focus on REPRODUCTION - ESHRE/media/sitecore-files/... · evidence-based medicine and good medical practice. All treatments known to be safe and effective should be available to all

focus onREPRODUCTION

� Gamete modification� Fertility preservation in females

PGS in the clinic

// JANUARY2017

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 2017

EXECUTIVE COMMITTEE // CChairman Kersti Lundin (SE) // Chairman Elect Roy Farquharson (GB) // Members Basak Balaban (TR), Mariette Goddijn (NL), Georg Griesinger (DE), Grigoris Grimbizis (GR), Borut Kovacic (SI),Nicholas Macklon (GB), Tatjana Motrenko (ME), Andres Salumets (EE), Petra De Sutter (BE), Rita Vassena (ES) Ex-officio members // Juha Tapanainen (FI, Past Chairman), Helen Kendrew (GB, Paramedical Group), Cristina Magli (IT, 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 defined by WHO, infertility is a complex pathology that requires appropriate investigation and treatment. One of the most effective treatments isIVF and its related technologies; these techniques cannot be replaced by other

procedures and have resulted in the birth of more than 6 million babiesthroughout the world. Denying the efficacy and accessibility of these treatmentsto infertile couples is not only unethical, but is also contrary to the principles ofevidence-based medicine and good medical practice. All treatments known to be

safe and effective should be available to all infertile patients, who should begiven the opportunity to make informed reproductive choices on the basis of

sound scientific evidence.’

These are the words of ESHRE, expressed recently in support of IVF inLithuania, where political opinion is yet again seeking to suppress IVF in thetreatment of infertility. Lithuania is not alone, and the conservative windsnow blowing through parts of Europe and the rest of the world may equallybe felt in the field of reproductive medicine, where other countries too arenow trying to impose stricter laws and limited access in assisted reproductiontreatments.

As the largest society in reproductive medicine and science ESHRE has aresponsibility to make its voice heard, not only to individual members of theSociety, but also to our patients and to those countries now being threatenedwith restricted – or even no – access to reproductive care.

It is a priority for us to express the importance that we all have equal andfair access to care. Anomalous national differences in the rules regulating IVFmay also increase ‘reproductive tourism’ and cross-border care by whichpatients travel to another country to receive a treatment which is outlawed intheir own country or down-prioritised with long waiting-lists as a result.

Cross-border care can thus be an acceptable option for some patient groups,but it may also jeopardise safety and quality - for example, in more aggressivestimulation regimes, or a higher number of embryos for transfer, or the use ofnon-proven adjunctive therapies. It’s for these reasons that we aim for asmuch harmonisation in treatment and care as possible - and to ensure thatlegislation in medical care is based on sound judgement and evidence-basedscience, safety and efficiency.

For this end ESHRE is working on several levels. We are increasing ournetworking, both on a global and European level, working with allimportant stakeholders. We work by trying to influence global, nationaland international legislation and directives, research funding andguidelines in order to increase accessability, harmonisation and

knowledge. We work with patient organisations to acquire information onlegislation and accessibility in different countries. And we try to educate andspread real knowledge, to diminish the influence of non-scientific arguments

through our workshops, our journals, our website and our guidelines.Kersti Lundin

ESHRE Chairman 2015-2017

CONTENTS

CHAIRMAN’S INTRODUCTION

// JANUARY2017

READY FOR GENEVA 2017 4

BEST OF ASRM AND ESHRE 6

GAMETE MANIPULATION 7

ESHRE NEWS 12

EIM CONSORTIUM UPDATE 16

FERTILITY PRESERVATION IN FEMALES 18

IN PROFILE: ROY FARQUHARSON 20

PGD CONSORTIUM 27

CERTIFICATION IN ENDOSCOPY 28

FROM THE SPECIAL INTEREST GROUPS 31

PARAMEDICAL GROUP 38

PGS IN THE CLINIC 22A practical solution to the ideological debate n PGS from Darren Griffin and Sally Sheldon

LAST WORD: ITALY’s FERTILITY ‘APOCALYPSE’ 41

ANNUAL MEETING 2017

4 Focus on Reproduction // JANUARY 2017

ESHRE’s next Annual Meeting - from 3 to 6 July- will be held for the first time in Geneva and forthe second time in Switzerland. Deadlines forabstracts and registrations are at their normaltimes, with all abstracts required online at ESHRE'sCentral Office before 1 February, and early birdregistrations available up to the end of April. Fulldetails can be found in the table opposite.

In Helsinki last year ESHRE ran a completely paper-free meeting through its own wireless network.Similarly, this year's congress app - improved yet again- will provide full programme and abstract details forlaptops and mobile devices.

The scientific programme will open with the twousual keynote lectures on Monday morning, with thefirst speaker representing the most downloaded articlefrom Human Reproduction in 2016, followed by apresentation on non-invasive prenatal testing. Theseopening keynote lectures usually take place before an

attendance of more than 3000 participants. Theprogramme will continue with one of several sessionsthis year on very hot topics in reproductive science -on the ‘rejuvenation’ of oocytes and ovarian tissue.

The former, in which injected autologous ‘eggprecursor’ cells energise the oocyte through thetransferred mitochondria, has been commerciallypromoted as AUGMENT, a procedure based on thecontroversial discovery of oogonial stem cells byJonathan Tilly a decade ago and on a similarly agedpilot study by US embryologist Jacques Cohen toimprove IVF results in poor outcome patients byooplasmic transplantation. In Geneva Cohen himselfwill review what we know so far about mitochondrialtransfer and ask if it really can improve oocyte quality.

Later that same day will be an invited session on anequally controversial and ethically difficult topic,editing the germline genome by techniques such asCRISPR-Cas 9. This was a heavily discussed subject ofa Campus meeting in September (see report on page7) but in Geneva Robin Lovell-Badge, a group leaderat the recently opened Francis Crick research institutein London, will review both the potential and the risksof the process. The HFEA in the UK approved alicence application from the Institute in February lastyear to include the gene editing of embryos. The workaimed to test the function of genes in early humandevelopment using gene editing systems.

Invited speakerson day 1

include RobinLovell-Badge

(left) ongermline

genome editing,and Jacques

Cohen onenergising

oocytes throughmitochondrial

transfer.

Ready for Geneva� Invited scientificprogramme in place � All abstractsubmissions to be with ESHRE by 1 February 2017

JANUARY 2017 // Focus on Reproduction 5

Bhattacharya, editor of ESHRE's new open accessjournal HROpen, and Sebastiaan Mastenbroek willopen Wednesday's invited programme in a sessionorganised with the Cochrane group. Mastenbroek willconsider evidence for procedures in the IVF lab.

The event’s precongress courses are provingincreasingly popular, with some courses nowattracting upwards of 500 participants. This year, onSunday 2 July, there will be 14 events, with courses onmale infertility, ultrasound in early pregnancy,molecular biology for embryologists, endometrialreceptivity, individualised stimulation for IVF,mitochondria, and transgenderism in reproduction. Inaddition there will be the exchange courses of theASRM and Middle East Fertility Society, and a courseon academic authorship hosted by the ESHRE journaleditors.

‘We trust that everyone will find topics of specialinterest - and of help for their everyday clinicalpractice or research,’ says local organiser Anis Feki.

Later that same day two presentations will examinethe effects of plastics on male fertility and miscarriage.Despite fears to the contrary, the European FoodSafety Authority recently concluded that bisphenol A,a chemical used in the manufacture of food contactmaterials and can coatings, poses no health risk toconsumers of any age group. Richard Sharpe, a deputyeditor of Human Reproduction and scientist who haslong studied the association between environmentalfactors and reproduction, will consider the effects ofthese endocrine-disrupting plastics on spermconcentration and quality.

On Tuesday the programme will continue withAustralia’s Debra Gook, one of the pioneers of oocytecryopreservation, asking if oocyte vitrification can yetcompete for efficiency with embryo and blastocystfreezing, and Kutluk Oktay from New York reviewingthe role of the BRCA genes in ovarian ageing andreproduction.

Two stalwarts of evidence-based medicine, Siladitya

ESHRE’s 35th Annual Meeting in 2019 to be held in ViennaThe 2019 Annual Meeting of ESHRE -the Society’s 35th - will take place in theAustrian capital Vienna from 23-26June. The event will follow Geneva laterthis year and Barcelona in 2018. Thecongress venue in 2019 will be theMesse Wien, one of Europe’s majorconvention centres and a host to manyof the world’s leading medicalcongresses.

This will be the second time that anESHRE Annual Meeting has beenstaged in Vienna, the first in 2002 whenalmost 4000 attended. Judging by recentevents, attendance in 2019 - and indeedat all forthcoming Annual Meetings - islikely to be around 10,000.

Main programme Before 30 April 2017 After 30 April 2017 After 26 June 2017Non-member of ESHRE 432,00 540,00 648,00Member of ESHRE 324,00 432,00 540,00Student or paramedical member of ESHRE 162,00 216,00 324,00

Precongress Course Non-member of ESHRE 216,00 324,00 432,00Member of ESHRE 108,00 216,00 324,00Student or paramedical member of ESHRE 54,00 108,00 216,00

* Prices are in euro and include VAT at 8%

REGISTRATION FEES AND DEADLINES FOR THIS YEAR’S ANNUAL MEETING


The fifth 'Best Of ' meeting ofESHRE and the ASRM will beheld in Paris from Thursday 23February to Saturday 25February at the city's Palais deCongrès. These joint meetingshighlighting the best of ESHREand ASRM recent gatheringshave quickly established atradition for bringing togetherworld authorities in the scienceof reproductive medicine, withupdates on the latest conceptsand developments presented ina framework of lectures, debatesand back-to-back sessions. Themeeting is now set on abiannual track, with venuesalternating between NorthAmerica and Europe, with Paristhe upcoming venue.

The Best Of meetings are aCME programme intended topresent evidence for bothestablished and emergingapproaches to reproductivehealthcare, with faculty fromESHRE and ASRM aiming tocompare global approaches andtechnologies for diagnosis andtreatment. This year’sprogramme thus brings togethersessions on gene editing,artificial gametes, energisedoocytes, preconceptional genetictesting, diagnosis by RNA, andsperm DNA fragmentation.While many of these topicsrepresent emerging concepts inreproductive medicine, moreestablished topics in theprogramme include uterine

BEST OF ESHRE & ASRM

‘‘Best Of’ congress in the best of cities

disorders, automation in theIVF lab, male factor infertility,and access to fertility care.

Reflecting the meeting’s

quickly growing place in thereproduction calendar, therewere more than 1000participants at the ‘Best Of ’

meeting in New York in 2015,and it’s our hope that Paris inthe early Spring will prove anequally attractive venue.

The pace at which new scientific developments areintroduced into everyday practice (quick, and gettingquicker) has been a matter of recent concern toESHRE, whose SIGs and journals have consistentlyurged caution and the weight of evidence beforeroutine application. On the other hand, the editor ofMolecular Human Reproduction, in lamenting the lackof long-term funding for research in reproduction, hasrecently described as ‘unacceptable’ the time it’s taken‘to develop a field such as PGS’.

Three recent and fast-moving developments frombasic science were under the spotlight of an ESHRECampus meeting in Amsterdam in September andeach of them reflect the speed and proximity at whichclinical application is now moving behind the science.Indeed, in her review of the ‘possible’ applications ofthe CRISPR-Cas 9 genome editing system formerESHRE chairman Anna Veiga reported that at leastfive different companies are already preparing CRISPRtechnologies as gene therapies (one to treat HIVinfections), all no doubt commercially packaged.Indeed, genome editing systems - ‘able to knockoutany gene’ and presumably targeted at somatic cells -are now widely available, even as do-it-yourself kits forstay-at-home garage scientists.

It was only in 2015 that three specialists writing inNature urged colleagues not to edit the human germline. ‘In our view,’ they wrote, ‘genome editing inhuman embryos using current technologies could haveunpredictable effects on future generations.’ But withina few months, in December 2015, an internationalsummit meeting in Washington agreed thatbasic and preclinical research in the specificalteration of genetic sequences shouldproceed subject to legal and ethical


This Amsterdam Campus, held over two days in September, proved verypopular, with 108 participants. The event was jointly organised by ESHRE’sSIGs Ethics & Law, Safety & Quality in ART and Stem Cells, co-ordinated

by Bjorn Heindryckx (below).

CAMPUS MEETING; GAMETE MANIPULATION

‘oversight’. The agreement added that ‘it would beirresponsible to proceed with any clinical use ofgermline editing unless and until the relevant safetyand efficacy issues have been resolved’, a cue forethical evaluation based largely on principle and theevidence of water-tight studies. A working group ofESHRE’s Ethical Committee and the European Societyof Human Genetics is indeed preparing a positionpaper of new recommendations for basic, preclinicaland clinical applications of genomic editing in thegerm line (see box onpage 9).

The CRISPR-Cas 9 genome editing system was oneof three technologies under discussion in Amsterdamas ‘safe, ethical, efficient and moral’; the other twowere nuclear transfer for the prevention ofmitochondrial diseases and stem-cell derived artificialgametes as an alternative to donor gametes.

Mitochondrial replacementBjorn Heindryckx, who as Co-ordinator of ESHRE'sSIG Stem Cells was one of the organisers of thismeeting, reported that the prevention ofmitochondrial diseases is a key research project of hisown group in Ghent and that in only a small number

of labs elsewhere - as in Newcastle, UK -prevention by mitochondrial replacement

therapy ‘is investigated in depth’. As nowseems clear, around one person per 5000

is clinically affected by mitochondrial

Expert workshop still urges caution in uptakeof new gamete modification technologies

Mitochondrial replacementtechniques, stem cell-derived

gametes, and gene editing were all considered for their safety,

efficiency and ethical acceptabilityat an Amsterdam Campus meeting.

disorders, although around one per 200 infantsinherits pathogenic mtDNA mutation. It is nowreckoned that for a disease to be clinically manifest themutational ‘load’ - that is the ratio of mutant tonormal DNA copies - would be around 60%.

In the absence of any remedy to ‘cure’ mtDNAdiseases, Heindryckx proposed that prevention (byprenatal diagnosis, PGD or germline nuclear transfer)is the only therapeutic reproductive option. PGD,which was later reviewed by US embryologist JacquesCohen, is not always appropriate, according toHeindryckx: it may not be possible to find mutation-free embryos; and PGD is not suitable for patientswith homoplasmic mutations or higher heteroplasmicloads.

In such cases mitochondrial replacement therapy -as germinal vesicle transfer, spindle transfer,pronuclear transfer or polar body transfer - is the onlyalternative, although concerns remain about safety andany residual mtDNA ‘carry-over’. Techniques exploredin Newcastle - the so-called ‘three-parent IVF’approved by the UK Parliament (though still awaitingthe green light from the HFEA) - were pronucleartransfers, while announcements from the US in 2013suggested that spindle transfer had been successfullyapplied in humans, with some of the ST oocytes foundcapable of developing to blastocysts and producingembryonic stem cells similar to controls. Then inAugust 2015 Zhang et al in New York reported a non-viable pregnancy from a nuclear transfer technique ina couple with repeated embryo arrest. However, inSeptember last year, the same group of Zhang reportedthe successful birth of a baby born following spindletransfer in a mitochondrial case. The group disclosedthat the procedure had been performed in Mexico tobypass regulatory restrictions in the US (see box onpage 10).


‘Three-parent’ embryo procedureof germline nuclear transfer.Following the injection of healthymtDNA from a donor oocyte, theresulting embryo will have nomore than 1% of the donor’s DNA.

Susana Chuva de Sousa Lopesfrom Leiden University said it was

‘difficult to prove or disprove’ theexistence of oogonial stem cells.

Reviewing progress with pronuclear transfer in theprevention of mtDNA disease, specialists from theNewcastle group and others reported in Nature that‘PNT has the potential to reduce the risk of mtDNAdisease, but it may not guarantee prevention’.1 Thus,responding to the Zhang live birth announcement inSeptember, Alison Murdoch from the Newcastle groupcautiously told the BBC that ‘the translation ofmitochondrial donation to a clinical procedure is not arace but a goal to be achieved with caution to ensureboth safety and reproducibility’.

