focus on REPRODUCTION/media/sitecore-files/Publications/...JANUARY 2016 //Focus on Reproduction 5...

focus onREPRODUCTION

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Sperm banking: crisis, what crisis?Reproductive genetics: 2015 in review

The maturity of in vitro maturation

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 2016

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

I have now been Chairman of ESHRE for half a year and have already foundthat it’s a big job, but very interesting and extremely rewarding. I meet somany positive people working inside or in collaboration with ESHRE, and it’sfantastic to see their knowledge, commitment and enthusiasm. It becomesvery obvious from these meetings that ESHRE is not a static Society. We areconstantly evolving, and necessarily must change and adapt to the nature ofour environment and to the needs of our members.

Although we are a European Society, one-third of our members are fromnon-European countries and one of these needs is to think increasinglyglobal. Fertility is being taken more and more seriously in low resourcecountries, which raises ever more demands on educational and policy matters. It is also important that we as the largest society in reproductive medicine andscience keep a critical eye on what is happening in our field. It is withoutdoubt becoming increasingly commercialised, with some new techniquesintroduced very rapidly and without sufficient evidence of effect or safety.

We are slowly adapting the structure of ESHRE to keep pace with thesechanges. We have for a number of years had Task Forces in place to deal witha defined question, ranging from the role of basic science in our Society toguidelines for viral screening, from clinical and educational policies in lowresource countries to implementation of the EU tissue directives ormanagement of fertility units. These Task Forces have now concluded theirspecific tasks, and I would like to thank the groups and their co-ordinators forall their expertise and the work they have done. Their closure, however, doesnot mean that their questions will be less important or forgotten. Many ofthese matters still need consideration and will therefore be directed into ourexisting SIGs or to a committee.

It is because of these emerging demands on our Society that we are alsoputting new structures in place. The importance of being politically aware andconnected is continually increasing. This is why we are involved in theAlliance for Biomedical Research in Europe (BioMed Alliance), whichrepresents the interests of 21 leading research-oriented medical societies withEuropean institutions. ESHRE also collaborates more and more formally withorganisations such as the European Union, Council of Europe and WHO.Similarly, new directives, guidelines and regulations are being proposed andimplemented, and it is clearly important that we are heard and involved inthese political and regulatory decisions. This is why we are now setting up anew European affairs committee, to keep special watch on matters arisingand be present in the political arena. Similarly, a new ethics committee isalready in place and we plan to establish a certification committee to

make sure that our booming certification programmes each works towardsharmonised and common goals. It is our hope and conviction that thesechanges will enhance and simplify communication within ESHRE and with

the rest of the world - and in so doing further strengthen the place ofESHRE in reproductive science and medicine.

Kersti LundinESHRE Chairman 2015-2017

CONTENTS

CHAIRMAN’S INTRODUCTION

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LOOK AHEAD TO HELSINKI 4

SPERM BANKING: WHAT CRISIS? 6

ESHRE NEWS 8

CLINICAL NEWS 13

ARNE SUNDE STEPS DOWN 15

IN PROFILE: FRANK BROEKMANS 16

FROM THE SPECIAL INTEREST GROUPS 23

TASK FORCE DEVELOPING COUNTRIES 31

PGD CONSORTIUM 32

THE MATURITY OF IN VITRO MATURATION 19Following Europe’s first IVM live birth in Brussels,

Michel De Vos argues that it’s now time ‘to embrace’ IVM as a useful approach in modern ART.

LAST WORD: THE RUSH TO PUBLISH 33

ANNUAL MEETING 2016

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Helsinki abstract submissions: Must be with ESHRE by 1 February 2016

ESHRE’s next Annual Meeting - from 3 to 6 July - willbe held for the first time in Helsinki, Finland. AfterLisbon’s altered schedule, Helsinki moves back to earlyJuly and as a consequence deadlines for abstracts andregistrations are later than last year - and back tonormal, with early bird registrations available up tothe end of April. Full details can be found in the tableopposite.

For the first time in Lisbon, ESHRE replaced thetraditional paper programme and abstract books withelectronic options. Now in Helsinki, ESHRE will haveits own wireless network. The congress app will offerimproved features, and will be available for laptopsand mobile devices. We believe that participants, eventhose with only moderate experience of apps, will bepleased with the result.

The scientific programme will start with the twousual keynote lectures, with the first speakerrepresenting the most downloaded article from

Human Reproduction in 2015, followed by apresentation on the long-term consequences ofmaternal obesity for the health of offspring. Theprogramme will continue with a session on thegenetics and development of the early embryoregulated by newly discovered genes. Other interestingtopics on Monday cover human stem cells, optimisedmonitoring of ovarian stimulation, cellular interactionsin oocyte physiology, anonymity in donor conception,sequencing of the embryo, reproduction and‘rhythmicity’, and consequences of an extra X-chromosome.

On Tuesday the programme will continue withseveral interesting topics covering standard IVFtreatments, epigenetic remodeling in embryos, andKlinefelter and Turner syndromes. Paramedicalsessions are no less interesting, with presentations onART monitoring, twinning, ultrasound imaging, therole of oxygen in embryo culture and insulin

JANUARY 2016 // Focus on Reproduction 5

the organisers are confident that you’ll need onlysunglasses - and, just in case, a very small umbrella.

Local organising committeeJuha Tapanainen, Aarne Koskimies,

Anne-Maria Suikkari, Aila Tiitinen, Timo Tuuri

sensitisers in reproduction. Wednesday starts with molecular elements in male

infertility, the contentious matter of endometrialinjury prior to embryo transfer, and embryo transferexclusively in FET. Other topics include the molecularregulation of implantation, premature ovarianinsufficiency and endometriosis. This final day - andthe entire meeting - will end with the traditionalaward and closing ceremony.

We trust that everyone will find many topics ofspecial interest - and of help for their everyday clinicalpractice or research work.

The event’s social programme will begin with theopening ceremony on Sunday, where all participantscan enjoy Finnish (but also international)entertainment. The meeting’s official charity run willtake place on Monday afternoon and will be as‘serious’ as always. This year the meeting’s get togetherwill be held separately from the run and will take placeon Tuesday evening, an affordable community eventfor all participants at Kaivohuone, a well knownHelsinki entertainment venue in Wells Park. Our localorganisers are doing everything to ensure that theevent is lively, relaxed and interesting to all. Food, livemusic and excellent company are guaranteed in thisseaside park landscape.

The weather in July in Finland is usually sunny, and

With its historic facade and traditional Finnishappeal, Kaivohuone creates a truly atmospheric venue

for this year’s get-together - with local foods andremarkable views over the famous marina.

