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focus onREPRODUCTION

Assessing the evidence for IUI ESHRE newsTwenty years of ESHRE’s PGD Consortium

40 YEARSof test-tube babies -

- and here’s the first

// JANUARY2018

All rights reserved. The opinions expressed in this magazine are those of the authors and/or persons interviewed and do not necessarily reflect the views of ESHRE.

JANUARY 2018

EXECUTIVE COMMITTEE // CChairman Roy Farquharson (GB) // Chairman Elect Cristina Magli (IT)) // Members Basak Balaban (TR), Thomas Ebner (AT), Mariette Goddijn (NL), Borut Kovacic (SI), Nicholas Macklon (GB), Anja Pinborg (DK), Karen Sermon (BE), Thomas Strowitzki (DE), Snežana Vidaković (RS), Rita Vassena (ES) Ex-officio members // Kersti Lundin (SE, Past Chairman), Cecilia Westin (SE, Paramedical Group), Estratios Kolibianakis (GR, SIG Committee)FOCUS ON REPRODUCTION EDITORIAL COMMITTEE // Susanna Apter, Christine Bauquis, Bruno Van den Eede, Hans Evers,Roy Farquharson, Kersti Lundin, Nick Macklon, Juha Tapanainen, Rita Vassena, Anna Veiga, Simon Brown (Editor)FOCUS ON REPRODUCTION is published by The European Society of Human Reproduction and Embryology, Meerstraat 60,Grimbergen, Belgium // www.eshre.eu

AS the cold grip of winter gradually descends on Brussels, activity in ESHREcontinues to keep us all warm and alert. It has been a busy autumn withseveral areas of development bringing change and challenge for the future. Inparticular, the ongoing strategic development of ESHRE to promote visibility,policy initiatives, education and membership has been championed by smallgroups of Executive Committee members to bear fruit in the future.

Impact factors for the ESHRE journals continue an upward trend. Of thefour titles, three will need new Editors-in-Chief before the current editorsretire at the end of 2018. Following advertisement, we are now ready forshortlisting and interviewing candidates in early 2018.

The theme and content for the ESHRE research grant applications for 2018was made available at the end of last year so that members can apply beforethe deadline date of 1 April.

We are also pleased to announce that the Union of European MedicalSpecialists Council (UEMS) gave formal approval for ESHRE to become theDivision of Reproductive Medicine under the section of Obstetrics andGynaecology. This will add further momentum to the planned EuropeanFellowship exam in Reproductive Medicine for clinical sub-specialist traineessupported by EBCOG. The Embryology Certification exam also received aboost from the UEMS assessors who came to study the entire process inGeneva. They noted many positive aspects in transparency, effectiveness,objectivity and efficiency in their report.

While learning facilities for ESHRE members have been traditionally wellsupported, we are often asked why, for example, there is no basic training instatistics. By way of reply, I can report that there are now three learning

tutorials on statistics available to all ESHRE members. Just follow thee-learning button on the ESHRE website.

The Annual Assembly of ESHRE in Geneva heard that fertilityawareness and infertility prevention should hold greater

priority for ESHRE. As a consequence, a Fertility Awarenessworking group under the leadership of Søren Ziebe from

Copenhagen has been set up so that progress can begin and aroad map constructed. In particular, we’re looking for young

members to get involved.November saw a lot of EU activity in collaboration

with DG Sante and associated stakeholders. Thefinalisation of our meeting programme at theCouncil of Europe in Strasbourg scheduled for22/23 February is complete. Registration for thisESHRE-sponsored event, titled ‘Access to anddiversity of medically assisted reproduction inEurope’, is free and your support is warmlywelcomed.

Roy FarquharsonESHRE Chairman 2017-2019

CONTENTS

CHAIRMAN’S INTRODUCTION

// JANUARY 2018

LOOK AHEAD TO BARCELONA 2018 4

IUI: NEW SHINE ON A ROUGH DIAMOND 6

20 YEARS OF THE PGD CONSORTUIUM 8

NEWS FROM THE JOURNALS 10

ESHRE NEWS 16

EIM CONSORTIUM 18

IN PROFILE: ANJA PINBORG 20

GERMANY; TIME TO REVIEW ART LEGISLATION? 27

FROM THE SPECIAL INTEREST GROUPS 28

LAST WORD: FoR FROM PRINT TO DIGITAL 40

FROM BIOLOGY TO EMBRYOLOGY 22Anna Veiga on 40 years in the IVF laboratory

4 Focus on Reproduction // JANUARY 2018

ESHRE’s next Annual Meeting - from 1 to 4 July - willbe held for the third time in Barcelona and for thefourth time in Spain. ESHRE’s 4th Annual Meeting, in1988, took place at the Princess Sofia Hotel inBarcelona with 800 attending; chairmen of thescientific committee were the late Jose Egozcue, whowould become Chairman of ESHRE in 1995, andPedro Barri, who will become an honorary member ofESHRE this year. Still in Spain, the 19th AnnualMeeting was held in Madrid in 2003 under the localchairmanship of Antonio Pellicer and with 4547 inattendance.

Deadlines for abstracts and registrations this year areas in previous years, with all abstracts required onlineat ESHRE’s Central Office before 1 February, and earlybird registrations available up to the end of April. Fulldetails can be found in the table opposite.

As in recent events, Barcelona will be a completely

paper-free meeting run electronically through its ownwireless network. The congress app will provide fullprogramme and abstract details for laptops andmobile devices.

The scientific programme will open with its twousual keynote lectures on Monday morning, with thefirst speaker representing the most downloaded articlefrom Human Reproduction in 2016, followed by apresentation from the Japanese biologist KatsuhikoHayashi. It was Hayashi who reported in 2016 a seriesof experiments culminating in the birth of mousepups derived entirely in vitro from pluripotent stemcells. The work was described as a monumentalachievement, with speculation that, if scientists coulduse a similar technique to transform human stem cellsinto fertile eggs, it could offer wholly new fertilitytreatment or preservation possibilities - even if in thedistant future.

Hola BarcelonaANNUAL MEETING 2018

Barcelona abstract submissions: Must be with ESHRE by 1 February 2018

JANUARY 2018 // Focus on Reproduction 5

consider the effect of lifestyle coaching aspreconceptional care ahead of IVF based on results ofa randomised trial.

ESHRE precongress courses are proving increasinglypopular, with some courses now attracting upwards of500 participants. This year, on Sunday 1 July, there willbe 16 events, a congress record, with courses on malegametogenesis, culture systems for IVF, surrogacy andits ethical implications, assessment of early pregnancy,PCOS, the function and detection of genes ininherited disease, endoscopy, stem cell therapies andfertility preservation. In addition there will be theexchange courses of the ASRM (on the techniques ofembryo transfer) and Middle East Fertility Society,and a course on academic authorship hosted by theESHRE journal editors.

As usual, Barcelona will feature a programme ofsocial events, beginning with the Opening Ceremonyon Sunday 1 July followed by a welcome reception inthe exhibition area. ESHRE will also host its annualcharity run, now in its fifth year and in 2018scheduled for Tuesday 3 July. This will be followedlater in the evening by an ESHRE networking event ata venue yet to be confirmed, with fingerfood, drinksand entertainment. The Closing Ceremony onWednesday afternoon will be marked by awards to thewinners of this year’s seven presentation prizes.

As news reports in this issue of Focus onReproduction suggest, AMH continues to be thehormone of interest in reproduction, but still a lessthan reliable marker of delivery after treatment. Aninvited session on Monday will focus on AMH, withpresentations on how best to measure levels and on itsrole in the pathogenesis of ovulatory disorders.Antonio La Marca, who will present the secondreport, has already made strong claims for the role ofAMH in personalising stimulation protocols.

Tuesday’s programme will begin with the male and aproposal from the distinguished andrologist JohnAitken of a mechanistic basis for the effects of ageing.His fellow-speaker Jörg Gromoll from Germany willconsider the germ cell in the ageing male.

Invited sessions later in the day on Tuesday coverPCOS (first-line treatment) and errors in the IVF lab(‘a true analysis’ from Maria Jose De Los Santos fromIVI in Valencia). It was at last year’s Annual Assemblyof ESHRE members (also on Tuesday this year) thatthe Danish embryologist Søren Ziebe remindedESHRE of its public responsibilities in infertilityprevention. This led ESHRE to the formation of aworking group briefed to consider opportunities,which may be helped by an invited session on fertilityawareness for the public. Lone Schmidt will assess theimpact of various fertility campaigns, while RégineSteegers-Theunissen from the Netherlands will

Main programme Until 2 May 2018 After 2 May 2018 After 20 June 2018Non-member of ESHRE 425,00 525,00 625,00Member of ESHRE 325,00 425,00 525,00Student or paramedical member of ESHRE 175,00 225,00 325,00

Precongress Course Non-member of ESHRE 225,00 325,00 425,00Member of ESHRE 150,00 225,00 325,00Student or paramedical member of ESHRE 75,00 125,00 225,00

* Prices are in euro and VAT is not applicable

REGISTRATION FEES AND DEADLINES FOR THIS YEAR’S ANNUAL MEETING


It was clear from the 20 presentations at this popularCampus meeting that the ‘revival’ of IUI inunexplained and moderate male factor infertility isreal - even if the evidence in favour of its resurgence isno greater now than it was in the doldrum days of 20years ago. But cycle numbers are increasing (if we canbelieve the registries), and indications have nowmoved on beyond the treatment of lesbian and singlewomen.

Anyway, who needs evidence? Egbert te Velde,speaking as an ‘old-timer’ of IUI, attributed the revivalof IUI partly to a more inclusive understanding ofevidence-based medicine and a recognition thatmultiple pregnancies were not - as had been feared -the inevitable outcome. But just how great that revivalhas been we have little chance of knowing fromregistry data. Diane De Neubourg from the Campushost city of Antwerp reported that IUI is much lessfrequently and less completely reported than IVF orICSI, even though cycle numbers (according toICMART data) seem to be increasing year on year. InEurope France seems to be by far the biggestuser of IUI (around 50,000 cycles per yearaccording to ESHRE figures), thoughregistration of IUI cycles elsewhere seemsrarely mandatory.

However, the Cinderella status of IUI seemsno better illustrated than in the patchwork ofevidence for its use. Willem Ombelet, jointorganiser of this meeting, summarised thebottom line of clinical evidence as: ‘If thetubes are open and total motile sperm count isadequate, there’s no reason not to do IUI.’ Thepatchwork of evidence, he added, wasessentially how to improve results. ‘Otherwise,’he said, ‘IUI is proven, it's cost-benefical, andit's of psychological benefit.’

CAMPUS MEETING IUI

The 'evidence' was sifted and analysed by BenCohlen from Zwolle in the Netherlands, who, withOmbelet and others, has been steering an apparentlydistant evidence-based guideline for the WHO. Thequestions for evidence to answer concerned when tostart and in whom, for how many cycles, with orwithout ovarian stimulation, at what point in the cycle,how to prepare semen and how to prevent multiplepregnancies.

On the question of indication, and despite a 2016Cochrane conclusion that ‘we are not able torecommend for or aganst IUI in couples with solelypoor sperm quality’, Cohlen seemed to favour theconclusions of a 2015 multicentre Dutch trial that ‘incouples with unexplained infertility and mild maleinfertility and a prognosis of spontaneous pregnancyof <30% within a year, it is recommended that IUI plusovarian stimulation is the treatment of first choice.’1This conclusion was further underlined in a studyreported at ESHRE last year which found a three-timeshigher live birth rate in couples having clomiphene-stimulated IUI than in expectant managementcontrols. Again, this result seemed at variance with theneutral findings of recent Cochrane conclusions. Sothe evidence ‘partly supports’ IUI, said Cohlen,doctors ‘believe in it’ - and importantly, ‘patients wantit’.

Indeed, further evidence proposed by Cohlensuggested that patient preference (over IVF)would continue for at least three cycles of IUI‘as the most cost-effective option’. Thispreference, he added, seemed unaffected byany risk of multiples, though studies suggestthat to avoid multiple pregnanciesstimulation should be limited to clomipheneor a maximum of 75 IU gonadotrophins, orcancelled in the presence of more than twodominant follicles at the time of hCG.

So much for what we do know. The list ofdon’t knows was reviewed by Aartjan Bijkerkfrom the Netherlands, who found ‘researchgaps’ in cut-off levels of sperm parameters,single or double insemination, the mostappropriate number of IUI cycles (‘three to

A new shine on therough diamond ofreproductive medicineDespite big research gaps, IUI continues tofind favour with clinics. A well attendedCampus meeting in November heard thebest and worst of the evidence.

Ben Cohlen: ‘Doctors believe in it,patients want it . . . ‘


First author of the studyJoukje van Ruijswijk:‘Results sufficientlystrong to render therecommendation for bedrest obsolete.’

CourseorganiserWillemOmbelet: ‘If thetubes are open,there’s noreason not todo IUI.’

six' most common), and semen preparation. Amongthese, said Bijkerk, there was an 'urgent need' forsemen cut-off values and a clear definition (correlatedto treatment) of mild, moderate and severe maleinfertility. Only RCTs could compare IUI, stimulatedIUI and IVF/ICSI in these categorised indications, andthat evidence was lacking.

However, on all these questions Willem Ombelethad a clearer idea of what was a ‘bad’ prognosis than agood one. He listed a duration of infertility of morethan four years, poor sperm quality (a total motilesperm count of 3 million or less), female age over 40,untreated endometriosis and distal unilateral tubalfactor as each associated with a poor outcome in IUI.Moreover, he was confident that ovarian stimulationwas beneficial with IUI in cases of unexplainedinfertility, with endometriosis and in mild male factor(with total motile sperm count was at least 10 million),However, IUI had proved ineffective in cases ofcervical factor.

Ombelet also reported intriguing data from his owncentre in Genk that results seemed better when theIUI was performed by midwives and nurses. Wouldthis, he asked, reflect a lower level of stress or a longerduration of procedure?

He also presented data on when to stop, somewhatfollowing the conclusion of Cohlen ‘that the majorityof pregnancies occur in the first three cycles’ - with asignificant drop in results thereafter. He thus proposed‘a minimum of three cycles for those who have timeup to six (and even nine) cycles’.

Simon Brown

A large randomsied trial whose preliminary resultswere presented at ESHRE's Annual Meeting in 2015has now been published and reports that the practiceof keeping female patients immobilised after IUI hasno beneficial effect on pregnancy rates.1Immobolisation was, however, according to AartjanBijkerk in Antwerp, one of several ‘research gaps’casting a shadow over IUI, which this trialapparently had not yet removed.

Its results, which were based on 498 couplesdiagnosed with unexplained or mild malesubfertility, were contrary to those reported byanother study of 2009. This, said Bijkerk, hadmerited testing by a larger RCT but now also raiseda question mark over the validity of results.2

In this second trial patients were randomlyassigned to 15 minutes of immobilisationimmediately after insemination or to immediatemobilisation. Results showed comparablecumulative ongoing pregnancy rates per couple ineach of the two groups (32.2% in the immobilegroup and 40% in the mobile group). Thesedifferences were not statistically significant, despitethe trend, indicating no benefit from a brief periodof bed rest after insemination. ‘In our opinion,’ saidfirst author Joukje van Rijswijk from Amsterdam,‘immobilisation after IUI has no positive effect onpregnancy rates, and there is no reason why patientsshould stay immobilised after treatment. We believeour results in such a large randomised trial are solid,and sufficiently strong to render therecommendation for bed rest obsolete.’

Bijkerk, however, described the quality of evidenceas ‘moderate’, no doubt in recognition of theinconsistent results of the two trials, and said theresearch gap persisted.

1. Van Rijswijk J, Caanen MR, Mijatovic V, et al.Immobilization or mobilization after IUI: an RCT. HumReprod 2017; doi.org/10.1093/humrep/dex302.2. Custers IM, Flierman PA, Maas P, et al. Immobilisationversus immediate mobilisation after intrauterineinsemination: randomised controlled trial. BMJ 2009; 339:b4080

Practice of short bed restafter IUI ‘not justified’,after RCT finds no benefit

IUI is a cost-effective first-line treatment for unexplainedand moderate male infertility

No single predictor of outcomeWell timed IUI with ovarian stimulation in a well selected

population (40 yrs or under, endometriosis treated, adequatesperm parameters) for at least three cycles can result incumulative pregnancy rates of 40-50% (six cycles)

IUI should be cheap, non-invasive, safe, patient-friendlyMajor risk = multiplesMore RCTs needed

Take-home messages

Already, said Santiago Munné, technology for PGSanalysis has moved on from version 1 to version 2 andnow to version 3. V3, he explained, would be NGS andnon-invasive methods through the analysis of usedculture media. Thus, the prevalent pattern ofaneuploidy testing - in the US at least - is now wholegenome sequencing with blastocyst (and never day 3)biopsy. One of the most recurring slides shown at thismeeting was the conclusion of Scott et al from theirpersuasive 2013 report that cleavage-stage biopsy‘impairs implantation potential’, while blastocystbiopsy does not.1 Hopes for non-invasive PGS wouldlie with the genome sequencing of used culturemedium, reportedly safer for the embryo and lessexpensive than biopsy techniques.

Moreover, said Munné, NGS will detect mosaicsbetter than any other method, 40% of which ‘canresult in an ongoing pregnancy compared to 50-70%of euploid’. Thus, he proposed a new ‘paradigm shift’in the classification of embryos: as normal, abnormalor mosaic, a scheme with a virtually non-existent errorrate and a likely mosaic rate of around 20%. ‘This way,’said Munné, ‘we wouldn't discard embryos with anychance of implanting.’