As the Nature authors suggested, safety, as reflectedin the level of mtDNA carry-over, remains ofparamount concern, and in Amsterdam zoologistKlaus Reinhardt from Dresden listed six ‘potentialrisks’ associated with mitochondrial replacementtherapy, not least the fact that no risk analysis hasbeen adequately performed in the countries nowheading towards clinical application. Potential risksinclude heteroplasmy, interacting nuclear andmitochondrial modifier genes, and epigenetic andsequence changes.

Artificial gametesAn indication for use of gametes derived fromspermatogonial stem cells was described at thismeeting as ‘non-controversial’, unlike oocytes - or ‘eggprecursor cells’ - derived from ‘oogonial’ ovarian stemcells. Indeed, no biological claim of the past decadehas raised such polarity as that of Jonathan Tilly in2004 when his group proposed the existence of femalegermline stem cells in the mammalian ovary whichare able to support new oocyte production duringadulthood. Thus, in just one or two reports, Tillyoverturned the basic biological doctrine that the


New overlaps in reproduction and geneticsA third interdisciplinary workshopoverlapped with this Campusmeeting in Amsterdam, bringingtogether as before experts fromESHRE and the European Society ofHuman Genetics (ESHG) to discussrecent developments in fertility andgenetics - and as before the grouphas prepared a position paper ontheir interaction from research toclinical application.

There will be eight new sections tothis third paper: expanded carrierscreening, genetic testing and donoranonymity, the genetics of fertilitydisorders, preimplantation genetictesting, mitochondria fromdiagnosis to treatment, non-invasiveprenatal diagnosis, epigenetics andgermline genome editing. As withthe two previous papers, this willalso be jointly published in HumanReproduction and the EuropeanJournal of Human Genetics.following a consultation periodperiod on the ESHRE website.

The first meeting of the jointESHRE/ESHG group was held inSeville in 2005 to review theinterface between ART and genetics.Under consideration were geneticstudies in IVF couples, PGD andscreening, selection of donors basedon genetic information, counselling,potential adverse effects of ART,safety and quality procedures andpublic policy.

The second meeting was held inBrussels in 2012 to review ‘currentmedical issues’ in ART and genetics.Discussed were cross-border

reproductive care, genetics of maleand female infertility, counselling,PGD and PGS, genomic variation inpreimplantation development,accreditation of labs, consumergenetic testing, epigenetics, stemcells, and funding for IVF.

Now, with so many new topics inso few years, this field continues tomove forward at remarkable pace,leaving little time in its wake forstrong evidence or newrecommendations of this kind.

Joyce Harper

� Soini S, Ibarreta D, Anastasiadou V, etal. The interface between assistedreproductive technologies and genetics:technical, social, ethical and legal issues.Eur J Hum Genet 2006; 14: 588-645.� Recommendations of the ESHG andESHRE. The need for interactionbetween assisted reproductiontechnology and genetics. Eur J.HumGenet 2006; 14,: 509-511.� Harper JC, Geraedts J, Borry P, et al..Current issues in medically assistedreproduction and genetics: Research,clinical practice, ethics, legal issues andpolicy. Eur J Hum Genet 2013; 21: 1-21.

The ESHRE/ESHG group in Amsterdam, standing, Milan Macek, Joep Geraedts,Aafke Van Montfoort, Wybo Dondorp, Sirpa Soini, Heidi Mertes, Inge Liebaers,

Stéphane Viville, Kelly Ketterson, Guido Pennings, Karen Sermon, Luca Gianaroli,and seated from left, Martina Cornel, Joyce Harper, Anna Veiga, Kristiina

Aittomaki, Kersti Lundin. Also part of the group but not pictured Guido de Wert,Claudia Spits, Mike Morris and Joris Vermeesch.

number of follicles in the ovary is finite anddegenerates until depletion and the menopause. Justtwo years ago, he described the isolation of theseelusive stem cells from human ovaries and theirmanipulation into bona fide oocytes. These same ‘eggprecursor cells’ are now the basis of a controversialadjunctive IVF treatment - known as AUGMENT -which seeks to energise oocytes from themitochondria of these same egg precursor cells.

Describing her broader work in the development ofgametes derived from ovarian stem cells, SusanaChuva de Sousa Lopes from Leiden University said it


was ‘difficult to prove or disprove’ the existence ofoogonial stem cells, adding first that the Tilly findingshave not been fully replicated and that many groupshave cast doubt on the reliability of the antibody-based method of their isolation. ‘No paper has shownthat these cells can differentiate to oocytes,’ said Lopesin Amsterdam. ‘Indeed, it's very unclear even if theyare stem cells.’

There are far fewer controversial matters in researchon spermatogonial stem cells, which, said presenterAns van Pelt from the Academic Medical Center ofAmsterdam, is not yet clinically applied, althoughpropagation and transplantation of SSCs have beensuccessfully achieved (offspring) in mice. Van Peltnoted that human adult and prepubertal SSCs cansurvive and proliferate in long-term culture, and thatthese cultured SSCs maintain their stem cellcharacteristics (and chromosomal stability) followingtransplantation.

Two therapeutic routes seem possible: first, in vitropropagation and transplantation; and second, in vitrogerm cell differentiation followed by ICSI. Theindications, said van Pelt, seem reasonably clear - formale infertility cases not amenable to ICSI, such as innumerical and structural chromosome abnormalitiesor Y-chromosome deletions, and for fertilitypreservation in prepubertal boys following cancertreatments.

The driver for these treatments, as other work at theAMC Amsterdam has suggested, is firstly safeconception, but genetic lineage is important too, saidvan Pelt, which gives this work an edge over gametedonation. But ahead of any clinical application lies theprospect of ethical approvals, and particularly theEuropean Advanced Therapy Medicinal Regulations,which recognise these and other developments asinvolving cells ‘subject to substantial manipulation’.

An interesting angle on the social value now placedon genetic parenthood came from Ghent bioethicistGuido Pennings, who proposed that this same highvalue would probably justify any ‘likely’ increase inhealth problems associated with SCD gametes. ‘Oursociety approves and contributes to this view througha devaluation of gamete donation and socialparenting,’ said Pennings, ‘and through thedevelopment of an increasing number of techniquesthat have the sole goal of genetically related children.’Any objections to the evolution of SCD gameteswould be difficult, he argued, because their

development would be just ‘onefurther step in an evolution that hasnever been questioned’.

Gene editingJust one week after this AmsterdamCampus, the Nuffield Council onBioethics in the UK issued adetailed opinion on the geneediting technique of CRISPR-Cas9 and acknowledged that it isalready transforming many areasof biological research, with ‘the

potential to change our expectations and ambitions abouthuman control over the biological world’.2 Reproduction,in the prevention of an inherited disease trait, was one offour areas of potential application identified by the report- alongside farming, industry and biomedicine.

However, according to Heidi Mertes from the Universityof Ghent speaking in Amsterdam, reproductiveapplications raise some of the most complex ethicalconcerns. Her approach was to address these concernsfrom the perspectives of basic research (the source ofembryos) and the clinical outcomes (prevention ofdisease). Concerns among the latter were off-target effects(mutations) and long-term germline modifications,especially when for most of these potential applicationsPGD is an established alternative.

A clear presentation on the technical details of geneediting in human reproduction by Oxford biologist BenDavies showed that there are more than 4000 knownsingle gene conditions, which collectively are thought toaffect approximately 1% of births worldwide and most ofwhich individually are amenable to prevention by PGD.CRISPR-Cas 9, he explained, is the most widely usedgenome editing technique, applauded for its ease of use,low cost and reliability. ‘It just works,’ said Davies. ‘If youjust apply the protocols, it works. We’re all excited by it.’

The system has two components: CRISPR, ‘clusteredregularly interspaced short palindromic repeats’, whichrefers to the basis of the guide system to find the target,

WWorld first spindle transfer baby

Birth of the world’s first baby following spindle nuclear transferwas reported by New Scientist magazine in September anddescribed in more detail at the ASRM Annual Meeting in SaltLake City in October. The treatment was performed in Mexicoby the New York group of John Zhang; the mother carries genesfor Leigh syndrome, a fatal condition that affects the developingnervous system. The syndrome had been responsible for thedeaths of two earlier children. When Zhang and his colleaguestested the new baby’s mitochondria, they found that less than1% carried the mutation, a level considered too low to cause anyproblems. In his ASRM report, Zhang said that the patient, a 36-year-old Jordanian, had elected to have spindle nuclear transferover pronuclear transfer for religious reasons.


and Cas 9, ‘CRISPR-associated protein 9’, the proteinwhich cuts the DNA at the target site. As Anna Veigareported, these CRISPR-Cas 9 systems target specificsequences and can be produced relatively easily in thelab or obtained as commercial kits. It was the twoseparate reports of Zhang and Church (in the sameissue of Science) on the use of CRISPR-Cas 9 inmammalian cells which laid the basis of a generalpurpose tool for editing the genome in living humancells.

According to Veiga, while PGD would be thepreferable alternative for preventing autosomalrecessive and autosomal dominant diseases, germlineediting would be necessary when both parents areaffected by the same monogenic disease (to correctthe affected gene in one parent or an embryo), whenone parent is homozygous for an autosomal dominantdisease (such as Huntington) or when one parent isaffected by a chromosomally structural aberration.Even further ahead, another potential application is to

reduce the risk of common diseases, or even to reshapenon-medical traits. Theoretically possible is the correctionof genes related to infertility (Y chromosome deletions orendometriosis), and, as Bjorn Heindryckx suggested, theelimination of mitochondrial DNA mutations present inthe oocyte, as has already been shown in the mouseoocyte.

As is invariably found, there was no common conclusionto the ethical assessment of these techniques, other thanan urge for caution. Some, like artificial male gametesderived from spermatogonial stem cells, seemed lesscontroversial than others - and, as Sjoerd Reppingsuggested, controversy would be non-existent if provedsafe and effective and if applied in iatrogneic oridiopathetic infertile men. But, as others clearly noted,there is real concern over the ethics of any interventionwhich modifies the genome with consequences for theentire lineage. As Heidi Mertes concluded, the mainconcern about clinical application of these techniques issafety. And at present, she said, it would be ‘irresponsible’to bring genome editing to the clinic, especially with thealternative of PGD applicable in most indications.However, she added, if the technique of genome editing ofembryos is perfected and becomes safe, for those rarecases in which PGD is not possible, it would be difficult toprovide a ‘well-founded’ reason to oppose reproductionwith genome editing for the prevention of diseases.

Simon BrownFocus on Reproduction

1. Hyslop LA, Blakeley P, Craven L, et al. Towards clinicalapplication of pronuclear transfer to prevent mitochondrial DNAdisease. Nature 2016; 534: 383-386.2. See http://nuffieldbioethics.org/wp-content/uploads/2014/06/Novel_techniques_for_the_prevention_of_mitochondrial_DNA_disorders_compressed.pdf.

CCell division without fertilisation?Just days before this meeting took place, newspaperheadlines were speculating that fertilisation was no longernecessary for childbirth. The claims followed a report inNature Communications in which scientists from theUniversity of Bath, UK, described cell division in a mouseoocyte which began without fertilisation. The oocytes werechemically treated to trick them into the beginning ofmitosis and were only then - as 'parthenotes' - injectedwith sperm. Once transferred to the uterus, the cellsdeveloped into normal embryos and went on to grow intonewborn mouse pups. According to reports, the pupsappeared to be healthy and were able to produce at leasttwo generations of their own offspring.

'Our work challenges the dogma ... that only an egg cellfertilised with a sperm cell can result in a live mammalianbirth,' said Dr Tony Perry of the University of Bath, a leadauthor on the study.

Despite a somewhat lukewarm response in Amsterdam,the research did appear to revise the wisdom thatmammalian sperm cells could only become mature spermcells when they were inside an egg — that only the oocyteprovided the environment for division to begin and anembryo to develop. But it now seems that a parthenote canserve the same function as an egg, though under the rightconditions.

Guido Pennings: ‘Anyobjections to the evolution ofstem-cell derived gameteswould be difficult’ because ofthe high value now placed ongenetic parenthood.

ESHRE NEWS

A year of change for ESHRE committee members� Five new nominees for the Executive Committee and a new Chairman Elect

The General Assembly of Members,which will take place during the AnnualMeeting in Geneva, will see theintroduction of a new ExecutiveCommittee for ESHRE and a farewell tothose members who have served twotwo-year terms: Petra De Sutter (BE),Georg Griesinger (DE), GrigorisGrimbizis (GR), Tatjana Motrenko(ME), and Andres Salumets (EE).

Five present members of the ExCowho have served just one two-year term,will remain in place: Mariette Goddijn(NL), Nick Macklon (GB), BasakBalaban (TR), Borut Kovacic (SI), andRita Vassena (ES). These five will nowbe joined by five new members, whowere nominated and selected by theExCo in November. The five newmembers are Thomas Ebner (AT), AnjaPinborg (DK), Karen Sermon (BE),Thomas Strowitzki (DE), and Snežana Vidaković (RS). Each of these newmembers was selected following awritten submission, a brief presentationto the ExCo and interview.

Also in Geneva the Britishgynaecologist Roy Farquharson, whosenomination was ratified at the 2015General Assembly, will take over asChairman of ESHRE. Farquharson, asreported in our interview on page 22, isa past member of the ExCo withresponsibility for the accreditation ofcentres for EBCOG sub-specialist

Two ESHRE research grants awarded for projects in endometrial receptivity

training, and a past Co-ordinator of theSIG Early Pregnancy. As a clinician, hewill continue the ESHRE tradition ofalternating the interests of its chairmenbetween science and clinical medicine.

At its same November meeting theExCo unanimously nominated theItalian embryologist Cristina Magli asthe Society’s next Chairman Elect. Shewill take over the chairmanship at theGeneral Assembly of 2019 in Vienna.Cristina too has a long record of activitywith ESHRE: she is currently a memberof the ExCo and Chairman of the SIGCommittee, having formerly been Co-ordinator of the SIG Embryology and aleading author of the SIG’s Atlas ofEmbryology.


First-round elections for membershipof ESHRE’s Committee of NationalRepresentatives (CNR) began last yearand hopes are that the second roundwill be complete and members ratifiedby April.

The Committee, whose principalresponsibility is to advise ESHRE onlocal matters, is made up of tworepresentatives of each country of 15or more members (one scientist andone clinician) elected for a period ofthree years, with the opportunity tostand for re-election once. Eachcandidacy in this latest election had tobe supported by two other members.

According to ESHRE’s internal rules,the CNR is in place as a ‘soundingboard’ for the ExCo (especially onlocal matters), as a source from whichto select future ExCo members, toreview abstracts and manuscripts forthe Annual Meeting and journals, andto chair sessions at the AnnualMeeting. The CNR may also be askedby the Scientific Committee forsuggestions on the scientificprogramme of the Annual Meeting.

Italian embryologist Cristina Magli willbecome Chaiman Elect in Geneva.

New election of ESHRE’sCommittee of National

Representatives

Abstract applications for the 2016 ESHRE research grantsclosed in April and over the following seven months 91proposals were assessed and evaluated in two rounds of review,the first for an award of €150,000 (with 51 abstractsubmissions) and the second for an award of €50,000 (with 40submissions).

The committees made the €150,000 award to Guiying Nieand colleagues in Australia (Hudson Institute of MedicalResearch amd Monash University) and Brussels (VUB) fortheir research proposal on elucidating a new mechanism ofendometrial receptivity (glycosylated transmembraneglycoprotein removal) and its clinical significance. The reviewpanel described the proposal as ‘innovative and exciting’.

The second award of €50,000 was made to Paola Vigano and

colleagues at the Ospedale San Raffaele in Milan for theirproposed project on uterine fluid exosomes as a ‘liquid biopsy’in the prediction of pregnancy in ART. This too was describedas ‘innovative’ in defining the possible correlation betweenuterine receptivity and proteomic profile as evident inblastocyst transfer.