Main programme Before 30 April 2016 After 30 April 2016 After 26 June 2016Non-member of ESHRE 496,00 620,00 744,00Member of ESHRE 372,00 496,00 620,00Student or paramedical member of ESHRE 186,00 248,00 372,00

Precongress Course Non-member of ESHRE 248,00 372,00 496,00Member of ESHRE 124,00 248,00 372,00Student or paramedical member of ESHRE 62,00 124,00 248,00

* Prices are in euro and include VAT at 24%

REGISTRATION FEES AND DEADLINES FOR THIS YEAR’S ANNUAL MEETING

There’s a perception that sperm banking in Europe is incrisis: a chronic decline in the number of donors (whoare only in it for the money), long waiting lists fortreatment, and ethical controversies too difficult to dealwith. Yet those perceptions, said UK andrologist JacksonKirkman-Brown speaking at a well attended Campusmeeting in December, belie the real facts - for the factsare that there continues to be a steady increase in thenumber of donors (who are motivated more by altruismthan money), many clinics, both state-run and private,have a good supply of donors and sperm, and any fearsabout screening and inherited disease are largelymisplaced. In fact, the only perception widely accepted asfact by this meeting’s large audience was that spermbanking is nevertheless ‘difficult’.

The other truth universally acknowledged was thatsperm donation in Europe is a patchwork of different

ESHRE CAMPUS: SPERM BANKING

regulations and practice. A 2015 survey performed byWillem Ombelet, one of the course organisers, found thatonly 14 of 22 European countries allowed donorinsemination in lesbian and single women (still outlawedin Italy and France), around half only allowedanonymous donation, and cross-border care (includingthe import of sperm, which is not allowed in France) is acomplication to any national legislation.

The subtitle to this Campus event was ‘medical, socio-cultural, ethical and juridical considerations’, and thatlargely defined its content. Those hoping for a fewpractical clues to overcome any practical difficultiesmight have been disappointed, for there was little on therecruitment of donors (other than examples ofadvertising) or on the demand for donor sperm. Therewas an assumption that demand was increasing, drivenlargely by lesbian, single and cross-border patients, but

Crisis? What crisis?Fears associated with screening and consanguinity are largely misplacedNo strong evidence for identity disclosure: the donor is not a parent

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little evidence to quantify the extent. Nathalie Dhontreported that the number of DI cycles in Belgium hadincreased from 8766 in 2008 to 13,048 in 2011, whileUK figures presented by Kirkman-Brown showedcomparable increases in the use of donor sperm inIVF. But otherwise, supply and demand remained inthe background, and the issues under this meeting’sspotlight were donor screening, consanguinity andanonymity.

Donor screeningDonor selection criteria for the prevention of inheriteddisease were among several ‘minimal standards’ forsperm banking listed by Nicola s Garrido, sperm bankdirector at IVI Valencia. He was largely of the view thatcurrent guidelines for the prevention of infectious diseasewere adequate, but, with the greater (and cheaper)availability of more comprehensive tests, there may bescope for more rigorous genetic screening.

He reported that screening for HIV, hepatitis B andC, syphilis, CMV and other transmissible diseases(depending on the donor’s origin) were common tomost legal requirements and, with a quarantinefreezing period to detect any seroconversion,appeared to provide a high level of safety. However,he saw greater scope for the prevention of Mendeliandiseases, whose consequences, however rare, can bedevastating for the offspring and family.

Garrido cited two benchmark standards for safety: first,that donor conception should be as safe as naturalconception between two healthy partners (as claimed bythe French national sperm bank CECOS); and second,that donor conception should be as safe as reasonablypossible. Thus, said Garrido pursuing the latter, if anyrisks of transmitting serious disorders can be tested for atreasonable cost, then this should be done. Partnerscannot be replaced, he said, but donors, as providers ofgametes, can be.1

This call for wider screening was also addressed byDutch bioethicist Wybo Dondorp, who was also firstauthor of ESHRE’s 2014 consensus on the geneticscreening of donors.2 Dondorp suggested there wasagreement that donors should not have major Mendeliandisorders, major malformations, significant familialdisease with major genetic component, or any

chromosomal rearrangement which could result inchromosomally unbalanced gametes. However, he foundinconsistency in screening for some autosomal recessivedisorders and even for chromosomal abnormalities (withonly France and UK requiring karyotypes of all donors).

Harmonisation of recommendation was thus one of theESHRE conclusions reported by Dondorp, while riskprofiling through wider screening (via next generationsequencing or array-based technologies) was described ‘atthe moment’ as ‘fully disproportional’. Dondorp thusproposed that donors should be treated as ‘interestedstakeholders’ and not merely as providers of geneticmaterial. Indeed, the ideal of the ‘perfect donor’, free ofany genetic mutation or gene variant, was a recurringtheme of this meeting. The idea of avoiding all risks isimpossible, said Dondorp, and testing should remain‘proportional’.

ConsanguinityThere was much less debate about the risks fromconsanguinity, with Dutch biologist Pim Janssensclaiming categorically that the ‘spread of geneticdisease is not affected by the number of offspring perdonor’. However, within the context of ‘responsiblecare’ and minimal standards, he acknowledged thatsome form of quota in terms of sperm donation and

offspring was desirable, ‘to recognise the potential harmpossibly resulting from a large donor quota’. It thus seemsreasonable, said Janssens, ‘to have some reasonable limit’.

A calculation based on Dutch national data found thatwith 200,000 births and 1250 donor children per year thechance of a consanguineous relationship for a donorchild was 0.011% when one donor was responsible for 10

children, and 0.101% when responsible for 100children. French calculations indicated thatinbreeding as a result of DI is around half thatresulting from other ‘accepted forms of mating’.Janssens thus concluded that offspring number perdonor should be 10-100 families, and that countingshould be of families, not individual children.

Anonymity The presentation by ethicist Guido Pennings on

disclosure or anonymity proved a masterclass in ethicaldebate - clear, structured and unequivocal. His argumentrested on a basic distinction between need and desire,and that ‘parents’ are those who raise the child, notnecessarily conceive it. Pennings could find no evidenceof a ‘need’ for children to know the identity of the donor,and certainly no evidence of the need for a relationship -just as it became clear a decade ago that there was no‘need’ for a father in the development of a child.

The reasons claimed in favour of donor identity were,said Pennings, largely spurious and insufficient to removeany requirement of anonymity. He thus proposedconsideration of a compromise system which allowed theexchange of identifying information only if desired by allparties. But to indulge the wishes of the child alone andassume that interaction with the donor is preferable andcorrect would be on the slope of a ‘slippery evolution’ (asis now happening in Australia), and just one step awayfrom acceptance of the ‘donor as parent’.


