into the basic scienceof oocyte metabolism and genetics and how these interactwith the developmental potential of the female germ cell.Next were two more clinically orientated presentations:Scott Nelson with a comprehensive update on the value ofAMH in ovarian reserve assessment and ART outcomeprediction, and Melanie Davies with a summary ofevidence on hormone replacement therapy in prematureovarian insufficiency patients. The last session was devotedto fertility preservation (Dror Meirow) and how delayedpregnancy affects society as a whole with respect topopulation size and the demand for fertility treatments(Siladitya Bhattacharya).The course once again showed how much can beachieved in a single day on a singletopic. It is expected that next year’sprecongress course in Istanbul -Optimising the IVF protocol andthe use of adjunctive therapies -with its strong focus on the clinicalside of IVF will continue in thistradition and will excite substantialinterest, so please register early if you are interested.The embryo as a patientFormer SIG coordinator Nick Macklon hosted a workshopin beautiful Winchester in southern England. The themewas an examination of how the ‘Barker hypothesis’, nowknown as the Developmental Origins of Health andDisease (DoHAD) concept, applies to the periconceptionalphase of development. Professor Barker, originator of theeponymous hypothesis, gave an inspiring introductorylecture outlining how evidence grew to support hishypothesis. A number of international speakers - rangingfrom developmental biologists (Tom Fleming and MarkHanson), to reproductive epidemiologists (Regine Steegers-Thuinissen) and to clinicians (Rob Norman and ScottNelson) - showed how nutrition, the early endocrineenvironment, and toxins may all affect early and laterdevelopment. Nick provides a full report on page 40.Upcoming eventsl What you always wanted to know about polycysticovary syndrome, Sofia, Bulgaria, 8-9th December 2011.This comprehensive meeting on PCOS, hosted by StanimirKyurkchiev, will cover the full spectrum of the syndrome,from definitions to pathogenesis, treatments forhyperandrogenism and infertility to long-term health risksand quality of life.l Anti-Mullerian hormone: An update, Lille, 10-12th May2012. Didier Dewailly will be hosting this workshop whichThe SIG RE’s new steering committee, from left to right, Co-ordinator Georg Griesinger, Deputies Frank Broekmans,Efstratios Kolibianakis, and new Junior Deputy Daniela Romualdi28 Focus on Reproduction September 2011

SAFETY AND QUALITY IN ART //Collaboration with the Cochrane groupFollowing the recent committeeelections, we welcomed two newmembers to the SIG steeringcommittee, Arianna D’Angelo andKelly Tilleman. Both Karl Nygren andChristina Bergh were thanked for theirmuch valued contribution to ouractivities, and we hope they continueto participate in the SIG SQART.Our precongress course in Stockholm (on the subject ofpatient centredness) was evaluated positively. About 80people attended and the presentations were judged asgood. Unfortunately, only three patient representativesattended, but there was some stimulating discussion.Future eventsThe programme of the 2012 precongress course is nowfinalised. The course will be organised jointly with the SIGReproductive Genetics and will be titled Getting themeasure of congenital, genetic and epigenetic risks forchildren born following ART: basic and clinical data. Theprogramme hopes to be of interest to reproductivephysicians, embryologists and basic scientists and will dealwith topics such as imprinting, retrotransposons, miRNA.Also featured will be the clinical aspects of epigeneticderegulation in IVF, karyotype abnormalities or othercongenital anomalies in children born after ART, low-birthweight and other long-term health implications of childrenSteering committeePetra De Sutter (BE), Co-ordinatorArianna D’Angelo (GB), DeputyWillianne Nelen (NL), DeputyJan Kremer (NL), Past Co-ordinatorKelly Tilleman (BE), Junior Deputyborn after IVF and ICSI.We also expect high interest in aCampus course scheduled for 2012in Dublin (Edgar Mocanu will beour host) in collaboration with theEUTD Task Force. This will dealwith implementation of theEuropean Tissue and Cellsdirectives, risk management, and quality and safety in theART laboratory, and will include several workshops onapplying the directive and dealing with inspections.Our precongress course in 2013 in London will be basedon the ethical aspects of safety issues and developed jointlywith the SIG Ethics and Law. The programme is still underconstruction, but will deal with the ethical aspects ofintroducing new technologies.Cochrane collaborationThe SIG SQART been asked by the Cochrane group tocollaborate in a project which aims to develop a tool tofacilitate implementation of the evidence from Cochranereviews at all the stages of an ART cycle into daily care.Cindy Farquhar and Willianne Nelen will work together onthis. This represents a high level of interest in the SIGSQART and we hope many ESHRE members will followsuit and join us!Petra De SutterCo-ordinator SIG SQARTwill explore all aspects of AMH - its function within theovary, relationship with follicle number throughout life,and its potential use for assessing ovarian reserve andpredicting the menopause.Business meetingOnly 30 people found their way to the SIG businessmeeting in Stockholm and accordingly one point ofdiscussion was how interaction with the SIG memberscould be developed. All agreed on the importance ofidentifying the needs of SIG members in terms of workshoptype (a science emphasis or a more training/educationalemphasis) and frequency.Overall, the feeling in the group was that workshopnumbers have reached a maximum in the last two years,and that accessibility, costs and expected participantnumbers will need to play a stronger role in deciding thefuture schedule. However, it was agreed that 2012 wouldbe timely for an update workshop on GnRH antagonists inART, following a similar event in 2003 in Brussels. Someproposals for the precongress course in London werediscussed, but no final decision has been reached as yet.Guideline developmentUnder the auspices of the SIG RE and with the support ofNathalie Vermeulen, ESHRE’s full-time researcher on theguideline programme, a clinical guideline on prematureovarian insufficiency (POI) will be developed. POI has beenidentified as a key subject for guideline development.Patients commonly receive inconsistent advice, anddisparate approaches to the management of this disorderexist between subspecialities.A group of experts has now been formed withrepresentatives from gynaecology, pediatrics, genetics,osteology, cardiology, immunology and embryology. Apatient representative will also participate in the guidelinedevelopment group in order to ensure that the patient viewwill be included. In Stockholm a scoping checklist wasfinalised, and hopefully by 2013 the guideline should beready for publication.Georg GriesingerCo-ordinator SIG Reproductive EndocrinologyFocus on Reproduction September 2011 29