The grants were available to projects running for up to threeyears, and were selected on the basis of scientific excellence,originality and feasibility. This year, in a bid to concentrate thescientific quality of the submissions, all research topics wererelated to the single theme of endometrial receptivity.

This is the second time that ESHRE has awarded its researchgrants, which are now on a biannual track and in the hands of adedicated research grant committee.

ESHRE et al’s appeal against European time-lapse patent decision


New ESHRE fellowships in fertility training and research� Collaboration with network of Danish and Swedish centres in reproductive medicineESHRE has reached an informalagreement with a Nordic network ofresearch and clinical centres to providefellowship funding for a number ofclinical and basic science traineesworking in fertility. The network -known as ReproUnion - is a consortiumof 13 centres in the Copenhagen regionof Denmark and Malmo and Lundregions of Sweden.

ESHRE’s collaboration withReproUnion would begin with a pilotproject in 2017-2018 providing three-and six-month fellowships of €5000 and€8000 respectively. This means thatESHRE would provide fellowshipfunding for a trainee to cover livingcosts, while ReproUnion would providethe laboratory space, equipment,supervision and training.

‘It’s a very exciting project for ESHRE,’says ExCo member Rita Vassena. ‘Thereare very few dedicated training

opportunities in reproductive medicine,but these fellowships can be used for allkinds of training, and not just researchprojects. Surgical, laboratory, clinical . . .they could all be considered.’

Applications for the fellowhsips wouldbe ongoing from the beginning of theyear, and ESHRE would manage aselection process every three months.Candidates would apply in the firstinstance to ReproUnion with theirtraining/research projects and, ifapproved, to ESHRE for the fellowship.Applications would include a descriptionof research/training plan, a CV, amotivational letter, and letters ofacceptance from a ReproUnion lab andcurrent employer/university.

ReproUnion is currently funded by a substantial EU grant to developprogrammes in the management andprevention of infertility. The cross-border collaboration between Denmark

and Sweden aims to establisha common reproductive medicine centrebased on a multidisciplinary conceptwhich includes research anddevelopment, education and careerdevelopment, treatment, and prevention.There are currently more than 50 PhDstudents working within the programme.

The fellowships in the pilot phase arefor ESHRE members only and those inthe early stages of their career.

The saga of ESHRE's objection to the European patentawarded to Stanford University for time-lapse microscopyrumbles on, with two articles now in press following thedecision of the European Patent Office to uphold andmaintain the Stanford time-lapse patent.1,2

ESHRE's opposition to the patent, along with that of Sterckxet al and with support of several professional organisations,was filed in 2014 largely on the grounds that patents shouldnot be granted to treatments of the human body 'by surgeryor therapy and diagnostic methods', arguing that time-lapseassessment was indeed a diagnostic procedure practised on ahuman body (ie, an embryo). The objection was overturnedby the European Patent Office, whose reasoning last yearsuggested that 'diagnosis' in this case was not to determinedisease but assess the competence of an embryo to develop.

Sterckx et al and ESHRE have now appealed the decision

and have argued in their RBMO comment that the EPO Boardof Appeal's interpretation of ‘medical diagnosis’ was toonarrow and thus unfounded and incorrect. Thus, theyexplain, the question of whether or not ESHRE et al will besuccessful in their appeal hangs on whether or not themethods to diagnose conditions which are not curablediseases are patentable - and thus whether those performingsuch diagnoses may be infringing patents.

In setting out his arguments why Sterckx et al might losetheir appeal, UK patent lawyer David Pearce says it is nowlikely to take a further two years for an appeal decision.

1. Pearce D. Time-lapse microscopy patent upheld in Europe. ReprodBiomed Online 2016; doi.org/10.1016/j.rbmo.2016.10.0122. Sterckx S, Cockbain J, Pennings G. Time-lapse microscopy patentupheld in Europe: response to Pearce. Reprod Biomed Online 2016;doi.org/10.1016/j.rbmo.2016.10.011

The Bridge

Rita Vassena:‘Too fewdedicatedtrainingopportunities inreproductivemedicine.’


CLINICAL NEWS FROM EUROPE

A 2015 amendment to the 2006 EU Tissue and Cells Directiveaimed to improve traceability by requiring a uniqueidentifier applied to all tissues and cells distributed in the EU.Known as the ‘Single European Code’, this SEC wouldprovide information on the main characteristics andproperties of those tissues and cells.

In support of the 2015 move the Commission has nowintroduced a web-based coding platform for tracing donatedtissues and cells from donor to recipient in the entire EU.1The platform is said ‘to provide users with a free, simple andefficient tool to build their SEC for a tissues and cellsproduct’.2 Excluded from the directive are reproductive cellsfrom partner donation.

According to the Commission, the requirements for theSEC as set out in the 2015 amendment should have beentransposed into national law by Member States by 29October 2016 and will become legally applicable from 29April 2017.

The 2015 amendment, Commission Directive2015/566/EU, was an amendment to Commission Directive2006/86/EC with respect to ‘traceability requirements,notification of adverse reactions and certain technicalrequirements’.

1. https://webgate.ec.europa.eu/eucoding/.2. See http://europa.eu/rapid/midday-express-06-10-2016.htm#9.

Online calculator to predict ART outcome� First online predictive model with cumulative estimates and cumulative cyclesThe British Medical Journal (impact factor 19.96) is not anatural habitat for even an eye-catching paper in ART, but that'swhere a report of the world’s first predictive ART model withcumulative estimates over multiple treatment cycles waspublished in November.1

The online calculator, developed from analysis of more than113,000 eligible patients in the HFEA database, is claimed toestimate the individualised chance of couples having a babyboth before and after their first IVF treatment, and overmultiple IVF/ICSI cycles thereafter.

The researchers, from the universities of Aberdeen andRotterdam, explain that the model will ‘aid clinicianscommunicating to couples their personalised chances of a livebirth over an entire package of IVF treatment’, but warn that it‘should not be used to make decisions around whether or notcouples should have IVF treatment’ (because of some missingbaseline data, such as BMI). They say it will also ‘help to shapecouples’ expectations’ and to plan their treatments moreefficiently.

Analysis of the 113,000 eligible patients in the HFEA databaseshowed that 29.1% had a live birth after a first cycle oftreatment and 43% after six completed cycles. And it’s thisanalysis which now provides the basis for two clinical models -one using information available before starting treatment andthe other based on additional information collected during thefirst IVF attempt. Both models can be found on the website ofthe University of Aberdeen (https://w3.abdn.ac.uk/clsm/opis).

As expected, results show that, independent of treatment, thechances of a couple having a baby decline after the woman’sage of 30 and with her increasing duration of infertility. Afterfemale age and following transfer of a fresh embryo in the firstcycle, an increasing number of oocytes collected (up to 13),embryo cryopreservation and stage of embryo transfer werethe next best predictors of outcome.

For example, a 30-year-old woman with two years of

unexplained infertility has a 46% chance of having a baby fromthe first complete cycle of IVF and a 79% chance over threecomplete cycles. As expected, in this same pre-treatment model,the odds of a live birth decreased with every increasingcomplete cycle of treatment; thus, the odds of a live birth aftercycle two was 21% lower than the odds after cycle one.

In the post-treatment model, after a fresh embryo transfer theodds of a live birth increased by 29% with the greater number ofeggs collected. This doubled in cases where frozen embryoswere used. Odds decreased by 9% if ICSI was used.

Explaining the logic of the two prediction models (of having alive birth over one or more complete cycles of IVF), theresearchers write: ‘At the point when the pre-IVF model will beused by clinicians to counsel couples as to their future chancesof success, the woman’s age, duration of infertility, type ofinfertility, previous pregnancy status of the couple, andtreatment type are known. The post-IVF model revises theseestimates using updated information from the first attempt at afresh embryo transfer.’

They also add in their conclusions that, before starting IVF orICSI, unexplained infertility and anovulation were associatedwith an increased chance of live birth, whereas male factor andtubal infertility had a negative association.

1. McLernon DJ, Steyerberg EW, Te Velde ER, et al. Predicting thechances of a live birth after one or more complete cycles of in vitro

fertilisation: population based study of linked cycle data from 113 873women. BMJ 2016; 355: i5735.

New EU traceability directive must be applied as law from April


Sperm counts of ICSI young men foundlower than in naturally conceived controls

From the very first births of the early 1990s, follow-up of its ICSI babies was always apriority at the Vrije Universiteit Brussel (VUB), from where in 1992 the group of VanSteirteghem and Devroey announced the first live birth.1 ICSI's widespread take-up overthe next few years would revolutionise the treatment of male factor infertility and finallymake fatherhood possible for a large number of men with non-obstructive azoospermia.Over the past three decades, as made clear by the registry data monitored by ESHRE andSART, the use of ICSI in most regions of the world for patients with borderline or evennormal semen characteristics has increased, without clear evidence of any benefit overconventional IVF.2,3,4

Throughout these decades the health anddevelopment of the ICSI babies have beenmonitored at the VUB, and the latestreport - ‘the first results from the world’soldest group of young men conceived bymeans of ICSI because of their fathers’infertility’ - published later last year showmedian sperm concentration, total spermcount and total motile sperm count weresignificantly lower than in spontaneouslyconceived controls.5 The findings came asno surprise to most commentators,particularly with the caveat that the studysubjects had all been conceived by ICSIbecause of male factor (or idiopathic)infertility.

‘These findings are not unexpected,’ saidVan Steirteghem in a journal press release.'Before ICSI was carried out, prospectiveparents were informed that it may well bethat their sons may have impaired spermand semen like their fathers. For all theparents this information was not a reasonto abstain from ICSI because, as theysaid, ‘if this happens, ICSI can then alsobe a solution for our sons’.

These results do indeed suggest (butnot prove) that some degree ofsubfertility has been passed on to thesons of fathers who had ICSI because ofimpaired semen characteristics.

A total of 54 men conceived by ICSIand 57 naturally conceived men wereincluded in the study, which, afteradjustment for potential confounders,showed that men conceived naturallyhad almost twice the sperm

concentration of the ICSIs, and more than twice the total motile count.Low sperm concentration, according to thelatest WHO criteria of less than 15million/ml, was present in 42.6% of menconceived by ICSI but only 21.1% of menconceived naturally.

However, while sperm concentrationsand counts were generally lower in theICSI men than in controls, the study didshow that a low sperm concentration andtotal motile sperm count in fathers did notcorrelate with corresponding values intheir sons. ‘The study shows that semencharacteristics of ICSI fathers do notpredict semen values in their sons,’ saidVan Steirteghem. ‘It is well established thatgenetic factors play a role in maleinfertility, but many other factors may alsointerfere. Correlation is not the same thingas causation.’

It was with this in mind that UKandrologist Allan Pacey (who gave last

year’s Annual Meeting keynote address onsperm morphology) described the resultsas ‘quite reassuring’. ‘The worry has alwaysbeen that ICSI-born males were destinedfor a poor reproductive future that may beequivalent to (or even worse than) theirfathers, whereas this paper suggests this isnot necessarily the case,’ said Pacey.

It was notable, however, that only 54 ofthe 215 young ICSI men on the VUBdatabase agreed to take part in the study,which may also have rendered the resultsless than complete.

1. Palermo G, Joris H, Devroey P, VanSteirteghem AC. Pregnancies afterintracytoplasmic injection of singlespermatozoon into an oocyte. Lancet 1992; 340:17-18. 2. Evers JLH. Santa Claus in the fertility clinic.

Hum Reprod 2016; 7: 1381-1382.3. Boulet SL, Mehta A, Kissin DM, et al.Trends in use of and reproductive outcomesassociated with intracytoplasmic sperminjection. JAMA 2015; 313: 255-263.4. Grimstad FW, Nangia AK, Luke B, et al.Use of ICSI in IVF cycles in women withtubal ligation does not improve pregnancy orlive birth rates. Hum Reprod 2016; doi:10.1093/humrep/dew247.5. Belva F, Bonduelle M, Roelants M, et al.Semen quality of young adult ICSI offspring:the first results. Hum Reprod 2016:doi:10.1093/humrep/dew245.

� But no close correlation between father’s sperm count and son’s in first follow-up study

Andre Van Steirteghem, pioneer of ICSI.


Members of the EIM Consortium outside the St Luc University Hospital in Brussels. In thecentre foreground is the Consortium’s Chairman Carlos Calhaz-Jorge, who will be succeeded in

Geneva by the Swiss gynaecologist Christian De Geyter, standing on his left.

The first year of online data collection by the EIMConsortium - for the year 2013 - has seen a recordnumber of submissions from national registries, mostof which were ‘consistent returns’, according toESHRE's scientific officer Veerle Goossens. Shereported that data on almost 700,000 cycles had nowbeen submitted for 2013, an increase of 8.5% on theprevious year. Those data represent around 80% oftotal ART activity in Europe, derived from around1200 centres in 38 countries.

Cumulatively since its formation in 1997, theConsortium has now assembled data on more than 7million cycles and 1.3 million babies born. Describingit as 'quick and efficient', Veerle said that everycountry in the Consortium is now using the newonline system, with only four submitting inconsistentreturns (which were all amenable to repair).

Traditionally, EIM data in its annual reports havebeen used as a marker of outcome, availability, andsafety (usually expressed in terms of multiples). Butnow, at the Consortium’s latest biannual update heldin November at the St Luc University Hospital inBrussels, there were several proposals that the very

submission of data by a clinic or the cumulativecollection by a national registry or ESHRE might goeven further and represent an assurance of quality inboth ART performance and safety.

Indeed, ESHRE's Chairman Elect Roy Farquharson,who was present at the meeting, noted that theEuropean Commission in informal talks with ESHREhad expressed its greatest interest in EIM data not as areflection of outcome but as a marker of ART safetyand quality. ‘The EU seems far less interested indelivery rates than in adverse events,’ saidFarquharson, who emphasised that there is no greaterdemonstration of quality assurance in European ARTthan in the huge database of EIM. Indeed, it wassuggested that a clinic’s very contribution to the EIMConsortium might even be considered as a‘verification’ (even ‘certification’) of its data collectionprocess and quality assurance.

Indeed, it was noted by former EIM ChairmanMarkus Kupka that the two data collection agencies inthe USA, SART and CDC, are already using their datato draw such quality conclusions far beyond theircrude performance numbers.

Of course, as Kupka also noted in qualifying theclaims, the EIM database does not represent 100%coverage of Europe, and the national registries fromwhich its reports are drawn are not on a consistentcycle-by-cycle basis. There were, for example, fourpresentations at this meeting - from Ioana Rugescufrom Romania, Carlos-Calhaz-Jorge from Portugal,Giulia Scaravelli from Italy and Dominique Royèrefrom France - each representing registries basedseparately on voluntary, mandatory, summary orcycle-by-cycle data. Nevertheless, the view was clearthat the value of this huge work of data collection bythe EIM had worth far beyond the simple plotting ofpregnancy rates or availability per million population.

It was noted from the floor, for example, that it wasEIM data which first showed the divergingdiscrepancy between IVF and ICSI fertilisations inEurope and how this trend might have implications forcost and even safety. Although observational and

Jacques de Mouzon:Oocyte freezing survey.

Oocyte freezing neglected in many registriesOnly 17 European countries arecollecting data on oocyte freezing,according to a 27-country surveycarried out by ESHRE and presentedhere by French epidemiologist Jacquesde Mouzon. While oocyte storageactivity has indeed increased over thepast five years, especially for eggdonation, there is still littlehomogeneity in how that activity isrecorded, even for medical indications(for which 14 of the 27 countriesprovide state funding). Oocyte use, saidDe Mouzon, ‘is not very well reported’.

EIM CONSORTIUM

ART datain supportof qualityassurance

US fresh delivery rate declines in latest SART update

A 2016 update on the activities of SART in the USA reports thatmembership comprises 375 clinics (83% of all those required toreport) and 91% of all reported ART cycles.1 The update notesthat the number of clinics in the USA continues to rise, but at aslower rate since 2000. Most clinics still report through SART(80%) and to the CDC using the National ART SurveillanceSystem (NASS) system, but a few do not report at all. All SARTclinics also report to CDC but apparently without the need forduplicate data entry.