With more than 160 registrations, this was among the best ever attendedCampus meetings of ESHRE. The event, which took place in Leuven in

December, was organised jointly by the SIGs Andrology, Ethics & Law, Socio-cultural aspects of (in)fertility, and Task Force Developing Countries.

Course jointorganiserWillemOmbeletfound a

patchwork oflegislation.

NicolasGarrido:Genetic

screening ‘assafe as

reasonablypossible’.

was around 25 years old, and had IUI in a low-dosestimulated cycle with motile sperm. The three definingfactors for high success, said Thijssen, were female age,type of ovarian stimulation, and grade A spermmotility. BMI and smoking did not affect outcome.

Nor did the meeting ignore the impact which suchtreatments might have on patients. A qualitative studyof 23 single women in the UK made it clear that solomotherhood was no simple choice - plan Z rather thanplan B, said Cambridge investigator Susanna Graham.

Simon BrownFocus on Reproduction

1. See, for example, Garrido N, Bosch E, Alama P, Ruiz A. Thetime to prevent mendelian genetic diseases from donated orown gametes has come. Fertil Steril 2015; 104: 833-835.2. Dondorp W, De Wert G, Pennings G, et al. ESHRE TaskForce on Ethics and Law 21: genetic screening of gametedonors: ethical issues. Hum Reprod 2014; 29: 1353-1359,

There was of course more to this meeting thanagonising over ethical considerations which may ormay not encourage the smooth running of a spermbank. However, it was clear that screening and thepossibilities raised by identity disclosure could have apractical effect on donor recruitment. Both NathalieDhont and Jackson Kirkman-Brown reported a lowconversion rate (of around 10%) from initial enquiryto sample provision in their own centres. Extendedtesting would increase the number of rejections andlower the recruitment rate even further - and this, saidNicolas Garrido, should thus be taken into account inany ‘risk/cost/benefit’ calculation.

So what about the benefits? A prospective studydescribed by Genk PhD student Annelies Thijssen ofmore than 900 donor IUI cycles in 306 couples foundan overall pregnancy rate of 15.6%. But, whenmultivariate analysis had deconstructed the results, apregnancy rate of 38% was found likely if the recipient


SART data study questions viability of cryopreserved oocytes


Applications for ESHRE’s second research grant now openTwo awards available; proposals must be on the theme of endometrial receptivity

Applications for the second ESHRE Research Grant arenow open, and all proposals must be with ESHRE by 1April. All first-round abstract submissions will beevaluated blind by three ESHRE reviewers, after whichapplicants whose proposals have passed this first-roundassessment will be asked to submit a second full proposal.First-round evaluation will be completed by 15 July and afinal decision made by 1 December 2016.

This year, two grants will be awarded, one for €150,000and a second for €50,000. The grants will be awarded toprojects running for up to three years, and will be selectedon the basis of scientific excellence, originality andfeasibility. This year, however, in a bid to concentrate thescientific quality of the submissions, all research topicsmust be related to the single theme of endometrialreceptivity.

All proposals for the first evaluation should be submittedas an abstract through the online portal on the ESHREwebsite. This portal is only accessible to ESHRE members -and co-ordinators of the projects should thus ensure thatthey are indeed an ESHRE member.

ESHRE's five Task Forces have been disbanded. The ideabehind the original formation of all ESHRE Task Forces wasto address a specific question through the assembly of data orconsensus. However, in the case of ESHRE’s five lastremaining TFs the Executive Committee has agreed that theinitial objectives behind their formation have now been met.

Some of the ongoing activities of the TFs will be absorbedinto other working groups or SIGs. For example, a basicscience interest will still be reflected in the composition ofSIG steering committees, and some of the interests of the TFDeveloping Countries will be taken up by the new SIG Socio-

cultural aspects of (in)fertility. The latter TF, it was noted,has been particularly active, having first raised the social(and clinical) extent of infertility in resource-poor countries,and latterly, under the guidance of Willem Ombelet, havingset in motion the protocols for very low-cost IVF. Ombeletreports on the first low-cost pilot project about to start inGhana on page 31 of this issue.

Some of the responsibilities raised by the TF EU Tissue andCells will be transferred to a new ESHRE committee aimingto forge better relations with the EU.

Responsibilities of ESHRE’s Task Forces shifted to SIGs

Chairman Elect Roy Farquharsondescribed the grant as ESHRE’s bid to

sponsor and reward research.

Collaboration between research groupsis encouraged, but not obligatory. For eachproposal, a maximum of six associatedinvestigators can be listed, and bothsingle-centre and multicentre studies areeligible. The grants will be awarded to thehost institution.

The ESHRE Research Grant is now inthe hands of a dedicated grant committee,and full details of the submission andselection processes as agreed by thecommittee are available on the ESHREwebsite (www.eshre.eu/grant) and in thegrant guide downloadable as a PDF.

All proposals for the first round will beblinded before review and scored by visual

analogue scale by at least three reviewers.The reviewers will be selected fromESHRE’s Executive Committee and Co-ordinators of the SIGs based on the topicof the proposal.

ESHRE’s Chairman Elect RoyFarquharson has described the grantscheme as ESHRE’s bid ‘to sponsor andreward’ research.

The 2014 grant of €150,000 was awardedto a project submitted by the Universitiesof Edinburgh and Rome TorVergata, led by Professor Norah Spears, totest the viability of tyrosine kinaseinhibitors in protecting the ovary againstloss of fertility during cancer treatment.

ESHRE NEWS


ESHRE NEWS

advanced maternal age for analysis of polar bodiesWhile there is no good evidence showing that polar

body biopsy is inferior to, for example, blastocyst biopsy,there is no scientific proof yet in support of biopsy at anytime point

Scientifically, ESTEEM will give an unprecedentedinsight into the genetics of human female meiosis

Participating centres in the study have a long trackrecord of conducting these types of study, and setting abenchmark for progressive clinical care.

Karen also emphasises that ESHRE, as the mainsponsor of the study, has reaffirmed its commitment tofunding, agreeing at its Executive Committee meeting inLisbon to continue financial support until the end of2016. This too, says Karen, is the cut-off date forIllumina’s incentive payments. ‘That will be the end offunding,’ she says, ‘not a day longer.’

Already, adds Karen, recruitment at the seven studycentres seems to be picking up, and ESHRE’s renewedcommitment has been an encouragement. However,some centres have had their own local difficulties, notleast Athens struggling at the heart of the country’sfinancial crisis. The original study design was for eachcentre to complete 82 cycles, but so far only the VrijeUniversiteit Brussel has met this target.