Also speaking at this symposium were all the pastChairs of the PGD Consortium, as well as an A-list ofthose who helped develop the science. The

It is now 20 years since the PGD Consortium wasfounded at ESHRE's 1997 Annual Meeting inEdinburgh (a meeting, it was noted, that hosted nosessions on genetics in fertility treatment). Accordingto Céline Moutou, chair of the Consortium's databaseworking group, data collection has been not only itsfirst declared aim but since then its greatest challenge,a ‘saga’ made all the more Odyssean by an ever-increasing number of reported cycles and aninadequate system to process the data. Thus, as thedelay between data submission and publication grewand the processing system shifted from paper todigital, those annual reports would become between2011 and 2015 two-year summaries. Now, with anonline system in place, hopes are that datasubmissions for 2017 will be with ESHRE by Marchthis year and ready for process.

Nevertheless, despite such challenges, Célinereported that a total of 57,000 PGD and PGS cycleshave been reported over these 20 years, with around10,000 babies born. Delivery rates, she added, haveimproved over time to around 25% per transfer, withfemale age and indication the greatest determinants ofsuccess. The data, said Alan Handyside, theConsortium’s first Chair, have had a ‘huge impact inestablishing the clinical validity of PGD’.

But beyond the data, this Campus meeting reallyshowed from a 20-year history the remarkable speed atwhich change and development in the field have takenplace. Of course, the structure of the meeting lent itselfto such a view, with applicable sections (counselling,embryo culture and freezing, biopsy, testing, andsafety) considered from a past, present and futureperspective. But appealing though they were, thoseglimpses from the past now seemed like tales fromancient history: Luca Gianaroli's protocol notesscribbled on the back of an envelope (indeed, asnostalgic as the photo of his 1980s hair cut), and AlanHandyside, filmed by the BBC shortly after his firstPGD report, removing a blastomere with the guidingpipette held between his lips like an unlit cigarette.Three hours of struggle, said Handyside, shrunk bythe BBC into just a few minutes.

Time moved on so rapidly, though the biopsyremained a constant focus throughout these twodecades: when to biopsy (polar body stage, cleavagestage, blastocyst?); how (FISH, arrays, NGS?); why(PGD, PGS?); and is it safe?


Alan Handyside, theConsortium’s first

Chair: ‘A hugeimpact on

establishing clinicalvalidity.’

How the past has shaped the futurePGD CONSORTIUM

The ESHRE PGD Consortium celebrated its 20thanniversary with a Campus symposium in Decemberattended by more than 200 participants

PGSproceduresfromversions 1and 2 toversion 3,accordingto SantiagoMunné.

Consortium's third Chair, Joyce Harper, paid tributeto ESHRE’s continued support. ‘Going right back toour very first meeting at Central Office,’ she said, ‘wecouldn’t have survived without ESHRE. Datacollection and analysis, meetings, working groups, ourown scientific officer, a journal to publish in . . . ‘

Despite the ongoing output, however, it was notalways plain sailing. ‘We created guidelines, datareports and controversy,’ said Joyce, referring notsurprisingly to the huge debates on the viability ofPGS and evidence for its role as a routine interventionto improve IVF results. Yet by the end of this meeting,as the whole affair was thrashed out yet again in adebate on the European and US approaches to PGS,there seemed less divergence between the two viewsthan ever before.

Consensus appeared to be that infertile coupleshoping to improve their chance of pregnancy withPGS should be informed of all the facts - advantagesand disadvantages - before making their owndecision. Thus Gary Harton, a former Chair of theConsortium, when asked to define the ‘advantages’,ignored the former attractions of higher delivery andimplantation rates but confined his list to a lowerchance of miscarriage and a reduced time to

All Chairs from the Consortium’s 20-year history spoke at themeeting. From left, Joanne Traeger‐Synodinos, Gary Harton,Martine De Rycke, Joep Geraedts, Karen Sermon, AlanHandyside, Joyce Harper and Edith Coonen.


pregnancy, both likely benefits for women of anadvanced maternal age. ‘PGS can't make an embryobetter,’ said Harton. ‘Maybe in the US we did go toofar in saying that everyone would benefit from PGS.’Dagan Wells, who despite Brexit was inexplicablyspeaking with Harton on behalf of the USA, seemedto agree, accepting that the data were plentifulenough and that patient choice could and should beadequately informed.

And this conclusion seemed too to be shared by theEuropeans, who quickly discarded their Yankeedoodle dandy outfits (‘We all used to be Americans’)in favour of a more cautious ‘holistic’ approach.Paying due respect to last year’s three big trials (Rubioet al, ESTEEM and STAR) Willem Verpoest from theBrussels group agreed that a few patients might wellbenefit from PGS. ‘I think PGS with small advantagescould be part of a programme for some patients,’ saidVerpoest, 'But we have to look at a broad picture ofIVF in which PGS is there not just for those who canafford it, but really for those who need it.’ Right now,especially in view of the Rubio trial, the PGSadvantage seems to be concentrated on a reducedmiscarriage risk, fewer transfers, and a shorter time topregnancy.2

So, if as Joyce Harper claimed, the PGD Consortiumhas produced its share of controversy, as well asguidelines and data reports, harmony finally seemed alittle nearer at this meeting, in a more vocalunderstanding that PGS can't improve the quality ofan embryo and that any advantage is probably moresubtle and selective than delivery rate alone.

It was noticeable too that many of the speakers hadquickly adapted to the new nomenclature of ART andwere seamlessly referring to PGT-A and PGT-Mwithout relapse to PGS or PGD. So what next for theConsortium after 20 years? The PGT Consortium,and a new era of consensus?

Simon BrownFocus on Reproduction

1. Scott RT Jr, Upham KM, Forman EJ, et al. Cleavage-stagebiopsy significantly impairs human embryonic implantationpotential while blastocyst biopsy does not: a randomized

and paired clinical trial. Fertil Steril 2013;100: 624-630.2. Rubio C, Bellver J, Rodrigo L, et al. Invitro fertilization with preimplantationgenetic diagnosis for aneuploidies inadvanced maternal age: a randomized,controlled study. Fertil Steril 2017; 107:1120-1129.

‘We all used to beAmericans.’ Edith Coonenand Willem Verpoest beforeremoving their US outfits inthe PGS debate in favour ofa more restrained Europeanstyle. Joyce Harper, below,singled out the controversyover PGS as one feature ofthe Consortium’s history.

oversight have been met.‘Regulators, funders, scientists and editors need to

continue working together to define the details ofthe path forward for germline genome editing,’ theNature editorial concludes.

1. Fogarty NME, McCarthy A, Snijders KE, et al. Genomeediting reveals a role for OCT4 in human embryogenesis.Nature 2017; 550: 67-73.2. Take stock of research ethics in human genome editing.Nature 2017; 549: 307.

In a remarkably short period of time the genomeediting technique of CRISPR-Cas9 has been used toidentify the necessary role of the pluripotencytranscription factor OCT4 in human embryogenesis.1By ‘efficiently and specifically’ deactivating the geneencoding OCT4 in diploid human zygotes, a largegroup of international scientists collaborating withKathy Niakan from the Francis Crick Institute inLondon found that blastocyst development wascompromised; by contrast, presence of the geneensured that blastocyst development was established.

As a conclusion to the study, the group explainedthat CRISPR–Cas9-mediated genome editing is apowerful method for investigating gene function inthe context of human development. ‘One way to findout what a gene does in the developing embryo is tosee what happens when it isn’t working,’ Kathy Niakanexplained to the Reuters news agency. ‘Now we havedemonstrated an efficient way of doing this, we hopethat other scientists will use it to find out the roles ofother genes.’

To test if OCT4 is required in human embryos, thegroup performed CRISPR–Cas9 editing on thawedsurplus IVF zygotes. The gene encoding OCT4,POU5F1, is first transcribed at the 4-8 cell stage.coincident with embryo genome activation. Thus, bythe eight-cell stage, cleavage arrest was observed in62% (23 of 37) of the targeted embryos compared to53% (9 of 17) of the control embryos. These effects arereported as ‘due to the loss of OCT4’.

The implications of the study - that genome editingcan be used efficiently to modify the DNA of a humanembryo - prompted an editorial in Nature ‘to takestock and discuss how they should navigate this typeof research’.2

The question at the heart of the debate, as has beenreported here before, is that scientists can now makepermanent modifications to the human germ line. Astatement from the US National Academies of Science,Engineering, and Medicine, summarised at the ESHREAnnual Meeting by Robin Lovell-Badge, advised thatediting the human germ line could be justified for thescientific purpose of research into fundamentalbiology. Clinical applications might only be consideredafter requirements of strong research groundwork and

CRISPR-Cas9: A guide RNA designed to target a specific sequence of DNAdirects the Cas9 system to the target DNA. Cas9 is then able to cut out the

mutant DNA sequence and deactivate the offending gene.

CRISPR-Cas9technologyidentifies genenecessary forembryogenesis

NEWS FROM THE JOURNALS

More studies to change point mutations The OCT4 report appeared in Nature just two months after ShoukhratMitalipov of the Oregon Health and Science University had describedcorrection of a mutation causing the heart condition, hypertrophiccardiomyopathy, using the CRISPR-Cas9 technology.1 ‘Every generation onwould carry this repair because we've removed the disease-causing genefrom that family's lineage,’ Mitalipov told the press.

The claim has since been disputed, with one group of scientists saying theresults of the study only show ‘an absence’ of the disease-causing mutation,not a repair.2 Mitalipov has promised to respond.

Meanwhile, what appears to be an advance on the CRISPR-Cas9technology has been partially successful in changing the base pair.3 ‘We arethe first to demonstrate the feasibility of curing genetic disease in humanembryos by base editor system,’ said the Chinese researchers.

The experiment took nuclei from skin cells taken from a patient with beta-thalassaemia, and inserted them into empty donor eggs (by somatic cellnuclear transfer), thus creating human embryos carrying the mutation.They then scanned the 3 billion base pairs DNA in the embryos for thespecific beta-thalassaemia point mutation, and changed it back to its correctsequence using an enzyme.

The paper drew the usual share of cautious comment. However, just weeksafer this first DNA surgery paper had appeared in Nature, two furtherdevelopments were reported, each claiming to be a further advance on the‘blunt instrument’ of CRISPR technology.

Two research groups, each from the Broad Institute of MIT and Harvardin Massachusetts, announced techniques that allow targeted alterations toDNA and RNA.

In what Science called ‘a new frontier’ for the CRISPR technology, editing


ongoing pregnancies, 11 (6%) led to biochemicalpregnancies, and 10 (5%) spontaneously miscarried.All (100%) of these blastocysts had mtDNA levelsconsidered to be normal/low. This left 57 embryoswhich failed to implant, including the nine with highmtDNA levels.

This meant that the ongoing pregnancy rate formorphologically good, euploid blastocysts, withnormal/low levels of mtDNA was 64%. In contrast,the ongoing pregnancy rate for the same type ofembryos but with elevated mtDNA levels was 0/9(0%). This difference was highly statisticallysignificant (P <0.0001).

The results, say the authors, ‘provide furtherevidence that mtDNA quantification has thepotential to serve as a new biomarker of embryoviability’, adding that a higher mtDNA level wasaccompanied by implantation failure in all cases inwhich it was detected.

However, the authors also note that other studiesover the past two years have not always been able toreplicate these results, finding no associationbetween mtDNA quantity and implantationpotential. This ‘controversy’ has been somewhatplayed out in the journals, with Fragouli et al hereexplaining the discrepancies by ‘technical issues’ and‘clinic-specific factors’. They thus remain a littlecircumspect in their conclusions, noting that mtDNAquantification ‘has the capacity’ to identify a subsetof blastocyst stage embryos with highly impairedimplantation potential. They also note that anexplanation why some non-viable blastocysts exhibitelevated mtDNA levels ‘remains to be determined’.

Thus, Dagan Wells, one of the authors of this study,reiterates in a Fertility and Sterility opinion piece thatnot all studies of mtDNA in human embryos havebeen able to detect the pattern seen here, adding that‘further work is needed in order to categoricallyconfirm or refute its existence’, ultimately, anotherrandomised trial.3

1. Fragouli E, Spath K, Alfarawati S, et al. Altered levels ofmitochondrial DNA are associated with female age,aneuploidy, and provide an independent measure ofembryonic implantation potential. PLoS Genet 2015;11:e1005241.2. Fragouli E, McCaffery C, Ravichandran K, et al. Clinicalimplications of mitochondrial DNA quantification onpregnancy outcomes: a blinded prospective non-selectionstudy. Hum Reprod 2017; 32: 2340-2347.3. Wells D. Mitochondrial DNA quantity as a biomarker forblastocyst implantation potential. Fertil Steril 2017; 108:742-747.

Two years after Elpida Fragouli and colleagues raisedthe potential of mitochondrial DNA quantification asa marker of embryo viability in IVF, the same grouphas now confirmed their findings in a blindedprospective study with highly significant results.1,2

The results, which were presented in preliminaryform at ESHRE’s 2016 Annual Meeting, replicate whatthe earlier studies had suggested - that euploidblastocysts of good morphology but with highmtDNA levels have a greatly reduced implantationpotential. Such a relationship, the investigatorssuggest, would thus partly explain the paradox that atleast 30% of chromosomally and morphologicallynormal embryos fail to produce an ongoingpregnancy. This latest study is the first test of mtDNAquantification in a prospective, blinded study.

The study was a mtDNA analysis of 199chromosomally and morphologically normalblastocysts of which nine (5%) contained unusuallyhigh levels of mtDNA. Of the others, 121 (60%) led to

RNA would remove some of the ethical concerns about DNA editing.4 Thestudy authors developed a new version of the DNA cutting enzyme - calledCas13b - to correct multiple mutations, which, they say, might not alterdisease risk alone, but combined might have additive effects and disease-modifying potential.

The second report describes new developments in rewriting individualbase pairs of DNA.5 This ability to alter single bases, says Nature, means thatresearchers can now attempt to correct more than half of all human geneticdiseases. ‘These new techniques are more like precision chemical surgery,’added David Liu, a chemical biologist at the Broad Institute.

The first reported base editor system could achieve only two kinds ofchemical conversions: a cytosine (C) into a thymine (T) or a guanine (G)into an adenine (A). The latest technique works in the other direction,converting T to C or A to G. It can therefore undo the most common typesof ‘point mutation’, which involve single aberrant bases.

1. Ma H, Marti-Gutierrez N, Park S-W, et al. Correction of a pathogenic genemutation in human embryos. Nature 2017; 548: 413-419.2. Egli D, Zuccaro M, Kosicki M, et al. Inter-homologue repair in fertilized humaneggs? BioRxiv 2017: doi.org/10.1101/181255.3. Liang P, Ding C, Sun H, et al. Correction of β-thalassemia mutant by base editor inhuman embryos. Protein Cell 2017; doi.org/10.1007/s13238-017-0475-64. Cox DBT, Gootenberg JS, Abudayyeh OO,. et al. RNA editing with CRISPR-Cas13.Science 2017; http://dx.doi.org/10.1126/science.aaq01805. Gaudelli NM, Komor AC, Rees HA, et al. Programmable base editing of A•T to G•Cin genomic DNA without DNA cleavage. Nature 2017;http://doi.org/10.1038/nature24644.

responsible for inheritable disease

High levels of mitochondrial DNA predict failedimplantation in chromosomally normal embryos

Previous findings confirmed in first prospective blinded study


First author ElpidaFragouli: moreevidence that

mtDNA is a ‘newbiomarker’ of

embryo viability.


A study aiming to determine thefinancial, demographic and culturaldeterminants of ART treatments inEurope has found that the ‘normativecultural acceptance of ART’ is themajor driver, above and beyonddifferences in a country’s wealth,demographics and religious composition.

The findings were based on a study ofmore than 30 European countries in 2010,where prevalence of ART uptake wascross-linked to demographic and cultural

factors.1Although the analysis showed that a 1%

increase in national GDP was indeedassociated with 382 additional ARTprocedures per million women ofreproductive age, this was reduced to 99when cultural and demographic factors

were accounted for. A one-pointincrease in ‘average approval’ ofART in a country was associatedwith 276 additional treatments permillion women of reproductive age.

1. Prag P, Mills MC. Culturaldeterminants influence assistedreproduction usage in Europe more thaneconomic and demographic factors. HumReprod 2017; doi:10.1093/humrep/dex298.

Acceptance of ART more thanGDP determines uptake

credibility, thus suggesting that ‘it may be necessary toreevaluate what an AMH level really means for awoman’s reproductive health’. What the author clearlyhas in mind - as has the JAMA press release - are‘commercial applications by the entrepreneurial sector’.

‘Some websites,’ the commentary notes, ‘offer fertilityassessment . . . and if AMH, among other tests,indicates low ovarian reserve, referral to a fertilityspecialist or egg freezing is recommended. Such athought process assumes that a lower-than-normalnumber of remaining ovarian follicles may suggest alower likelihood of future fertility.’

Lead author Anne Steiner told the Reuters newsagency that, while ‘these blood tests do predict howwell a woman will respond to fertility treatment, theydo not predict her likelihood of conceiving naturally.This challenges the clinical dogma that diminishedovarian reserve is a cause of infertility.’

In IVF, female age has long been considered themost accurate predictor of ongoing pregnancy, withAMH (and AFC), added to age, useful predictors ofresponse to stimulation, especially poor response.

1. Steiner AZ, Pritchard D, Stanczyk FZ. Association betweenbiomarkers of ovarian reserve and infertility among olderwomen of reproductive age. JAMA 2017; 318: 1367-76.2. Santoro N. Using antimüllerian hormone to predictfertility. JAMA 2017; 318: 1333-1334.

There was never any strong evidence that anti-müllerian hormone was effective as a marker offertility. Studies suggested that it was useful as apredictor of response to ovarian stimulation for IVF,and possibly of menopause onset, but never a markerof pregnancy or delivery.