Among the other trends identified in the update is a continuingrise in the number of treatment cycles performed. The USA’scontinuing high overall delivery rate is now considerably drivenby the high success rate of frozen cycles, which now, says SART,exceeds that of fresh, ‘likely due to a combination of factors,


IncomingChairman of the

EIM SteeringCommittee

Christian DeGeyter: ‘Still a lot

to do.’.

retrospective in nature, such registry trend-spotting, itwas argued, does represent real-life practice.

It was also clear in a presentation from JesperSmeenk of the Netherlands that registry data cansupport - or even drive - major policy decisions, ashappened in 2011 when the Dutch Ministry of Healthpledged to reduce the number of reimbursed cycles ofIVF/ICSI from three to just one. A counter plan fromthe Netherlands’ 13 IVF clinics and health insurers wasdeveloped to make cost savings of €30 million a yearbased on an expectant management model, a policy ofSET, and reduced medication cost. Now, said Smeenck,the first registry returns show that the expected savingswere indeed achieved by the alternative plan - that in2012-13 there was a 10% drop in the number oftreatment cycles, and in 2013-14 a further 7% drop.The new policy has also seen a significant fall in thenumber of multiple pregnancies, said Smeenck,without any decline in the overall pregnancy rate.

So what next for the EIM? Incoming ChairmanChristian De Geyter accepted that there was still ‘a lotto do' to guarantee quality assurance through ARTsurveillance programmes, but he did reaffirm that‘quality assurance is the main target of collectingoutcome data in ART’. Underreporting, he added, ‘isthe major flaw of data collection and tends to

overestimate treatment effectiveness and tounderestimate safety’. He described live birth rate asthe gold standard measure of ART performance andsimilarly noted that compulsory registries are moreeffective than voluntary - yet many returns, as manymembers at this meeting confirmed, continue to bedrawn from voluntary systems.

In terms of quality assurance, De Geyter identifiedfive trends likely to compromise any hard conclusionsdrawn from EIM data: the patchwork of ARTlegislation in Europe; cross-border reproductive care;treatment by segmentation (notably freeze-all); long-term storage of gametes (such that outcome may notbe reached until long after the started cycle); and thetransport of biological material (in that gametes arenow just as likely to 'travel' as patients).

The challenge for EIM - or any other registry - ishow to incorporate these emerging trends into theonline database. De Geyter suggested an individualpatient code system, which could therefore follow thepatient from stage to stage and site to site. But who tooperate such a system? The EU . . . OECD?

Meanwhile, the immediate challenge is to ensure thatnational registries provide as full and accurate data toEIM as possible, and in this the online data submissionsystem seems already to be playing a useful part.

including the more physiological endometrial development of anon-stimulated cycle, and the improved embryo selectionfollowing PGS/PGD’. By contrast, the update found a slightdecline in the fresh delivery rate, 'likely due to increasing use ofsingle blastocyst transfers'. Maternal age, however, remains 'thestrongest influence' on the success of the cycle. The rate of singleembryo transfers continues to rise (to around 30%), and with it adecline in the twin rate to just under 25%.

The update also identifies three trends not yet manifest in theSART reports: PGS for aneuploidy screening in thawed embryos;embryo transfers with embryos 'accumulated' from more than oneretrieval; and freeze-all approaches for varying indications.� Speaking at the EIM meeting in Brussels reported above, AaronLevine from the School of Public Policy at Georgia Tech and a‘guest researcher’ for the CDC also highlighted the difficulty ofaccommodating cross-border treatments within nationalregistries. Levine said that almost 3% of all US ART cycles in 2013were in non-US residents, though adding that registry attempts tocollect cross-border information from clinics ‘have suffered fromlow response rates and incomplete data’. His disclosures followed astudy of NASS data between 2006 and 2013 of cross-bordertreatments in US clinics which found a high traffic in ‘specialised’procedures such as oocyte donation, PGD and surrogacy.However, the study found no bias in outcome, reportingcomparable rates of embryo transfer and live birth for US andnon‐US residents.

1. Toner JP, Coddington CC, Doody K, et al. Society for AssistedReproductive Technology and assisted reproductive technology in theUnited States: a 2016 update. Fertil Steril 2016: 106: 541-546.


Fertility preservation in femalesRisk assessment and family discussion essential to define strategy

ESHRE has staged two Campus meetings on fertilitypreservation in the past few months, the first inGermany on procedures in males and the second inParis on comparable techniques in females. Both werewell attended - there were more than 150 present inParis in November - reflecting today’s widespreadintent to restore quality of life in cancer patients,especially those diagnosed at a young age. As HamishWallace from the very active Edinburgh group said inParis: ‘Cure is not enough. We must pay attention toquality of life.’

Behind his assertion lay a pattern of increasingcancer incidence - especially in those under 19 - but a‘steady decline’ in mortality, such that around 80% ofcases are now long-term survivors. Thus, while there isstill ‘a very low chance’ of children getting cancer, aproportion of those who do are at high risk ofinfertility. However, said Wallace, it’s not the diagnosisitself which determines that risk, but the stage of thedisease. It’s the stage of disease which determines thetreatment - and that’s where the risk lies.

Overall, the options for fertility restoration in males- as the Edinburgh algorithm below suggests - arefewer and more simple than in females. Semencollection and storage in post-pubertal boys arerelatively straightforward, although testicular tissuebiopsy and cryopreservation, the only option forprepubertal boys, remain experimental. Similarly, theoptions in females depend on puberty and the level ofovarian function in post-pubertal females. Necessaryin all cases, said Wallace, is careful risk assessment andsympathetic family discussion. A starting point for

that discussion, said Wallace, might be the Edinburghselection criteria for gonadal tissue cryopreservation(see box below).

Ovarian tissue cryopreservation remains the onlyviable option for prepubertal girls, while a 2015 reviewof more than 50 transplantations in 41 adult women inCopenhagen showed that grafted ovarian tissue iseffective in restoring ovarian function in a safemanner. The pregnancy rate in this series was about30%. So far, around 60 babies are believed to havebeen born worldwide following ovarian tissuecryopreservation, some from spontaneous conceptionsand some from IVF - and more than half of them inCopenhagen.

In December the world’s first birth was reported inthe UK in a 24-year-old woman born with beta-

CAMPUS MEETING ONCOFERTILITY

This well attended meeting in Paris in November was organised by ESHRE’s SIG Safety & Quality in ART.

The Edinburgh criteria for ovarian tissuecryopreservation.Algorithm for fertility preservation in male and females.1

• Age younger than 35 years• No previous chemotherapy orradiotherapy if aged 15 years orolder at diagnosis, but mild, non-gonadotoxic chemotherapy isacceptable if younger than 15 years• A realistic chance of 5-yearsurvival• A high risk of premature ovarianinsufficiency (>50%)• Informed consent (parent and,when possible, patient)• Negative HIV, syphilis, andhepatitis serology• Not pregnant and no existingchildren


thalassaemia whose ovarian tissue wasfrozen pre-treatment and before her onsetof puberty. The cryopreservation wasperformed in Leeds, and the transplantationin Denmark.

In these difficult prepubertal cases,Wallace explained that AMH is detectablebefore puberty and may thus be importantin risk assessment. AMH levels fall duringcancer treatment (in pre- and pubertalgirls) and recover in those deemed at low ormedium risk of gonadotoxicity. Only whenAMH levels fail to recover might the risk beindicative of future ovarian failure.

Depending on risk assessment, MichaelGrynberg from the University of Parisdescribed oocyte cryopreservation as ‘thebest option for sure’ in female cancerpatients, an established procedurerecommended in guidelines but one clearlycontraindicated in patients recently exposed tochemotherapy (within six months). Given that ovarianstimulation would be necessary to generate sufficientfollicles, Grynberg also noted as contraindications adiagnosis of estrogen-sensitive tumours and ovarian orcervical cancers. He advised that patients should bereferred as early as possible for ovarian stimulation andegg collection before their cancer treatment - and thatstimulation should be performed in an antagonistprotocol (with agonist trigger to avoid OHSS).

Presentations at this three-day meeting, which wasorganised by ESHRE's SIG Safety & Quality in ART,covered preservation of the whole range ofgametogenesis, from primordial and growing folliclesto mature eggs. In vitro maturation, according to themeeting's organiser Daniela Nogueira from theClinique Saint Jean Languedoc in Toulouse, is bestapplied in cases where cancer therapy cannot bedelayed and ovarian stimulation is contraindicated.Follicles, said Nogueira, can be collected either in vitroor ex vivo, with comparable maturation results ifcollected in the luteal or follicular phase of the cycle,but oocyte development potential seems related to thesize of the collected follicle. For example, studies havefound inconsistent patterns of developmentalcompetence from small antral follicles. However, whilemore studies are needed to confirm protocols,Nogueira described IVM as ‘a necessary tool’ in urgentcases of fertility preservation in postpubertal women,with IVM better completed before (and not after)vitrification.

On the emerging question of using oocytes for IVMcollected ex vivo, Ingrid Segers from the VUB Brusselsgroup - and based on very limited data - agreed thatthese oocytes taken from ovarian tissue do seem of‘true benefit to fertility preservation patients’, butefficiency and safety data remain very limited. Shereported a 37% maturation rate (27% in prepubertalgirls and 39% in adults) in Brussels.

Of course, underlying most of these presentations

was this question of safety and whethermalignant cells are or remain present in thecryopreserved material. Mikkel Rosendahl,whose group in Copenhagen probably hasthe world’s greatest experience of ovariantissue cryopreservation, said ‘there willalways be a risk', though so far the real lifeoutcome data seem 'reassuring'. He reportedthree distant relapses from 41transplantations in Copenhagen, a 7%chance of relapse, with the risk apparentlyhighest in leukaemia patients. He thusrecommended evaluation of all cells beforetransplantation, even if the histology wasnormal, with xenotransplantation of ovariancortex likely to be the most accurate ofseveral methods. Isabelle Demeestere fromthe Erasme Hospital in Belgium, whoreviewed the accuracy of markers of

malignant cells in preserved tissue, also stressed theimportance of screening for malignant cells, especiallyin patients with normal histology.

With so many of these safety studies described asanecdotal and limited, there was much talk at thismeeting of the need for a comprehensive registry tomonitor activity. Arianna D’Angelo, Co-ordinator ofthe organising SIG Safety & Quality in ART, in herpresentation on setting up a fertility preservationservice, noted the Oncofertility Consortiumestablished a decade ago in the USA(http://oncofertility.northwestern.edu) and othernational registries in Australasia, Brazil, Japan andFertiPROTEKT in Europe representing activity in 100centres in Germany, Austria and Switzerland (http://fertiprotekt.com). The monitoring and auditingassociated with such registries are essential safetyrequirements, said D’Angelo.

While most of the cryopreservation techniquesdescribed over the three days of this Campus wereessentially exercises in fertility restoration, there wasone presentation on true fertility preservation throughthe adjunctive use of GnRH agonists duringchemotherapy. However, Zev Blumenfeld in presentinga huge amount of data conceded that the evidence forovarian protection during chemotherapy with agonistco-treatment was still controversial, despite its recentincorporation into several guidelines, notably last yearin the clinical consensus of ESMO (European Societyof Medical Oncology). The ‘pendulum’ of evidence,said Blumenfeld, had thus swung towards a positiveeffect, with ‘quite convincing’ evidence displayed inmeta-analyses. Indeed, he said, failure to offer GnRHagonist co-treatment ‘may disadvantage many patientswho could benefit from such a clinical combination’.


1. Anderson RA, Mitchell RT, Kelsey TW, et al. Cancertreatment and gonadal function: experimental andestablished strategies for fertility preservation in children andyoung adults. Lancet Diabetes Endocrinol 2015; 3: 556-567.

Local courseorganiser Daniela

Nogueira describedIVM as a necessary

tool in fertilitypreservation.


IN PROFILE

FoR: You'll be taking over the chairmanshipof ESHRE in Geneva. Will that affect yourclinical career?RF: I retired a year ago as a full-time clinicianin O&G - 30 years as a consultant inLiverpool. I was clinical director forgynaecology with a £25 million turnover andhad a hand in the design of the new LiverpoolWomen’s Hospital, which opened in 1995. Mymain clinical and research interests were - andstill are - in early pregnancy and recurrentpregnancy loss. We set up a miscarriage clinicin 1987, which became a national referralcentre with around 250 new referrals a year.

And do we now have a good explanation forrecurrent pregnancy loss?

We are certainly able to diagnosechromosome disorders more accurately, andthat’s reinforced our understanding thatchromosome disorders are the commonestcause of random miscarriage. But forrecurrent pregnancy loss, there are otherdisorders to exclude, so the chromosomeabnormality rate is lower. But it’s stillsubstantial and requires testing.

And prevention? Would you recommendPGS in recurrent cases?Well, HR recently published a study fromStanford suggesting that expectantmanagement is as effective as PGS. The maintheme of recurrent pregnancy loss is a highspontaneous cure rate, which was first

recorded by Percy Malpas in Liverpool in1938. So treatment intervention is notalways needed and should not necessarilyreplace counselling and patience.

So now you are moving from a lifedominated by these clinical and researchinterests to be Chairman of ESHRE. Willyour life be different now?Yes, different, certainly, but ESHRE is still acomparable and exciting challenge. There’sa lot of good work still to be done inreproductive medicine, and ESHRE, as theworld’s leading organisation in the field, canmake a big contribution - in education,practice, research and teaching. ESHREcan’t do it alone, and there’s much to be saidfor increasing collaboration with all ourpartners, especially those outside Europe.So I think ESHRE now has to take more ofa global view of its function and strategy.

How has a clinical career in Liverpoolprepared you for this? Today, the Chairman of ESHRE is in asenior executive position, and believe methere’s a lot of strategy, change andimplementation required in Britain’s NHS.I've also worked a lot for the RCOG, andwith NICE - so all this has given me a solidfoundation for an executive role in ESHRE.

Taking the wider view‘We must still look at the global nature of

reproductive science and medicine.’

The British gynaecologist

Roy Farquharson will

become Chairman of

ESHRE in Geneva.

He talks to Focus on

Reproduction about his

career in Liverpool and his

view on the challenges

and opportunities now

facing ESHRE.


PROUST QUESTIONNAIRE*� What trait do you most dislike inyourself?Laziness

� And in others?Lack of clarity

� If not Liverpool, where would you mostlike to live?Akaroa, New Zealand

�What’s your greatest extravagence?Good wine

� Which phrases do you most overuse?‘Better to travel in hope than expectation’(RL Stevenson, Travels with a Donkey)

�Which talent would you most like?To play a musicalinstrument

�Where did youspend your latestvacation?New Zealand

� Your favorite non-working pastime?Ballroom and Latin dancing with my wifeKaren, reading and poetry

� Your most treasured possession?A home

� Your favourite writers?Many, but no single choice

�The last film you saw?The Shawshank Redemption. . . again!

�Beer or champagne?Champagne

� Strict exercise or aleisurely stroll?Both in moderation

� Sporting interests?Rowing and watching football

�Your greatest achievement?Being a grandfather

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

You’ve also been very active with ESHRE, sothere’s been a hands-on preparation too. Yes, I've been involved in education, teaching,improving practice and research. In 2005, Ibecame Co-ordinator of the SIG EarlyPregnancy when it was clear that we needed areal update. Our first challenge was tostandardise the terminology - and then wemoved on to an ESHRE guideline. After this,we began our first original work, and slowlydeveloped an international network ofresearch centres. This would culminate in therandomised trial recently published in theNew England Journal of Medicine onprogesterone support in women withrecurrent miscarriage. We can’t say it wasexclusively a SIG study, and funding - £1.6million - came from the research arm of theNHS. But several of the main study centres inthe trial did originate from the SIG EarlyPregnancy.