‘It’s an important trial,’ says Karen, ‘with muchneeded results. So I hope the other centres can meettheir objectives. The outcome will be crucial for embryoselection, and this is a once-and-for-all opportunity.’

ESHRE’s commercial partner in support of theESTEEM trial has pledged €70,000 as an addedincentive for the further recruitment of patients intothe study. The study, which is the first to assess oocyteviability by polar body analysis, has two primary aims:to improve live birth rates in women of advancedmaternal age, and to estimate the likelihood of havingno euploid embryos in future ART cycles.

Illumina is already providing the materials neededfor the trial’s genetic analysis and will now provide theextra incentive funding for recruitment at studycentres. According to the study’s steering committeeco-ordinator Karen Sermon, about 300 patients arestill needed to complete recruitment; this means thatcentres will receive around €230 per recruited patient.Illumina has agreed to pay these sums to ESHRE fordistribution among the seven centres.

The study’s target recruitment for a meaningfulresult was a total of 560 cycles randomised to polarbody analysis or no screening. However, says Karen,patient recruitment remains slower than anticipatedand she is keen to emphasise ESHRE’s commitmentand the new financial incentives to bring recruitmentback on target. And to this end she has written to allcentres reaffirming the added values of the trial, that:

ESTEEM is the methodologically correct way toaddress the important scientific question of polarbody analysis

ESTEEM is the only RCT recruiting patients of

ESTEEM co-ordinator

Karen Sermon

ESHRE reaffirms commitment to ESTEEM trialRecruitment incentive to centres in study of PGS by polar body analysis

Testing the uneasy relationship between science and commerceThe relationship between commercialinterest and good medicine becomesincreasingly uneasy. Few of the world’slarge-scale clinical trials are now withoutmanufacturer involvement and in recentyears a whole literature has evolved onthe process of publishing results. A recentstudy of 1224 cardiovascular trialspublished in the top eight journalsbetween 2001 and 2012, for example,found that results from those sponsoredby industry were more than twice aslikely to be ‘positive’ than government-sponsored studies.

Reproductive medicine has neither thevolume of such studies nor the hugeindustry involvement, but it is fair to say

that few developments in the field arenow without a commercial edge. This hasmost evidently been seen - and debated -in the introduction of ‘new’ techniques,most of them without preclinical safetystudies or early phase human studies -and many promoted directly to patientsas the next big thing in IVF.

This and the whole gamut of reactionsto commercialisation in reproductivemedicine will be the subject of a closedexpert meeting to be staged by ESHRE inFebruary. Any conclusions drawn fromthe many expert presentations and thediscussion will hopefully find their wayinto a consensus paper not unlike therecent proposal from the SIG Ethics &

Law on distinguishing betweenexperimental, innovative and establishedtreatment in reproductive medicine.1

The main two topics of this meetingwill be ‘responsible innovation’ and‘advertising and promotion’, of which thelatter will even consider the implicationsof sponsorship for ESHRE and othermedical societies. Other sessions willcover advertising directly to consumers,reporting study results and the journals.

1. Provoost V, Tilleman K, D'Angelo A, et al.Beyond the dichotomy: a tool fordistinguishing between experimental,innovative and established treatment. HumReprod 2014; 29: 413-417.

// Focus on Reproduction 11

An ESHRE events app: Campus courses in the palm of your hand

New ESHRE ethicscommittee will have impartialadvisory role

ESHRE’s Executive Committee hasagreed to the formation of an EthicsCommittee whose role would beadvisory and whose judgement wouldbe impartial. The Committee wouldthus be asked by the ExCo to provideopinion on ethical questions inreproductive medicine, help determineESHRE’s position on controversialsubjects, or give advice on legal matters.The Committee might also be calledupon to provide an opinion on mattersinvolving conflict of interest.

The ExCo is now concluding thecomposition of the Committee, whichwill comprise a mix of clinicians,scientists, paramedics and ethicists. Atits meeting in November the ExCoagreed that the committee would adviseon matters in reproductive medicineand science with potential impact onpatients, professionals and society.

The Ethics Committee is one ofseveral new committees proposed byESHRE; others include a ResearchGrant Committee and CertificationCommittee, both developed fromexisting working groups, and aEuropean Affairs Committee.

Update on ESHRE guidelinesThree completed, implementation nextThree ESHRE guidelines have so far been completed, thelatest in December on the Management of women withpremature ovarian insufficiency. In her report to ESHRE’sExecutive Committee in November Research SpecialistNathalie Vermeulen, pictured right, noted recurrentmiscarriage, Turner syndrome, and implementation as thepriorities for 2016.

Management of women with endometriosisThe guideline has been briefly evaluated and was apparentlywell received. As the SIG explains on page 24, next task is todevelop of a set of quality indicators based on patient and professional input tomonitor the management of endometriosis in European hospitals. Results areexpected this year. Meanwhile, a full update to the guideline is scheduled for 2017.

Routine psychosocial care in infertility and medically assisted reproduction: Aguide for fertility staffFinalised in March 2015; a short version was published in Human Reproduction inSeptember 2015. A patient version of the guidelines has been circulated recently to allExCo members and the document has been approved.

Management of women with premature ovarian insufficiency Final comments on the full text were made in December, with approval by guidelinedevelopment group and ExCo before year’s end. A summary paper has also beendrafted and sent for approval before submission to Human Reproduction.

Nathalie also reported that ESHRE had been invited by the European Society ofEndocrinology to collaborate on a guideline on Turner Syndrome, which has beenagreed by the ExCo. ESHRE’s revised guidelines on good practice in IVF labshas been finalised and published for review on the ESHRE website. The document wasapproved by the ExCo in December and will be ready for publication early in 2016.

With an increasing number of European guidelines in place, their implementatiionhas been put in the hands of a small working group, whose aims are the evaluation ofcurrent indicators for implementation, how dissemination can be improved, and thedevelopment of tools to increase the impact of ESHRE guidelines.

Those attending ESHRE’s last four AnnualMeetings have been able to read the abstracts,browse the programme and take notes withtheir smartphone or tablets via an ESHREapp, which aims to improve congressexperience by providing all relevantinformation – updated in real-time - in aneasily accessible way.

Now, the app’s function will be extended toall Campus courses, with the same objectivein mind: to provide a simple tool to helpmaximise benefits from the meeting.

The events app will be the single-accesspoint to all course information, withcentralised scientific (programme, syllabus,abstracts, speakers) and logistic details(venue, maps, hotel).

ESHRE Campus events are also aboutnetworking so attendees can check theparticipants lists to send messages andexchange their electronic business cardcontained in the app. Other useful functionsinclude note-taking, answering surveys, andthe latest news about the course and ESHRE.