SPECIAL INTEREST GROUPS// ANDROLOGY //A new check-list on semen quality available soonOur precongress course inStockholm was on the theme ofLifestyle and male fertility. Ourspeakers presented recent data andopinion from the latest studies on arange of topics from those wellpublicised risks such as obesity,STIs, cancer and recreational drugsthrough to such less discussedtopics as the relationship between exercise (and evenintellect!) with semen quality. The meeting was very wellattended and each lecture generated vigorous discussion.We followed the PCC with our annual business meetingwhere our retiring co-ordinator Roelof Menkveld gave hisfinal annual report and then welcomed the new steeringcommittee. We thank Roelof for his unstinting work andwisdom during his term of office and are very glad he willremain as Past-coordinator to keep us on track! Followingthe elections the steering committee is now composed ofthose listed above. We are delighted that all those electedhave agreed to serve and we look forward to a vibrant SIGunder their leadership.Forthcoming activitiesOur first event is an upcoming Campus workshop inassociation with the SIG Psychology and Counselling onthe theme of The whole man to be held in Seville on 22-23rd September. This joint workshop will ensuremultidisciplinary connections and an opportunity for quitedifferent sectors of the ESHRE membership, fromclinicians, psychologists, infertility counsellors andparamedical staff to embryologists and andrologists; allwith an interest in male fertility can share their knowledge.The workshop has been designed to provide a uniqueopportunity to update social, psychological and medicalknowledge in the area of male infertility. It will discuss theimpact of infertility on men’s well-being and provide anupdate on male infertility, reaching from an overview onmale reproduction to diagnostic procedures and the impactof diagnosis and treatment on men’s psychological wellbeingto current laboratory test procedures and the longtermhealth of children conceived by ART. The venue isbeautiful Seville where we also have a terrific socialprogramme planned. We are looking forward to thedevelopment of new networks and collaborations that willlead to greater understanding of the needs and care of ourmale patients.The SIG Andrology also has an Education and(laboratory) Semen Quality Control sub-committee andClinical Andrology Training sub-committee. In the comingSteering committeeSheena Lewis (UK), CoordinatorWillem Ombelet (BE), DeputyStefan Schlatt (DE), DeputyDavid Mortimer (CA), International AdvisorCharlotte Heavisides (UK), Junior DeputyRoelof Menkveld (ZA) Past Coordinatoryear we aim to promote both thesecommittees actively and developlinks with other European societiesto strengthen our programmes.Goals and future projectsWhen in Stockholm we began ourterms of office with a brainstormingsession on specific goalsfor the next two years. From this meeting and much e-mailing between committee members, we have agreedseveral priorities:l To encourage clinical andrologists (both clinicians andscientists) to make a commitment to active participation inthe SIGA. To this end, we will endeavour to designCampus workshops of interest to each. Already we haveplanned two Campus workshops for the forthcoming year:one on a clinical theme to interest clinical andrologists andurologists (to be co-ordinated by Stefan Schlatt and held inMünster, Germany) and a further one on a scientific/laboratory theme in Thessaloniki, Greece, to be coordinatedby Ulrik Kvist and Sia Zeginiadan. Furtherdetails will be available soon.l To finalise and publish a specific ESHRE guide onseminal quality and improving the accuracy, transparencyand completeness of studies by means of a specific checklistand a flow diagram. The final check-list produced willhave various areas of application: designing andconstructing a seminal quality study, reviewing a paper onthe question, educational purposes, or as an instrument forquality appraisal of research articles in this field. This willbe available soon.l To provide practical training and accreditation in semenanalysis performance to ESHRE standards throughcontinuing ESHRE semen analysis courses. The next willbe the first in the UK- to be held in Birmingham and runby Jackson Kirkman- Brown and Lars Björndahl inassociation with the British Andrology Society on 16-17thSeptember 2011.Sheena LewisCo-ordinator SIG Andrology30 Focus on Reproduction September 2011

PSYCHOLOGY AND COUNSELLING //A first step into Eastern EuropeThe new board was introducedduring the SIG business meeting inStockholm. Chris Verhaak succeededPetra Thorn as Co-ordinator and willfrom now on represent our SIG. JanNorré and Uschi Van den Broeckcontinue as Deputies and our newJunior Deputy is Sofia Gameiro. Wewould like to thank Petra for her input over the past threeyears and wish the new board the best of luck!The main programme in Stockholm provided an updateon the practices of infertility counselling with excellentpresentations by Chris Verhaak and Eric Blyth.Participants in our precongress course enjoyed excellentpresentations on theory and practice ‘in third partyreproduction’. Discussions were plenty and in depth, andgave both researchers and clinicians a chance to interactand exchange experiences. This is after all what aconference like ESHRE is all about! We now look forwardto the new precongress course in Istanbul in 2012 whichwill focus on ‘the burden of treatment’.Our first joint Campus workshop with the SIGSteering committeeChris Verhaak (NL), Co-ordinatorJan Norré (BE), DeputyUschi Van den Broeck (NL), DeputyPetra Thorn (DE) ,Past Co-ordinatorSofia Gameiro (PT), Junior DeputyAndrology will take place in Sevillein September on the theme of Thewhole man. The course is targetedat both medical and psychosocialprofessionals and will introduceparticipants to issues they may notyet have addressed in their dailypractice. It will provide informationand an opportunity for discussion on the needs and waysof providing for the latest psychological and medical careof the infertile man in our clinics.In March 2012 we will move into Eastern Europeanregions with a Campus course in Budapest. The course willfocus on developing competence in psychosocial care andcounselling and is devised for medical and administrationstaff to improve their understanding of the psychosocialneeds of patients in difficult situations - breaking badnews, third party reproduction or loss and bereavement.Special attention will be paid to issues relevant to EasternEurope and to cross-border reproductive care.Uschi Van den BroeckDeputy Co-ordinator SIG Psychology & Counselling// REPRODUCTIVE GENETICS //A new steering committee, and events planned for 2012At our business meeting inStockholm the former steeringcommittee (chaired by StéphaneViville with Deputies Sjoerd Reppingand Filipa Carvalho, Junior DeputyClaudia Spits and Past Co-ordinatorKaren Sermon) handed over to thenew team of Joyce Harper, DeputiesClaudia Spits and Ursula Eichenlaub-Ritter, JuniorDeputy Tania Milachich and Past Co-ordinator StéphaneViville), as seen in the photo.A huge thanks to the outgoingco-ordinators, who have organisedmany fantastic courses andworkshops. These included theprecongress course ‘From genes togestation' (with the SIG EarlyPregnancy), ‘Basic genetics forART practitioners’ in Bucharest,‘Accreditation of a PGD laboratory’(with the PGD Consortium andSteering committeeJoyce Harper (GB), Co-ordinatorClaudia Spits (BE), DeputyUrsula Eichenlaub-Ritter (DE), DeputyStéphan Viville (FR), Past Co-ordinatorTania Milachich (BG), Junior DeputyEuroGentest) in Athens, and‘Comprehensive preimplantationscreening: dynamics and ethics’(with the SIG Ethics and Law) inMaastricht.Our precongress course in 2012is on Known and unknowncongenital, genetic and epigeneticrisks for children born following ART. We are alsoorganising a Basic genetics for ART course in Rome anda quality management meeting inIstanbul. We will also be involvedin the 7th Campus course onmammalian folliculogenesis andoogenesis organised in Stresa,Italy, in April with the SIGEmbryology, SIG ReproductiveEndocrinology, and Task ForceBasic Science.Joyce HarperCo-ordinator SIG RGFocus on Reproduction September 2011 31