It's been a very successful SIG in ESHRE'srecent history?Yes certainly. Our guideline on theinvestigation and medical management ofrecurrent miscarriage was one of ESHRE’sfirst guidelines, and shortly after we begancollaborations with other groups in Campusmeetings and precongress courses, both atESHRE and the ASRM. So we’ve been activein research, guidelines and education. Wenow have plans for ultrasound training.

And your next big step in ESHRE was theinvitation to be Chairman Elect. Did youhave any second thoughts?I saw it as a challenge, yes, but don’t forgetthat I’d also spent four years before that as amember of the Executive Committee. Thesewere very informative years for me. Beinggiven responsibility for the accreditation oftraining centres helped me understand whatESHRE was all about in terms of progress,collaboration and ambition. So the truth is Iwas very keen to be approached for ChairmanElect. The Executive Committee’s first formalquestion was whether I’d wear my kilt at theOpening Ceremony. Of course, I said yes - soI guess that was the right answer.

I suppose that raises the question aboutyour Scottish heritage. Scotland, of course, has always played a bigpart in the history of reproductive medicine,and in the history of ESHRE - David Baird,David Barlow as editor of HumanReproduction, Nick Macklon on the presentExecutive Committee . . .

Is there a Scottish characteristic that weshould be looking out for?

I left Scotland more than 30 years ago, so Ihave become quite anglicised. However, earlyon I was told by a colleague that ‘you Scotsare just like haemorrhoids - once you’re downyou stay down and are a constant source ofirritation!’

Well, you will certainly be the first Scot tobecome chairman of ESHRE. Do you seeany obvious challenges ahead?Inevitably, there will be many challengesduring my chairmanship, because that’s whatbeing a chair is all about. Trying to foreseethem all is difficult, so being ready for themis essential - and that requires a quickresponse and flexibility.

So no specific challenge?One of the biggest in my view is to be aWHO-recognised organisation. We need tobe a non-state actor and be sure we have arole. WHO is currently investing in infertilityas a clinical problem and we have to respondto that. The WHO definition of infertility isnot just the inability to conceive but also tomaintain a pregnancy and carry it to a livebirth. So we’re talking about inability toconceive and pregnancy loss, and this reflectsa bigger agenda. It's a whole new portfolio forWHO with investment, and that’s whyESHRE has to be at the table.

But ESHRE has broadened its scope overthe past few years.Yes, ESHRE is a mature organisation but itmust become a more active participant in theglobal setting. There are many countrieswhich look to ESHRE for leadership and wehave to respond to that.

But where does that leave ESHRE members- especially when most are from Europe?The challenge is to listen to the membershipand address the areas they have prioritised. Inthat way we must still look at the globalnature of reproductive science and medicineand also at the young people who are thefuture of the Society. I feel there’s been anunderinvestment in the young membership ofESHRE in terms of attention and support.

So how would you hope to be rememberedas an ESHRE chairman?Two years as Chairman is a short time toachieve big changes, but I would like us tohave improved our relations and activity withother major societies. That might be simplyin the form of workshops or guidelinedevelopment, but with further growth andconsolidation thereafter. A future youngmembers forum would also allow them anopen channel to the Executive Committee.


reimplantation genetic screening (PGS, aka PGD-A), assayingfor chromosomal abnormality in IVF embryos followed by theselective transfer of those thought to be euploid, has beencontroversial from the very beginning. Reports in the UK press

and in a BBC investigation programme in November mention PGSas one of the candidates for ‘unnecessary add-on' treatments offeredby fertility clinics, along with immunology, time lapse imaging andendometrial scratch.1,2,3 On the other hand, both thePreimplantation Genetics Diagnosis International Society (PGDIS)and the Controversies in Genetics (CoGEN) forum have issuedstatements about the sensible use of PGS, along with guidelines onwhat to do when mosaicism is detected. Ten years ago theproponents and opponents of PGS were passionately arguing theircase. Little changes.

The basic rationale behind PGS is sound, and few contest thispoint. We know that a large proportion of embryos are aneuploid(and would not develop, would lead to miscarriage or wouldproduce an affected child) and we have had, for several years, thetechnology to detect aneuploidy in single cells. The question iswhether PGS works in practice given the complications ofmosaicism, for example, and the possible effects of biopsy onembryo development.

COVER FEATURE

PGSin the clinic‘Jacob’ vs ‘Giuseppe’

P

The opposing sides in the great PGS debate seem no closertogether, even ten years after the Amsterdam trial showinglower live birth rates in PGS subjects. Is there a way round

this impasse such that PGS has a legitimate place in today’sIVF clinic? Darren Griffin and Sally Sheldon propose that arevised ‘gentler’ model of evidence-based medicine may

bring together ‘Jacob’ and ‘Giuseppe’, two protagonists stillideologically apart in this PGS debate.


It is now a matter of historical record thatconvincing randomised trial data from about 2007onwards suggested that PGS was ineffective oreven harmful.4-11

With the benefit of hindsight, the decade-longera of cleavage-stage biopsy followed by FISHdiagnosis might have been handled better. Hadsufficient evidence (including single centreretrospective studies, meta-analyses andrandomised trials) been presented earlier andaccepted more readily, there might never have been acontroversy. Equally, the key to broad agreementwithin the clinical and scientific community lies in ourability to react to evidence, improve technology wherenecessary, and consider whether sufficient evidenceexists to advise patients wisely and authoritatively.

In the case of PGS there is broad agreement thatcleavage stage biopsy followed by FISH with 5-7probes had high false positive and false negative ratesand did not have sufficient power to make ademonstrable difference to clinical pregnancy rates.

Equally, sub-optimal biopsy procedures (perhapsclinic or trial-specific) may also have negated (orreversed) any beneficial effect that would have beengained from screening for aneuploid embryos. Indeed,to this day there is ongoing argument about the extentto which the potential harm to patients (reducedsuccess rates) caused by the procedure was a generalphenomenon or peculiar to the team performing thoseparticular studies. A switch to trophectoderm biopsyand to more sophisticated genome-wide analysisprotocols (array CGH, NGS) seems, in the eyes ofmost, to show more convincing results in bothretrospective analyses and prospective (randomised)trials.12,13,14,15

But is there enough evidence to recommend PGS topatients who may often be vulnerable? To address thisquestion, it might be appropriate to consider theunique nature of reproductive medicine in generalamong the panoply of healthcare options. In most (orat least many) areas of reproductive medicine weencounter patients seeking treatments which mightnot be thought motivated primarily by benefit to theirown health. This is rare in medicine. Indeed,reproductive medicine is the only medical discipline inwhich the physiologies of two individuals combine(even if not meet, as in sperm donation) for the solepurpose of producing a third (or fourth, or fifth . . . ).In addition, there can be few fields in whichimperceptible ‘good gardening’ skills of such a largecombination of different academic disciplines

(including clinical medicine,anatomy, physiology, cell biology, genetics,biochemistry, physics, endocrinology, etc.) can havesuch a profound effect on success. With all this inmind, what we consider to be ‘good evidence’ to justifygoing ahead with a treatment is not as easy to defineas, for instance, assessing the efficacy of an antibiotic.

One view of evidence-based medicine (EBM)generally is that a therapy should only be introducedinto the clinic after a double-blind randomisedplacebo-controlled clinical trial. For many standardtherapies (antibiotics are an example) this is entirelyappropriate. Thus, it may not be unreasonable tosuggest that novel IVF treatments should be governedby equivalent strictures. Indeed, in reproductivemedicine, RCTs could be considered a gold standardfor examining the efficacy of procedures such as ICSI,oocyte preservation, testing for sperm DNA damage,time lapse imaging, metabolomic analysis anddevelopment of new culture media. Problems arise inpractice, however, with the classic evidenced-basedmodel. As an example, consider a trial on the efficacyof ICSI (where standard IVF is the control): it is hardto imagine that operators are blinded to the fact thatthey are injecting the embryo.

Perhaps more than in any other area of medicine,therefore, evidence of the efficacy of a protocol change(for example, a small change in culture medium) reliesin part on anecdote and retrospective single centreanalysis as much as on multicentre meta-analysis andprospective RCT data. Clinics (especially privateclinics) depend for their survival and the employmentof their staff and on their ability to innovate quickly.Indeed, it has been suggested that ICSI (perhaps evenIVF itself) would never have been introduced had itbeen subject to the rigours of an RCT before beinglicenced. We can also assume that many new variantson IVF culture media would not be introduced ifsubjected to such a degree of scrutiny.

Moreover, when RCTs are designed (for example,those currently assessing the efficacy of screening forsperm DNA damage), it can often take several years toobtain funding and perform the trial, while the


Our first straw man, ‘Jacob’, is a medical statisticianwho opposes PGS. In this imaginary world, Jacob getsvery angry when he reads any evidence in support ofPGS and will usually find an excuse to criticise it. Hismantra is ‘evidence-based medicine’, advocating thatmore and more complex analyses must be donebefore PGS is put into clinical practice. In his ownpublications, he will be selective about evidence insupport of his point of view.

Our second straw man, ‘Giuseppe’, is a clinicianwho advocates PGS. He is motivated in part by goodpress for his IVF unit and generating income to keepit open. His mantra is ‘I will always do what I think isbest for my patients’ while maintaining that PGS iseffective, whatever the evidence. In his ownpublications he is selective about evidence suggestingthat PGS is ineffective and has made a career out oftreating patients with PGS, always publishing hisfindings that show it in a positive light.

In a reasonable world, we may not always agree, butwe would try to find common ground. Why then dothe Jacobs of this world continue to criticise ordisregard the mounting evidence of the efficacy ofPGS? Why do the Giuseppes not listen to thewarnings of the advocates of EBM? In short, toomany people have built their careers on their ownpoint of view, and backing down is not an easy task.

So what is the solution? First of all, we are not in aposition to apply the ‘mountain model’ of EBM withthe goal of capturing the ‘flag’ that is the placebo-controlled clinical trial. A placebo is near impossibleto achieve. The skill of the operator (or lack of it) cannegate any beneficial effect of the treatment and anyrandomisation can thus be rendered meaningless.IVF is more reliant on ‘good gardening’ skills thanmany other areas of medicine. There is rarely such athing as a ‘blind’ study - do the embryologistsperforming micromanipulation not know they’redoing it? We need to consider that the accumulationof results (for example, retrospective) from singlecentres may be just as useful to the big picture asrandomised trials. We need also to be aware thatmeta-analyses may mask particularly bad (or good)practice by individual clinics.

We thus propose the model of a ‘gentler hill’ (ratherthan a mountain) as an approach to visualising EBMfor PGS and reproductive medicine generally. Ratherthat just simply chopping off the top of the mountainthis model gives more weight to retrospectiveanalyses and case reports to gain a bigger picture ofthe evidence base.

Provided patients are kept informed about the stateof the art with respect to the evidence base for anyparticular treatment (PGS included) and, whencarefully explained to them what the pros and consare at each point on the hill, then they are more in aposition to make their own decisions.

Of course, a reliance on informed consent does notentirely solve the problem. It is important torecognise that patients may not always be good atdealing with complex information; this is a

The standard model of evidence-based medicine, with the summit flagged at itspeak by the double-blind placebo-controlled trial.

Our proposed ‘gentler’ model of evidence-based medicine, developed for thepurposes of reproductive medicine.

benefits of the treatment may already be apparent andthe appetite to perform the trial may have waned. Acontemporary example here is the ESTEEM trial onthe efficacy of array CGH for PGS.15 This is anexcellent study in principle, but one that may never bepublished because of criticisms of its recruitmentstrategy and mixed skill variance in its methodology.In any event, ESTEEM has taken so long that the fieldhas in the meantime moved away from array CGHand towards sequencing. Conversely, a motivation tobe seen as innovative (and one associated withcharging patients for ‘the latest’ therapy) is proposedby some to be sufficient reason for clinics to offer newtreatments, regardless of the evidence supporting theirefficacy. We thus await the outcome of the most recentSTAR trial.16

So where are we with the PGS debate and what’s itsplace in the modern IVF clinic? Whatever theevidence, it seems that the opposing sides are still nocloser to agreement. So, to take a ‘straw man’approach, we mischievously represent the argument ofeach of the sides by creating two imaginary characters(Jacob and Giuseppe) at the extreme ends of thedebate. While such individuals may not represent realworld characters, they do perhaps usefully offer anextreme example of the practices and mind-sets thatare all too present in our clinics.

JANUARY 2017// Focus on Reproduction 25

particularly vulnerable patient group and there aresignificant financial implications for many in pursuingfurther treatment. We do not pretend that this is aperfect solution, but it may be the best on offer.

We need to apply careful scientific judgment androbust evaluation to consider the broader definition ofEBM, namely:

An approach to medical practice intended to optimisedecision making by emphasising the use of evidence

from well designed and well conducted research. But, in the context of reproductive medicine generally(and PGS specifically), what do ‘well designed’ and‘well conducted’ mean? We should perhaps notautomatically assume that EBM = RCT to theexclusion of all else. Indeed, even the model of the‘gentler hill’ pictured opposite could be seen asdeceptive in its acceptance of a clear hierarchy of studymethods. Although RCTs will, and should, remain thegold standard, nonetheless just because a study is anRCT does not mean it is necessarily a good study(especially if badly executed). Equally, just because astudy is not an RCT does not necessarily mean it’s abad study: a well designed study can be badly executedand vice-versa. We need to appreciate that RCTs havealready been performed on the most recent versions ofPGS, mostly showing it in a positive light.

We thus need to understand better and stratify thepatient groups who would ultimately benefit fromPGS. So we should constantly improve our externalquality assessment schemes and consider appropriatelystaged introduction protocols for new innovationssuch as blastocentesis and karyomapping.

We also need to consider the mechanisms ofmosaicism better in the light of therole of meiotic vs. post-zygoticerrors. It is incontrovertiblethat a significantproportion of embryosare mosaic. Butmosaicism can eitherarise from a meioticaneuploidy in whichsome cells becamenormal or from anormal conceptusthat acquired

aneuploidy post-zygotically. A mosaic embryo with ameiotic aneuploidy will either not implant, lead to amiscarriage, lead to obstetric complications or lead toan affected child. It may also display uniparentaldisomy in the ‘normal’ cells. Similarly, an embryo withmultiple chromosome abnormalities will not develop,regardless of how it arose. We should not betransferring these embryos.

Equally, some post-zygotic mosaic trisomies will benormal and we need to get better at detecting these,asking whether they will lead to normal live births orhave an altered reduced chance of implantation. SNPchip analysis (eg, karyomapping) has, in conjunctionwith sequence analysis, the power to distinguish thesemechanisms. In reality, despite the promising results ofthe current PGS trials, the basic question of the level ofaneuploidy in each germ layer in human blastocystshas not been satisfactorily answered.

So, our call to the committees (who often form thearbiters of what is meant by EBM) is to reconsider theEBM model that supports IVF innovation in general(and PGS in particular) in this unique setting, takinginto account the relative value of anecdotal andretrospective studies and the possible pitfallssurrounding reliance on RCTs alone. We should notautomatically assume that an RCT, however welldesigned it was, has necessarily been well performed.

There is much debate on the statistics that need to beused (for example, those which consider that anembryo, once transferred, is an independent variable,which it is not). Innovations are, by definition, newand we may be missing something. The Jacobs of thisworld need to realise that the majority of the IVF

community appear to be convincedby the evidence (RCT and

retrospective analyses)supporting PGS (if theoverwhelming results ofpolls at recent PGDISand CoGEN meetings

are anything to go by).They need to apply their

expertise in refiningthe technique and

making theevidence base

Our men of straw, Jacob, left, and Giuseppe. Jacob is a medical statistician whose mantra is ‘evidence-basedmedicine’ and who is steadfastly opposed to PGS. Giuseppe is a clinician who always puts his patients first and

believes PGS is effective.

even stronger. The Giuseppes of this world must not becomplacent and should realise that we can, and do,often get things wrong.

A final parting shot is this. Against the potential harmscaused by offering a therapy of disputed benefit, weneed always also to consider the implications of notoffering it. A failure to offer PGS means a failure tooffer the opportunity for a patient to avoid a range ofadverse outcomes . Weighing potential harms againstpotential benefits is never easy, nor is it quick.However, with rigorous study and minds that areappropriately open to new evidence, we will get there.