The app was introduced in December atESHRE’s last Campus course of 2015, onsperm banking, in Leuven, Belgium. Morethan 100 participants there (from 165)downloaded the app, with users praising itsconvenience.

The app will be available to all thoseattending each Campus course in 2016, andwill be accessible for Android and iOSdevices, as well as a desktop version.

Up and running. TheESHRE events app, now asingle access point for all

Campus information.


One of the talking points along the corridors oflast year’s Annual Meeting in Lisbon was atechnique of energising IVF oocytes withmitochondria from the patient’s own ‘eggprecursor cells’. The technique had beenpublicised a few weeks before byannouncements of the first live birth and pressreports of ‘a new chapter in medical history’.Time magazine said that the birth would be ‘thefirst in a wave of babies expected to be born thissummer through a technique that some expertsthink can dramatically improve the success rateof IVF’.

There appeared to be two historical preludes to thetreatment, each of which were somewhatcontroversial at the time: first the work of JacquesCohen and others in the late 1990s to improve oocytequality by the injection of cytoplasm from healthydonor eggs (with resulting pregnancies); and second,the discovery by Jonathan Tilly and colleagues of‘oogonial’ stem cells (‘egg precursor cells’) in thelining of the ovarian cortex. Thus, in terms ofimproving oocyte quality, any ethical or proceduralproblems inherent in the former (a third-party sourceof mitochondria) might apparently be resolved by therewritten biology of the latter (an autologous source).

Tilly himself is described as one of the ‘scientificfounders’ of OvaScience, a US company established in2011 which has commercialised the use ofmitochondria from egg precursor cells as‘Augment’. At the time of the first-baby pressreports in May and an off-programmesymposium in Lisbon in June, there were nopeer-reviewed papers to describe the techniqueor its outcome. But that changed in Augustwhen Fakih et al published their ‘physicianreported outcomes’ of Augment treatment inthe open access Journal of Fertilization: InVitro, IVF-Worldwide, Reproductive Medicine,Genetics & Stem Cell Biology.1 The report,which described treatment in two series ofpoor prognosis patients at two centres, one inCanada and one in Dubai, had been muchanticipated; use of Augment treatment, it said, isbased on case reports of donor egg cytoplasminjection and animal studies demonstrating ‘that theaddition of mitochondria during IVF treatment is

safe, improves the quality of the embryos, andincreases the success of IVF’.

A statement recently issued by ESHRE’s SIGStem Cells has considered the publication and,after raising five unresolved safety concerns,‘urges all stakeholders to perform extensive safetystudies and prove the beneficial effect ofmitochondria transfer on infertility beforeconsidering the possible clinical applications’.

The statement notes a lack of qualityassessment in the report (reagents, the isolatedmitochondria, oocytes) and an ill-defined

minimal threshold number of mitochondrial copies.One study has even found that excessively high copynumbers can have detrimental effects in mice - whilerecent studies from Fragouli et al appear to support anadverse correlation between mtDNA copy number andblastocyst quality and implantation rate in thehuman.2

The SIG statement notes potential sources of bias inthe study methodology and timing anomalies in thestudies cited to support some of the investigators’claims. It also raises reasons for caution in the lack ofany evidence of a direct beneficial effect oftransferring mitochondria from egg precursor cells onembryonic development, even in animals - and thatthere is still controversy over the very existence of eggprecursor cells in adults.

The SIG’s concluding advice is that the results of thepublished study should be interpreted withcaution and that more safety reassurance isneeded before clinical introduction. So far, theOvaScience website notes, the treatment is onlyavailable in limited countries, and not in the USAwhere, apparently, the FDA considers suchtreatments as ‘gene therapy’ and thus subject to ahigh bar of regulatory approval.

1. Fakih MH, Shmoury MEl, Szeptycki J, et al. TheAUGMENTSM Treatment: Physician ReportedOutcomes of the Initial Global Patient Experience. JFIVReprod Med Genet 2015; 3: 154. doi:10.4172/2375-4508.1000154

2. Fragouli E, Spath K, Alfarawati S, et al. Altered levels ofmitochondrial DNA are associated with female age,aneuploidy, and provide an independent measure ofembryonic implantation potential. PLoS Genet 2015;11(6):e1005241.

ESHRE NEWS

SIG raises safety doubts over widelypublicised mitichondrial transfer technique

First data published as ‘physician reported outcomes’SIG urges caution in interpretation of results

Jonathan Tillyexplaining his work

on oogonial stemcells in 2012.

Björn Heindryckx,Co-ordinator of

ESHRE’s SIG StemCells, whichproduced the

opinion inNovember last.


As you were in treating unexplained infertilityLetrozole has ‘no advantages over clomiphene’ in large RCTIVF more expensive than IUI, but no more effective

CLINICAL NEWS

This was a cost-efficiency analysis performedalongside a randomised non-inferiority trial in 602couples with unexplained infertility and a poorprognosis at 12 Dutch centres. The couples wererandomly allocated to three cycles of SET IVF plussubsequent frozen embryo transfers, six cycles ofmodified natural cycle IVF or six cycles of stimulatedIUI - and followed for 12 months after randomisation.

There was a delivery rate of 52% in the SET IVFgroup, 43% in the modified natural cycle group, and47% in the IUI group. However, the mean costs percouple were €7187 for SET IVF, €8206 for modifiednatural cycle IVF, and €5070 for IUI. The costs forboth IVF approaches were significantly higher thanfor stimulated IUI.

As a result, the investigators concluded that there isno evidence in support of IVF as a first-line treatmentin unexplained infertility. ‘Both IVF strategies aresignificantly more expensive when compared withIUI-COH,’ they write, ‘without being significantlymore effective.’ And they thus recommend thatstimulated IUI remains the first-line treatment.

It is noteworthy too that they draw attention to thelatest NICE guidelines in the UK and theircontroversial recommendation to proceedimmediately to IVF in such cases after two years‘expectant management’. Roy Homburg, speaking atlast year’s ‘Best of ’ ESHRE and ASRM meeting in NewYork, described the UK recommendations asincomprehensible, and they are now branded‘unsustainable’ by the Dutch.

1. Diamond MP, Legro RS, Coutifaris C, et al. Letrozole,gonadotropin, or clomiphene for unexplained infertility.NEJM 2015; 373: 1230-1240.2. Tjon-Kon-Fat RI, Bensdorp AJ, Bossuyt PMM, et al. IsIVF—served two different ways— more cost-effective thanIUI with controlled ovarian hyperstimulation? Hum Reprod2015; 30: 2331-2339.