TASK FORCES// CROSS-BORDER REPRODUCTIVE CARE //New research projectabout to start, but it’snot too late to joinESHRE’s annual meeting is always a time for strengtheningcollaboration among members and this year was noexception. It is also a time for organisational changes, andso Guido Pennings is now the Co-ordinator of the CrossborderReproductive Care Task Force, whose membershipnow comprises Anna Pia Ferraretti (the new chairman ofthe European IVF Monitoring Consortium), Jacques deMouzon (a new member of ESHRE’s ExecutiveCommittee), Tonko Mardesic, Amparo Ruiz, VeerleGoossens (from ESHRE’s Central Office) and FrançoiseShenfield as Past Co-ordinator (who will co-ordinateESHRE’s SIG sub-committee for the next two years).Data collection on egg donation in EuropeWith our Good Practice Guide for practitioners involvedin cross-border reproductive care now published, 1 ourplans to collect data on egg donors in Europe werefinalised in Stockholm, with the confirmed participation of10 European countries and a study start date in September.Thus, a meeting in Stockholm of Task Force membersand agreed country co-ordinators - whose role is to enrolnational centres performing a large number of eggdonation cycles - found that several members had alreadytranslated the egg donors anonymous questionnaire andwere finalising their list of collaborating centres. Thesecentres have agreed to give the questionnaire to consecutiveegg donors over a 1-4 month period, depending on thenumber of donation cycles they perform, so that aminimum of 10 questionnaires per clinic is obtained.Another questionnaire, on the clinic’s own egg donationactivity, is also required and will be sent to ESHRE’sCentral Office for collation. As an encouragement, anyclinic returning more than 10 egg donor questionnaireswill receive a free annual ESHRE membership to a memberof its team. So, if your clinic is not yet included, pleasecontact one of the mentioned country coordinatorsl Belgium, Petra De Sutter ( Czech Republic, Tonko Mardesic ( Finland, Viveca Soderstrom-Anttilla ( France, Jacques de Mouzon ( Greece, Dimitri Loutradis ( Poland, Rafal Kurzawa ( Portugal, Carlos Calhaz-Jorge ( Spain, Juana Hernandez and Amparo Ruiz(, UK, Siladitya Bhattacharya and Françoise Shenfield( ( for academic and private centresl Ukraine, Valery Zukin ( hope that this project will provide reliable data aboutoocyte donation in Europe. Transparency about practice isthe best way to counter any rumours about misconductthat are frequently found in the media.Françoise Shenfield Past Co-ordinatorGuido Pennings Co-ordinator1. Shenfield F, Pennings G, de Mouzon J, et al. ESHRE Goodpractice guide for cross-border reproductive care for centres andpractitioners. Hum Reprod 2011; 26: 1625-1627.// PREIMPLANTATION GENETIC SCREENING //Mission accomplishedFollowing completion of its pilot study of polar bodyarray CGH for preimplantation genetic screening, theTask Force will be disbanded and its responsibilitiespassed on to the PGS trial study group. This is in linewith ESHRE policy that Task Forces should betemporary groups dealing with specific questions.The PGS Task Force was set up after the annualmeeting in Lyon in 2007, where it became clear thatcleavage stage biopsy and FISH were not reasonableapproaches to PGS. It was then that the idea of a proofof-principlestudy developed. The positive outcome ofthat study is now behind the design of a randomisedclinical trial in women with advanced maternal age. Thetrial has two aims: first, to assess the impact of 24-chromosome polar body PGS on live birth rates; andsecond to estimate whether consistent oocyteaneuploidy in one cycle is predictive of consistentaneuploidy in future cycles.All the prerequisites for a successful trial are now inplace - a sponsor (the Cambridge-based companyBlueGnome, a specialist developer of microarray-basedscreening technologies), the study and training centres,and ESHRE’s data management. Following the move ofMarkus Montag, one of the pilot study co-ordinators,from Bonn to the University of Heidelberg, both siteswill now operate as a joint training and trial centre.Joep GeraedtsTrial co-ordinator32 Focus on Reproduction September 2011

DEVELOPING COUNTRIES & INFERTILITY //The recurring exampleof Mahmoud FathallaIn May this yearEgypt’s ProfessorMahmoud Fathallareceived the degree ofDoctor HonorisCausa from theUniversity of Hasseltin Belgium inrecognition of histremendous researchon the origin andadvantages ofdiversity inreproductive health. Fathalla is recognised thrughout theworld as an exceptional champion of the health and rightsof women in poor countries.We chose this occasion to organise a steering committeemeeting of the Task Force to discuss future activities. Wehave now selected ten pilot countries where accessiblefertility centres will be introduced. With the support ofWHO, we hope to persuade the politicians and healthcareproviders of these countries to get involved in the projectand recognise the severity of involuntary childlessness.In the meantime we finalised the protocol of our firsttrial to examine the value and effectiveness of a newmethod of low-cost IVF; the study will take place at theGenk Institute for Fertility Technology. If the results arereassuring, many other studies will be organised indifferent centres in resource-poor countries.‘Women’s health and diversity’A May symposium on Women’s health and diversity sawSheryl Vanderpoel of WHO stress the essential importanceof infertility care in reproductive health, especially indeveloping countries. She cited the World Population Planof Action 1974 in which the following statement wasmade: ‘All couples and individuals have the basic right todecide freely and responsibly the number and spacing oftheir children and to have the information, education andmeans to do so.’ She also drew inspiratin from M Fathalla:‘Family planning services are not demographic posts.Women are not targets for contraception, from whichpolicy makers and administrators set quotas for services toaccomplish. Family planning programmes work best whenthey are part of, or linked to, broader reproductive healthprogrammes that address closely related health needs.’Guido Pennings also commented on the ethical issues ofinfertility treatment in developing countries. He drew theStudy group meeting on social aspectsof fertility care in developing countriesThe social study group of our Task Force will organisean expert meeting in Genk, Belgium, on 21-22ndNovember 2011, in co-operation with WHO andWalking Egg npo. The meeting will studyl Barriers to infertility care and how to overcome theml Infertility care in times of HIV/AIDSl Quality of care in counselling, patient-staffinteraction, privacyl Ethical concerns and clinical practicel Male involvement in infertility care and masculinityThe meeting will also make an inventory of the currentstate of infertility care in developing countries.following conclusions:l Efforts should be made to reduce excessive socialreactions to infertility inspired by pronatalism.l Infertility treatment should be part of an integratedreproductive care programme which includes familyplanning, mother care, and reproductive health.l Education, empowerment of women and economicprosperity are the most effective solutions to mostproblems related to both population growth and infertility.l Access can be improved by strongly reducing the directcosts of treatment.And Mahmoud Fathalla himself gave a memorablelecture on women’s right to health. He suggested sevenpropositions, which included the right to safe motherhoodand the right to the benefits of scientific progressResearch - Infertility in resource-poor countriesNathalie Dhont, one of the active members of our TaskForce, has successfully defended her PhD at the Universityof Ghent on the Clinical, epidemiological and socioculturalaspects of Infertility in resource-poor settings -Evidence from Rwanda. The most important conclusionsof this very interesting thesis were the following:l A history of sexual violence, HSV-2 infection and HIVinfection are important predictors of infertility in Rwandal Obstetric events, HIV and other STIs contributeapproximately equally to secondary infertilityl The risk of acquiring HIV is increased in infertile couplesl Infertile couples should be targeted for HIV preventionprogrammes and their infertility problems addressed; thiscalls for accessible and affordable infertility servicesl There is an urgent need for political willingness to putinfertility care on the public health agenda in resource-poorcountries.Willem OmbeletCo-ordinator TF Developing Countries and InfertilityFocus on Reproduction September 2011 33