Yet a press release issued by JAMA highlighting astudy of AMH as a marker of fertility claims that‘biomarkers of ovarian reserve are being promoted asmarkers of reproductive potential’.1 The study, infinding no association between time-to-pregnancy andlevels of AMH, advises that ‘women should becautioned against using AMH levels to assess theircurrent fertility’.

The study, which took place at the University ofNorth Carolina at Chapel Hill, was a prospectivecohort study starting in 2008 of 750 women aged 30-44 years with no history of infertility. They had allbeen trying to conceive for three months or less. Fromblood samples taken at baseline (and with adjustmentfor BMI, smoking and age), follow-up showed thatwomen with low AMH (<0.7 ng/mL) did not have asignificantly different predicted probability ofconceiving by six cycles (65%) from women withnormal values (62%) - or after 12 cycles of trying.Similar results were found for inhibin and FSH values.

An accompanying editorial confirms that AMHmeasurement has been part of the clinical evaluationof infertility for more than a decade, and that‘knowing a woman’s AMH before she beginsstimulation is helpful in medication management’.2Low AMH levels, adds the commentary, might helpthe physician proceed with a more aggressive protocol,but remain a poor indicator for live birth.

The commentary goes on to note that the large sizeof the North Carolina study, its community-based‘robust’ measurement methods give the findings much

AMH ‘a poor prognostic indicator of live birth’ . . .Study finds conception probablity no different with low or normal levels of AMH


poor responders trial, where upward adjustments ofdose (to a maximum of 450 IU per day) made nodifference to outcome - 42% cumulative LBR in theindividualised dose group and 45% in the standard150 IU group, thereby confirming that ‘high dosagesof gonadotrophins will not improve IVF outcomes inpredicted poor responders’.

This trial and the cohort study also found that theindividualised approach was more expensive than thestandard - but did reduce the occurrence of mild andmoderate OHSS in predicted hyper-responders, andsubsequently the costs for management of these OHSScategories.

1. Van Tilborg TC, Oudshoorn SC, Eijkemans MJC, et al.Individualized FSH dosing based on ovarian reserve testingin women starting IVF/ICSI: a multicentre trial and cost-effectiveness analysis, Hum Reprod 2017;doi:10.1093/humrep/dex321. 2. Van Tilborg TC, Oudshoorn SC, Torrance HL, et al.Individualized versus standard FSH dosing in womenstarting IVF/ICSI: an RCT. Part 1: The predicted poorresponder. Hum reprod 2017; doi:10.1093/humrep/dex318 .3. Oudshoorn SC, Van Tilborg TC, Eijkemans MJC, et al.Individualized versus standard FSH dosing in womenstarting IVF/ICSI: an RCT. Part 2: The predicted hyperresponder. Hum Reprod 2017; doi:10.1093/humrep/dex3.4. Nyboe Andersen A, Nelson SM, Fauser BCJM, et al.Individualized versus conventional ovarian stimulation for invitro fertilization: a multicenter, randomized, controlled,assessor-blinded, phase 3 noninferiority trial. Fertil Steril2017; 107: 387–396.

The OPTIMIST study, a large prospective studyperformed in the Netherlands in which tworandomised trials were embedded, indicates thatindividualised FSH dosing based on antral folliclecount makes no overall difference to outcome whencompared with a standard protocol.1 The sameconclusion was reached in each of the two embeddedRCTs, where dose was adjusted for predicted poor orhyper-response.2,3 In the latter trial, however, a lowerFSH dose did reduce the incidence of mild andmoderate OHSS, but had no impact on severe OHSS.

The results of the studies were presented inpreliminary form at ESHRE's 2016 Annual Meeting inHelsinki, where an individualised approach tostimulation for IVF was a notable feature ofproceedings. The ESTHER trial, for example, alsodescribed in Helsinki, similarly found comparableoutcomes (‘non-inferior’) and a lower incidence ofcomplications when individualised dosing wasstratified according to AMH and other baselinecharacteristics and compared to a standard approach.4This and other studies were deemed by the OPTIMISTinvestigators as of ‘no sound evidence’ for thewidespread practice of dose adjustment based onovarian reserve - hence the need for their trial.

The study was performed between 2011 and 2014,with subjects allocated to the cohort study or two trialsdepending on their baseline AFC: predicted poorresponse trial (RCT1) AFC 0-7 and 8-10; predictedhyper-response (RCT2) AFC >15; or the cohort (AFC11–15). In both the RCTs subjects were randomised toan individualised dose of FSH (RCT1 450 or 225 IU;RCT2 100 IU) or to a standard FSH dose (150 IU).Women in the normal cohort all received the standarddose of 150 IU. A total of 1515 women were includedin the study, with roughly a third in each of threearms.

The authors state by way of background thatcurrently AFC and serum AMH are ‘the most practicaland reliable ovarian reserve tests available’ and aremost often used for personalised dose adjustment indaily clinical practice. However, based on their results- 56% cumulative LBR in the individualised strategyand 58% in the standard - they now caution that‘individualized FSH dosing for the IVF/ICSIpopulation as a whole should not be pursued as it doesnot improve live birth rates’ and increases costs.‘Women scheduled for IVF/ICSI with a regularmenstrual cycle are therefore recommended astandard FSH starting dose of 150 IU per day.’

These results were especially evident in the predicted


. . . while an individualised approach based onAFC makes no difference to cumulative birth rate

High doses of FSH ‘will not improve outcomes in predicted poor responders’

First author Charine van Tilborg presenting results of the OPTIMISTtrial in Helsinki. The published study report now cautions that

‘individualized dosing as a whole should not be pursued as it does notimprove live birth rates’.


Numbers of embryos transferred in all US transfers infresh non-donor cycles in 2015: CDC data.

Single embryo transfer was linked to a10-15% lower live birth rate than doubleembryo transfer but a 47% lowermultiple birth rate in a new analysis ofUS ART data submitted to SARTbetween 2204 and 2013.1 The findings,says SART, ‘present an opportunity toincrease the rate of SET across theUnited States and thereby reduce themultiple birth rate and its associatedpoor perinatal outcomes’.

Similar sentiments are echoed in anaccompanying journal editorial, whichlists improvements in embryo selection,more blastocyst transfers andcumulative outcomes with sequentialSET as likely ‘to convince physicians,patients, and insurance providers of thebenefits and feasibility of SET’.2 Ahealthy singleton delivery should be thegoal of all IVF cycles, and ‘this is bestachieved by SET’, the editorial says.

The study population of the SARTanalysis included more than 200,000women having fresh autologous ordonor IVF, or subsequent frozen cycles.In those with a favourable prognosis -defined as younger maternal age, withblastocyst transfer, and additionalembryos cryopreserved - the gain in thelive birth rate from SET to DET wasaround 10–15%; however, the multiplebirth rate increased from approximately2% to greater than 49% in bothautologous and donor fresh andfrozen–thawed transfer cycles.

The study also made other findingswhich in the report are presented as‘predicting high pregnancy rates withSET’: maternal age, blastocyst transferin fresh cycles, and additional embryosfor freezing. For example, when noembryos were frozen in both cleavage-stage and blastocyst transfers, the LBRwas lower and declined with advancingmaternal age than with transfers inwhich embryos were frozen.

However, the editorial describes the

decline in LBR between SET and DETtreatments as ‘not attractive to eitherphysicians or patients, for whom IVFpregnancy rates matter a great deal’. Suchsentiments no doubt account for thecontinuing high twin delivery rate in theUSA, which SART says have been risingsince 1980, reaching an all-time high of23% in 2014.

As a result, the ASRM earlier this yearrevised its guidelines on embryo transferto call for SET for women under the ageof 38 with a favourable prognosis.3However, according to this latest SARTreport, in 2012 the average number ofembryos transferred was 1.9 in womenaged <35 years, 2.2 in women aged 35–40years, and 2.7 in those aged >40 years.The US rate of eSET in patients aged <35years) was 15.3%.

1. Mersereau J, Stanhiser J, Coddington C, et al.Patient and cycle characteristics predicting highpregnancy rates with single-embryo transfer: ananalysis of the Society for AssistedReproductive Technology outcomes between2004 and 2013. Fertil Steril 2017; 108: 750–756. 2. Van Vourhis B, Mejia RB. Single-embryotransfer point—it is the way forward. FertilSteril 2017; 108: 757.3. Practice Committee of the Society forAssisted Reproductive Technology. Guidanceon the limits to the number of embryos totransfer: a committee opinion. Fertil Steril2017; 107: 901–903.

US clinics failing to follow singleembryo transfer guidelines

SART study confirms lower LBRs with SET,but significantly lower rates of multiple delivery


No raised cancerrisk in childrenconceived withdonor gametes

A cross-linkage study of cancer risk inART children by Alastair Sutcliffe andUK colleagues won the ClinicalScience Award for oral presentation atthe 2013 Annual Meeting in London.The study, which was later publishedin the New England Journal ofMedicine, linked the HFEA records ofall 106,381 children born after ART inthe UK from 1992 to 2008 to nationalcancer records to calculate thenumber of ART children whosubsequently developed cancer.1Results showed that there was nooverall increased risk of cancer in theART children born throughout the17-year study period. Overall, 108cancers were identified in the ARTchildren, which was comparable withthe 110 cases which would have beenexpected from general populationfigures.

The group’s latest study, of a similardesign and construction, has nowanalysed the link between ART andcancer risk in children conceived withdonor gametes and again found nooverall increased risk.2

This study again linked the recordsof all children born in Britain (via theHFEA database) after all forms ofdonor ART between 1992 and 2008 tothe UK National Registry ofChildhood Tumours (NRCT) todetermine the number whosubsequently developed cancer by 15years of age. Twelve cancers weredetected against 14.4 expected in thegeneral population, again providingresults described as ‘reassuring forfamilies and clinicians’. The group'searlier linkage study did not includechildren born af er donor ART.

1. Williams CL, Bunch KJ, Sutcliffe AG.Cancer risk among children born afterassisted conception. NEJM 2014; 370: 975-976.2. Williams CL, Bunch KJ, Murphy MFG,et al. Cancer risk in children born afterdonor ART. Hum Reprod 2017;

Niels Skakkebaek, theDanish andrologistwhose 1992 study ofdramatically decliningsperm counts causedhuge controversy, hascalled for urgentresearch into malefertility following further reports ofdeclining sperm counts.1 A meta-analysis earlier this year concludedthat Western sperm counts had fallenby 52% between 1973 and 2011 - awarning described by investigators as‘the canary in the coal mine’.2

Writing in the British MedicalJournal, Skakkebaek said the declinein sperm counts should be comparedto trends in testicular cancer, where aclear inverse correlation was evident.‘This leaves little doubt,’ he wrote,‘that we should look intoenvironmental causes – including

A cohort study based on seven-year datafrom the HFEA database indicates thatwomen who had miscarried or had a livebirth in their first complete cycle of IVFhad a higher chance of live birth in theirnext two cycles of treatment than thosewho had no pregnancies.1 This, say theauthors, is the first time that cumulativechances of conception have beencalculated after IVF miscarrage.

The retrospective study, which was

lifestyle effects.’ Healso urged moreresearch into theimpact of hormone-disrupting chemicals,such as pesticides, andsaid that maternalexposure could be

linked to testicular dysgenesissyndrome, a male reproductivecondition.

In 1992, Skakkebaek and colleaguesfound a ‘genuine decline’ in semenquality over the previous 50 years. Thestudy had analysed a total of 61reports published between 1938 and1991, providing data on almost 15,000men, and found that mean spermcount had fallen from 113 million/mlin 1940 to 66 million/ml in 1990.

1. Skakkebaek N. Disturbing trends inmen’s reproductive health demand urgentattention. BMJ 2017; 359: 4517.

2. Levine H, Jørgensen N, Martino-Andrade A, et al. Temporal trends insperm count: a systematic review andmeta-regression analysis. HumReprod Update 2017; 23: 646-659.3. Carlson E, Giwercman A, Keiding N,Skakkebaek NE. Evidence fordecreasing quality of semen during thepast 50 years. BMJ 1992; 305: 609-13.

based on a cohort of 112,549 women whostarted their first IVF treatment between1999 and 2008, found that those whomiscarried during their first cycle had a40.9% chance of having a baby over theirnext two further cycles. However, thosewho had not conceived in their first cyclehad only a 30.1% chance of live birth, whilewomen who had given birth following theirfirst full cycle of IVF had a 49% chance ofgiving birth again in subsequent IVF cycles.

The study’s lead author, Natalie Cameronfrom Aberdeen, UK, pictured left, told theBBC that miscarriage can be devastating forany couple, but especially those who havealready struggled with infertility.

‘This,’ she said, ‘coupled with theemotional and financial burden of multiplecycles of treatment can make many coupleslose confidence and give up. We hope ourfindings will provide reassurance to thesecouples as they consider their options forcontinuing treatment.’

Indeed, say the auhors in theirconclusion, ‘although both pregnancy lossand non-pregnancy are viewed as a“failure”, our results show that the two havevery different prognoses’.

As background to the study, theinvestigators cite increasing maternal age,previous miscarriages and PCOS as riskfactors associated with miscarriage, withadditional IVF-specific risk factors noted asthe transfer of frozen embryos, cleavage-stage embryo transfer, poor response toovarian stimulation (linked to maternalage), previous miscarriages in IVFconceptions and certain causes of infertilitysuch as uterine factor and endometriosis.

The authors also add that cumulativeLBRs are a better representation of successrates than traditional live birth rates - ‘soour analysis of success rates over multiplecomplete cycles will aid informed decision-making and help tailor expectations forthese couples’.

1. Cameron NJ, Bhattacharya S, Bhattacharya S,McLernon DJ. Cumulative live birth ratesfollowing miscarriage in an initial complete cycleof IVF: a retrospective cohort study of 112 549women. Hum Reprod 2017; 32: 2287-2297.

Declining sperm counts: expert calls formore research into lifestyle factors

Live birth and miscarriage both linked to betteroutcome in next two IVF treatment cycles

Results ‘reassuring’ to those considering further treatment after pregnancy loss


16 Focus on Reproduction //JANUARY 2018

ESHRE NEWS

ESHRE takes next steps for subspecialist trainingSuccessful application for formal status as accredited education provider

ESHRE is facing an ever-growing demandfrom reproductive medicine centres acrossEurope to provide subspecialist trainingfor young clinical trainees who havesuccessfully completed their basic trainingin Obstetrics and Gynaecology. In thepast, an enhanced syllabus for training inaccredited centres was supported by anelectronic log book for trainees to recordall their education and competence stepsover the three-year training period. Thiseducational opportunity was (and still is)particularly welcome in many EUcountries where a recognised trainingauthority cannot provide subspecialisttraining and where ESHRE can help to fillthis gap.

Now, however, in a logical move toenhance ESHRE’s role in the provision ofsubspecialist training, the Society hassuccessfully applied to UEMS (Union ofEuropean Medical Specialists) to berecognised as the first subspecialistorganisation in O&G and as the firstprovider of subspecialist training inreproductive medicine. ESHRE is nowrecognised as the ‘Division ofReproductive Medicine’ within the UEMSSection of O&G, which means thatESHRE can now develop its own specialistexamination in reproductive medicine.

This specialist exam (EFOG-RM, theEuropean Fellowship in Obstetrics andGynaecology for Reproductive Medicine)is being developed in conjunction withseveral educational experts from EBCOG.This is now moving ahead rapidly in orderthat the first exam may be held inBarcelona in July to coincide with theAnnual Meeting. A great deal of help fromthe SIGs has been invaluable here increating a pool of MCQ, EMQ and SBAquestions.

The advantage of being an ESHREaccredited training centre is twofold andnot only restricted to providing the fullESHRE syllabus of reproductive medicine:first, training itself may encourage theretention of a future generation ofspecialists in reproductive medicine; andsecond, the Executive Committee ofESHRE hopes to extend its presenttravelling fellowships to encourage andfinancially support young ESHRE

ESHRE-accredited centres

Country

Austria

Belgium

Belgium

Greece

Greece

Greece

Italy

Slovenia

Slovenia

Centre

Vienna University Hospital (AKH)

Universitair Ziekenhuis Brussel (VUB)

University Hospital Gasthuisberg, Leuven

University of Athens Medical School

University Hospital of Larissa

Aristotle University of Thessaloniki

Humanitas Research Hospital, Milan

University Medical Centre Ljubljana

Hospital Univerzitetni Klinicni, Maribor

Valid until

31.08.21

31.08.20

31.12.20

31.03.19

30.09.17

30.09.20

30.03.20

31.10.21

30.06.21

Spain

Spain

Spain

Sweden

Sweden

Switzerland

Instituto Bernabeu, Alicante

IVI Madrid

IVI Valencia

Karolinska University Hospital, Stockholm

Uppsala University Hospital

Basel University Hospital

30.06.16

30.06.18

31.01.18

31.12.18

31.12.18

31.07.16

Subspecialist in reproductive medicine: what it meansThe Reproductive Medicine Subspecialist is a specialist in O&G who has hadadvanced theoretical and practical training in:1. Medical and surgical management of infertilityThis may involve treatment of the male if practised by the gynaecologists inthat country. It will involve a range of ART techniques.2. Reproductive endocrinologyComprehensive management includes diagnostic and therapeuticprocedures and audit of outcome.After completion of their training, subspecialists continue to devote at leasthalf, and probably more, of their working time to reproductive medicine.ESHRE emphasises that the role of a subspecialist is complementary andnot competitive to the specialist in O&G.

members to spend 3-6 months in anESHRE-accredited centre pursuingresearch or advanced training tocomplement their educationalportfolio.This fellowship scheme beganwell with ESHRE’s collaboration withthe ReproUnion centres in Scandinavia.