Darren K Griffin is Professor of Genetics, School ofBiosciences, at the University of Kent, Canterbury, UK.Sally Sheldon is Professor of Medical Law at the Universityof Kent, UK.

Acknowledgments We would like to thank Professor Simon Fishel for hiscomments on the manuscript and would particularly like tothank the ‘real’ Jacob and Giuseppe (PhD students inDKG’s lab) for being good sports and allowing theirimages to be used.

References1. Heneghan C, Spencer EA, Bobrovitz N, et al. Lack ofevidence for interventions offered in UK fertility centres. BMJ2016; 355: i6295. doi: 10.1136/bmj.i6295. 2. http://www.dailymail.co.uk/femail/article-3976278/BBC-


Panorama-investigation-finds-lack-evidence-support-effectiveness-pricey-add-fertility-treatments.html3. http://www.dailymail.co.uk/news/article-3930970/The-great-IVF-rip-Clinics-charging-desperate-couples-thousands-pounds-extras-not-work.html4. Mastenbroek S, Twisk J, van Echten-Arends B, et al. Invitro fertilization with preimplantation genetic screening. NEngl J Med. 2007; 357: 9-17.5. Blockeel C, Schutyser A, De Vos W, et al. Prospectivelyrandomized controlled trial of PGS in IVF/ICSI patients withpoor implantation. Reprod Biomed Online 2008; 17: 848-854.6. Hardarson T, Hanson C, Lundin K, et al. Preimplantationgenetic screening in women of advanced maternal age causeda decrease in clinical pregnancy rate: a randomized controlledtrial. Hum Reprod 2008; 23: 2806-2812. 7. Mersereau JE, Pergament E, Zhang X, Milad MP.Preimplantation genetic screening to improve in vitrofertilization pregnancy rates: a prospective randomizedcontrolled trial. Fertil Steril 2008; 90: 1287-1289. 8. Staessen C, Verpoest W, Donoso P, et al. Preimplantationgenetic screening does not improve delivery rate in womenunder the age of 36 following single-embryo transfer. HumReprod 2008; 23: 2818-2825.9. Meyer LR, Klipstein S, Hazlett WD, et al. A prospectiverandomized controlled trial of preimplantation geneticscreening in the “good prognosis” patient. Fertil Steril 2009;91 :1731-1738.10. Schoolcraft WB, Katz-Jaffe MG, Stevens J, et al.Preimplantation aneuploidy testing for infertile patients ofadvanced maternal age: a randomized prospective trial. FertilSteril 2009; 92: 157-62.11. Debrock S, Melotte C, Spiessens C, et al. Preimplantationgenetic screening for aneuploidy of embryos after in vitrofertilization in women aged at least 35 years: a prospectiverandomized trial. Fertil Steril 2010; 93: 364-373.12. Yang Z1, Liu J, Collins GS, et al. Selection of singleblastocysts for fresh transfer via standard morphologyassessment alone and with array CGH for good prognosisIVF patients: results from a randomized pilot study. MolCytogenet 2012; 5: 24.13. Forman EJ, Hong KH, Ferry KM, et al. In vitrofertilization with single euploid blastocyst transfer: arandomized controlled trial. Fertil Steril 2013; 100: 100-7 e1.14. Scott RT Jr, Upham KM, Forman EJ, et al. Cleavage-stagebiopsy significantly impairs human embryonic implantationpotential while blastocyst biopsy does not: a randomized andpaired clinical trial."Fertil Steril 2013; 100: 697-703.15. https://clinicaltrials.gov/ct2/show/NCT01532284.16. https://clinicaltrials.gov/ct2/show/NCT02268786.

Darren Griffinand Sally

Sheldon: ‘Weneed to

understandbetter andstratify the

patient groupswho wouldultimately

benefit fromPGS.’


A new Steering Committee of the PGD Consortium isnow in place. We are grateful to Jan Traeger-Synodinos(past Chair) and Sioban SenGupta for theircontributions over the past years. Edith Coonenstepped down as Chair in November and will stay on asPast Chair. Martine De Rycke is the new Chair. GeorgiaKokkali remains for another term of two years, whileCeline Moutou becomes a special advisor for the onlinedatabase. New members of the Steering Committee areMadelon Meijer-Hoogeveen, Filipa Carvalho andCarmen Rubio. Cristina Magli remains asrepresentative of ESHRE’s Executive Committee andwill be appointed in the coming months.

Data collectionWe are in a time-lag phase and a catch up plan has beenworked out. Data collections XIV and XV (covering2011-12) will be combined in one manuscript, whilesummary data for 2013-2015 will be combined inanother. Both papers are on course. The new onlinedatabase for prospective data collection should beavailable at the end of this year.

Education activitiesIn April last year we organised a well attended and wellreceived Campus workshop in Maastricht titled Allabout preconception, preimplantation and prenatalgenetic testing. This was the first workshop to beorganised in collaboration with the European Society ofHuman Genetics (ESHG), combining the best of bothgroups. A little over 130 participants from 34 differentcountries enjoyed three days of excellent scientificlectures and the renowned Burgundian life. Topicscovered in the preconception genetic testing partincluded the need for carrier screening, geneticcounselling, what results to report, and testing/reporting strategies.

The prenatal genetic testing parts included a state-of-art lecture on NIPT and a debate on whether allpregnant women should be offered prenatal genome-wide testing. The meeting further highlightedimportant topics such as EQA and physician liability,and non-invasive genetic testing. Finally, thepreimplantation genetic testing section comprised anupdate lecture on application of genome-wide analysistechniques alongside lectures on blastocoelic fluid assource of DNA for PGD, predictive value ofmitochondrial DNA, predictive value of cumulus cellanalysis, metabolomics/proteomics and EQA.

Following an interactive webinar on trophectoderm

biopsy hosted by Georgia Kokkali in December, anothertwo webinars have been selected for PGD Consortiummembers; a first about NGS-based technologies inPGD/PGS and a second on blastocentesis planned forearly 2017.

As 2017 marks the 20th anniversary of the PGDConsortium, a celebration Campus event is planned inDecember. Here we will pay tribute to many key playersin the field - and also look back to the early days fromthe perspectives of counselling, biopsy and technologies,The meeting will also be an opportunity to report on thecurrent state-of-the-art, and to look ahead at what thefuture holds for PGD and PGS.

Martine De RyckeChair, PGD Consortium

PGD CONSORTIUM

The new Steering Committee of the PGD consortium met in Brussels inNovember. The committee comprises, from left to right, Filipa Carvalho (PT),

Veerle Goossens (ESHRE), Carmen Rubio (ES), Celine Moutou (FR), EdithCoonen (NL, Past Chair), Martine De Rycke (BE, Chair), Madelon Meijer-

Hoogeveen (NL) and Georgia Kokkali (GR).

A new SteeringCommittee appointedand now in place

Filipa Carvalho isAssistant Professor of

Genetics at theUniversity of Porto,Portugal. She is a

previous Deputy ofESHRE’s SIG

Reproductive Genetics.

Madelon Meijer-Hoogeveen, is Medical

Coordinator for PGD anda fertility physician atthe University Medical

Center, Utrecht. She hasworked in PGD since

2009.

Carmen Rubio is Directorof the PGS and

molecular cytogeneticslaboratory at

IGENOMIX Valencia,Spain. She has long

experience in the field ofPGD and PGS.

New members


CERTIFICATION IN ENDOSCOPY

ECRES, the ESHRE Certification of ReproductiveEndoscopic Surgery, remains the only internationalcertification programme in reproductive endoscopicsurgery and is now moving into its fourth year. Theelectronic certification platform enables the quickinsertion of data by applicants, and fast and accurateadministration by ESHRE Central Office. Theprogramme’s e-log books, as well as the ‘e-loading’ ofunedited videos, works very well and the systemfacilitates efficient reviewing, which is performed by atleast two reviewers; if there is more than a 30% scoringdifference, a third reviewer is asked to score.

At last year’s Annual Meeting in Helsinki 21colleagues applied for ECRES, 16 applicants at thePrimary level and five at the Master level. The tenendoscopic stations used for the certification processhave also been used for training and testing sessions -and more than 30 doctors received the 3-hour trainingsession in hysteroscopy and laparoscopy. Theparticipants were happily surprised by their rapidlyacquired skills in such a short time of training andasked for further information about proper trainingsessions. Thus, ESHRE’s SIG Reproductive Surgeryprovides twice yearly courses in Leuven onreproductive endoscopic surgery, with lectures andhands-on-training. A reading list and an e-learningplatform are provided on the ESHRE website forECRES applicants.

The ECRES committee has increased the number ofprogramme tutors, who in 2016 included ProfessorStephan Gordts, Professor Grigoris Grimbizis,Professor Anis Feki, Dr Sylvie Gordts, Dr PietroGambadauro, Dr Jaana Seikkula, Mrs SannaMustaniemi, Dr Razvan Socolov, Professor GeorgePados, Professor Michelle Nisolle and ProfessorVasilios Tanos.

ECRES certification programmeECRES now offers TESTT, 100 multiple-choicequestions designed to test theoretical knowledge infundamental areas of endoscopy and in specific areas ofexpertise according to the level. As with the onlineMCQs of the Winners Project for gynaecologicalendoscopy, the TESTT questions are constructedaccording to universally accepted rules and guidelinesand were centrally reviewed by European experts.

Practical endoscopic skills examTesting endoscopic skills includes three training

Testing for the ECRES certification in endoscopy:The skills and theoretical exams explained

� ESHRE certification programme now moving into its fourth year

models: Laparoscopic Skills Training and Testingpackage (LASTT®); Suturing Training and Testingpackage (SUTT®); and Hysteroscopic Training andTesting package (HYSTT®).

LASTT®. Three exercises measuring the ability of anindividual to correctly handle the laparoscopicinstruments. The exercises have proven construct andcontent validity.1,2,3 Results are expressed as the timeneeded to perform the exercise correctly. This single,objective parameter reflects both judgement error andmovement efficiency. Misplacements or inappropriateobject handling result in time delay and reduceperformance scores. Thus, time limits are imposedduring testing. When an exercise is not completedwithin the time limit, the last accomplished task isrecorded. Each exercise has to be performed threetimes to be able to calculate the mathematicalgorithmic final score. Both the consecutive runs andscore calculation are based on a large benchmarkdatabase of expert laparoscopic surgeons.

SUTT®. The SUTT module tests for complex and finelaparoscopic skills, like needle manipulation, intra-corporeal knotting, cutting, and tissue approximation.The candidate must use both the dominant and non-dominant hand. The exercises are performed in astandard pelvi-trainer with a 0°, 10-mm optic and two


needle holders. The trainee can initially locate andinsert the trocars as preferred, but thereafter theycannot be repositioned. The camera is manipulated byan assistant. The SUTT II pad is designed for theECRES Primary level. It provides four exercises:stitching with both the dominant and non-dominanthands targeting eight dots in a predefined pathway;stitching and knot tying with the right and left hand;vertical stitching, tissue approximation; knot tyingwith the dominant hand. The exercises are evaluatedwith several criteria: the time to perform the fullexercise, correct needle manipulation through apathway of predefined dots, knot quality, tissueapproximation, and absence of trauma. Testproficiency confirms that the candidate possessessufficient, fine LPSs, including stitching andintracorporeal knotting.4

HYSTT ®. Two exercises measuring the psychomotorability to perform hysteroscopy. The HYSTT modelsimulates a normal uterus, with correct spatialdistribution and orientation of the different planes andangles. The exercise is done with a 2.9 mm 30° optic,housed within a 5 mm hysteroscopic operative sheet,using a 5 French grasping forceps, and without the useof distention medium.

The first exercise, camera navigation, consists ofidentifying and correctly positioning several differentsmall targets which are placed in random order withinthe model. The trainee must manipulate the optic suchthat the depicted character is displayed within a ringpositioned on the monitor. The assistant or mentorindicates the anatomical position of the target andaccepts the correctness of target positioning beforegoing to the next one. In order to provide a score, theexercise needs to be done three times and the finalscore is calculated using the same principle asdescribed for the LASTT calculation.

The second exercise measures instrument handlingand hysteroscopic skills. Fourteen pin objects areavailable in the trainer model and must be picked upand released within the cavity of the model. Again,time for correct performance is the outcome measure.

The +he Academy online scoring system All results are registered in a cloud-based onlineplatform and the scores are calculated automatically. During testing sessions the individual receives detailedinformation on each exercise performed.

Testing sessionThe Academy has developed a unique and dynamiconline scoring platform to register participants’ dataand test results in a central database. For each

participant, the previous exposure to gynaecologicallaparoscopy is registered and documented accordingto a scoring system of three groups: G1, one or lessthan 30 procedures as an assistant (= minimal); G2,more than 30 procedures as assistant but less than 50as first surgeon OR more than 50 as first surgeon butless than 200 (= intermediate); G3, more than 200endoscopic interventions as first surgeon (= major)

All tested individuals with large experience (G3) areused as reference values to calculate the groupallocation.

The central database provides an online calculationof the results and an appreciation of the skills of theparticipant with a colour code. The green codeindicates an excellent level of proficiency and isassigned to results within two standard deviations ofthe reference values. The yellow code indicates fairskills and is assigned to results between 2 and 4 SD ofthe reference values. The red code indicates that thereis still a lot of room for improvement and is assignedto results more than 4 SD of the reference values.Thus, the final skill passport provides a global pictureof psychomotor skills and can be used as an objectivecriterion to enter different training programmes. Thebenchmark database is continuously supplied with testresults of the first test of an individual and saved inrelation to its score of exposure to laparoscopy at thetime of the test procedure. Therefore, the database isdynamic and the cut-off values can change over time

Certification and scoringThe online scoring platform provides the examinerwith results of all tests performed. If more than twored scores are present, no deliberation is possible and afail is automatically generated. In case of one red scorethe examiner or the committee has to make ajudgement individually. The ECRES committeereviews all individual complaints every September.The overall result is displayed with a colour code toindicate the competence level.

Vasilis Tanos Co-ordinator ECRES, for the ECRES Committee

1. Molinas CR, Win G, Ritter O, et al. Feasibility andconstruct validity of a novel laparoscopic skills testing andtraining model. Gynecol Surg 2008; 5: 281–290. 2. Campo R, Reising C, Belle Y, et al. A valid model fortesting and training laparoscopic psychomotor skills. GynecolSurg 2010; 7: 133–413. The European Academy of Gynaecological Surgery.http://www.europeanacademy.org/Gynaecological_Surgery.html (accessed Dec 27, 2014). 4. Campo R, Molinas CR, De Wilde RL, et al. Are you goodenough for your patients? The European certification modelin laparoscopic surgery. FVV in ObGyn 2012; 4: 95–101.

EIM CONSORTIUM

The urgent need for reliable up-to-date data


In an attempt to catch-up on previous delay in ourdata collections and annual reports on ART activity inEurope, we have now published our reports on 2011and 2012 data.1,2 Their results show that the overallnumber of ART cycles in Europe continues to growyear by year, that pregnancy rates in 2012 remainedstable when compared with those reported for 2011,and that the number of transfers with multipleembryos (3+) and multiple delivery rates were lowerthan ever before.

Now, taking advantage of the new electronicplatform designed specifically for EIM datasubmission, the 2013 report is almost ready and wehope to have it published in the first months of 2017.It will break an EIM record, with 38 countriescontributing with their registry data. Data collectionfor 2014 is now well on its way and we will be pleasedto see data from a more complete registry in Spain.

As reported in last September’s issue of Focus onReproduction, a new requirement for all Spanish clinicsto submit cycle data to a Ministry of Health registryrun by the Spanish Fertility Society has seen a hugeescalation in the number of clinics reporting data andin the number of cycles recorded in Spain. ProvisionalEIM data presented in Helsinki for 2013 recorded just78,152 cycles submitted from Spain (and 164 clinics).Now, in the latest figures for 2014 calculated by theSpanish Fertility Society, the number of clinicsreporting (ART and IUI) has risen to 278 and thenumber of ART cycles performed to a remarkable totalof 116,688.