COVER STORYEmbryo selection for IVFIs there a signal in the noise?It has been claimed that vitrification will render embryoselection redundant. Simon Fishel and embryologistAlison Campbell disagree, saying that embryo selection isin the best interests of the patient. They here describe thelatest - and foreseeable - techniques of embryo selectionand propose where their value is likely to lie.34 Focus on Reproduction September 2011

There are few, if any, serious IVF practitioners whowould not support research to improve the efficacyof the technique. Stimulation drugs and protocols,optimisation of endometrial and humoural factors,and assessment of embryo viability are some of theareas of investigation, albeit of high complexity.Why is embryo selection considered to be vital? There aretwo reasons. First is the axiom that embryos are not equalin their capacity to make a viable pregnancy and baby -because fewer than two in ten implant. 1,2 And second, thecurrent system of ‘grading’ embryos according to a range ofmicroscopic morphological criteria - which are either highlysubjective or semi-quantitative and all with varying degreesof apparent correlation to viability - is unsatisfactory. 3The embryo, once in vitro, is an independent entity; it isseparated from the complexity of female physiology anddevelops on a predetermined metabolic pathway. Itsparentally derived genetic make-up and its maternalcytoplasmic composition have predetermining features. Andit is the examination of several aspects of these elementswithin defined culture media which may provide us withmeaningful, quantitative information.‘Meaningful quantitative information’ is perhaps at theheart of the concept of embryo selection. And essentially,we have two options for realising that concept: a binaryoption - that is, the embryo is viable or non-viable, normalor abnormal; or a probability option - that is, a ranking ofone embryo over another, often based on putative datathought to be indicative of a propensity to implantation ordelivery. An example of the former is whether the embryohas monosomy at chromosome 1, or trisomy atchromosome 18. The ranking approach, however, relies onsophisticated algorithms which may or may not have anybiological fidelity and are based on observations postembryotransfer, when the embryos are at the mercy ofcomplex female physiology.Time and tide wait for no (wo)manA recent journal commentary has, by spurious argumentand statistical sophistry, suggested that, because all embryoscan be frozen, there is no need for embryo selection as thiscould ‘never lead toimproved live birthrates’. 4 The argument,as presented by theauthors, was actuallypredicated on selectionbeing essential because‘embryos that arecryopreserved have areduced chance ofimplanting’, but, theysaid, as long as we can freeze and serially transfer allembryos - now that cryopreservation is efficient andendometrial receptivity better understood - ‘the live birthrate per cycle can never be improved’.Yet efficient IVF is about maximising the chance of a livebirth per single attempt - be that per cycle started, per eggcollection or per embryo transfer. Hence, the propositionmisses the mark, because most patients wish to avoidmultiple visits to an IVF clinic - either for reasons of cost,social and emotional stress, or both.Mastenbroek et al do concede that ‘the only parameterthat could possibly be improved by embryo selectionwould be time to pregnancy’. Time in reproductivemedicine is a valuable commodity, and is inversely relatedto reproductive efficiency - indeed, time should be reducedat all cost. So a 35-year-old patient with eight frozenembryos will not be too impressed if on the transfer of thelast embryo her ‘success’ results in a singleton pregnancyfrom an egg collection performed several months or yearsearlier - when, by a method of selection, her success mighthave been gained much sooner.This same patient may well have achieved the 100%success per cycle started which the commentary implied(provided the successful egg collection was the only cyclestarted), but the result might also have been perceived asone live birth per seven attempts (one egg collection andsix embryo transfers). And not to mention that in acountry such as the UK the government regulator (HFEA)must be paid for every attempt, equating to £731.50 forthe seven attempts, as well as the clinic's fees pertreatment. A further point in this stark example is that,should the couple wish for a second child, a much longergap than ideal has been created. Patient age and time tocompletion of their family is critical for optimum success.Selecting viable embryos at each attempt, therefore,should be beneficial to the patient for many reasons. Thisis why for several decades there has been so muchdetermined work by scientists to find ways of doing thiseffectively. Necessity should be the mother of robustscientific innovation!ALISON CAMPBELL, SIMONFISHEL: ‘FOR EMBRYOSELECTION TO BE RELIABLE,WE REQUIRE BOTH THEROBUST TECHNOLOGY ANDITS DIRECT RELEVANCE TOBIOLOGICAL OUTCOME.’Focus on Reproduction September 2011 35