The list of ESHRE-accredited centrescan be seen above, while the EBCOGwebsite hosts a list of recognised centresfor basic training in O&G.

Anis FekiESHRE Lead for Subspecialist Training in

Reproductive Medicine


Representing the interests of ARTsector in EU tissue developments

Greater interaction between ART and authorities

In October ESHRE as a collaborating group with specific interest in ART took part in a'dissemination' meeting of ARTHIQS (Assisted Reproductive Technologies &Haematopoietic Stem Cells – Improvements for Quality & Safety), a joint actionfinanced by the European Commission and led by the Agence de la Biomédecine,France.

ESHRE's participation reflects the specifics which the ART sector now requires inapplication of the 2004 EUTCD (European Union Tissues and Cells Directive) withrespect to the regulation of ART activities and inspections of ART establishments.

The project also recognises as very beneficial the interaction of competent authoritieswith professionals and professional societies, and to this end ESHRE was the scientificsociety in ART chosen to participate in this event. Borut Kovacic, a member of theESHRE Executive Committee, presented the position of the 'ART Professional andScientific Society', while others presented the view of different national authorities insubjects such as governance and regulation in ART, inspections, role and missions ofCA, and ART activity registers.

In these past few years both professionals and competent authorities have workedtowards co-operation and learning; indeed, cross-participation in meetings such as thismay help to strengthen common understanding and goals.

One major outcome from this event was the establishment of a network of EuropeanART-dedicated competent authorities which may share resources from Europeanmember states on sensitive ART areas such as information to donors and recipients, orfollow-up of offspring through appropriately adjusted registers. It is also hoped thatsuch a network will allow efficient paths of communication between competentauthorities and professionals, to integrate discussion on key challenges at the legal,social and ethical levels.

'Dissemination', the subject of this October meeting, is one of five work packageswithin the project's organisation. More information at http://arthiqs.eu

Carlos E. Plancha Chair of Organising Committee

Dissemination Meeting of the European Joint Action ARTHIQS

Remote exam for embryology certificationA pilot project to allow ESHRE-member embryologists to sit theircertification exams in their homecountry will take place later this year.The scheme was proposed by the IndianFertility Society and now, having beenexamined and developed by ESHRE incollaboration with IFS, will allowIndian embryologists to take thecertification exams in New Delhi at thesame time as the regular exams arehappening in Barcelona.

‘If succesful, the scheme will allowcandidates in distant countries tocomplete their certification withouthaving to travel long distances,’ said

Borut Kovacic, Chair of theCertification Committee.

The online exams will take place atthe All India Institute of Local SelfGovernment in New Delhi on 30 June.Mock exams were trialled last year, with12 candidates tested within ESHRE’sguidelines and strict invigilation policy.

The trial of e-exams in India willallow ESHRE to assess their suitabilityfor other certification exams at theAnnual Meeting or even in other partsof the world, being of huge benefit tohundreds of members who for financialreasons are not able to travel to Europefor the exams.

The Executive Committee has agreedto go ahead with a scheme to awardESHRE certification to those centreswhich meet an agreed and clear set ofstandards. These will be defined by‘general criteria’, laboratory and clinicalcriteria, and results. Centres wouldapply for certification and be evaluatedby a team of three trained assessors.

Initial applications will be made by acheck-list form covering basic details ofstaffing, facilities, treatments availableand quality management. Assessmentswould follow to ensure compatibilitywith the required criteria.

The proposals for centre certificationwere made last year by formerChairman Luca Gianaroli, who nowheads the working group developingthe programme. He expects operationsto begin in early 2018 with a call forinspectors, qualified professionals whowill be specifically trained to carry outsite visits at applicant centres. Centreswill be encouraged to contact ESHRE'sCentral Office about applications inSpring 2018.

What will clinics gain from ESHREcertification? ‘There are several things,'says Gianaroli. ‘Quality managementand improvement, an objective qualityassessment for patients andprofessionals, and reduced fees for staffmembers attending ESHRE educationalactivities.’ During the initial phase ofthe project, only European centres willbe entitled to apply. This will allowvalidation of the programme before anywider introduction.

ESHRE centrecertification to go

ahead in 2018

Luca Gianaroli: Multiple gains forcentres achieving ESHRE certification.

18 Focus on Reproduction // SEPTEMBER 2017

Swiss gyneacologist Christian DeGeyter, new Chairman of the EIM

steering committee.

Within the past 18 months ESHRE'sEuropean IVF Monitoring (EIM)Consortium has published threereports on data generated by Europeanregistries in IVF - for the years 2011,2012 and 2013.1,2,3 Centresparticipating in the scheme - whichrepresent around 90% of all ARTtreatments performed in Europe -have just completed their datasubmissions for 2014, which will bepresented in preliminary form inBarcelona later this year. Allsubmissions are now completed via anelectronic system, which has made theexercise more efficient for centres andfor ESHRE's analysis.

Indeed, says the EIM's newChairman Christian De Geyter, thegap between data submission andpublication could not now be as shortas three years without the onlinesystem. 'The software has muchimproved the completeness and thequality of the incoming data,' he says.'It's reduced the work load, and helpedto speed up data analysis andinterpretation.'

However, adds De Geyter, despitethe record number of centresparticipating (85% of all Europeaninstitutions), data collection is notcomplete, and this remains one ofseveral challenges now facing EIM.The main explanation for thecontinuing shortfall is the apparentdiscrepancy between voluntary andcompulsory data reporting, the latter,says De Geyter, 'being more completeand of better quality'.

A further challenge is the hugechange which ART has experienced inthe past few years - cross-border care,cryopreservation of gametes, tissues

and embryos, elective single embryotransfers, segmentation of treatments,and long-term follow up. Can the EIMregistries keep pace with theseadvances?

'From the outset,' says De Geyter,'our data collection was cross-sectional, with results reported eachyear. But cross-sectional data analysiscannot reflect today's clinical reality ofsegmentation and cryopreservationunless we can incorporate cumulativedata analysis. Similarly,cryopreservation of gonadal tissues atall ages is slowly becoming moreroutine and surveillance of theseprocedures can only be assessed with along-term vigilance approach.'

And vigilance is what really intereststhe political observers of EIM data,not so much its cycle numbers, hugethough they may be.

De Geyter's vision is that any initialmovement towards ART and/orcryopreservation of gametes or tissuewould be identified by a uniqueindividual code, which would become'an integral part of early infertilitycare', and thus a quality label for allstakeholders.4

'The code should follow theindividual or couple during thevarious steps of infertility care,'explains De Geyter, 'even if it changesthe treatment unit or the country ofresidence. All reporting to the nationalART registry should be accompaniedby this individual code and alltreatment results should be labelledwith the code, even after ten or moreyears. This system woul allow the truecumulative data analysis.'

Such a system, he suggests, would bethe biggest challenge of the next five

years, enhancing the development ofEIM 'from mere ART surveillance toreal vigilance'.

Meanwhile, EIM's safety monitoringremains confined to data on multipledeliveries, prematurity, OHSS, andincidental complications after oocytecollection. This, however, has been nosmall contribution, as today reflectedin the continuing decline in multipletransfers and reduction in ARTcomplications, especially OHSS.Already, public reassurance in ARTmust owe much to the continuing EIMreports, however great their remainingchallenges in vigilance must be.

1. Kupka MS, D'Hooghe T, Ferraretti AP, etal. Assisted reproductive technology inEurope, 2011: results generated fromEuropean registers by ESHRE. Hum Reprod2016; 31: 233-248.2. Calhaz-Jorge C, De Geyter C, Kupka MS,et al. Assisted reproductive technology inEurope, 2012: results generated fromEuropean registers by ESHRE. Hum Reprod2016; 31: 1639-1652.3. Calhaz-Jorge C, De Geyter C, Kupka MS,et al. Assisted reproductive technology inEurope, 2013: results generated fromEuropean registers by ESHRE. Hum Reprod2017; 32: 1957-1973.4. De Geyter Ch, Wyns C, Mocanu E, et alData collection systems in ART must followthe pace of change in clinical practice. HumReprod 2016; 31: 2160-2163.

The challenge of ‘vigilance’for European ART analysis

EIM CONSORTIUM

Can registries keep pace with ART’s advances?The limits of cross-sectional data analysis


Twelve years after Ireland’s Commission on AssistedHuman Reproduction report containing 40recommendations was published, the IrishGovernment has finally put forward a Bill on AssistedHuman Reproduction and is planning to introducestate-funded ART support for patients.1,2 Proposalshave been agreed by the Irish Parliament whereby anAssisted Human Reproduction Bill would cover ‘thewhole area’ of ART. This, said the Health Minister,would include ethical considerations and state funding.‘I made it very clear that I want to put in placesupports to help subsidise the cost of IVF for families,’added the minister.

The bill was approvd by the Irish government inOctober, and, following cabinet approval,the proposals seem likely to become law inIreland sometime in 2018, with publicsubsidies introduced a little later.

As in Poland, progress with legislation inART has been complicated by the strongopinion of the Roman Catholic Church.Termination of pregnancy remains amatter of political debate in Ireland, withpro-life/pro-choice campaigns lobbyingpoliticians before a promised amendmentto the Constitution, which will need to beput forward by referendum.

The ART proposals also makeprovision for an independent Assisted ReproductionRegulatory Authority to oversee clinics and regulate

the conditions surrounding the broad practice of ART,including gamete and embryo donation. Regulationsare expected to include prohibition of commercialsurrogacy and payment for donor gametes. Allresearch involving embryos and stem cells will beregulated. The authority will also have responsibility toensure 'the welfare and best interests of children' bornthrough ART.

Edgar Mocanu, a member of ESHRE's EIM steeringcommittee, Past-Chair of the EU Affairs committee,and an IVF specialist in Ireland, told Focus onReproduction: ‘The decision to regulate the practice ofART in Ireland is long overdue. An ending to thislegislative vacuum in this fast-advancing and far-reaching field of medicine promotes the interests andprotects the patients and their future children.

‘At the same time, it clearly establishes practitionerresponsibilities and practice boundaries. In recenttimes, the Irish government has sought expertopinions from countries where ART laws have been inplace for many years and we hope this process of duediligence will result in a fair law, one that offers accessand is not over conservative.

‘The regulatory authority will assume an overarchingrole to ensure that patients receive appropriate caredelivered by qualified practitioners. Furthermore, it ishoped that reporting ART result will becomemandatory, a significant change from currentreporting which is voluntary and vastly missing.

‘We all welcome this initiative and look forward toworking with the Department of Health and towards implementing a fair law that benefits everyonein the ART field, and a law that can also quickly adaptto practice changes and societal needs.’

1. http://health.gov.ie/wp-content/uploads/2014/03/Report-of-The-Commission-on-Assisted-Human-Reproduction.pdf.2. http://health.gov.ie/blog/publications/general-scheme-of-the-assisted-human-reproduction-bill-2017/.

Irish IVFspecialist andEIM steering

committeemember EdgarMocanu: ‘The

decision is longover due.’

Ireland at last commits to ART legislationGovernment approves proposals, which are expected to become law in 2018Reporting ART results hoped to become mandatory

A publiccampaignfor fertilityawarenessESHRE has established a working group to develop campaign tacticsfor enhancing public fertility awareness and prevention of infertility.The move follows a comment made by the Danish embryologistSøren Ziebe at last year’s Annual General Assembly that ESHREshould do more in the public’s awareness of infertility. The result is aworking group set up under his chairmanship to consider ways inwhich public awareness might be increased. Included in theprogramme is the ‘Fertility on Tour’ programme of talks foruniversity students, whose pilot edition in Barcelona last year provedso successful. ‘Young people’ are one of the declared objectives of theworking group, to ensure they have ‘the right information to makean informed choice about their own fertility’.


IN PROFILE

FoR: Anja, you're well known to ESHREmembers for your registry studies on thesafety of IVF. How did they begin?AP: The Danish Fertility Society had beenrecording all IVF treatments in Denmark andbased on that the Danish IVF registry was setup in 1994. It was Professor Anders NyboeAndersen and consultant Anne Loft atRigshospitalet in Copenhagen who had theidea of using this data much more. We startedslowly, first looking at risks in IVF twins. Afew years later we got involved in theGothenburg randomised trial of single anddouble embryo transfer, and this confirmed tome that twins were a higher risk outcome.This was part of my doctoral thesis and reallystarted my interest in research. But I knew the

work would include lots of figures and I hadno wish to give up clinical work. But finally, Idecided that the research would be veryinteresting. So it all started gradually.

And do you do any clinical work today?Yes, I have a part-time clinic, and still dooocyte pick-ups and transfers. Anything inIVF. So for the last four years I’ve been doingone week in clinic and one week research. Soabout 50-50. From February I'll be headconsultant and professor in Rigshospitaletand will then have to do a little less clinicalwork - but I won’t skip the clinic.

So that’s still your main interest?Well, I'm vey interested in my research, but I

think if you need inspiration for yourresearch it's important to have contact withpatients and do clinical work.

So the registry studies we know you bestfor are not such a big part of your work?They are a big part of my work, but so arethe clinical studies. People ask me when I'mlecturing, oh but you're not doing clinicalwork, but I tell them actually that's mymain interest.

I guess a lot of your safety research - andindeed how you got started with it - issimply because Denmark has suchcomprehensive registries.Yes. Like Sweden, Finland and Norway, wehave a system in which every citizen has anID number which allows us to follow themothers and crosslink to the children.Because of this link between mother andchild we can identify those born after IVFand follow their short and long-term health.

Do you think these registry studies arereliable? They're retrospective,observational, but the numbers are big?Yes, I do. Their major strength is the bignumbers, which to a large extend cancompensate for their limitations. I think inthe future we'll have to rely even more on

Reliance on registries‘We have seen a twin rate of 30%reduced to 5% in some countries.’

The Danish gynaecologist AnjaPinborg has recently joinedESHRE’s Executive Committee butwill be best known for her studieson ART safety derived from thecomprehensive national registriesof the Nordic countries. Sheexplains what we have so farlearned from these studies andhow reliable they are.


PROUST QUESTIONNAIRE*What’s your idea of perfect happiness?

A career and family life that go hand inhand. And in Denmark a little bit moredaylight in winter

Your greatest fear?Losing my children

The trait you most deplore in yourself?My temper

And in others?Mediocrity

What’s your greatest extravagance?Clothes and shoes

What quality do you most like in a man?His sense of humour

. . . and in a woman?Her sense of humour

What is your favoritepastime?Skiing

The last novel you read?The Goldfinch by DonnaTartt

. . . and your favouritewritersEinar Mar Gudmundsson and PauloCoelho

If not Denmark, where would youprefer to live?Amsterdam, Stockholm, Northern Italy

Where did youspend your latestvacation?Rome

Which talentwould you mostlike to have?To be musical

Groceries online, or the supermarket?Both, traditional stuff online and excitingstuff in the shops

* A personal questionnaire celebrated andoriginally made popular by the French writerMarcel Proust

this kind of big data, because what we havefound is consistency in the big Nordicregistry studies. So if we in Denmark findthat babies born after frozen embryo transferare large for gestational age, we also find it inSweden and Finland. We have never seendifferent patterns. OK, in some countriesthere might be less risk, in others higher risk,but we have always seen the same patternregarding birth weight, gestational age,malformations. So I think we can rely onthese studies because the numbers are so bigand the findings consistent. Of course, thereare mistakes and missing values, and we needto have randomised trials to compare theeffectiveness of different treatments, but it'simpossible to provide the safety data onchildren in a randomised trial.

What have you learned from the registrystudies you've done? Would you say they’veprovided strong reliable conclusions thatreally will affect how IVF is performed?I think the registries have shown beyonddoubt the risks associated with IVF twins.Before these studies many people said IVFtwins were dizygotic and so didn’t carry thesame risk as the naturally conceived ones. Butwe saw that they did carry the same risk. Sothere the registers have proved important.We’ve seen a twin rate of 30% reduced to 5%in some countries. And that’s made aconsiderable contribution to the improvedhealth of the children born after IVF.

And what else?We shouldn’t forget that many of our registrystudies have been hypothesis-generating. Forexample, our findings on large-for-gestationalage associated with frozen transfers has givenus some evidence that you cannot just changeyour methods without having a longer-termeffect. Things will influence the children.

But as I understand registry studies, theirwhole purpose is to generate a hypothesis tobe tested. Yes, the studies are hypothesis-generating, butthey are also changing our minds about thedifferent methods we use.

So frozen embryo transfers. They’reincreasing in popularity. What's your view?In terms of safety I would still say it’s best totransfer a single embryo and then freeze therest. It is quite clear that outcome doesn’t justdepend on the couple, it also depends onwhat we do. It’s the same with blastocysttransfer. We'll have to wait and see, but so far,on malformations, cancers, the evidence hasbeen reassuring.

And we need the evidence for publicreassurance as well?Yes, very much so. We have to do thesestudies to show that we are committed tosafety. To show that the treatments are to alarge extent safe. Perhaps the most importantpurpose of these large-scale registry studies isto show that our IVF babies are healthy.

So overall you must feel that IVF is safe?Yes, when I sit in front of an infertile couple Ifeel very comfortable saying that thistreatment is safe. But overall, I think in viewof the manipulations we do it’s amazing thatoutcome is so good. Human embryos are veryrobust. I guess that is the most importantfinding of these registry studies. That’s whywe must keep surveying our new techniques.

Yes, there’s a lot of public reassurance inthese studies.I’m sure this is the reason why IVF is so wellaccepted today. We can say that we havelooked into this and know that there’s a slightincrease in risk here, we know that twins arelinked to a higher risk. So we’ve done thework and can reassure the public. ESHRE hasalso ensured that knowledge of these registersis spread and made its own assessments ofEuropean IVF treatments. We now seeregistries throughout the world and they’vehad great impact on the acceptance of IVF -and even how it's funded - in many countries.