Data requirements for an effective registryIn support of our continuing efforts to help countrieswith a non-robust or even non-existent nationalregistry, a ‘core dataset’ as a prequisite for registrydevelopment has been defined by Markus Kupka andcolleagues from the EIM Steering Group. The three-page PDF, with simply described fields andparameters, is now posted under open access on theEIM page of the ESHRE website.

A complete and reliable European ART registry inthe future is a very hot topic for EIM. At the politicallevel we have stressed to the ESHRE Chairman and theExecutive Committee the importance of convincingthe European Commission and its institutions that ourexpertise and experience with registry data makeESHRE a natural partner of the Commission inevaluating the safety and quality of ART in Europe.This idea has been well received by the ExCo, andboth informal and formal contacts have made betweenESHRE and Commission representatives on thissubject in recent months.

However, we have a very real concern that the greatchanges now taking place in the clinical performance

of ART may run the risk of making the classical type ofregistry obsolete. A forward-looking paper on thissubject has now been published by some of the EIMSteering Committee members under the initiative ofChristian De Geyter, Chairman Elect of theConsortium.3 The report argues that ART nowincludes so many more diverse approaches with‘sequential’ results (eg, short- or long-term freezing ofgametes, gonadal tissues or embryos, and cross-borderreproductive care) that the conventional parameters ofART registries may no longer be comprehensive. Thus,long-term cumulative treatment rates and aninternational approach are urgently becoming anecessity.

As reported on page 16 of this issue, most membersof the EIM Consortium met in Brussels to exchangeexperiences, confront their different problems and tryto find solutions for them. Dealing with such rapidlychanging parameters in ART was just one suchproblem.

In our activities next year - in addition to an evergreater collection of data and publication of our 2014annual report - we plan to perform a survey on thedifferent legal and public funding provision of ART inEurope. We will also co-host an ESHRE Campusmeeting in Helsinki with the SIGs Safety & Quality inART and Global and Socio-cultural Aspects ofInfertility. We hope this initiative will highlight therelevance of data collection in the field and the need toimprove the quality of registries in European countries.

Carlos Calhaz-JorgeChairman EIM Consortium

1. Kupka MS, D'Hooghe T, Ferraretti AP, et al. Assistedreproductive technology in Europe, 2011: results generatedfrom European registers by ESHRE.Hum Reprod 2016; 31: 233-248. 2. Calhaz-Jorge C, de Geyter C, Kupka MS, et al. Assistedreproductive technology in Europe, 2012: results generatedfrom European registers by ESHRE.Hum Reprod 2016; 31: 1638-1652. 3. De Geyter Ch, Wyns C, Mocanu E, et al. Data collectionsystems in ART must follow the pace of change in clinicalpractice. Hum Reprod 2016; 31: 2160-2163.

EIM ConsortiumChairman Carlo Calhaz-Jorge: A concern that theclinical changes nowtaking place in ART raisethe risk that traditionalregistry parameters willbecome obsolete

SIG ENDOMETRIOSIS AND ENDOMETRIAL DISORDERS

Upcoming events planned for a busy 2017

The SIGEED has a full and excitingprogramme of educational eventsplanned for 2017. In Sofia, Bulgaria,from 27-28 January, we are hosting aCampus workshop on Effects of ARTand endometriosis on pregnancyoutcome. This is a joint venture withthe SIG Implantation and EarlyPregnancy.

On 17 May we are running a jointESHRE/ASRM precongresscourse prior to the 13th World Congresson Endometriosis(www.endometriosis.ca/wce2017) inVancouver, Canada. This is a half-daycourse titled Unravelling the mystery ofinfertility and endometriosis.Registration for the congress (early bird)

closes on 31 January. On 2 July we will be holding our own annual

precongress course ahead of the ESHRE AnnualMeeting in Geneva on Endometrial receptivity.

From 18 -19 September this year we are running aCampus workshop on Methodological approachesfor investigating endometrial function andendometriosis in Edinburgh, another joint venture ofthe ASRM and SIGEED.

And to close the year we are joining the SIGs EarlyPregnancy and Safety & Quality in ART to run ahands-on practical Campus on Ultrasound in assistedreproduction technologies (ART) and earlypregnancy: blended training approach. This will takeplace on 16-17 November 2017 in Cardiff.

Our SIG Steering Ccmmittee had avery successful and productive meetingin October in Milan where we wereable to review our plans for meetingsthroughout 2017 and beyond, discussproposals for plenary sessions and ourprecongress course for the 2018Annual Meeting, and review andupdate the contents of our website. Ifany SIGEED member has any feedback

about our educational events or ourwebsite please contact a member of the committee.Our next face-to-face meeting is planned for July inGeneva.

The WERF Endometriosis Phenome and BiobankingHarmonisation Project toolsAs many of you will be aware, we supported the WERFEndometriosis Phenome and BiobankingHarmonisation Project (EPHect). This aims to enablelarge-scale, cross-centre, epidemiologically robustresearch into the causes of endometriosis, noveldiagnostic methods, and better treatments, through thedevelopment of (1) standardised detailed clinical andpersonal phenotyping data collection instruments, and(2) Standard Operating Procedures (SOPs) forcollection, transport, processing, and long-term storageof biological samples.

Initial development involved collaboration between34 academic institutions and three medical/diagnosticcompanies. The resulting data collection instrumentsand sample collection protocols were published inFertility and Sterility in 2014 (Fertil Steril 2014; 102:1213-1222, 1223-1232, 1233-1243, and 1244-1253). andare freely available at http://endometriosisfoundation.org/ephect. The tools are designed to facilitate thedesign and interpretation of collaborative studies acrossthe entire endometriosis research field, includingstudies into its pathogenesis and identification ofdisease sub-types, biomarker and targeted treatmentdiscovery, and assessment of treatmentoutcome/effectiveness in clinical trials.

Based on user feedback, as well as further systematicsearches, the tools are reviewed every three years andupdated where necessary. The next round of review ishappening this year, with results to be presented at theWorld Congress of Endometriosis in May. If you areusing the tools and would like to provide feedback, wewould like to hear from you athttp://endometriosisfoundation.org/ephect/#3.

Andrew HorneCo-ordinator

SIG Endometriosis and Endometrial Disorders


STEERING COMMITTEEAndrew Horne (GB), Co-ordinatorCarla Tomassetti (BE), Deputy Andrea Romano (NL), DeputyAntonio Simone Laganà (IT), Junior DeputyGerard Dunselman (NL), Past Co-ordinatorKrina Zondervan (GB), Basic Science OfficerLone Hummelshoj (GB), International Officer

SIG’s support for WERF harmonisation project

SIGEED Steering Committee members in Milan, left to right, Gerard Dunselman,Krina Zondervan, Andrea Romano, Andrew Horne, Carla Tomassetti, Lone

Hummelshoj and Antonio Simone Laganà.


SIG SAFETY AND QUALITY IN ART3

Consideration of guidelines on ultrasound standards

We aim to achieve our educationalgoal by promoting scientificinformation on safety and qualitythrough the events we organise,mainly precongress and Campuscourses. We hope that participantswill learn to identify and mitigaterisks with user-friendly tools to driveimprovement in ART practice.

Recent and upcoming eventsWe held a very exciting Campus course in Septemberwith the SIGs Ethics & Law and Stem Cells on Novelgamete manipulation technologies in ART: SEEM(safety, ethical, efficient, moral) OK? The meetingtook place in Amsterdam and focused on some of therecent breakthroughs in gamete manipulationpublicised as possible new treatments for infertilepatients. The meeting, which is reported in detail onpage 7, proved very interactive, with much time forstimulating discussion.

On a more clinical subject, we organised in Paris inNovember a very well attended course on Innovativecare and technologies for female fertilitypreservation. The course, again reported in this issueof Focus on Reproduction, had a pragmatic emphasisand described the development of multidisciplinarycryobiological platforms and the use of differentfertility preservation approaches dependent ongonadotoxic urgency. Different strategies appropriateto specific patient groups and oncology conditionswere described along with their risk/benefit balanceand ethical considerations. Oncofertility, although aspecific sub-speciality in fertility centres, is still anextremely topical subject and draws much attentionamong fertility and non-fertility specialists.

Both these events are now available on the e-learning ESHRE platform.

Plans for our precongress course inGeneva - Transgenderism andreproduction: State of the art infertility options for transgender andpeople with sex reassignment - arenow complete. The course has beenjointly organised by the SIGs Safety &Quality in ART, Psychology &Counselling, Ethics & Law and Globaland Socio-cultural aspects in ART.

Despite pervasive discrimination andinvisibility, transgender people have in recent yearsexperienced significant advances in social acceptanceand media attention. Reproductive transgender care is atrue niche in the ART community, and it is clear thatmore and more people are ‘coming out as trans’ and willmake their wishes known at ART centres. Ourprecongress course will be a first for ESHRE to bringtogether experts in this specialty.

A Campus course titled What can we learn fromART disparities in Europe? Safety, quality and socio-cultural factors is being organised with the EIMConsortium and the SIG Global and Socio-culturalAspects of Infertility to take place in Helsinki on 28-29September this year. It aims to provide up-to-dateinformation, interpretation and discussion on treatmentpatterns and trends in fertility treatment in Europe.Data buried in national registries have the power toreveal many interesting perspectives on fertilitytreatment, not only from laboratory/clinical point ofview but also economical. Outcome parameters can belinked to health of the children and global socio-cultural trends.

Finally, on 16-17 November the first hands-onCampus course on ultrasound in ART and earlypregnancy will take place in Cardiff (UK). This course isa joint venture between ESHRE and the British Societyof Gynaecological Imaging (BSGI) and will usesimulators to learn or improve USS skills. Because of itspractical nature the course will be limited to 70participants on a first-come first-served basis.

Ultrasound guidelines, EU projectWe have plans to develop a new ESHRE guideline onprofessional working standards in ultrasound practice.Ultrasound plays an important role in the managementand treatment of women with gynaecological problems,with difficulties to conceive and in early pregnancy.However, it seems that current standards in performingbasic ultrasound examination and interventionss are notwell defined. Safety and quality aspects of interventionalultrasound guided procedures (cyst drainage, folliclereduction, HyCoSy/saline sonography) and

Involvement in a new EU ‘work package’ on tissue and cells in ART

STEERING COMMITTEEArianna D’Angelo (GB), Co-ordinatorKelly Tilleman (BE), Deputy Ioana Rugescu (RO), DeputyZdravka Veleva (FI), Junior DeputyWillianne Nelen (NL), Past Co-ordinatorAugusto Semprini (IT), International AdvisorDaniela Nogueira (FR), Basic Science Officer

SQART SteeringCommittee at theParis Campus:Willianne Nelen,Iona Rugescu,AriannaD’Angelo, KellyTilleman,DanielaNogueira,Zdravka Veleva,and AugustoSemprini.


transabdominal embryo transfer are notcovered in a uniform way across countries.Three SIGs (SQART, Endometriosis andEndometrial Disorder, and Implantation &Early Pregnancy) have met to explore thepossibility of developing a guideline tostandardise practice. Before embarking onsuch an ambitious project, we would like toask your opinion on this matter. Is there arole for ESHRE to collate the differentrecommendations given by the othersocieties and develop standards ininterventional ultrasound that could beimplemented in Europe and beyond?Please answer the quick questionnaireand let us know your views. Complete thequestionnaire at https://www.surveymonkey.co.uk/r/ESHRESurveyUSS.

We are also pleased to report that ESHRE will beinvolved in a very important EU project, Euro GTPII

(www.goodtissuepractices.eu), a three-yearproject to set up a schedule of good practicesapplied to tissues and cell preparation andpatient follow-up procedures. Our deputy,Kelly Tilleman, is work package leader for ARTin this project and together with ESHRE andan international team, she will embark on thisproject later in 2017. The project aims toprovide practical tools to assist tissue and cellcentres in the implementation of requirementsdefined for the assessment and verification of thequality, safety and efficacy of therapies usinghuman tissue and cells. The specific ART workpackage - ‘good practices for demonstrating safety& quality through recipient follow-up in ART’ -aims to determine essential criteria for the

implementation of ART products or clinical ARTapplications, including a risk assessment tool for ART.

Arianna D’Angelo Co-ordinator SIG Safety & Quality in ART

Upcoming eventsPlease don’t forget to submit yourabstract for the next Annual Meetingin Geneva. which must be donebefore 1 February. I am sure that theAnnual Meeting will yet again be agreat opportunity to shareexperiences and learn more about

very recent research in the area (andalso to taste the Swiss chocolate).

Our precongress course in Geneva will be on fertilityawareness and should provide (a) an understanding ofwhy fertility awareness is linked to infertilityprevention, (b) an in-depth understanding of the levelsof fertility awareness among people of reproductive agein Europe, (c) an update on evidence-basedinterventions to increase fertility awareness, and (d) anupdate on evidence-based interventions for fertilitydecision-making. We are looking forward to seeingyou there. We are also preparing other Campusmeetings, and will have definite news soon.

Juliana PedroJunior Deputy SIG Psychology & Counselling

A recent highlight of the SIGPsychology & Counselling was aCampus basic training course forinfertility counselling held in Vienna,at the end of October. The coursecovered many of the issues related tocounselling in infertility, providinghighly attractive content topsychologists and counsellors. The hands-on workshops were a good opportunity todiscuss counselling in third-party reproduction,gender differences, bereavement in the course ofinfertility process and the evidence-based approachesto infertility counselling. High-quality speakerscontributed to an increase in the knowledge ofeveryone present in the workshops.

A diverse group of participants was present:clinicians, nurses, students and others. Most were verysatisfied with the content of the course. The majorityreported that what they had learnt was important andwould have an impact on their work. The groupdiscussions were perceived as very useful for their ownpractice. For those unable to be present, all the contentwill be available for members on the ESHRE website.

SIG PSYCHOLOGY & COUNSELLING

STEERING COMMITTEESofia Gameiro (GB), Co-ordinatorMariana Martins (PT), Deputy Giuliana Baccino (ES), DeputyJuliana Pedro (PT), Junior DeputyUschi Van den Broeck (BE), Past Co-ordinator

‘Fertility awareness’ is our precongress topic for Geneva


SIG STEM CELLS3

The full cycle of germline development in vitroRecent and upcoming activitiesOur recent Campus event on Novelgamete manipulation technologies inART held in Amsterdam in Septemberwas very well received with close to 100attending. As our report on page 7indicates, three of the currently hotresearch topics in ART were covered(nuclear and mitochondrial transfer,stem cell derived gametes and genomic editing),which led to a lively debate and discussion.

This year, the SIG Stem Cells precongress course inGeneva will concentrate on the crosstalk and overlapbetween ‘human embryology’ and ‘human embryonicstem cells’. First presentations will be on the influenceof embryo quality and culture conditions on bothhuman embryonic development and embryonic stemcell derivation. Next, recent genome widetranscriptomics performed at the single cell level inhuman embryos by two pioneer labs (in theNetherlands and in Sweden) generated fascinatingnew insight into how human embryonic developmentis regulated.

We are now planning a further symposium in late2017/early 2018 on In vitro modelling: from embryoto gametes behind which lie the many and bettersystems now being developed which allow the studyof processes such as embryo implantation in vitro.

BreakthroughsIn a real tour de force, the Japanesegroup of Katsuhiko Hayashi working ina mouse model has produced eggs fromwhich fertile pups could be obtained in agermline cycle starting from pluripotentstem cells. Through a fascinating three-step in vitro culture system, both

embryonic stem cells and inducedpluripotent stem cells were developed to generatefunctional oocytes - and embryonic stem cells derivedfrom these IV-developed eggs could in turn generateeggs, thereby completing the reproductive cycle

This is a remarkable achievement, to enable in vitrothe production of functional mouse oocytes over andover again entirely in a petri dish, and to achieve thiscompletely in vitro without in vivo steps.