One of the largest reported randomised trials forseveral years has found that ovarian stimulation forunexplained infertility is most effectively performedwith gonadotrophins. The study, conducted by theNIH in 12 US centres and published in the NewEngland Journal of Medicine in September last,involved 900 couples with unexplained infertilitygiven (injectable) gonadotrophins, or (oral)clomiphene and the aromatase inhibitor letrozolebefore IUI.1

As background to the report the investigators notethat aromatase inhibitors have already been usedsuccessfully to induce ovulation in women with PCOS,and in multiple reports have been proposed aseffective alternatives for ovarian stimulation inunexplained infertility, with monofolliculardevelopment reported in many cases and lower ratesof OHSS.

Following treatment for up to four menstrual cyclesin this study, a pregnancy rate of 35.5% was found inthe gonadotrophin group, 28.3% in the clomiphenegroup, and 22.4% in the letrozole. Live birth rates were32.2%, 23.3%, and 18.7%, respectively. The pregnancyrates with letrozole were significantly lower than therates found with standard therapy (gonadotrophin orclomiphene) or gonadotrophin alone, but not withclomiphene alone.

The clomiphene group had the fewest multiplepregnancies, at 1.3%, followed by 2.7% in the letrozolegroup and 13.4% in the group receivinggonadotrophins. All multiple pregnancies were twinsin the clomiphene and letrozole groups; for thewomen receiving gonadotrophins, 24 multiplepregnancies involved twins and 10 involved triplets.

Thus, because gonadotrophins resulted in the mostmultiple pregnancies of the three treatments, andletrozole resulted in the lowest pregnancy rate, thestudy authors concluded that clomiphene is the mostappropriate to stimulate ovulation in unexplainedinfertility treated with IUI.

In a press statement issued by the NIH, study authorEsther Eisenberg said that letrozole treatment offeredno advantages over clomiphene. ‘Women in theletrozole treatment group had fewer live births, butfour times as many multiple pregnancies as women inthe clomiphene group,’ she said.

Another large-scale trial involving stimulated IUI inunexplained infertility - this time from theNetherlands - has confirmed that IVF strategies aresignificantly more expensive than stimulated IUIwithout being significantly more effective.2

NICE guidelines updated in 2013. Described as ‘unsustainable’following a large-scale cost efficiency analysis in the Netherlands.

‘No evidencein support of

IVF as afirst-line

treatment inunexplained

infertility.’


What turned out to be one of the most remarkable fertility stories of last yearcame in the journal Science in November in a report from California thatparasitic roundworm infection can increase the reproduction rate in(Amazonian) women - while hookworm infection can decrease it.1

Apparently, parasitic worms infect 2 billion peopleglobally and, while it’s known that some parasites cancause cognitive and nutritional impairment, this newstudy now suggests that reproduction rates can also beaffected. The investigators propose a hot-topicmechanism behind this correlation: the immune system.‘Infection with intestinal helminths results inimmunological changes that influence co-infections,’ theywrite, ‘and these might influence fecundity by inducingimmunological states affecting conception andpregnancy.’

Helminths are parasitic worms that feed on a livinghost for nourishment and protection, while causing poornutrient absorption, weakness and disease in the host.These worms and larvae live in the small bowel, areusually referred to as intestinal parasites, and includenematodes or roundworms.

To test the effects of these parasites on reproductionrates, Aaron Blackwell and colleagues from the Universityof California at Santa Barbara used data collected overnine years from Tsimane women in the lowlands ofBolivia, a population with an average birth rate of ninechildren per woman. The analysis was performed in 986Bolivian forager-horticulturalists with proven naturalfertility and a 70% helminth infection prevalence.

‘We found that different species of helminths - a familyof parasitic intestinal worms - could have either positiveor negative effects on the timing of a Tsimane woman’snext pregnancy,’ said Blackwell. ‘Hookworm infectiontended to increase the length of the intervals betweenbirths . . . consistent across all ages. But younger womeninfected with roundworm had shorter birth intervals.’

They similarly found that women who were repeatedlyinfected with hookworm were likely to have up to threefewer children in their lifetimes than uninfected women,while women infected with a species of roundworm werefound to have up to two more children than thosewithout infections.

Infection with roundworm (Ascaris lumbricoides) wasthus associated with earlier first births and shortenedinterbirth intervals, whereas infection with hookwormwas associated with delayed first pregnancy and extendedinterbirth intervals. Helminths may thus have importanteffects on human fertility reflecting immunologicalconsequences of infection, the authors write.

These two parasites, they explain, are known to invokedifferent immune changes; the changes followingroundworm infection happen to be reflective of thosethat occur during pregnancy. Specifically, as a womanproceeds through her menstrual cycle, levels of type 2(Th2) T-cells increase and, if conception occurs, thisincrease continues through pregnancy and helps suppresstype 1 (Th1) T cells. Because roundworms are known toincrease Th2 levels, and hookworms have been reportedto evoke a mixed Th1/Th2 response, the authors suggestthat these parasites are indirectly affecting reproductionrates by changing immune cell balances.

‘Reproductive immunology’ has become a hot topic inrecent years, based on the idea that the developingembryo can be ‘rejected’ by these immune cells.Adjunctive treatments - usually given in cases of previousimplantation failure - have included steroids, intravenousimmunoglobulin (IVIg), tumour necrosis factor-a (TNF-a) blockers, and intralipid infusions. Trials of thesetreatments are virtually non-existent and, in the case ofone of several examples, the UK’s Royal College ofObstetricians and Gynaecologists said last year that ‘thereis no rationale for the use of intralipid infusions infertility treatment’. Similarly, a recent review of severalclinical trials found that IVIg treatment did not increaseIVF success rates, while another recommended that IVIgfor recurrent miscarriage should not be offered unless itis done as part of a clinical trial

1. Blackwell AD, Tamayo MA, Beheim B, et al. Helminthinfection, fecundity, and age of first pregnancy in women.Science 2015; 350: 970-972.

CLINICAL NEWS

Worms may have immunological effect infertility - at least in the Amazon valley

No fertility problems for women of the Tsimane people ofBolivia infected by parasitic roundworms.Picture: Michael Gurven

‘Womeninfected with a

species ofroundworm

were found tohave up to twomore children

than thosewithout

infections’


The last ESHRE pioneer to stepdown from his university post

Arne Sunde’s 30-year involvement with ESHREIt's a sign of the times that most of those ESHRE pioneers who formed theSociety in London in 1984 and went on to join the first ExecutiveCommittee have either retired from their university posts orare no longer with us. ESHRE is now in the hands of a newgeneration, though the past is never forgotten.