Do you see support of its registries as a bigfuture challenge for ESHRE? You've joinedthe Executive Committee now, so you're in aposition to know!Yes, though I think PGS is still the bigquestion for ESHRE - it’s expensive, but is iteffective, can it improve birth rates, are thechildren healthier? There are many questionsstill to be answered. These new technologiesare another challenge for ESHRE as well asthe data collection of the EIM Consortium.

Well, ESHRE has the PGD Consortium andran the ESTEEM trial. That showed quiteclearly that if your endpoint is a healthybaby, there's not much you can do about thequality of the embryo. That's a strongmessage to come out of the trial.Yes, and that’s why so many are worried aboutthe cost of PGS. It won't be affordable foreveryone, but there’s still huge pressure to doit. This is what’s happening in Denmark.

And your advice ?I think they'll have to start it and monitor it,to get the knowledge and skills, but maybenot as routine treatment.


n July this year Louise Brown will turn 40. She was bornin the UK and is the first human being conceived in vitro.Amandine, Oliver and Maria (36 this year), Tina,Stephanie, Troels and Alessandra (35), Victoria, Antti andMona (34) and Isidoros (31) followed Louise - in France,

Germany, Sweden, Belgium, the Netherlands, Denmark,Italy, Spain, Finland, Norway, and Greece, and were the firstbabies born in their countries by the IVF technique inspiredby Robert Edwards - ‘Bob’ to those who had the privilege ofmeeting him and learning from him.1

But it was not until the early 1980s that dedicated IVFlaboratories really began to emerge throughout the world,closely following the lead of Edwards himself and centres inthe USA and Australia. Europe, however, became rapidlyand enthusiastically involved in this new and fascinatingmethod of artificial conception. Most of the teams began asan initiative of local gynaecologists and biologists interested

I

From biology to embryology40 years in the IVF lab

As we mark the fortiethanniversary year of IVF,embryologist Anna Veiga, whowas the biologist responsible forSpain’s first IVF baby in 1982,highlights the landmarkdevelopments of those fourdecades in the IVF lab.

COVER STORY


in human reproduction - though fertility treatmentwas, at that time, quite limited. Ovulation inductionwas performed with the first gonadotrophin injectionsand vaginal or intracervical insemination wasindicated for couples with male problems. But therewas little else, and today, in just 40 years, it’sremarkable to imagine that more than 7 million babieshave been born throughout the world with the IVFtechnique. Moreover, ART has achieved completesocial acceptance, for which a continuing bioethicaldebate on many aspects has been essential.

My professional activity as an IVF biologist (we werenot known as embryologists at the time) started withPedro Barri, head of the Reproductive Medicine at theHospital Universitari Dexeus in 1982, and I believe myown personal experience was quite similar to that ofmany colleagues starting out in the 1980s.

IVF laboratories were usually set up quite close tothe operating theatres where the oocytes were collected- by laparoscopy at the time, as ultrasound-guidedretrieval had not yet been introduced. In many cases,we had to rely on a few shelves in an incubator andmicroscopes from cell culture and genetic laboratoriesbefore any proper dedicated IVF lab was established.No specific material for the handling and culture ofhuman gametes and embryos was available, andextrapolation from research labs working withthe mouse model was the usual rule.

This scarcity of material and equipmentposed a problem, especially in certaincountries. In the case of our lab in Barcelona,for example, I would periodically have to driveto Montpellier for Falcon tubes, as none wereavailable in Spain. The same with culturemedia. Most of the labs produced their ownmedia with a very limited (if any) qualitycontrol. Others were using culture mediadesigned for other species (the cow, forexample). Yet today there are many companiesproducing reliable culture media for use in IVFlaboratories. Quality control is compulsory andthe results obtained are extremely consistent.

Training of professionals in both the clinicand the lab was also very complicated. Nospecific academic training existed at the time,with no postgraduate degrees in this specialtyas we have today. Young students, bothclinicians and laboratory specialists, can nowbe properly trained, with certificationprogrammes put in place by scientific societies,with ESHRE at the forefront.

My initial contact with the real IVF worldcame in 1982, when I was admitted as a visitorto the IVF laboratory at the Centre HospitalierUniversitaire de Montpellier. Professor BernardHédon took me for three weeks to learn fromtheir experience as one of the first IVF centresin France. I perfectly remember whenProfessor Flandre, the biologist in charge,asked me to remove my metal bracelets toenter the lab, as they were thought to transport

ions detrimental to embryos! This was the first time I would actually see a human

embryo, in that dark laboratory down in the basementof the Hôpital Arnaud de Villeneuve. This view of thefirst human embryo and the beating cardiomyocytes

arising from embryonic stem cells I observedmore than 20 years later are for me the mostimpressive views I have ever had looking down amicroscope.

As I have already suggested, standardisation ofmethodology in IVF laboratories in the 1980swas very limited and we were mainly followingwhat the pioneering groups published in thenascent literature. We established our ownmorphological criteria to assess embryo quality.Not surprisingly, the implantation rate of theembryos we produced at the time was muchlower than we achieve today and, as a result, wereplaced two, three, four and even moreembryos to try to get one implanted. Twins,triplets and even higher order pregnanciesoccurred, something which would now beunacceptable in our present ART programmes.

It was in the 1980s too that the protocols forhuman embryo cryopreservation weredeveloped, following initial pioneering work inanimal models. The report of the first pregnancyafter the transfer of a cryopreserved humanembryo by Alan Trounson and Linda Mohr in1983 in Nature would be the starting point ofcryobiology in the IVF laboratories.2 My owninitial contact with cryopreservation was at thelaboratory of Jacques Testart, the controversialIVF pioneer in France, where I learned how tofreeze human embryos with a protocol adaptedby the French group and widely used for manyyears to come. Incubators designed forpremature babies were used in that lab for theculture of human embryos, a peculiarequipment that was abandoned later on.

ANNA VEIGA: ‘IN MANYCASES, WE HAD TO

RELY ON A FEWSHELVES IN AN

INCUBATOR ANDMICROSCOPES FROM

CELL CULTURELABORATORIES BEFORE

ANY PROPERDEDICATED IVF LABWAS ESTABLISHED.’

Edwards and Cohen announcedformation of a European societyat the World Congress of IVF inHelsinki in 1984.The first issue

of that Society’s journalappeared the following year.

It was during the third World Congress of IVF andEmbryo Transfer in Helsinki in 1984 that a Europeansociety was announced by Bob Edwards and theFrench gynecologist Jean Cohen. The first annualmeeting was held the following year in Bonn with 650participants, who were each welcomed individually byBob, the first Chairman of the Society. And it was Bob,of course, who paved the way for the development ofclinical and basic research in human reproduction andinfertility. The journal Human Reproduction waslaunched in 1986 and is now the reference journal inthe field.

New protocols for ovarian stimulation weredeveloped and, as a consequence, more oocytes werecollected. Methods in the lab also improved, withbetter culture conditions, better equipment andoptimised culture media. We became aware thattemperature should be checked and maintained forbetter embryo development. The culture of humanembryos to the blastocyst stage was described in 1990by Yves Ménézo with the use of feeder cells and thisdevelopmental stage became a factor in our labs at thattime.3 The first human blastocysts we saw looked tome much more ‘real and alive’ than the humble 4-cellembryos we had grown used to. In fact, Yves was oneof the few biologists with a biochemical background,and this allowed him to understand the requirementsof human embryos in vitro and to develop the onlycommercially available (and one of the most widelyused) culture media at the time.

However, it was previous experience in animalmodels which usually paved the way for developmentsto improve our results with IVF. The firstmicromanipulation technique to facilitateoocyte/sperm interaction was described by JacquesCohen in a letter to the Lancet in 1988, reporting apregnancy with a technique called partial zonadissection (PZD), which we took up to overcome failed


fertilisation.4 This was followed by SUZI (nice name,poor results!). Finally, the development ofintracytoplasmic sperm injection in 1992, initiallyindicated for male factor infertility and nowuniversally applied (in certain centres and certaincountries unnecessarily) changed the whole scenarioin IVF. Gianpiero Palermo in the laboratory of AndréVan Steirteghem in Brussels ‘inadvertently’ injected asperm into the cytoplasm of a mature oocyte - and themost efficient technique of assisted fertilisation wasborn.5 Again, limited tools were available and we allbecame craftsmen, preparing glass pipettes in the labwith microforges and pulling equipment. A well-madeICSI pipette was a treasure at the time. What a hugedifference today, with such availability of differentsizes and types of micromanipulation pipettes.

Embryo biopsyTwo years before the introduction of ICSI, a report onpregnancies obtained after the transfer of biopsiedhuman preimplantation embryos sexed by Y-specificDNA amplification was published in Nature by thegroup of Alan Handyside at the HammersmithHospital in London.6 They reported two cases of X-linked disease in which sexing and the transfer offemale embryos avoided the birth of affected offspring.Our own experience in PGD began in a similar waywith the group of Jose Egozcue at the AutonomousUniversity in Barcelona and we obtained a twinpregnancy in a couple in whom the woman was ahemophilia carrier - also by sexing the embryos.

These first births after PGD were the demonstrationthat embryo biopsy could be performed to assess thegenetic characteristics of an embryo through theanalysis of one cell. Thus, the skills of the biologists inthe lab were now needed not only for the preparation

NUMBERS 650 2.4 millionattended ESHRE’s first Annual Meeting in Bonnin 1985; 10,379 took part in Geneva in 2017

IVF cycles estimated by ICMART nowperformed each year worldwide

The first IVF birth

Louise Brown was bornshortly before midnight atOldham hospital in thenorth of England on 25July 1978. Since thenmore than 7 million IVFbabies have been bornthroughout the world.

Steptoe PC. Edwards RG.Birth after the reimplantationof a human embryo. Lancet1978; 2: 366.

Stimulated IVFAlthough Louise Brownand Australia’s first IVFbaby were born followingegg retrieval from anatural cycle, the USA’sfirst IVF birth was in acycle stimulated withhMG; Trounson inMelboure had describedthe first cycles stimulatedwith clomiphene citrate.

Trounson AO, Leeton JF,Wood C, et al. Pregnanciesin humans by fertilization invitro and embryo transfer inthe controlled ovulatorycycle. Science 1981; 212:681–682.

Embryo freezingGerard Zeilmaker (1936-2002) froze embryosfrom three patients inRotterdam in February1983; one transferred inMay resulted in the birthof twins, ‘considerablybefore such a baby wasborn in Australia’.

Trounson A, Mohr L.Human pregnancy followingcryopreservation, thawingand transfer of an eight-cellembryo. Nature 1983; 305:707-709.

Zeilmaker GH, Alberda AT,van Gent I, et al. Twopregnancies followingtransfer of intact frozen-thawed embryos. Fertil Steril1984; 42: 293-296.

Egg donation

The first report of apregnancy resulting fromthe transfer of a fertiliseddonor oocyte came fromthe Monash group in1983.

Trounson A, Leeton J,Besanko M, et al. Pregnancyestablished in an infertilepatient after transfer of adonated embryo fertilised invitro. BMJ 1983; 286: 835-838.

In the beginningin December 1968Edwards, with colleaguesBavister and Steptoe,first describedfertilisation of a humanoocyte. A few years later,the Melbourne group ofCarl Wood reported twoIVF pregnancies, whichwere both lost.

Edwards RG, Bavister BD,Steptoe PC. Early stages offertilization in vitro of humanoocytes matured in vitro.Nature 1969; 221: 632-635.

De Kretzer D, Dennis P,Hudson B, et al. Transfer of ahuman zygote. Lancet 1973;302: 728-729.


of glass pipettes but especially to perform an efficientbiopsy on day 3 at the 8-cell stage without harming theembryo.

It was not possible at the time to diagnose specificgenetic diseases because of technical problems, whichhave been largely solved today by molecular biology. Asa result, all diseases with a genetic mutation in whichthe causative gene has been determined can now bedetected in embryos; today this is performed in mostcentres by blastocyst biopsy and mostly by lasertrophectoderm dissection. Laser technology had in factbeen introduced in IVF labs for zona drilling to improveimplantation, but is now extensively used for embryoand blastocyst biopsy. The first laser prototypesdeveloped at the École Polytechnique de Lausane inSwitzerland were so big that steps were needed to reachthe eyepiece!

It was not until 1996 that Yuri Verlinski proposed forthe first time the analysis of the chromosomalconstitution of oocyte polar bodies to allow thereplacement of euploid embryos; the aim was toimprove IVF outcomes and reduce implantation failuresand miscarriage.7 The practice quickly moved to moreinvasive cleavage stage biopsies and more recently toblastocyst biopsy. Today, the analysis of thechromosomal constitution of human embryos andblastocysts is achieved by array comparativechromosome hybridisation and next generationsequencing, which both allow analysis of the 23chromosomal pairs. The new nomenclature proposedfor this technique is preimplantation genetic testing foraneuploidy (PGT-A).

Broader research fields have now been developed as aconsequence of IVF and a publication in 1998 by JamesThomson described for the first time the derivation ofembryonic stem cell lines (hESC) from human embryos

donated for research.8 In fact, the methodology was areplication of previous work done by Martin Evans inthe mouse model in 1981 in Cambridge, UK.9 Thepillars of research in pluripotency and regenerativemedicine were thus established at that time.

Today, induced pluripotent stem cells (iPS) generatedthrough the overexpression of pluripotency factors arean alternative to hESC.10 Both cell lines are used fordifferentiation into a multitude of cell types, includinggametes. Functional oocyte-like and spermatid-like cellshave been obtained with pluripotent stem cells in themouse model, with healthy offspring achieved in bothcases.11,12 It is a truly astonishing and very relevantachievement to reproduce gametogenesis in in vitroconditions. Meiosis in the petri dish! We could neverever have imagined this when we were starting out inIVF 40 years ago.

Reproducing similar results with human pluripotentstem cells in the human model will take some time.Ethical questions on the generation of embryos from invitro-produced gametes will also need addressing.Confirmation of the safety of the methodology will benecessary before clinical application. And the veryconcept of infertility will need to be revisited after that.

Technical advances in the labNew and very efficient techniques for oocytevitrification are now routinely used in our labs, even fornon-medical indications such as postponement ofmaternity.13 And other equipment improvement isevident in the IVF lab. Laminar flows with gas andtemperature control, incubators for individual patientsand time-lapse monitoring of embryo development nowrepresent reliable tools for the embryologists, suggestingthat the complete mechanisation of the IVF laboratorywill probably be a reality sooner or later.14 This will

19.2% 530,000 7 million estimated delivery rate peraspiration in ART worldwide

estimated ART babiesnow born each year

estimated ART babies bornsince the first in 1978

Vitrificationwas introduced andtested around 2005 -mainly in Japan - withexcellent results withembryos and lateroocytes.

Kuwayama M, Vajta G,Ieda S, Kato O. Comparisonof open and closed methodsfor vitrification of humanembryos and the eliminationof potential contamination.Reprod Biomed Online 2005;11: 608–614.

Oocyte freezingThe first successfulattempt at freezing andthawing a human oocytewas reported by Chenfrom Adelaide in 1986.The first live birth withvitrification of a humanoocyte was reported byGianaroli and colleaguesfrom Bologna workingwith Trounson in 1999.

Chen C. Pregnancy afterhuman oocyte cryopres-ervation. Lancet 1986; 327:884-886.

Kuleshova L, Gianaroli L,Magli C, et al. Birth followingvitrification of a small numberof human oocytes: casereport. Hum Reprod 1999; 14:3077-3079.

ICSIICSI was developed -somewhat accidentally -at the VUB in Brussels bythe group of VanSteirteghem and Devroey,with first live birthsreportedin 1992.By 2006,aroundtwo-thirdsof all ARTfertilisations in Europewere with ICSI.

Palermo G, Joris H, DevroeyP, Van Steirteghem AC.Pregnancies afterintracytoplasmic injection ofsingle spermatozoon into anoocyte. Lancet 1992; 340: 17-18.

PGDThe first reported case ofPGD was achieved bysexing embryos from theDNA of a biopsied cell byamplification of a repeatsequence specific for theY chromosome by AlanHandyside et al in Londonin 1988, who laterreported the firstpregnancies using thissame technique incouples at risk oftransmitting recessive x-linked diseases.

Handyside AH, PattinsonJK, Penketh RJ, et al. Biopsyof human preimplantationembryos and sexing by DNAamplification. Lancet 1988; 1:347-349.

Fertility preservationThe restoration of fertilityafter the transplantationof frozen–thawed ovariantissue was reported forthe first time in the sheepin 1994, but not until2000 was ovarianautotransplantationdescribed in the human.

Oktay K, Karlikaya G.Ovarian function aftertransplantation of frozen,banked autologous ovariantissue. N Engl J Med 2000;342: 1919.


allow embryologists to standardise their methods,minimise human errors and improve results.

But whatever the technical advances, professionalstoday are much better trained than we ever were and caninteract with those from other fields to cover a muchwider range in human reproduction and fertility. Suchinteraction is evident in reports describing the editing ofthe embryonic genome through CRISPR/Cas 9 systemswith the purpose of repairing disease mutations orunderstanding the role of certain genes.

There are of course still many roads to explore in ourspecialty and young embryologists are now lucky to havethe instruments to do so. We were also very privileged toparticipate in the exciting beginnings of IVF. So thankyou once again to Bob and happy birthday to Louise andthe rest of those original test-tube babies!

Anna Veiga was Chairman of ESHRE from 2011 to 2013, andis presently head of R+D+i Reproductive Medicine Service atDexeus Women's Health, and Director of the Barcelona StemCell Bank at the Centre of Regenerative Medicine ofBarcelona.