Sadly, however, we are all too well aware of the flawedtechnologies, the flawed analysis and erroneousconclusions, which have deleteriously entered the IVFpsyche - the story of fluorescence in situ hybridisation(FISH) for aneuploidy assessment, for example. And unlessand until a robust technology emerges - such that thecomputed data have high fidelity - any significant biologicalrelevance must always be treated with utmost caution.Thus, if the ploidy of the inner cells mass could be assessedaccurately, the next step should be to ascertain withcertainty that the data have biological relevance. Does ananeuploid inner cell mass indeed beget an aneuploid fetusor result in a miscarriage? Or would an euploid inner cellmass guarantee only euploid babies once the embryoreaches delivery? Or does some astonishing form ofbiological correction out-manoeuvre all our attempts atselection, even with highly accurate information at a precisemoment in time? Thus, for embryo selection to be reliableand enduring we require both the robust technology and itsdirect relevance to biological outcome.Speaking of aneuploidyBecause human oocytes and embryos carry a significantamount of aneuploidy, and because aneuploidy is believedto be the single largest cause of embryo implantationfailure and miscarriage, chromosomal status has become aprime candidate for analysis during IVF. 5 Unlike most otherembryo assessment approaches, aneuploidy has clearclinical relevance, is binary in itsrelationship to biologicalsignificance, and is of highenough prevalence to make it apriority for screening.Just like the ‘polywater story’in the 1960s and 70s, earlyapproaches using FISH became afashion which, unlike polywater,took decades to unravel before itsflaws were appreciablyunderstood. 6,7 IVF history willrecord the use of FISH only inthis failed context, and in thefuture we must avoid similartraps by recognising the weaknessof any new technology, selectivepublishing, meaningless studies,and biased messengers.However, despite the failure ofFISH as it was used and interpreted, the biologicalrelevance and clinical imperative of aneuploidy per se tohuman IVF remains. Logic still determines that byeliminating such embryos each attempt at IVF will be moreefficient; and, in some cases, patients will learn importantinformation about their gametes and embryos, therebyhelping them make progress.In 2008 our group and BlueGnome (Cambridge, UK)pioneered the development of array CGH for clinical use,first in polar bodies and then in blastomeres andtrophectoderm tissue for assessment of the cell’s fullchromosome complement. 8,9 It soon became apparent thataneuploidy assessment could be undertaken within 48 then24 hours, making fresh embryo transfer feasible.We considered polar body analysis initially in the beliefthat, if the oocyte is aneuploid, the embryo will also be(and early studies confirmed this) - though we recognisedthat paternally-contributed and post-fertilisation mitoticaneuploidy would not be detected. But until there isappreciable data on the incidence of mosaicism in theblastomeres of day 3 embryos and the relative risk of falsepositive and negative results, we need to remaincircumspect in the use of blastomere analysis. Similarly,until we fully understand concordance between thetrophoblast, both mural and polar, and the inner cell mass,caution is also needed in the assessment of blastocystaneuploidy. Significantly, the ESHRE PGS Task Force hasAbove, array CGH analysis of polar body 1,correlating to an euploid pattern in thecorresponding oocyte; below, polar body 1correlating to an aneuploid pattern (-7, +14,+18, -19) in the corresponding oocyte.36 Focus on Reproduction September 2011

also backed polar body assessment for its studieson aneuploidy for IVF; 10 the highly importantdata from the randomised trial is muchanticipated.Other platforms such as microarray molecularkaryotyping, SNPs, and (q)PCR are emerging asdependable technologies. However, it is essentialfor commentators to appreciate the variationsand limits of each when making comparisonsbetween them; for example, comparing arrayCGH with metaphase CGH may lead todifferences in chromosome gains because of theinherently greater signal noise in the lattertechnology - thus distorting what might beenvisaged as biological fact.However, these concerns about the fidelity ofthe data will soon be in the past; what isessential to the future of these technologies is the certaintythat the data are of biological relevance. For example,recent studies demonstrate that single chromatid errors areprobably of much greater incidence than meiotic nondisjunctionin human aneuploidy; 11 and that the effect ofadvancing maternal age on aneuploidy is more pronouncedin M2 than previously considered at M1. 12The future of clinical treatment could thus changesignificantly should the reliable assessment of aneuploidybecome routine. For example, now that blastocystvitrification is efficient and successful, by assessing thetrophoblast and by freezing and subsequently transferring asingle euploid embryo, we could maximise singletonpregnancies, reduce multiple pregnancies and potentiallyeliminate OHSS. For those patients with fewer eggs orethical concerns, assessment of the first and second polarbody may remain an option.Finding correlates - the ranking approachCurrently, embryo selection methods rely primarily on amorphological evaluation of the embryo derived from fiveor six single conveniently scheduled observations during itsin vitro development. In many centres, selection of theembryo(s) for transfer tends to be weighted towards itsmorphology just prior to transfer - a single time pointwhich focuses on cell number and the degree offragmentation represented by various grading schemes.Apart from the subjective nature of the assessmentsthemselves, inter-laboratory comparison makes reliabilityvery difficult.The Istanbul consensus workshop on embryo assessmentwas convened by the Alpha Scientists and ESHRE to definecommon terminology and the minimum criteria for oocyteand embryo morphology measurement. 13 It was hoped thateffective comparisons and standardised reporting wouldprovide an evidence-based grading scheme claimed to beassociated with embryo viability (as summarised in the tableabove), and covering all stages of development from theoocyte to the blastocyst. Whilst standardisation is essential,how the adoption of the scoring system will relate toIstanbul consensus on oocyte and embryo morphologyAssessment - topics coveredOocyte, zygote and cleavage-stage embryo scoring defined by Spain's ASEBIRUK ACE grading scheme for cleavage-stage embryos and blastocystsUSA SART scheme for cleavage-stage embryos and blastocystsMolecular and cellular anatomy of the oocyteFertilisation and zygotesCleavage-stage embryosMultinucleationMorulae and blastocystsEmbryology morphology - cell number, fragmentation, cell sizeCumulus-complex scoringZona pellucida, polar body, pervitelline space, ooplasmic and vaculorisation scoringPronuclei scoringoutcome is yet to be determined.There is growing evidence to support the selection ofembryos which display ‘optimal’ morphokineticcharacteristics. But these can be difficult to determinewhen using standard incubation and embryo visualisationmethods when only limited observations are made (both tominimise stress to the embryos and ensure workingconvenience). Furthermore, there is always inter-patientvariability in the timing of these observations, even thoughmany of the developing embryo’s morphological featuresmust be accurately assessed at specific time points; some ofthese, for example, will be directly related to the momentof sperm entry and egg activation. 14,15,16 Hence, althoughthe assessment needs to be performed at strict timeintervals - for example, ‘post-insemination’ - we do not yetknow if these assessments are accurate enough forcomparison between embryos.Recent advances in time-lapse microscopy have resultedin several reports of improved embryo selection based onthe analysis of images of embryo development. TheEmbryoScope, for example, provides time-lapse imagestaken at several planes, allowing the undisturbedassessment of embryos at multiple time points per hourthroughout the entire culture period. Our own(unpublished) assessment of time-lapse microscopysuggests that for some quality indicators, such asTime-lapse microscopy images of the same zygote, demonstrating thediffering appearance of pronuclei just one hour apart.Focus on Reproduction September 2011 37