The last of those earliest pioneers to step down from hisacademic post - though not to ‘retire’ - is Arne Sunde, theNorwegian biologist who was gently coerced into ESHRE'sfirst temporary committee by Bob Edwards himself andwould within a few months be given responsibility forESHRE’s training programmes. Eighteen years later - in 2003- Sunde was named as the tenth Chairman of ESHRE.

His retirement from St Olav’s Hospital in Trondheim wasmarked by a short symposium in September last, withpresentations from his Norwegian colleagues Jarl Kahn andBerge Solberg, and from ESHRE’s past and present chairmenJuha Tapanainen and Kersti Lundin.

Sunde was appointed professor in cell biology at theUniversity of Trondheim in 1994 but before then had beenpart of the team responsible for the first IVF babies inNorway (in 1984) and the first baby in the Nordic countriesborn after embryo cryopreservation (in 1988).

As with many other IVF ‘retiremens’ in recent years, Sundewill now head to the private sector and a new clinic inTrondheim, to serve as a senior embryologist and consultant.For ESHRE he will continue his membership of the culturemedia working group, campaigning for greater clarity in thecomposition of different media and aiming to produce asummary report.

Over the years Sunde has been one of the most active andinfluential ESHRE members, notably in the development ofthe Campus programmes, precongress courses and strategicdirections. Yet his introduction to ESHRE had been nothingbut fortuitous, when he wandered into a meeting room (topass a little time, he said) at the third World Congress of IVFin Helsinki in 1984. There he would find Edwards and abunch of keen Europeans determined to set up a society torival the Americans and it was they who made him welcome.

It was during Sunde’s chairmanship of ESHRE from 2003to 2005 that the Society found itself in a far more politicalenvironment than ever before. Under his leadership theSociety formally opposed the restrictive legislation proposedin Italy (enacted in 2004), and formally supported embryoand stem cell research (which appeared under threat fromEU funding and a ‘rumoured’ tissue and cell directive). Itwas also under Sunde’s chairmanship that ESHRE finallybought its own Central Office in the suburbs of Brussels. Itwas, said Sunde, as if ESHRE were now acting more as abusiness, without actually being a business.

Arne Sunde, seated left, became ESHRE’s tenth Chairman in2003. He is here seen with his nine predecessors, from left toright standing, PierGiorgio Crosignani, Basil Tarlatzis, JoséEgozcue, Lynn Fraser, Klaus Diedrich, Jean Cohen, RobertEdwards, André Van Steirteghem and, seated, Hans Evers.

Sunde’s groupin Trondheimwas the first inNorway toachieve a liveIVF birth, ababy girl bornin July 1984.


IN PROFILE

FoR: You’re running one of the world’s mostactive research groups in reproductivemedicine here in Utrecht. FB: Well, we certainly have a powerful group -although our research in reproductive ageingand PCOS is really a collaboration withRotterdam. We also do a lot of research oncost efficiency - and that’s a real Dutchenterprise, which we do with many otherhospitals nationwide.

So how many papers do you produce a year?Up to 30 or 40 in total, many of thempublished in high ranking journals.

And how many research projects are goingon at any one time?

In this hospital we’re always involved in threeto five national trials in reproductivemedicine, and one of them will be directed byus. On top of that there are five or sixprojects which we run alone, with a PhDstudent allocated to each one.

It’s clearly a huge responsibility. Is there anyobvious pattern to your working day?The only pattern is that Monday, Tuesday andWednesday I collect a lot of work, coach myPhDs and do my clinics. Then I resolve thisaccumulation of work with a home workingday on Thursday and on Friday there’s eitherthe operating theatre or a symposium or myactivities as Chairman of the Dutch Society ofObGyn.

You’re also Co-ordinator of ESHRE’s SIGReproductive Endocrinology. It's been abig year for them with publication of thefirst major guidelines on prematureovarian insufficiency. What are their mainrecommendations?First, that the diagnosis of POI is importantand that its causes need long-termmanagement - especially in terms of otherhealth threats to these young women. It’s nota diagnosis and goodbye condition, butdiagnosis and take care.

And hormone therapy?Yes, the guidelines advise that this is the bestchoice - for its general health benefits -although the hard evidence is not alwaysthere on the balance of side effects.

And in practical terms how is a diagnosisof POI confirmed?Absence of cycles, elevated FSH and lowestradiol. AMH can provide furtherconfirmation if there’s any doubt.

Which brings us nicely on to AMH andwork which is very closely associated withyour group here in Utrecht. So where doyou see AMH right now - has thefundamental work been done?AMH is still a concept of promise. It’s a veryhigh promise, but we still need to consider afew things. We are still waiting for a

The science of stimulation‘You cannot change the fate of poorresponders. You can predict, but you

cannot change the outcome.’

Frank Broekmans, Professor ofReproductive Medicine at the

University Medical Centre in Utrechtand Co-ordinator of ESHRE’s SIG

Reproductive Endocrinology, arguesthat approaches in ovarian

stimulation for IVF need to be moresteered by science than by ‘belief’.

There is no evidence for a doseresponse beyond 225 IU, he says,

even in poor responders. Theessential role of AMH, he adds, ameasurement whose validity was

established by his group in Utrecht,is to predict response to stimulation.


universally acceptable assay for speedyreliable results. We still need an internationalstandard for AMH measurement where wehave cut-offs for different clinical conditions.And then we have to be clear what thosemeasurements mean - and here we’re mainlytalking about response prediction in IVF andindividualised treatment.

So only response to stimulation? Theprediction is not taking you as far aspregnancy or live birth?No, it’s about predicting response in IVF andthe individualisation of management. Thereare now two big trials which will report laterin 2016 - the OPTIMIST trial on the costeffectiveness of individualised FSH dosagesand the ESTHER trial, and both will probablyshow the same - that you cannot change thefate of poor responders. You can predict, butyou cannot change the outcome. Highresponders are different - you can predictand you can alter their fate in terms ofefficacy and safety.

OK, so risk prevention justifies predictionin high responders, but what’s the benefit inpoor responders? Why do we want to know?Many centres today, in predicted or observedpoor responders, still use 300, 450, 600 unitsday after day and it doesn’t work. You caneasily use 150 units in these cases to get thesame results. But don’t spend all that moneyon a poor responder. These trials willdemonstrate once and for all that using hugedosages in these patients just doesn’t work.

But don't we know that already?Yes, but it seems we don’t really believe it.

So AMH as a test will give us the best ideaof how a patient will respond tostimulation, but nothing more?Well, the question is, what will it do for yourwhole programme, and the answer is that itwill probably not create more pregnancies.But it will create lower cost and greater safety.