1. Steptoe PC, Edwards RG. Birth after the reimplantation of ahuman embryo. Lancet 1978; 12; 366.2. Trounson A, Mohr L. Human pregnancy followingcryopreservation, thawing and transfer of an eight-cell embryo.Nature 1983; 305: 707-709.3. Menezo YJ, Guerin JF, Czyba JC. Improvement of humanearly embryo development in vitro by coculture on monolayersof Vero cells. Biol Reprod 1990; 42: 301-306. 4. Cohen J, Malter H, Fehilly C, et al. Implantation of embryosafter partial opening of oocyte zona pellucida to facilitate spermpenetration. Lancet 1988; ii: 162.5. Palermo G, Joris H, Devroey P, Van Steirteghem AC.Pregnancies after intracytoplasmic injection of singlespermatozoon into an oocyte. Lancet 1992; 340: 17–18.6. Handyside AH, Kontogianni EH, Hardy K, Winston RM.Pregnancies from biopsied human preimplantation embryossexed by Y-specific DNA amplification. Nature 1990; 344: 768-770.7. Verlinsky Y, Kuliev A. Preimplantation diagnosis of commonaneuploidies in infertile couples of advanced maternal age. HumReprod 1996; 11: 2076–2077.8. Thomson JA1, Itskovitz-Eldor J, Shapiro SS, et al. Embryonicstem cell lines derived from human blastocysts. Science 1998;282: 1145-1147.9. Evans M.J Kaufman M.H Establishment in culture ofpluripotential cells from mouse embryos. Nature 1981; 292:154–156.10. Takahashi K, Tanabe K, Ohnuki M, et al. Induction ofpluripotent stem cells from adult human fibroblasts by definedfactors. Cell 2007; 131: 861-872.11. Hikabe O, Hamazaki N, Nagamatsu G, et al. Reconstitutionin vitro of the entire cycle of the mouse female germ line. Nature2016; 539: 299–303.12. Zhou Q, Wang M, Yuan Y, et al. Complete meiosis fromembryonic stem cell-derived germ cells in vitro. Cell Stem Cell

‘So thank you onceagain to Bob andhappy birthday toLouise and therest of thoseoriginal test-tubebabies!’

2016; 18: 330-340.13. Kuwayama M, Vajta G, Kato O, Leibo SP. Highly efficientvitrification method for cryopreservation of human oocytes,Reprod Biomed Online 2005; 11: 300-308.14. Meseguer M, Herrero J, Tejera A, et al.The use ofmorphokinetics as a predictor of embryo implantation. HumReprod 2011; 26: 2658-2671.


NATIONAL REGULATIONS3

Time for Germany to revise its ‘antiquated’embryo protection legislation?

It’s now almost 30 years since Germany’s EmbryoProtection Law was approved by Parliament, and sincethen in 1990 the statutes have never been updatedexcept for a single paragraph on strict rules for PGDin 2011.

It has now been argued by the Leopoldina academy,presently the German National Academy of Scienceand one of the oldest science academies in the world,that the current law has not kept pace with today’srapid progress in reproductive medicine; it does notcover most of the ART techniques used or social anddemographic changes. The Leopoldina largelyrepresents the German scientific community and isknown to speak out on social and political questions,providing a factual framework for discussion.

Currently, more than 80,000 ART cycles areperformed each year in Germany, which is why there’sbeen constant debate for more than a decade - amongdoctors, scientists, jurists, politicians and patients - toreplace this antiquated Embryo Protection Law by amodern statute for reproductive medicine. However,no legislative initiative has been announced so far.

Now scientists of the German National Academy ofScience Leopoldina have published a paper on thisissue, demanding new legislation appropriate totoday’s reproductive medicine within the nextlegislative period. They and many other scientistsfirmly believe that many parts of the EmbryoProtection Law are no longer appropriate inreproductive medicine and that the ban on certaintechniques should be withdrawn.

The Leopoldina paper addresses some decisiveneeds, which should be regulated in new legislation:

Elective single embryo transfer should be possibleand encouraged. This would help reduce the numberof multiple pregnancies without impairing successrates.

Egg donation should be allowed, but anycommercialisation should be avoided through strictregulation. Since sperm donation is allowed, a ban onegg donation clearly repesents an inequality whichcannot be justified. Studies on children born after eggdonation have found no negative effects on theparent-child relationship, nor any negative impact onchild development.

Embryo adoption is performed in Germany, but

should be addressed and regulated in law. Aspects of family law should be updated and

regulated for the benefit of children born after donorinsemination to unmarried couples. Rights ofparenthood should be guaranteed at birth.

The family status of children born after surrogacy inforeign countries should be regulated. However,surrogacy in Germany isn’t advocated in thisstatement.

Conditions for elective ‘social’ egg freezing andfertilisation should be agreed and included in law.

According to the Embryo Protection Law post-mortem use of semen for insemination is strictlyprohibited. However, the application of this restraint isnot clearly defined. Clarification of certain aspects - forexample, time limits to the storage of germ cells orembryos - and clearly defined regulations are urgentlyneeded.

The Leopoldina paper has now been distributed tomembers of the German Parliament and other

stakeholders and has arousedtremendous interest.

The discussion paper in itsGerman version can be foundat:https://www.leopoldina.org/en/publications/detailview/publication/ein-fortpflanzungsmedizingesetz-fuer-deutschland-2017/

Thomas StrowitzkiESHRE Executive Committee

National Academy of Science makes proposalsfor new legislation in reproductive medicine

SIG SAFETY & QUALITY IN ART

Potential for a guideline on embryo transfer

Meet our new Junior DeputyAlessandra Alteri is an ESHREcertified Clinical Embryologist from2015 and obtained her PhD in cellularbiology and development at theSapienza University of Rome. For thelast six years she has been working asan embryologist in Italy, currently atthe IVF Centre of San RaffaeleHospital in Milan. Alessandra’s mainareas of interest include safety andquality in the IVF laboratory, particularly with failuremodes and effects analysis (FMEA) for identifyingpotential failures in the work processes.

During her term as junior deputy, Alessandra will beour social media voice to publicise activities and newsabout SQART and to host our Facebook page. She ispictured below with Steering Committee colleagues:above from left, Kelly Tilleman, Daniela Nogueira,Ioana Rugescu, and below, Arianna D’Angelo, ZdravkaVeleva, Alessandra Alteri and Enrico Semprini.

groups moving from station to stationto give enough time to fully practisethe newly acquired skills and askquestions. This gave the opportunity tonovices to learn the skills and to theothers to validate their knowledge.Both trainers and trainees seemed toenjoy the experience very much. Thetake-home message from the course,clearly delivered by Arianna D'Angelo,

Neil Pugh, Emma Kirk and AndrewHorne, was to be systematic in performing theultrasound for the best quality and safest examination.

Roberto Marci showed an extensive range ofultrasound images related to adnexal pathologies,cleverly matched to corresponding laparoscopic andhistological findings, thus giving the complete pictureof the ultrasound potential as diagnostic tool. ZdravkaVeleva pointed out how radiological contrast test likeHSG are nowadays totally replaced by USS contrast test(HyCoSy,HyFoSy). Best ways to clean the USS probeand its safety implications were thoroughly describedby Kelly Tilleman.

The need for setting standards on how to performUSS was also an important message. This wasillustrated by Costas Panayotidis who described themost common shared practice in egg retrieval underUSS guidance. Finally, an overview on training andcertification was given by Grigoris Grimbizis andNazar Amso, who both answered the many questionsraised by the trainees. Education in USS is still poorlyavailable during general training, the need has beenwidely acknowledged and it is in the ESHRE agenda.This course surely has the potential to be more than aone-off.

Quality and safety in embryo transferWe have plans to develop a new ESHRE guideline onworking standards for embryo transfer. The history ofIVF has seen a dramatic reduction in the number oftransferred embryos, from four and even more to justone or two. This transition has led to a decrease in thenumber of twins and higher order pregnancies, with animmediate effect on the number of obstetrical,neonatal and paediatric complications. The strategy tobest minimise complications is the transfer of a singleembryo. However, sometimes a strategy is lacking incases where, for example, two embryos might beappropriate in combination with the presence orabsence of a high quality freezing programme. Whatabout the effect on reimbursement in the embryotransfer policy of certain centres? To provide background and identify commonly


STEERING COMMITTEEKelly Tilleman (BE), Co-ordinatorZdravaka Veleva (FI), Deputy Ioana Rugescu (RO), DeputyAlessandra Alteri (IT), Junior DeputyArianna D’Angelo (GB), Past Co-ordinatorDaniela Nogueira (FR), Basic Science OfficerEnrico Semprini (IT), International Officer

Full house (almost) for first Campus on ultrasound in ART and early pregnancy

Campus course on ultrasound The first hands-on Ultrasound in AssistedReproduction and Early Pregnancy Campus coursetook place in Cardiff, UK, on 16-17 November 2017.The event was organised by the SIGs Safety & Quality,Implantation & Early Pregnancy, Endometriosis &Endometrial Disorders and the Paramedical Group incollaboration with the British Society ofGynaecological Imaging (BSGI). The meeting proveda mix of entertaining state-of-the-art lectures andpractical demonstrations of ultrasound onmannequins and simulators. There was a participantlimit of 70 to allow each to enjoy the hands-onpractice without rushing. The course was almost fullybooked and the delegates were divided into small


perceived problem areas, we would like to ask youropinion in the following survey before taking the nextstep in this project. You’ll find the survey athttps://www.eshre.eu/sqart/questionnaire, or via theQR code opposite. Your input will be valuable.

If you wish to get in touch with us, you can find ourcontact info on the ESHRE SQART web page. Or visit

our web pages for interesting reads, or follow SQARTon Facebook (https://www.facebook.com/SafetyAndQualityESHRE/) and join our Facebookgroup for discussion, advice, feedback and remarks.

Kelly TillemanCo-ordinator SIG SQART

Surely more than a one-off. Almost a full-house for an ultrasound Campus training course in November,

SIG PSYCHOLOGY & COUNSELLING3

Now communicating with colleagues via social media& Counselling is the use of socialmedia. With Facebook and Twitter weare now hoping to reach more of ourfriends and colleagues and reach outto potential new members andcollaborators with like mindedinterests. So to be updated with newsof SIG activities please follow us athttps://www.facebook.com/ESHRE

PsychologyandCounselling.We also have an exciting and interesting programme

of activities for 2018, with a Campus meeting inBarcelona in January on egg donation, coveringmedical, psychological and ethical aspects. In March wewill be hosting a basic training course on informationprovision and communication with patients – a course,co-organised with the Nurses and Midwives groupfrom the Paramedical Board.

Finally, we are pleased to present the theme for ourupcoming precongress course in Spain: How to engagemen within reproductive health and MAR. Men havebeen overlooked in past decades; only few studies haveincluded them and even fewer have focused on them.However, we hope to address this in Barcelona, andhope too that you will participate and communicatewith us on this much neglected topic.

Yoon FrederiksenJunior Deputy SIG Psychology & Counselling

As noted elsewhere in this issue ofFocus on Reproduction, the year 2018represents the 40th anniversary of thebirth of the first IVF baby, LouiseBrown. Medical development andresearch have grown rapidly sincethen, now with highly advancedprotocols and more than 7 millionbabies born - and hopefully manymore. In the psychology and socialfields, studies and perspectives on quality of life,communication, ethics, cultural inequalities ordiscrepancies and shared decision-making haveemerged and gained recognition as highly valuedknowledge areas, leading to improved patientguidelines, a focus on equality in fertility treatmentsand fertility awareness.

This focus on psychosocial issues is nowunderpinned by the need for a certificationprogramme in psychology and counselling, whichwould provide the backbone for evidence-basedpatient care whether in a patient-centred manner inthe clinic or as an appropriate intervention whencounselling fertility patients. We are therefore happy toannounce that a working group has been set up towork on prospects for future certification for thirdparty-reproduction counselling.

Another step into the future for the SIG Psychology

STEERING COMMITTEEMariana Martins (PT), Co-ordinatorJuliana Pedro (PT), Deputy Giuliana Baccino (ES), DeputyYoon Frederiksen (DK), Junior DeputyBrennan Peterson (UAE), International AdvisorSofia Gameiro (GB), Past Co-ordinator

SIG EMBRYOLOGY3

Culture systems for 2018 precongress courseWe held two very successful Campusmeetings in the second half of 2017,In September we hosted an oldfavorite, From gametes to blastocysts– a continuous dialogue, inEdinburgh. This course has now beenheld several times and enjoyed by all,but especially now by those aiming tobecome ESHRE-certifiedembryologists. The success of thecourse has been due in large part to organisers ChrisBarratt and Denny Sakkas, who have used innovativeinteractive problem-solving sessions to get everyoneinvolved.

We followed this up in November with a course onReproductive medicine between science andcommercialization in Ljubljana. The course took amultidisciplinary approach to the safety and efficacyof infertility treatments by minimising the role ofcommerce. We thank all who made these coursespossible - the local organisers, lecturers, participants,and, of course, ESHRE support staff.

Looking aheadIn May we invite you to Athens to study Evidence-based practice in the IVF laboratory. Evidence-based medicine should be a cornerstone in humanART. However, novel and less novel technologies andmethods are not always applied with an appropriatevalidation of efficacy, efficiency, safety or quality.This course will review and critically assess thosemost widespread and significant introductions to theIVF laboratory, and consider the extent to which theyconform to the criteria of evidence-based medicine.The scope of the course additionally includes theapplication of evidence-based medicine to improveperformance of the IVF laboratory.

At the Annual Meeting in Barcelona we will, asusual, organise a precongress course which we hopewill be of interest. As the title suggests, Foundationsand developments in culture systems in IVF willoffer a comprehensive review of the culture systemsused in IVF and describe the various components ofthose systems. The course will also cover practicaltopics such as optimisation and limitations of timelapse microscopy systems.

To provide more flexibility and decreased travelcosts, the SIG-E has made the decision to enter theexciting world of the webinar. We will start on a smallscale to test if this is something worthwhile for ourmembers. The two first webinars will cover KPIs andvitrification. Information on dates and how to attendwill be sent out soon.

We are the largest of ESHRE’s SIGs and we are reallykeen to hear from you. We encourage you to contact

us with your ideas and thoughts ontopics that you would like hear inupcoming Campuses and PCCs. Thisis an important way of letting us knowwhat’s important and interesting toyou, so that we can keep organisingattractive courses.

At the moment we have an ongoingsurvey on our online Atlas of Human

Embryology. We want to know what youenjoy, what you are missing, what you would like us todevelop. Please, give us a few moments of your timeand give us your suggestions for improving the Atlas.

MembershipIn addition to our current members, we are nowhappy to welcome all members of the ParamedicalGroup working as BSc-educated staff in an IVF labwhose primary interest lies in embryology. For its lasttwo years of activity before being disbanded,Paramedical Group members are represented on theSIG-E steering committee by PG members Leonie vanden Hoven and Yves Guns. So we are now all enjoyingbeing part of a new SIG Embryology, with a broaderrange of members but still committed to future eventsfocused on the common interest of all members newand old.

We have recently started a SIG-E group onFacebook, so please follow us there and visit us on theESHRE website (https://www.eshre.eu/Specialty-groups/Special-Interest-Groups/Embryology) to makesure you don’t miss news of our activities. Our E-campus pages hold videos from our previous courses –and please feel free to use Facebook to get in touch!

Susanna ApterCo-ordinator SIG Embryology


STEERING COMMITTEESusanna Apter (SE), Co-ordinatorDebbie Montjean (FR), Deputy Ioannis Sfontouris (GB), DeputyMónica Marques (PT), Junior DeputyRoger Sturmey (GB), Science OfficerGiovanni Coticchio (IT), Past Co-ordinator

SIG GLOBAL & SOCIO-CULTURAL ASPECTS OF INFERTILITY

Infertility: prevention as important as treatment


ESHRE has agreed to establish a workgroup for fertility awareness andprevention of reproductive diseases. Itwill operate as an activity of the SIGGlobal and Socio-cultural Aspects ofInfertility.

The background to ESHRE’scommitment to the prevention ofreproductive diseases as a target is theembarrassing fact that, from the origins of ourspecialty, we as the experts in reproduction have neverreally addressed the topic of prevention. This is incontrast to our colleagues in almost all other areas ofmedicine (cancer, diabetes, cardiovascular diseasesetc) who spend a significant proportion of theirscience, communication and discussion on preventingdisease risks.

The establishment of this work group is actually acontinuation and internationalisation of the ongoingwork of the Danish-Swedish collaborationReproUnion, which has shown that reproductivedisease is now the most prevalent chronic disease ofpeople aged between 25 and 44. Consider the figures:9% of Danish children are now conceived in a fertilityclinic; one in five Swedish and Danish men will neverbecome a father; and one in ten women will eithernever have children or have fewer children thanwished for.

Implicit in these figures and in the objectives of thework group is that we should change our perspectivefrom treating childlessness to ‘building families’.Indeed, infertility affects whole families, not just anindividual couple.

It now seems clear that we as reproductivespecialists should have addressed this a long time ago,especially as it’s also clear that having children takestime. The more children you want, the earlier in lifeyou should start.

We know that young people worldwide havesignificant knowledge gaps about their fertility andbiology. We have a responsibility to start filling thesegaps, for which education is essential for preventingreproductive recognition of lifestyle factors andsexually transmitted diseases.

We also need to address the myths and beliefs thatcause young people to postpone childbearing and toremind politicians and policymakers that they have apivotal role in the organisation of societies in a waycompatible with young couples having children whenand if they wish to.

We need to convince employers that having childrenis central to the lives of most of us and that thisshould be recognised and embraced by companies,universities and employers.

But most of all we should have thecourage to address this message in theopen.