Examples of current methods for studying embryo viabilityMeasurement Comment Suggested referencesOxygen consumption Embryo culture media Tejera et al 2011; Wiener-Megnazi et al 2011Quantitative amino acid profiling Embryo culture media Sturmey et al 2008Ca(2+)-induced ooplasmic flows Particle image velocimetry Ajduk et al 2011Birefringence imaging Oocyte assessment Montag, Van der Ven 2008Gene expression Discarded oocytes Steuerwald et al 2007Gene expression Cumulus cells Hamamah, Fallet 2010Soluble HLA-G Embryo culture media Warner et al 2008Protein profiling The secretome Katz-Jaffe, Gardner 2008Metabolomics using RAMAN and NR spectroscopy Embryo culture media Nagy et al 2008Metabolomics using HPLC-MS Embryo culture media Marhuenda-Egea et al 2010Light-induced dielectrophoresis Direct embryo measurement Valley et al 2010pronuclear scoring, even strict time-point scoring may notbe enough to support traditional grading because of thedynamic nature of the pronuclei. The two images on page37 illustrate the very different appearance (and grade) of thesame zygote’s pronuclei only one hour apart.The time of the first cleavage related to insemination hasalso been shown to be predictive of both embryo qualityand implantation potential. 17 ‘Early’ cleavage on day 1 hasbeen correlated with poor prognosis when more than twocells result, 18 and even such 'simple’ measurements requirestrict timing, generally considered to be 25-27 hours postinsemination.Insemination method, culture media and incubationconditions may also have an influence on timing of earlydevelopmental events. 19 Transient characteristics, such asmultinucleation, have also been reported to have adetrimental effect on embryo implantation, pregnancy andbirth rates, and these can be missed when embryos arelimited to a single daily observation. 20Time-lapse imaging and analysis are thus powerful tools;they not only ensure that such phenomena are observed andrecorded without disruption to culture, but confirm that thetiming and duration of an event could also be predictive ofoutcome. Wong et al recently demonstrated that theduration of the first cytokinesis and the second cell cyclecan be used to predict development to the blastocyst stagein human embryos. 21 In a retrospective analysis ofEmbryoScope-acquired time-lapse human embryo data, asignificant association was also demonstrated between thetiming of pronuclear fading, the first three cleavage eventsand successful implantation, with an inverse relationshipalso demonstrated between the ability of embryos todevelop to the blastocyst stage and the length of time forzygote division. 22There also now exists a range of metabolomic, proteomicand genomic techniques purporting to assess embryoviability and enhance embryo selection; a slightly dated butuseful overview has been provided by Brison et al. 23 Thetable above highlights some of the areas being investigated.Given the rise and fall of some previously acclaimedmetabolomic tests and their associated algorithms, it seemsthat the aforementioned pitfalls will unfortunately continuefor sometime to come - at the expense of the patient!Summary thoughtsThe best means of embryo selection is non-invasive, eitherby harmless observation of the embryo per se, or analysisof its environs. The information obtained should be precise,and preferably binary; ranking is always likely to createdilemmas and, by definition, reduced efficiency. However,most biological data will inevitably be graduated, andtherefore any ranking would need to generate highlycorrelative data for specific parameters. Ideally, data shouldbe obtained independently of the influential reproductivetract - never an easy task.Thus, we are currently faced with few genuinely usefultechnologies to help practitioners make choices and patientsachieve maximum success at each attempt. The onlygenuine binary data, coupled with known prognostic effectsindependent of the reproductive tract, is ploidy. Hi-fidelityploidy data provide independent biological informationwhich is clinically well understood. Unfortunately, themethodology is invasive and the data are expensive toobtain. However, this same information is relied uponprenatally throughout the world, and with our increasingknowledge of primary embryo ploidy (that is, postconception,as distinct from post-implantation) it shouldbecome an increasingly essential predictor of clinicaloutcome following IVF.Aneuploidy screening remains a clinical imperative; butthe technological imperative is making it more efficient,available and cheaper. In the meantime, we wait withanticipation developments in other non-invasive methodsfor potentially reliable candidates for embryo selection. Inany event, nothing will replace good practice and attentionto the finest detail in all departments of an IVF programme.Simon Fishel is Professor of Human Reproduction and Managingand Scientific Director of CARE Fertility Group, Nottingham, UK.Alison Campbell is Head of Embryology, CARE Fertility Group,CARE Manchester, UK.38 Focus on Reproduction September 2011

References1. SART. Assisted Reproductive Technology Success Rates.National Summary and Fertility Clinic Reports. USA: Centers forDisease Control; 20062. Patrizio P, Kovalevsky G. High rates of embryo wastage withuse of assisted reproductive technology: a look at the trendsbetween 1995 and 2001 in the United States. Fertil Steril 2005; 84:325-330.3. Centers for Disease Control and Prevention, 2008. AssistedReproductive Technology Success Rates: National Summary andFertility Clinics Reports, US Department of Health and HumanServices, Atlanta, 2010. Mastenbroek S, van der Veen F, Aflatoonian A, et al. Embryoselection in IVF. Hum Reprod 2011; 26: 964-966.5. Hassold T, Hall H, Hunt P. The origin of human aneuploidy:where have we been, where are we going. Hum Mol Genet 2007;16: 203-208.6. Mastenbroek S, Twisk M, van Echten-Arends J, et al. In vitrofertilization with preimplantation genetic screening. N Engl J Med2007; 357: 9-17.7. Fragouli E, Escalona A, Gutierrez-Mateo C, et al. Comparativegenomic hybridization of oocytes and first polar bodies from youngdonors. Reprod Biomed Online 2009;19: 228-237.8. Fishel S, Gordon A, Lynch C, et al. Live birth after polar bodyarray comparative genomic hybridization prediction of embryoploidy - the future of IVF? Fertil Steril 2010; 93: 1006.e7-1006.e109. Fishel S, Craig A, Lynch C, et al. Assessment of 19,803 pairedchromosomes and clinical outcome from first 150 cycles of polarbody array CGH for embryo selection and transfer. Submitted forpublication.10. Geraedts J, Collins J, Gianaroli L, et al. What next forpreimplantation genetic screening? A polar body approach! HumReprod 2010; 25: 575-577.11. Gabriel AS, Thornhill AR, Ottolini CS, et al. Arraycomparative genomic hybridisation on first polar bodies suggeststhat non-disjunction is not the predominant mechanism leading toaneuploidy in humans. J Med Genet 2011; 48: 433-437.12. Fragouli E, Alfarawati S, Goodall N, et al. The cytogenetics ofpolar bodies: insights into female meiosis and the diagnosis ofaneuploidy. Mol Hum Reprod 2011;1 7: 286-295.13. Alpha SRM and ESHRE SIGE, The Istanbul consensusworkshop on embryo assessment: proceedings of an expertmeeting. Hum Reprod 2011; 26: 1270-1283.14. Bos-Mikich A, Whittingham DG, Jones KT. Meiotic andmitotic Ca2+ oscillations affect cell composition in resultingblastocysts. Dev Biol 1997; 182: 172-17915. Ozil JP, Banrezes B, Toth S, et al. Ca2+ oscillatory pattern infertilized mouse eggs affects gene expression and development toterm. Dev Biol 20006; 300,:534-544.16. Toth S, Huneau D, Banrezes B, Ozil JP. Egg activation is theresult of calcium signal summation in the mouse. Reproduction2006; 131: 27-34.17. Hesters L, Prisant N, Fanchin R, et al. Impact of early cleavedzygote morphology on embryo development and in vitrofertilisation-embryo transfer outcome: a prospective study. FertilSteril 2008; 89: 1677-1684.18. Hardarson T, Selleskog U, Reismer E, et al. Zygotes cleavingdirectly into more than two cells after 25-27 hours in culture arepredominantly chromosomally abnormal. Hum Reprod 2006; 21:i102.19. Munoz M, Cruz M, Roldan M, et al. Does inseminationmethod, in vitro fertilisation (IVF) or intracytoplasmic sperminjection (ICSI) influence embryo division kinetics? Hum Reprod2011; 26: P-11620. Van Royen E, Magelschots K, Vercruyssen M, et al.Multinucleation in cleavage stage embryos. Hum Reprod 2003; 18:1062-1069.21. Wong CC, Loewke KE, Bossert NL, et al. Non-invasiveimaging of human embryos before embryonic genome activationpredicts development to the blastocyst stage. Nat Biotechnol 2010;28: 111-12122. Cruz M, Perez-Cano I, Gadea B, et al. Time-lapse videoanalysis provides a correlation between early embryo divisionkinetics and subsequent blastocyst formation and quality. HumReprod 2011; 26: P-115.23. Brison DR, Hollywood K, Arnesen R, Goodacre R. Predictinghuman embryo viability: the road to non-invasive analysis of thesecretome using metabolic footprinting. Reprod Biomed Online2007; 15: 296-302.Focus on Reproduction September 2011 39