If the process can be translated into the human,which is thought to be more difficult than in themouse, de novo eggs from patient’s own stem cellscould be produced, which would revolutionise theentire field of female infertility. However, we still needto recognise that the efficiency of obtaining offspringfrom these in vitro generated oocytes was much lowerthan their control counterparts. So much moreresearch is warranted before we can even think ofpossible clinical applications in human.

Björn HeindryckxCo-ordinator SIG Stem Cells

STEERING COMMITTEEBjörn Heindryckx (BE), Co-ordinatorCristina Eguizabal (ES), Deputy Susana de Sousa Lopes (NL), DeputyMieke Geens (BE), Junior DeputyRita Vassena (ES), Past Coordinator

pregnancy outcome, will take placein Sofia, Bulgaria, and will explorethe effect of ART and endometriosison pregnancy outcome. Both localand international speakers areparticipating.

One of the SIG’s main current aimsis to improve education and trainingin the ultrasound diagnosis of early

pregnancy problems. We are thereforepleased to announce our first theoretical course onThe role of ultrasound in early pregnancy as part ofthe precongress programme at this year’s AnnualMeeting in Geneva in July. The first practical courseis planned for November in Cardiff, UK.

Emma KirkCo-ordinator SIG Implantation & Early Pregnancy

In October the SIG Implantation &Pregnancy represented ESHRE indeveloping and hosting a precongresscourse at the ASRM’s 49th AnnualCongress in Salt Lake City. The course,titled Optimal Prevention andDiagnosis of Miscarriage, was anupdate of new advances in imaging andclinical concepts of miscarriagediagnosis and prevention. There weresome excellent interactive presentations onnomenclature, miscarriage diagnosis and themanagement of recurrent pregnancy loss.

On 27-28 January we will host our WinterSymposium, this year in collaboartion with the SIGEndometriosis and Endometrial Disorders. Themeeting, titled Effects of ART and endometriosis on

SIG IMPLANTATION AND EARLY PREGNANCY3

Ultrasound a focus of this year’s training programmeSTEERING COMMITTEE

Emma Kirk (GB), Co-ordinatorPetya Chaveeva (BG), Deputy Bettina Toth (DE), DeputyMerel van den Bergh (NL), Junior DeputySiobhan Quenby (GB), Past Co-ordinatorMaria Krog (DK), Basic Science Officer


SIG EMBRYOLOGY3

ESHRE/Alpha KPI projectThe SIG Embryology, designatedESHRE members and the Alphascientists in embryology are sharingtheir best expertise to formulate aconsensus on key performanceindicators (KPIs) in the IVFlaboratory. A meeting was held inSeptember in Vienna wheredefinitions of KPIs were proposed foroocytes, sperm, fertilisation, cleavage, blastocysts andPGS/PGD. The workshop included expert opinion anddata from questionnaire responses from IVF labs andnational embryology societies. A consensus wasestablished, with minimum performance levels for eachKPI representing the basic competency andaspirational benchmarks of each as a best practicetarget.

At this stage, a consensus document on the outcomeof the workshop is being finalised by ESHRE andAlpha. We would like to thank Alpha and therepresentatives of national societies for theircollaboration in this major and ambitious project. Weare also grateful to the ESHRE Chairman KerstiLundin, the SIG Committee Chair Cristina Magli,ESHRE’s scientific officer Nathalie Vermeulen andESHRE members Arne Sunde and Alison Campbell fortheir participation and support.

Optimising IVF successOur collaboration with the Paramedical Group in aCampus meeting in Gothenburg in November proved avaluable opportunity for the 108 participants -laboratory technicians, embryologists and paramedics -to improve their understanding of basic biology andembryogenesis and update their knowledge oflaboratory techniques. Participants also had theopportunity to attend hands-on workshop sessions in

time-lapse and cryopreservation,and to discuss quality control in theIVF lab. Overall, a very large panelof topics was addressed during thethree-day programme, withadditional sessions on basicstatistics, how to review and writean article, and troubleshooting.

Forthcoming activitiesThe beautiful city of Milan will be host to our nextCampus on 11-13 May covering those aspects ofgamete development to implantation which aresensitive to the time factor. Carlos Plancha and DavidAlbertini will provide a comprehensive overview ofthe kinetics of oocyte development and how ageingdoes adversely affect its quality. Chris Barratt will alsoexplain how culture may have an effect on spermover time with a potential impact on fertilisation andembryo development. The target audience coversclinical embryologists, reproductive biologists andART specialists. Places are still available and thedeadline for abstract submission is 9 April.

Cellular and molecular biology for clinicalembryologists is the topic of our precongress coursefor Geneva. This advanced course is planned to be ofmajor scientific interest and will be open toembryologists, andrologists, technicians andclinicians aiming to improve their understanding ofthe cellular and molecular factors in gamete andembryo function. David Albertini, Keith Jones andMarie-Helene Verlhac will review molecular functionin oocyte division and maturation while Chris Barrattwill address the changes which sperm must undergobefore fertilisation. Catherine Combelles will describethe fertilisation process and why fertilisation failureoccurs in IVF. Eva Hoffmann, Roger Sturmey andAntoine Peters will consider the preimplantationembryo.

From gametes to blastocyst is a Campus takingplace in Edinburgh on 12-14 October and co-organised with the SIG Reproductive Genetics. Thiscollaboration has designed a high-level scientificprogramme covering all aspects of gamete maturationand selection for IVF through embryo developmentand function to fertilisation. This three-day meetingwill also be marked by breakout sessions on clinicalcases led by Danny Sakkas and Chris Barratt. Thesesessions will address lab problems seen in dailypractice - fertilisation failure, atypical embryodevelopment, etc.

Giovanni CoticchioCo-ordinator SIG Embryology

Key performance indicators in the IVF labSTEERING COMMITTEE

Giovanni Coticchio (IT), Co-ordinatorSophie Debrock (BE), Deputy Susanna Apter (SE), DeputyDebbie Montjean (FR), Junior DeputyRoger Sturmey (GB), Science OfficerMaria José De los Santos (ES), Past Co-ordinator

Milan, hostcity for ourMay Campuson the timefactor ingamete andembryodevelopment.

36 Focus on Reproduction // JAMUARY 2017

Historicalperspective inHelsinki: Past

and present SIGRE Co-ordinators

(Kolibianakis,Griesinger and

Broekmans) withJunior Deputy

Giorgios Lainas.

SIG REPRODUCTIVE GENETICS3

The year 2016 was very active for theSIG RE. With a very well attendedprecongress course on Managing thedifficult IVF patient, a combinedCampus meeting with the SIGReproductive Surgery, and a veryenthusiastic start for the guidelinedevelopment group on OvarianStimulation For ART, first in Helsinkiat the Annual Meeting and then for astart on the real work in Brussels inNovember, the SIG RE has continued its efforts inpromoting education and consensus in good infertilitytreatment practice.

Business mattersFollowing directives from ESHRE’s ExecutiveCommittee, we have welcomed two new members tobroaden the scope of the Steering Committee. RoyHomburg, as International Advisor, and Jenny Visser,as Basic Science Officer, have accepted a role in fieldswhere decisions may be difficult and to promote basicresearch in our educational programmes.

Lastly, and notably, Michael Grynberg and DrorMeirow, two members of the International Society forFertility Preservation, have joined the SIG RE; theirknowledge not only of fertility preservation per se butalso of ovarian function and the effects of oncologytreatment on folliculogenesis and ovarian reserve willbe invaluable in developing our future programmes.

This year will also see the effects on daily practice ofthe two large IVF trials on the individualisation of FSHdosage on ovarian stimulation. Both, the ESTHER andOPTIMIST trials, were presented at the AnnualMeeting in Helsinki last year.

Presenting new evidence on do’s and don’ts, bothstudies may well provide important information for theprocess of developing the ESHRE guideline on ovarianstimulation. It will be an extensive work package andmuch of it has already been planned at a veryconstructive and laborious meeting in Brussels inNovember. With various new members on board,reflecting expertise from many EU member countries,topics such as FSH dose, protocol type, responsemonitoring and OHSS prevention have all now beenrephrased into PICO questions (population,intervention, comparator and outcomes) and firstresults of the literature searches discussed. Practicevariation here is tremendous, and this first guidelinewill aim to reduce that variation - to cut expenditureon medication, to enhance safety and patientcompliance with treatment, and possibly to improve onthe most important outcome, the chance of an ongoingpregnancy and live birth achieved within a ONE-yeartreatment time frame. Our plans are that the guidelineworking groups will complete their review and analysisin the summer, so that a first draft of the text will be

available for review early in 2018.

Upcoming eventsIt was unfortunare that the Campus

meeting organised by Bulent Urmanfor Istanbul in December had to bepostponed. But now this sameworkshop on The multifacetedchallenge of female reproductiveageing, with a focus on the

physiology of ageing and themanagement of couples with age-related fertilitydecline, will take place in Athens on 5-6 May.

Our precongress course in Geneva will consider howovarian stimulation can be optimised byindividualisation (using tools such as responseprediction and patient profile), the pharmaco-dynamics of stimulation drugs, and the physiology offolliculogenesis.

Later, in Vienna on 15-16 September we are hostinga Campus workshop on the impact of adjuvanttreatments on pregnancy potential in IVF. Thissymposium will offer update information on therationale for adjuvant treatments at the level of ovary,oocyte, spermatozoa, embryo and endometrium,provide scientific evidence on treatment efficacy andpotential risks, and look ahead to future developmentsin this field.

Altogether, the year is buzzing with activities, andthe SIG RE is looking forward meeting you all andeach other in Geneva in July.

Frank BroekmansCo-ordinator SIG Reproductive Endocrinology

Moving forward with ovarian stimulation guidelineSTEERING COMMITTEE

Frank Broekmans (NL), Co-ordinatorPeter Humaidan (DK), Deputy Daniela Romualdi (IT), DeputyGeorgios Lainas (GB), Junior DeputyRoy Homburg (GB), International AdvisorJenny Visser (NL), Basic Science OfficerStratis Kolibianakis (GR), Past Co-ordinator

LAST WORD

Italy's birth rate has more than halvedsince the ‘baby boom’ of the 1960s, withthe number of births now falling lowerthan at any other time since the modernstate was formed in 1861.

Italy has introduced some measures totry and stimulate its birth rate, but an€80-a-month ‘baby bonus’ for lowincome families in 2014 has done littleto reverse the decline. In May last yearItaly's health minister pledged to doublethe amount to avoid what she describedas a 'catastrophic' fall in birth rate, an'apocalypse' for the Italian economy.

Later, as a further incentive for morebambinos, the Italian governmentplanned a 'fertility day' campaign for theautumn which now, in its promotionand schmaltzy advertising, has beenbranded so patronising that even pre-resignation Prime Minister MatteoRenzi appeared embarrassed. 'As far as Iknow,' he said, 'none of my friends hadtheir kids after seeing an advert.'

The fertility ads in question prompteda venomous outcry in Italy, particularlyagainst an image of a bemused youngwoman touching her stomach with onehand and holding an ever emptyingegg-timer in the other - which manytook to imply that women had onlythemselves to blame for putting offpregnancy for too long. Reaction wasfierce, prompting the beleagueredhealth minister to withdraw thepromotion - though not the conceptand activities of 'Fertility Day'.

The public outcry also drewaccusations that Italy's demographicdecline deserved more than just a fewpatronising and sexist ads. And raisedtoo the question of whether the state

Italy faces up to afertility ‘apocalypse’

even had a role in the encouragement ornot of procreation.

Most European countries - includingthe EU itself and Italy - do havepopulation policies, which recognisethat the reasons why couples are nothaving children are not just biological(even if partly explained by a socialtrend of delayed pregnancy). Child care,

working hours, paid maternity (andpaternity) leave, affordable housing,family tax allowances, and nurseryschooling all combine to influence therates of conception. The place of ARTwithin those policies - withreimbursement, state funding and greateraccess - has been controversial, but theexperience of Denmark suggests that agenerous reimbursement system for ARTcan be considered in the mix of severalexplanations for a buoyant fertility rate.

Continued over page

According to Eurostat, the statistical office of the EU, Italy now has the lowest crudebirth rate in Europe. As of January 2016, Eurostat put Italy’s birth rate at 8.0 per1000 residents, just below that of Portugal (8.3 per 1000) and Greece (8.5 perthousand). These depressed figures were in contrast to those found in Ireland (14.2per 1000, the highest in Europe) and France (12.0 per thousand) - but still wellbelow the EU average of 10.0 per 1000.1


Trends of FERcycles aspercentages oftotal transfers insix Europeancountries. Italy’ssteady increase inART has beenlargely driven byFER following itsrehabilitation in2009.

� Ad campaign branded ‘sexist and patronising’ 'Beauty has no age. But fertility does,'ran the saccharine caption, which

many took to imply that women hadonly themselves to blame for putting off

pregnancy too long.

Giulia Scaravelli, head of Italy’sNational ART Register, says that ARThas never been considered as part of apopulation policy in Italy - until now.‘But today things are changingand ART techniques should be includedin the LEA - the essential level ofassistance - in the next finance bill. Sothe situation might steadily improve.’EIM data show that ART availability inItaly (at less than 1000 cycles per millionpopulation) is consistently settled amongEurope’s lower provision rates.

However, Giulia also told Focus onReproduction that the use of ART in Italycontinues to grow, driven largely by anincrease in frozen embryo transfers (ifnot fresh). Embryo freezing was bannedin Italy under 2004’s Law 40 and wasonly reintroduced in 2009 after thedraconian legislation of 2004 wasdeclared ‘unconstitutional’.

Meanwhile, Italy, the world's ninthbiggest economy, seems still reeling froma long period of economic austerity;unemployment remains high and

domestic demand low. A higher birthrate as an economic expedient may welloffset some of the demands of an ever-ageing population in Italy, but they seemunlikely to be met by misguidedadvertising or even the unsteady hand ofthe state in matters of procreation.


1. See http://ec.europa.eu/eurostat/documents/2995521/7553787/3-08072016-AP-EN.pdf/c4374d2a-622f-4770-a287-10a09b3001b6

PARAMEDICAL GROUP

More than 100 take part in training workshop The Paramedical Board incollaboration with the SIGEmbryology were pleased tohost a Campus course inGothenburg in November onOptimising IVF success.The course attracted 108delegates from around Europeand beyond, with presentationson basic biology, embryogenesis,what to do when sperm andoocytes fail, embryodevelopment and time lapse, basicstatistics and information on how to review and write anarticle. A panel discussion chaired by Kersti Lundin allowedparticipants to ‘Ask the expert’; here there was muchhealthy debate, which continued on into the evening.

An afternoon of hands-on workshops gave delegates theopportunity to access time-lapse systems, vitrification andquality control. This practical session was well received, sothank you to all the speakers who gave time out from theirschedules and special thanks to local organiser CeciliaWestin.

CertificationThe Nurses and midwivescertification committee met inSeptember and have reorganisedthe reading list. The committeeare preparing questions for thenext exam, scheduled for 1 July2017 in Geneva.

The Paramedical LaboratoryTechnicians are creating a helpfulstudy guide using many of thearchived e-learning lectures

available via the ESHRE website forthe Embryology Certificate course.

As mentioned before we are always keen to hear fromESHRE Paramedical Group members. If there are anyburning issues or topics which you would like us to addressor courses that you feel would be valuable, please feel freeto contact me directly.

Helen KendrewChair Paramedical Board

[email protected]

PARAMEDICAL BOARDHelen Kendrew (GB), ChairCecilia Westin (SE), Chair ElectValerie Blanchet de Mouzon (FR), MemberEline Dancet (BE), MemberAnnick Geril (BE), MemberYves Guns (BE), MemberUschi Van den Broeck (BE), MemberLeonie Van Den Hoven (NL), MemberHelle Bendsten (DK), Past Chair

Paramedical hands-on training in Gothenburg.

38 Focus on Reproduction // JAMUARY 2017

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focus on REPRODUCTION - ESHRE/media/sitecore-files/... · evidence-based medicine and good medical practice. All treatments known to be safe and effective should be available to all