Two meetings of this new work grouphave so far taken place, with theparticipation of Petra De Sutter (BE),Willem Ombelet (BE), Lone Schmidt(DK), Rita Vassena (ES), Søren Ziebe(DK), and Adam Balen (GB).

First steps are to draw up an inventory of whatdifferent countries are doing in terms of awarenessand prevention with a view to what’s working andwhat’s not. Although not yet final, the followingobjectives have been agreed:a) To decrease the prevalence of infertility.b) To ensure that young people have a greaterunderstanding and awareness of fertility andreproductive health so they are equipped with theright information to make an informedchoice about their own fertility journey.c) This includes increasing fertility awareness in thegeneral public and providing continuededucation among healthcare professionals andeducators.d) To equip legislative and administrative bodies withevidence-based information for prioritised decisionmaking, including the reproductive consequences ofinfertility.e) To develop, implement and communicate solutionsand strategies addressing reproductivechallenges in Europe.

A brainstorming and inspirational expert meeting islikely to be held in March in Brussels, where wordswill hopefully be turned into action.

Søren ZiebeWillem Ombelet, Co-ordinator SIG Global and

Socio-cultural Aspects of Infertility

STEERING COMMITTEEWillem Ombelet (BE), Co-ordinatorVirginie Rozée (FR), DeputyPaul Devroey (BE), DeputyDmitry Nikiforov (IY), Junior DeputyFrançoise Shenfield (GB), Past Co-ordinator

Danishembryologist SørenZiebe, whosecomments at lastyear’s ESHREAnnual Assemblyraised the neglectedmessage of fertilityawareness.

SIG STEM CELLS3

A monumental keynote lecture for BarcelonaI must confess that I am very excitedafter my first SIG business meeting! Asthe Co-ordinator of the SIG Stem Cellsit is a pleasure to note that many of theupcoming ESHRE events will involvestem cells.

Firstly, at the next Annual Meeting inBarcelona the keynote lecture will begiven by the widely acclaimed Japanesegroup leader Katsuhiko Hayashi. His group was ableto produce mouse oocytes completely in vitro,starting from pluripotent stem cells and resulting infertile pups. The method involved a fascinating 3-stepin vitro culture system. I am sure that he will deliver acaptivating presentation of this significantbreakthrough.

Secondly, our upcoming precongress course inBarcelona will focus on Stem cell therapies inclinical applications: Progress and challenges. Thecourse will include presentations on clinical gradestem cell banking and HLA typing, and will furtherdiscuss recent clinical trials of endometrial and otherstem cells in female and male infertility. Finally, wewill consider the possible future use of humanpluripotent stem cells, with a focus on treatment ofblindness and diabetes. Our aim in this PCC is toprovide state-of-the-art insights into stem celltherapies in infertility and the tools required forfuture clinical trials in reproductive medicine.

Our next Campus event is a meeting on In vitromodelling: from embryo to gametes, which will be

held in Bilbao on 20-21 September. Weare extremely excited to invite severalexperts in 3D modelling of the embryo,ovary and testis, artificial humanblastocysts, embryo imaging, novel invitro implantation strategies for studyingendometrial and blastocyst interactions,as well as the epigenetics of human

primordial germ cells. Right now. these arethe most trending topics in the fields of earlydevelopment and gametogenesis, currently providing agreater understanding of previously uncharted in vivoprocesses. These investigations will certainlycontribute to the future of reproductive science andeven future treatments for infertility. This Campusevent is already announced on the ESHRE Educationpages, so please do not forget to register!

I am also pleased to announce a few further detailson the 2019 Annual Meeting in Vienna. First andforemost is that the subject of one of the openingkeynote lectures will be the much acclaimed geneediting technology of CRISPR/Cas. I am sure theaudience will be very excited to hear the latest news onthis breakthrough in both the stem cell andreproductive fields.

I should further add that our main session topic inVienna will focus on 3D reproductive organs. Here wewill discuss the new biotechnological approaches ofusing stem cells to generate male and female organs.

Finally, we are planning two new Campus events in2019. The first, organised with the SIG ReproductiveGenetics and titled Gene editing technology: willCRISPR/Cas be the future?, will cover topics such asthe CRISPR/Cas methodology, CRISPR tools, andexperience in vivo, as well as its associatedmethodological limitations such as mosaicism inhuman embryos.

Our second Campus event will be organised withthe SIG Embryology and will focus on 20 years ofhuman embryonic stem cells. Already planned forthe programme are topics that couple stem cells withdevelopment, such as trophectoderm stem cells, theartificial blastocyst, pluripotency factors, the conceptof potency (pluripotency, totipotency) and chromatinremodelling.

Both events will be very relevant for the entirereproductive community, providing the latest updatesin both stem cell research and exciting futureapplications in the reproduction field.

Cristina EguizabalCo-ordinator SIG Stem Cells


STEERING COMMITTEECristina Eguizabal (ES), Co-ordinatorSusana de Sousa Lopes (NL), DeputyMieke Geens (BE), Deputy Mina Popovic (BE), Junior DeputyBjörn Heindryckx (BE), Past Coordinator

Keynote attraction:Katsuhiko Hayashi,whose group was ablein a series ofexperiments to producemouse oocytescompletely in vitro,starting frompluripotent stem cellsand resulting in fertilepups.


SIG REPRODUCTIVE ENDOCRINOLOGY3

A year for guidelines: ovarian stimulation and PCOSLooking backLast year was full of decisive eventsand fulfilments for the SIGReproductive Endocrinology.After the success of our AthensCampus on female reproductiveageing and the sold-out precongresscourse in Geneva, we met again inSeptember in Vienna with almost100 participants considering theimpact of adjuvant treatments onpregnancy potential in IVF. This very successfulmeeting was run under the graceful guidance of localorganiser Professor Andrea Weghofer, to whom weoffer our sincere thanks. Discussion and theinteraction between speakers and audience were livelyand open-minded, and the feedback receivedenthusiastically positive.

Last year was also notable for the strong progressmade in our ‘purely’ ESHRE guideline developmentfor ovarian stimulation and the collaborativecomprehensive guideline on PCOS, developed inassociation with the Australian Center for ResearchExcellence in PCOS and the ASRM.

Please note too that our Junior Deputy, JuliaBosdou, now has responsibility for our social mediaand has created an amazing Facebook page. Just swipeyour mobile and like us.

Moving aheadA very productive meeting of the SIG-RE steeringcommittee took place in Brussels in November. In anon-stop marathon from morning to evening, weaddressed all the points of our full agenda, so definingour plans for the next two years. Great attention wasgiven to forthcoming educational events.

Our Campus workshop on The luteal phase, theneglected part of assisted reproduction? will be held

in Hamburg, Germany, on 25-26 May2018, hosted by local organiser GeorgGriesinger. Our objective here is toshed light on many grey areas of oureveryday practice: the endocrinology ofthe luteal phase, the diagnostic tests ofendometrial receptivity, new drugs androutes of administration for lutealphase support, the validity of lutealphase manipulations to increase

ovarian response and adjuvant treatmentsat the time of embryo implantation. A vibrantprogramme has already been agreed and is available onthe ESHRE website, together with all the informationyou may need to take part.

We also put the final touches to our precongresscourse for Barcelona later this year: if you are makingplans to take part in the next Annual Meeting, don’tforget to also register for our PCC The PCOsyndrome: from diagnosis to health riskmanagement. PCOS is back in the headlines, withbreaking news on this old subject delivered bydistinguished speakers from all over the world.

Let’s communicateWe look forward to keeping in touch with allcolleagues who share an interest in reproductiveendocrinology: so in order to receive our newsletter,just flag the SIG-RE as your affiliation on the ESHREwebsite (under MYESHRE, Personal Details), orsimply like us on our Facebook page ESHRE SIGReproductive Endocrinology (search for@ESHRESIGRE to find the page easily!). We arebecoming more and more social, and we hope toenrich our media supplies with Twitter, Instagram andLinkedIn accounts.

Daniela RomualdiCo-ordinator SIG Reproductive Endocrinology

STEERING COMMITTEEDaniela Romualdi (IT), Co-ordinatorGeorgios Lainas (GB), Deputy Peter Humaidan (DK), DeputyJulia Bosdou (GR), Junior DeputyFrank J. Broekmans (NL), Past Co-ordinatorRoy Homburg (GB), International AdvisorJenny Visser (NL), Basic Science Advisor

A full-house at our Campus meeting in Vienna, with faculty pictured right.

surgery should be performed. TheWorld Endometriosis Society joinedlater. The aim now is to provideinformation not only in writtenformat, but also by video library withspoken comments.

ESHRE, ESGE and WES are nowproud to present the result of the firstphase of this project, a paper onrecommendations for surgical

treatment of endometrioma acceptedfor publication simultaneously in HROpen, ESHRE’sopen access journal, and Gynecological Surgery. Nextwill be a further set of surgical recommendations onthe various types and presentations of deependometriosis. The next work group meeting isplanned for January, with further developments ofthis vast project.

Events of 2017In September last year our Campus meeting onMethodological approaches for investigatingendometrial function and endometriosis took placein Edinburgh. The course, organised jointly by theESHRE and ASRM SIGs, was a great success, withmore than 80 attending. On the programme werestate-of-the-art overviews of biobanking, genomicsresearch, local steroid signalling and metabolism(intracrinology), biomarker discovery, research withanimals and clinical trial design.

Of particular interest was the enlighteningpresentation of Siladitya Bhattacharya (Aberdeen)explaining how to design a randomised trial inendometriosis, while emphasising the numerouspotential pitfalls - from the lack of objective outcomeparameters to theoretical, statistical andinterpretation biases. Final recommendations were touse pilot studies to test study feasibility, to selectclearly predefined outcome parameters and reportthem correctly, to thoroughly discuss distinct aspectsof the study in a multidisciplinary manner, and totake care with final data interpretation, weighting allbiases that may have occurred.

Krina Zondervan opened the meeting with anelegant lecture on genome wide association studiesand next generation sequencing. She explained thedifferences about study designs in genetics andgenomics, and overviewed the latest data generatedwithin the Endogene Consortium. She said that only10% of disease heritability has so far been discovered ,and we face challenges to better define and phenotypethis disease. The emerging area of somatic mutationanalyses, which is already changing some paradigms


SIG ENDOMETRIOSIS & ENDOMETRIAL DISORDERS

We now have a Facebook page(https://www.facebook.com/EndometriosisAndEndometrialDisorders/), a socialmedia connection between the SIGand its members to keep youinformed about precongress andCampus courses and otherdevelopments. To date, our webpage has more than 500 followers,so come on and join us!

Steering committeeA new steering committee was installed during lastyear’s Geneva congress. Andrew Horne (Edinburgh)has now become Past Coordinator, and former DeputyCarla Tomassetti (Leuven) has taken over as Co-ordinator. Andrea Romano stays on as Deputy, andAntonio Simone Laganà – former Junior Deputy –joins as Deputy after being elected by our members.Our enthousiastic committee is very pleased towelcome a brand new member, Umberto LeoneRoberti Maggiore, who was selected as Junior Deputy.He is a clinician and researcher interested in thediagnosis of endometriosis/adenomyosis, on the roleof medical and surgical treatment for these diseasesand on the impact of endometriosis on obstetricoutcomes. The committee is completed by LoneHummelshoj and Krina Zondervan (Oxford), who stayon for another two years as International Advisor andBasic Science Officer respectively.

Surgical management of endometriosis Back in 2015, the chair of the Endometriosis GuidelineDevelopment Group and President of the EuropeanSociety for Gynaecological Endoscopy (ESGE) began aproject to develop a joint guideline on the surgicalmanagement of endometriosis, more specifically todescribe technical guidance on how endometriosis

Planning under way for a third guideline on themanagement of endometriosis

STEERING COMMITTEECarla Tomassetti (BE), Co-ordinatorAndrea Romano (NL) DeputyAntonio Simone Laganà (IT), DeputyUmberto Leone Maggiore (IT), Junior DeputyAndrew Horne (GB), Past Co-ordinatorKrina Zondervan (GB), Basic Science OfficerLone Hummelshoj (GB), Inernational Adivser

Steering committeemembers, from left,

Carla Tomassetti,Umberto Maggiore,

Antonio SimoneLaganà, LoneHummelshoj,

Andrea Romano,and Andrew Horne.

SIG IMPLANTATION & EARLY PREGNANCY


in cancer research, was also illustrated by ProfessorZondervan.

The final session was given by Caroline Gargett(Australia) on endometrial stem cell populations. Shedescribed the largely undiscovered journey thatendometrial and progenitor cells undertake during themenstrual cycle in their migration from the basalis,through the functionalis until the luminal epithelium.She also emphasised how little we know about theendometrial morphological changes and molecularbiology processes which underly these events and havesuch important impact on endometrialpathophysiology.

The syllabus and e-learning platform with fullCampus content are available on the ESHRE website.

Guidelines on the Management of EndometriosisIn 2005 the first ESHRE guideline for the diagnosisand treatment of endometriosis was published, alandmark document which laid the path for manyother ESHRE guidelines on different topics. In 2014the second edition of the endometriosis guidelinebecame available accompanied by an app and a highlypopular patient-friendly version. Many countries have

adopted this guideline for their national societies.We are now keen to ensure that the guideline

includes all newly available evidence. Consequently,the chair of the ESHRE Guideline DevelopmentGroup for endometriosis, Christian Becker (Oxford),and ESHRE Research Specialist Nathalie Vermeulen,together with the current and past co-ordinators ofthe SIG, Carla Tomassetti and Andrew Horne, arecurrently re-assembling the development group for athird edition. More than 50 people replied to themembers consultation put out last year.. The newguideline will build on the strengths of the previoustwo and in addition will include more patientrepresentation and input in areas previously notincluded, such as psychology, pain medicine,sexology, imaging and physiotherapy.

Looking forwardIn May this year during the Annual ScientificMeeting of the BSGE (British Society ofGynaecological Endoscopy) we are presenting a fullday’s precongress course focusing on Advances inreproductive endoscopic surgery: robotics and newclassifications. Continued over page

Guidelines now out on recurrent pregnancy lossWe are excited to have just launchedour guideline on the Management ofRecurrent Pregnancy Loss. Its overallaim is to supply healthcare providerswith the best available evidence forinvestigation and treatment ofwomen with recurrent pregnancyloss. RPL is here defined as the lossof two or more pregnancies. Itexcludes ectopic pregnancy andmolar pregnancy. The guidelineprovides an overview of suggested treatments for RPL,and which of those are recommended. In addition,recommendations are made on investigations toidentify the origin of the pregnancy losses and possibletherapeutic targets. There are also recommendationson the organisation of care for couples faced with RPL.

We have also been working with the SIG Safety &Quality in ART and SIG Endometriosis andEndometrial Disorders, with whom we jointlyhosted a Campus Symposium in Cardiff inNovember on Ultrasound in assistedreproduction technologies (ART) and earlypregnancy. There were interactive lectures ondifferent aspects of ultrasound in ART,gynaecology and early pregnancy, plus a chanceto practice skills on ultrasound simulators:. Thethree SIGs are planning to develop some goodpractice recommendations on the use of

ultrasound in these areas, where oftenthere is little or no good qualityevidence to support practice.

Future eventsAt this year’s Annual Meeting we willbe running a precongress course onthe Provision of an effective earlypregnancy assessment and supportservice. We feel that this is a very

important area as the provision of carefor women in early pregnancy across Europe variesconsiderably. In some countries, dedicated EarlyPregnancy Assessment Units have been created andhave revolutionised the care for women withcomplications in early pregnancy. At recent Campusmeetings and precongress courses, delegates have

requested more information on how to providesuch a service. This course would hopefullyaddress these needs, with sessions on manygeneral topics.

Venturing further afield, in April we are veryexcited to have been invited to host an ESHRECampus meeting in Buenos Aires at the annualmeeting of the Asociación Latinoamericana deMedicina Reproductiva (ALMER).

Emma KirkCo-ordinator SIG Implantation & Early Pregnancy

STEERING COMMITTEEEmma Kirk (GB), Co-ordinatorBettina Toth (AT) DeputyPetya Chaveeva (BG), DeputyMerel van den Berg (NL), Junior DeputySiobhan Quenby (GB), Past Co-ordinatorMaria Christine Krog (DK), Basic Science OfficerMary Stephenson (GB), Inernational Adviser


to provide a general overview of allrelevant issues related to oocytedonation. These include matterssuch as cross-border movement ofpatients and donors, recruitment ofdonors (including alternativesystems such as egg sharing),

genetic screening of donors, qualitymeasures for egg banks, and donor anonymity andidentifiability. The course will approach two issues inmore depth: the organisation of the collection(recruitment) and distribution of donor eggs, andcounselling of donors and recipients.

Our precongress course in Barcelona, Surrogacy: agift with consequences, will focus on this highlycomplex and controversial technique, which is eitherbanned in several countries, or allowed by law orcontract with varied conditions both for the surrogate(and her family) and intended parent(s). The processrequires a high level of knowledge and expertise tolook after all parties of the contract, alongside thewelfare of the future child. Commercialism is alsohotly debated both at national and at internationalcross border levels. We will discuss the variousaspects of the process, from indications to the socialand ethical questions raised when the number ofstakeholders is so varied.

The SIG is also planning more Campus Coursesand working on a pre-congress course for Vienna2019. If you have any ideas and topics you want us toaddress please get in touch.

Lucy FrithCo-ordinator SIG Ethics & Law

SIG ETHICS & LAW

The new co-ordinator of the SIGEthics & Law is Lucy Frith from theUniversity of Liverpool, who replacesProfessor Guido Pennings. Lucy is abioethicist and a social scientist with aparticular interest in the intersectionbetween ethics and social science andempirical bioethics methodologies. Shehas published widely on a range of topics in bioethics,with a long-standing interest in the social and ethicalaspects of reproductive technologies.