FEATUREThe embryo as a patientToday, success in IVF is defined not just as a positive pregnancy test, but one with lowcomplication and multiple pregnancy rates. However, there is now growing evidence thatresponsibility in IVF goes much further than that. In May this year ESHRE's SpecialInterest Group in Reproductive Endocrinology held a Campus meeting to explore wherethese limits may lie. A number of renowned speakers posed the question: How does thedevelopmental environment of our patient, the embryo, impact on its long-term health?The meeting’s organiser, Nick Macklon, reports.More than 20 years ago David Barker, an epidemiologistworking in Southampton, showed convincingly in a cohortof men born in southern England (for whom bothmaternity and long-term health records had been kept) thatmarkers of prenatal development predicted the risk of latercardiovascular disease and diabetes. 1 Developing hishypothesis, he proposed that malnutrition and otheradverse environmental exposures during development altergene expression and programme the body’s structures andfunctions for life. This seminal work formed the basis ofthe Developmental Origins of Health and Disease(DoHAD) and of the concept of fetal programming, whichclaimed that diseases of later life - such as coronary heartdisease, stroke, type 2 diabetes and hypertension, and evencertain cancers such as breast cancer - originate throughdevelopmental plasticity in response to malnutrition duringfetal life and infancy.These concepts were supported by observations thatpeople who had been small at birth differed biologically interms of muscle and kidney functional capacity,metabolism and insulin resistance, and hormonal stressresponses. Indeed, even parameters of intellectualperformance were shown to be linked to birthweight.An important development in this work was therecognition that compensatory growth above the normalrate after a period of slow growth, as is frequentlyobserved in small babies, may have detrimentalphysiological and metabolic consequences in later life. Itwas shown that males who were taller at age seven thantheir birthweight and length had predicted were at greaterrisk of premature death than those who had notdemonstrated such compensatory growth. 2The diseases linked to early developmental programmingare among the most important causes of mortalityworldwide, accounting for 60% of all deaths globally. Thekey implications of the DoHAD concept are that thesediseases are preventable, and that the earlier theintervention, the more substantial the risk reduction40 Focus on Reproduction September 2011

Interventions can modify risk, but early interventionsduring the periconceptional period may provide the mostreturn in terms of risk reduction. (With thanks toM.Hanson and K.Godfrey.)Periconceptional nutrition and the embryoThe increasing evidence that programming may begin inthe periconceptional period has profound implications forthose of us caring for couples trying to conceive. And aswith the fetus, the story starts with nutrition.Work by Tom Fleming’s group in Southampton hasdemonstrated that even very short-term changes inmaternal diet in the periconceptional period can have asignificant impact on birthweight. In a mouse model, theyshowed that when blastocysts originating from a motherwho had been fed a low protein diet at conception andblastocysts from a normally fed mother were transferredinto a foster mother fed a normal diet, those which hadbeen exposed to the low protein maternal diet for just afew days around conception were significantly lighter atlate gestation. 3 They also showed that the embryos can‘sense the nutritional environment by upregulating proteinsynthesis rate and by increasing the rate of endocytosis inthe visceral yolk sac’.Maternal nutritional status has also been shown toinfluence the periconceptional establishment andmaintenance of epigenetic marks. A key regulator of thisprocess is the one carbon pathway. Disruption of thisThe relationship between standardised mortality ratio fromcardiovascular disease and birthweight. 1pathway can be caused by inadequate availability offolate resulting in hyperhomocysteinemia. This inturn can lead to failure of appropriate DNAmethylation. Recent studies have shown thatpericonceptional folate levels can also impact onfollicular fluid homocysteine levels, and may reduceoocyte number and embryo quality after IVF. 4Translating these findings into dietaryinterventions, Steegers Thuinissen from Rotterdamworking with our group in Southampton has shownthat a Mediterranean diet richer in folate andvitamin B12 is associated with an increased chance ofpregnancy after IVF (OR 1.4; 95% CI 1.0-1.9). 5 TheRotterdam group has also demonstrated clear beneficialeffects of a periconceptional Mediterranean diet on the riskof congenital heart disease and cleft lip.IVF and the embryoThe DoHAD principles may also be helpful inunderstanding how IVF itself may affect the health of thechildren born after. The crucial periconceptionalestablishment of epigenetic marks occurs during the phaseof in vitro embryo culture. While contemporary culturemedia are designed to mimic the in vivo environment inwhich these key developmental processes occur, the extentto which they achieve this is unknown. The preciseconstitutions of commercial culture media remain closelyguarded commercial secrets, but analytic studies havedemonstrated large variations in basic components such asfolic acid concentrations.Given our increasing understanding of the sensitivity ofthe period of in vitro culture for future development andhealth, the commercial imperatives which currently limitour knowledge of the early developmental environments ofIVF embryos must be balanced with the need tounderstand and optimise this environment for long-termhealth and not just pregnancy rates.The impact of IVF on early growth has been shown tobe small in absolute terms, but, since Barker and othershave shown that the associations between early growthand later disease are not limited to extremes but extendacross the range of birth weight, small absolute effects mayhave measurable long-term consequences.Recently, a Dutch study looked at cardiovascular risk inchildren born after IVF. 6 After correction for confounders,IVF children were found to have a significantly highersystolic blood pressure than spontaneously conceivedcontrols. In a subsequent analysis of the same cohort, IVFchildren were observed to have lower mean birthweight, asFocus on Reproduction September 2011 41