The SIG also has a new Deputy in Heidi Mertes. aBelgian bioethicist who has been a member of ESHREfor 12 years. She currently holds a position as apostdoctoral researcher at Ghent University and is alsoa founding member of the Bioethics Institute Ghent.She has described as ‘enormously important’ ESHRE’swork in stimulating interaction between the scientific,clinical, psychological, paramedical, ethical and legalaspects of infertility.

Future eventsWe are organising a number of events in 2018, notablyEgg donation: medical, psychological and ethicalconsiderations on 26-27 January in Barcelona. Thiscourse aims to cover the latest developments in theethical, psychological and social aspects of oocytedonation. There is huge variation in how oocytedonation is perceived and implemented across Europe.This variation is evident in recruitment methods, agelimits for donors and recipients, and donor anonymity.While egg donation is still controversial and/orforbidden in some countries, others often struggle tomeet demand for donor eggs. The course was designed

Surrogacy for Barcelona precongress courseSTEERING COMMITTEE

Lucy Frith (GB), Co-ordinatorHeidi Mertes (BE) DeputyGuido De Wert (NL), DeputyGuido Pennings (BE) Past Co-ordinator

The aim of our precongress course at the ESHRE AnnualMeeting – entitled Endometriosis – from beginning toend - is to understand how endometriosis affects women'squality of life and the risk of diseases that occur duringperi-menopausal or postmenopausal ages, from a life-course epidemiological point of view. This will beaddressed via lectures and open debates.

Later, in the second half of 2018, Campus courses onendometriosis and pain and on fibroids and heavymenstrual bleeding are being planned; in the course of thefollowing weeks, more details can be found on ESHRE’swebsite.

Carla Tomassetti, Co-ordinator SIG Endometriosis & Endometrial Disorders

Continued SIG Endometriosis & Endometrial Disorders


Upcoming eventsMay we also note that in 2018 we lookforward to our Current approaches ingenetics and reproduction course, whichwill take place in Sofia, Bulgaria, from26-28th April, to our precongress courseat the Annual Meeting, which will focuson Genes in gametogenesis andgenetically transmitted diseases and to a

practical training course on SNP arrays,which is currently being organised by the PGDConsortium for October. For the Sofia course there isan abstract submission system in place for allparticipants (submission deadline 26 March 2018)and abstracts will be selected for poster/oralpresentations. We await your contributions!Georgia Kakourou, Claudia Spits, Francesco Fiorentino,

Antonio Capalbo, Filippo ZambelliOn behalf of SIG Reproductive Genetics

SIG REPRODUCTIVE GENETICS

As we’ve seen elsewhere in this issue,we celebrate in 2018 40 years since thebirth of Louise Brown. During thisperiod, more than 7 million babies havebeen born through IVF while we haveseen huge advances in the field ofgynaecology, embryology andreproductive genetics, all applied with asingle aim: the birth of healthy babies.

The incredible amount of knowledgethat has accumulated over the years has influencedour everyday practice as scientists and doctors, andhas inevitably led to more questions and a need tounderstand better the processes involved in thecreation of human life. So it’s a pleasure for the SIGReproductive Genetics to recognise those scientificdevelopments in a short multiple choice questionnaireto inspire all of us towards more learning!

An inspiration from 40 years of IVFTake our 20-question quiz and get ready for 2018

STEERING COMMITTEEGeorgia Kakourou (GR), Co-ordinatorFrancesco Fiorentino (IT), DeputyAntonio Capalbo (IT), DeputyFilippo Zambelli (IT), Junior DeputyStephane Viville (CH), Basic Science OfficerClaudia Spits (BE) Past Co-ordinator

20 multiple-choice questions. Answers at the end.1. You see a patient with congenital bilateral absence of the vas deferens. For which genetic condition would you consider

testing him?a. Huntington’s diseaseb. Cystic fibrosisc. Beta thalassemiad. Fragile X syndrome

2. Carrying a pre-mutation in the Fragile X syndrome is a well-established cause of:a. Polycystic ovary syndromeb. Endometriosisc. Premature ovarian insufficiencyd. Primary ovarian insufficiency

3. Haemophilia B is:a. Autosomal recessiveb. X linked dominantc. X linked recessived. Y linked

4. Women carrying heteroplasmic variants in their mitochondrial DNA will transmit them to the oocytes/embryos:a. At the same frequencyb. At a higher frequencyc. At a lower frequencyd. At an unpredictable frequency

5. Which of the following is not true with regards to mitochondrial disorders and human reproduction?a. Mitochondria have been found to play a role in both female and male fertility (oocyte ageing and sperm quality)b. Mitochondrial replacement therapy aims to prevent transmission of disease-causing oocyte mtDNAc. Preimplantation or prenatal genetic diagnosis may be used for homoplasmic or heteroplasmic mtDNA mutations

to identify embryos with a reduced risk of mitochondrial disease d. Attempts for therapeutic intervention in selected mitochondrial diseases involve use of engineered mitochondrially-targeted zinc finger nucleases (ZFN) and transcription activator–like effector nucleases (TALENs)


6. What are the most common segregation pathways leading to aneuploidy in IVF-generated human oocytes?a. Reverse segregation (split of all sister chromatids at meiosis I) and precocious separation of sister chromatids (PSSC)

causes the majority of aneuploidy in activated/fertilized oocytes as detected by direct Haplotyping and fluorescence time-lapse imaging.

b. Meiotic I non-disjunction of homologue chromosome is the main cause of errors in female meiosis.c. Mitotic non-disjunction of homologue chromosome is the main cause of errors in female meiosis.d. Several studies showed anaphase lag causes the majority of aneuploidy in activated/fertilized oocytes

7. Which of the following is true about human preimplantation embryo development?a. The embryonic cleavage stage is characterised by chromosomal stabilityb. Spindle assembly checkpoint controls chromosome segregation during meiosis but not mitosisc. Spindle assembly checkpoint controls chromosome segregation during mitosis but not meiosisd. Meiotic recombination affects homologue segregation at meiosis I

8. Which of the following is a pre-requisite(s) for a couple willing to undergo PGD with HLA-typing to achieve matched HSCT for their affected child?

a. Maternal age is less than 35-years-oldb. The affected child is over 5-years-old c. Prospective parents should also require use of assisted reproductive technology due to infertilityd. An HLA-matched donor has not been found within the family or in national or international donor registries

9. Which of the following cases are expected to lead to the detection of at least three transferable embryos from a single ART-PGD cycle with 16 embryos biopsied for genetic diagnosis (assume all ART-produced embryos to be of good quality, reaching the blastocyst stage of development by day 5 and based on data that 50% of blastocysts are aneuploid)?

a. A couple undergoing PGD-HLA for identification of unaffected HLA-matched embryos to serve as donors for their child affected with beta-thalassaemia (autosomal recessive inheritance)

b. A couple (40-year-old female) undergoing preimplantation HLA typing with aneuploidy screening for identification ofHLA-matched embryos to serve as donors for their child affected with acute lymphoblastic leukemia (acquired disease)

c. A couple undergoing PGD-HLA for identification of unaffected HLA-matched embryos to serve as donors for their child affected with severe congenital neutropenia-1 (autosomal dominant inheritance)

d. A couple (maternal carrier) undergoing PGD-HLA for identification of unaffected HLA-matched embryos to serve as donors for their child affected with X-linked adrenoleukodystrophy (X-ALD) (X-linked recessive)

10. Currently, use of aCGH and low-coverage genome sequencing in preimplantation genetic screening enables detection of:a. Complex chromosomal rearrangementsb. Balanced chromosomal rearrangementsc. Whole-chromosome aneuploidiesd. Microdeletions

11. Which of the following is not true for whole genome amplification (WGA) methods employed in PGD/PGS?a. When applied on a single cell (7 picograms of DNA), nanograms of DNA are producedb. PCR-based WGA methods are preferred for genotyping analysis.c. Limitations of WGA include allele dropout, nucleotide misincorporations and chimera formationd. Multiple Displacement Amplification (MDA) is a non-PCR based WGA method that employs random primers and highfidelity bacteriophage Phi29 DNA polymerase

12. Which of the following is not true with regards to advantages of single cell haplotyping by SNP arrays?a. As a generic test, it does not require prior DNA testing of family members or optimisation b. Can detect meiotic or mitotic origin of recombination and uniparental disomyc. Can detect balanced chromosomal rearrangementsd. Can be used to detect both monogenic and chromosomal disorders

13. The potential of an embryo to successfully implant and grow has so far been associated with (choose the incorrect):

a. Genomic compositionb. Levels of mitochondrial DNAc. Morphokinetic parametersd. Epigenomic characteristics


14. What is embryonic chromosomal mosaicism?a. The presence of chromosomally distinct cell lines within the same embryo.b. The presence of a mixture of blastomeres with different morphology within an embryo.c. A phenomenon characterised by the presence of a mixture of blastomeres with different HLA within an embryod. An inherited disorder

15. Embryonic mosaicism arises from:a. Mitotic errors occuring after fertilizationb. Meiotic errors occuring in spermc. Meiotic errors occuring in oocytesd. Meiotic errors occurring after fertilisation

16. NGS may enhance detection of chromosomal mosaicism:a. Because of the rapidity of the protocol b. Because less DNA is requiredc. Because quantification of sequencing read counts provides an improved dynamic ranged. Because it may also determine mtDNA quantity

17. Which of the following statements is not true?a. Mosaic aneuploid/euploid blastocysts are able to lead to euploid pregnanciesb. Blastocysts contain relatively lower proportions of aneuploid cells than cleavage-stage embryosc. Embryo self-correction involves the loss of aneuploid cellsd. Any level of mosaicism can very accurately be detected in a blastocyst biopsy

18. The most commonly studied foetal chromosomal aneuploidies by non-invasive prenatal diagnosis are:a. Chromosomes 13, 18, 21, X and Yb. Chromosomes 15, 16, 21, X and Yc. Chromosomes X and Yd. Chromosomes 15, 18, 21 and Y

19. Which syndrome is not caused by imprinting defects?a. Angelman syndromeb. Kearns-Sayre syndromec. Prader-Willi syndromed. Beckwith–Wiedemann syndrome

20. Selfish selection can happen in spermatogonial stem cells with:a. No mutationsb. Neutral variantsc. Gain of function mutationsd. Loss of function mutations

Answers

1 b, 2 c, 3 c, 4 d, 5 c, 6 a, 7 d, 8 d, 9 a+d, 10 c, 11 b, 12 a, 13 d, 14 a, 15 a, 16 c, 17 d, 18 a, 19 b, 20 c


Focus on

REPRODUCTIONEuropean Society of Human Reproduction and Embryology // JANUARY 2010 //

� ESHRE news� EU Tissues and Cells Directives� Poland is braced for IVF legislation

Ready and able

Sperm preparation in the ART lab

Focus on


lESHRE newslFertility preservation in womenlCharting the progress of IVF in Germany

Robert Edwards honoured as Nobel prize winner

Focus on

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

ESHRE newsSweden: a gold mine of epidemiologyThe oncological impact of IVF

The rights and wrongs of

egg donation

Focus on

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

ESHRE newsA record-breaking annual meetingThe embryo as a patient

Is there a signal in the noise?

Embryo selection for IVFEmbryo selection for IVF

Focus on


ESHRE newsConception in HIV-infected couplesThe whole man - and not just his sperm

The urgent needfor new sperm

biomarkers

Focus on


ESHRE newsMeet ESHRE’s Chairman ElectThe first ASRM-ESHRE ‘best of’ meeting

The problem with

culturemedia

Focus on


ESHRE newsThe clinic and the lab in ART today

New atlas of embryology now online

Focus on


ESHRE newsA new era for the ESHRE journals

Happy families

The children conceived by assisted reproduction

Focus on


Preventable complications in IVFESHRE ready for LondonIVF in Britain since Louise Brown

Sir Robert Edwards 1925-2013End of an era in IVF

Focus on


Fertility and female obesityLatest on European IVF monitoringESHRE journals hit the high spots

Another record-breaking congress

From print

JNANUARY 2018 // Focus on Reproduction 41

referendum to review the legislation had failed toattract a required quorum of voters, though just twoweeks before the referendum the Vatican newspaperL'Osservatore Romano declared on its front page thata boycott of the polls would be ‘to defend human life’.

Focus on Reproduction also took up the case of IVFclinics in Poland in 2010, when the country’s firstlegislative proposals to regulate IVF threatened tolimit practice in much the same way that Italy’s Law40 had done five years earlier. Since then Focus onReproduction has followed the vacillating legalposition of IVF in Poland, from those initial battles of2010 to the implementation of a supportive bill in2015 and its peremptory withdrawal just a year later.The politics of IVF in Europe - and elsewhere - hasbeen a recurring editorial interest.

Cover features have also explored some of the mostimportant emerging clinical concepts andcontroversies in ART: vitrification in 2007; mild IVFthe following year; the apparent discrepanciesbetween ART in Europe and the USA; theburgeoning preference of ICSI over IVF for oocytefertilisation in 2008; the place of reproductive surgeryin an age of IVF; the -omics in 2009; the decline inEurope’s fertility rate; embryo selection by time-lapse

This will indeed be the last word of Focus onReproduction - at least in print. From the May issueonwards Focus on Reproduction will be an enhanceddigital publication with its home as a micro-site on themain ESHRE website and as an app for phones andtablets. The online publication will continue to offer itsregular menu of news and features and will thusmaintain its central role in ESHRE’s communications -but, as a print medium in a digital age, it must diversifyand adapt to the inclinations of its readers.

News - both from the Society itself and from thebroader field of clinical medicine and science - will bepresented in a continuous flow, without the hardboundaries of an issue. The stories behind the news,currently seen in profiles and features, will continuebut with added multimedia content in blogs, podcasts,forums, live interviews and rapid access to social

LAST WORD

. . .

media. We will also aim to cover all Campus meetingswith short (and longer) reports of key conclusions.

This inevitable next step of a Focus on Reproductionapp will find its rolling content available for smartphones and tablets - and which hopefully can bepersonalised to each ESHRE member’s interests.

As the front covers opposite indicate, Focus onReproduction has had a vibrant 12-year run as ESHRE'smembers magazine. The title did exist long before then,but publication was erratic at best. When I wasrecruited as editor by Paul Devroey in 2006 to impose astrict frequency on publication and greaterprofessionalism in production, it was, I am sure, myexperience as a journalist which proved the attraction.And since then good journalism has been my guide, topresent a well produced mix of ESHRE and clinicalnews, with background features for commentarybehind the news.

Thus, our first issue of January 2007 led with thereality of ART in Italy, two years after the infamous Law40 was introduced by the Italian Parliament. A 2005

From May Focus on Reproduction will be published from a new digital platform available from theESHRE website and as an app for phones and tablets. News will roll as and when it happens; features

will be multimedia. All you need to know and enjoy about ESHRE will be there.

imaging; the composition of culturemedia in 2012; freeze-all embryos in2016; and most recently the revivalof IUI in unexplained infertility.

Focus has also kept abreast of theongoing debates in PGS, mostrecently - and controversially - witha feature by the UK geneticistDarren Griffin which appeared toaccept that a definitive answer to thequestion of efficacy was beyond thepractical scope of a randomised trialand that new definitions of evidencewere perhaps in order. That,however, was before the disclosure ofresults from ESHRE’s ESTEEM trial,which appeared to confirm that PGS(in this case by polar body analysis)could do little to improve deliveryrates. Embryos were just embryos,and no intervention could improvetheir quality.

As in this 40th anniversary year ofthe birth of Louise Brown, we havealso kept up with the history of IVF.Robert Edwards himself, the 'father'of IVF and of ESHRE, has featuredon two covers, first as the recipientof a Nobel prize in 2011, and second,sadly, on his death in 2013.

42 Focus on Reproduction //JANUARY 2018

Some of the distinguished authors who have written features for FoR: From left. Alan Trounson in 2007 on ART and stem cell research;the late Lynette Scott on embryology in the USA; Bruno Lunenfeld on gonadotrophins; Juan Garcia Velasco on egg donation in Spain;Nick Macklon on endometrial receptivity; Simon Fishel on embryo selection in IVF; Petra De Sutter on safety in IVF; Susan Golombokon today’s ART families; Filippo Ubaldi on the shift of influence to the IVF lab; and most recently Roy Homburg on the place of IUI in

unexplained infertility.

Print as a journalistic medium isnow in serious decline. In my owncountry, the Daily Express had acirculation of more than 4 million aday at its peak in the 1950s and early1960s. By 2017 that figure hadcollapsed to 392,000. However, notall declines in print have been socatastrophic. The Daily Mail, forexample, still sells more than 1.6million paper copies a day, not muchless than in the 1950s, but this everresourceful title also commands oneof the world’s highest online dailybrowser rates of more than 14million - with numbers stillincreasing.

Focus on Reproduction will notcompete with that, but we do hopeits new online format will keepESHRE members well informed andentertained. Last year’s Septemberissue of Focus was downloaded 1700times from the ESHRE website,which, added to its papercirculation, suggests a very healthyreadership. We hope that FoR Onlinewill continue that trend.

Simon BrownFocus on ReproductionA Focus on Reproduction app as proposed

by ESHRE’s Central Office.

ESHRE CAMPUSESHRE Campus courses always attract the world’s leading specialists in human reproduction and represent great opportunities to attend state-of-the-art lectures.

www.eshre.eu/campus

www.eshre.eu

Documents

focus on REPRODUCTION/media/sitecore-files/Publications/Focus/ESH… · gametogenesis, culture systems for IVF, surrogacy and its ethical implications, assessment of early pregnancy,