has been previously reported, but also demonstrated aremarkable degree of catch-up growth - which meant thatby one to two years of age the initial differences in weight,length and BMI at birth had disappeared (see figure above).On the face of it, this would appear reassuring, but, aspredicted by Barker, rapid weight gain during earlychildhood in IVF children appeared to be related to higherblood pressure levels at follow-up, independent ofbirthweight, gestational age and height. This study providesan elegant but salutary example of how subsequent catchupgrowth may worsen rather than ameliorate outcomes.However, the periconceptional and perinatalenvironment influence development in other ways.IVF babies have a lower birthweight, length and BMI thancontrols, but demonstrate remarkable catch up growth in thefirst year or two of life. 6The subfertile fetusThe implications of the DoHAD concept for future fertilityare beginning to emerge. Interest in this area has beenparticularly strong in male infertility, whose incidence withother disorders of male reproductive health has been risingin recent years. It is now estimated that one in sixEuropean males demonstrate abnormal sperm counts.Together with other common male reproductive disordersin the male, such as testicular germ cell cancer and lowtestosterone levels, low sperm concentrations are nowconsidered to be part of a ‘testicular dysgenesis syndrome’,which has its origins in fetal life as a result of insufficientandrogen exposure.A simple clinical marker for fetal androgen exposure isthe anogenital distance (AGD) between the anus to theroute of the penis or clitoris. This is around 1.5 timeslonger in boys than in girls. Animal studies havedemonstrated that the AGD correlates with the risk ofcryptorchidism, hypospadias, penis length and testis size inadulthood. Recently, a correlation was found betweenAGD and sperm count in the human. 7 Together, thesefindings point to a ‘masculination programming window’during early fetal life, by which the level of exposure toandrogens at 8-12 weeks determines later reproductivefunction.This window may be disrupted by a number ofenvironmental or lifestyle exposures. Evidence for thisincludes the increased risk of cryptorchidism in boys bornto obese mothers and to mothers who had used high dosesof painkillers such as paracetamol in early pregnancy. Thislatter effect may be explained by rat studies showing thatparacetamol reduces fetal testicular testosterone levels.Morever, maternal smoking during pregnancy has beenshown to reduce sperm counts and testes size. In a recentstudy male fetuses of smokers undergoing termination ofpregnancy were shown to have significantly fewer Sertolicells than those unexposed to periconceptional maternalsmoking. Since each Sertoli cell can support a fixed numberof germ cells, their numbers are key determinants of spermcount. The same group has shown a similar effect ongranulosa cell numbers in female fetuses exposed topericonceptional maternal smoking. 8The impact of smoking on ovarian volume, weight andindeed follicle numbers has been demonstrated in a numberof animal models. This effect appears to be greater thanthat of periconceptional maternal nutritional status. Studieslooking at the effect of periconceptional malnutrition, suchas occurred during the Dutch famine, showed nosignificant impact on markers of ovarian function in theoffspring. However, recent animal studies from our group42 Focus on Reproduction September 2011

geneticists and reproductive epidemiologists to ensureoptimal care for our increasingly complex patients.At the interface of these specialities, a new area ofexpertise is developing. ‘Periconceptional medicine’ is thatnew field in which we meet to ensure the long-term healthof our patients: the sub-fertile couple, and the embryo.Nick Macklon is Professor of Obstetrics and Gynaecology,University of Southampton, UK, and Director of the CompleteFertility Centre, Southampton, UK.Periconceptional medicine is developing at the interface ofrelated specialities.indicate that the high fat western diet may havedetrimental effects on ovarian morphology and folliclenumbers.Treating the embryo as a patientIt is now clear that the most crucial phase of developmentdetermining long-term health takes place in the phase caredfor by reproductive endocrinologists, fertility nurses andembryologists. In other words, us.This realisation greatly increases our responsibilitybeyond achieving a positive pregnancy test in our subfertilepatients. A focus on optimising the conditions inwhich we produce and culture embryos is crucial, but, inorder to truly optimise outcomes, we should also adoptpreconceptional care into our fertility programmes. Anumber of groups, particularly in Adelaide, Rotterdam andour own in Utrecht and Southampton, are now doing this,and beginning to report encouraging results from simplepericonceptional nutritional and lifestyle interventions.As we enter the second generation of IVF, the goal ofwhat we define as success is changing. And as the averageage of women presenting for IVF increases, and theindications for IVF extend beyond fertility treatment toinclude fertility preservation, preimplantation diagnosisand ‘saviour sibling’ treatments, the impact of our field onother specialities is increasing. At the same time fertilityspecialists are working more closely with obstetricians,AcknowledgementsSome aspects of this article are adapted from presentations madeby D Barker, T Fleming, R Sharpe, S Nelson, M Hanson, CCooper, K Tryde Schmidt, R Steegers Thuinissen, C Burger, ASutcliffe and R Norman during the ESHRE Campus meeting on‘The Embryo as a Patient’, held in Winchester, UK, in May 2011.References1. Barker DJ, Winter PD, Osmond C, et al. Weight in infancy anddeath from ischaemic heart disease. Lancet 1989; 2: 577-580.2. Eriksson JG, Forsén T, Tuomilehto J, et al. Catch-up growth inchildhood and death from coronary heart disease: longitudinalstudy. BMJ 1999; 318: 427-431.3. Watkins AJ, Ursell E, Panton R, et al. Adaptive responses bymouse early embryos to maternal diet protect fetal growth butpredispose to adult onset disease. Biol Reprod 2008; 78: 299-306.4. Boxmeer JC, Brouns RM, Lindemans J, et al. Preconceptionfolic acid treatment affects the microenvironment of the maturingoocyte in humans. Fertil Steril 2008; 89: 1766-1770.5. Vujkovic M, de Vries JH, Lindemans J, et al. The preconceptionMediterranean dietary pattern in couples undergoing in vitrofertilization/intracytoplasmic sperm injection treatment increasesthe chance of pregnancy. Fertil Steril 2010; 94: 2096-2101.6. Ceelen M, van Weissenbruch MM, et al. Growth during infancyand early childhood in relation to blood pressure and body fatmeasures at age 8-18 years of IVF children and spontaneouslyconceived controls born to subfertile parents. Hum Reprod 2009;24: 2788-2795.7. Eisenberg ML, Hsieh MH, Walters RC, et al. The relationshipbetween anogenital distance, fatherhood, and fertility in adult men.PLoS One 2011; 6: e18973.8. Lutterodt MC, Sørensen KP, Larsen KB, et al. The number ofoogonia and somatic cells in the human female embryo and fetusin relation to whether or not exposed to maternal cigarettesmoking. Hum Reprod 2009; 24: 2558-2566.Focus on Reproduction September 2011 43

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