So the best predictor of pregnancy remainsfemale age?Yes, age - and a little bit of AMH! Withincertain age categories AMH may identifycases with a very poor prognosis - but this isonly in older women and the estimates aremostly based on a one-cycle observation.

And counting follicles?Counting follicles could be another test. Wehave learnt that both tests, AMH and AFC,could be similar in their prediction, but onlyif you have rigorous quality control on yourantral follicle count. Here in Utrecht we only

do AFC with two specialists, otherwise wefeel we are moving away from precision. SoAMH is probably the best way to go, becausewe can leave quality control to the lab.

Going back to this question of poorresponders, there’s some discussion aboutthe ESHRE criteria, and whether poor,normal and high are too simplistic.One of the interesting features of thoseBologna criteria is that they put in high age aspredictive of poor response. But what wemissed here is that a ‘poor responder’ who isyoung is probably not a ‘poor’ responder.She’s just somebody with not many eggs butstill young enough to get a pregnancy. I’verecently reviewed a huge dataset from China,and I wrote back saying this is your chance toshow that a poor responder below the age of,say, 36 is not actually a poor responder. Here’sa chance to make the Bologna criteria moreexplicit. I think we’re looking at a group hereof the same age - 30 to 36 - with a differentnumber of eggs but only a very marginaldifference in pregnancy prospects.

You’re saying that these so-called poorresponders - or even the genuine poorresponders - will not be helped by higherdoses of FSH. But isn’t there anyway ageneral move towards milder stimulation inIVF; isn’t this the explanation?My view on the outcome of stimulation isthat it doesn’t depend on dosage but on thenumber of follicles capable of responding. Sothere’s always a group of follicles which arecapable of responding - and which may bedifferent in number from patient to patient.There is a dose response curve, but it only

goes from about 100 to 200 units, and abovethat dose will make no difference. So responseis not mathematics, it’s not volume - what youget is simply what the ovary has in stock. Itdepends a little bit on dosage, but mainly onthe ovaries of the patient. So our message is,get eggs, but whether it’s a little more or lessdoesn’t really make any difference. And whydo we say that? Because of the study of JuanCarles Arce in 2014, who demonstrated in adose response study that you get increasingfollicle numbers and oocytes between 100 and200 units, but you don’t see any effect on thenumber of good quality blastocysts or on thenumber of ongoing pregnancies, even whenmeasured cumulatively with fresh and frozentogether. You can argue that those with manyeggs get more frozen embryos, so have bettercumulative pregnancy rates, but it’s not true.Of course, the Arce study is a pharma study,performed in a more optimal patient group,but it helps us rethink our beliefs.

That seems counterintuitive to me. How doyou explain the higher cumulative rates ofpregnancy? Is it not true that the more eggsyou have, the better your chances?The Arce study clearly demonstrates that thismay not be true. In fact, this goes back to aconcept first proposed by Esther Baart andBart Fauser, who said that, if you have three orfour eggs instead of ten, you will still get thegood eggs. You'll get a lot of rubble from thoseten eggs, and that will keep you busy - youhave to fertilise them, freeze them, replacethem. It’s time consuming but at the end of theday fresh plus frozen doesn't give better resultsin terms of babies. This is a real change in ourviews on ovarian stimulation.

Fundamental toBroekmans’argument is thestudy of Arce et al(Fertil Steril2014; 102:1633-40.e5), whichshowed that anincreasing FSHdose yielded moreoocytes but thesame number ofgood qualityblastocysts - andthe samecumulativeongoingpregnancy rates.


screening of either cleavage or blastocyststage embryos will create more pregnanciesthan conventional selection. We’ve failed toprove that. Here in the Netherlands we’re notin commercial IVF, but elsewhere there areincentives which force you to offer newdevelopments. Nobody in the Netherlandsdoes aneuploidy screening. All we are doingis a large trial of time-lapse, another toolwhich could replace invasive techniques - butso far, where is the evidence? It’s not there,and we really need it. We are trying tocontribute. We have government funding fora large trial on these time-lapse systems, andwe hope to add to the literature to see if itreally makes a difference.

Do you think it will?I personally have high hopes. Time-lapse canimprove lab conditions and we can observethe embryos without disturbing them. That’sone possible gain. It’s always been afrustration in the Netherlands that we don'thave the resources to improve our labs.

So it does make a difference here that youdo your IVF in a public health system?We’ve shown that we can do the same withour lab quality as other clinics docommercially. Our cumulative live birth rateis 32-36% per started cycle, which I think ismuch more comparable with outside theNetherlands than ten years ago. And that’smainly because we’re much more rigorous inall lab procedures.

But you’ve also had to show that you can doIVF efficiently, to prove it to the Ministry.Yes, we had to put a lot of effort intomaintaining three reimbursed cycles bycutting back our budgets - and that wasachieved by cutting the costs of FSH andlowering the rate of twin pregnancies. Ourcurrent twin rate nationwide is 4% in ARTpregnancies, which represents a huge saving.

And your plans for ESHRE? A newguideline on ovarian stimulation?I think this is a real possibility. The new trialsare likely to show that our views onstimulation will change, and we needguidelines to reflect these views. There areseveral groups already busy in this area,including WHO, but I believe ESHRE needsto take this up. There is so much that is new,so many myths that can now be broken downwithout jeopardising a couple’s chances. Butwe need to move away from the view thatwe’re harming our patients if we don’t get 20eggs. If you get one egg, you don’t beat nature,but if you get three, four, five eggs, that mightalready be optimal.

You believe that, but won’t you need moredata to make everyone else believe it? Howare you going to convince the world?Well, I’m lecturing on Friday, and probablythe week after that. And there will be resultsfrom the OPTIMIST and ESTHER trialswhich could further support this view.

So you’ll keep talking?Yes, keep talking and discussing. In fact we’realso doing some studies on the effect of FSHbioavailability on ovarian response . . . howlevels of FSH in a poor responder or normalresponder are the same. So it’s not true that apoor responder is a poor responder becauseshe didn’t get enough FSH in her system.What you also see is that the FSHmeasurements themselves are highly variable.And what does this mean? A difference inbioabsorption of the drug? The assay notpicking up the FSH properly? But in terms ofdosage and response there is no relationbetween what you get in serum and what youget in the lab.

This sounds like a crusade for you,something you're evangelical about?Well, I'm trying to steer a proper discussion.As clinicians with a scientific responsibilitywe have to rely on a strong evidence base.Our work is too much driven by belief. Theresults of Arce et al are remarkable. They arethe kind of studies which we as specialistsshould be doing. But we lack the spirit andthe resources to do them. Even the studieswhich have been done have not beenembraced in the field. That study found adose response relationship, but after 225 unitsit had gone. We have accepted that in theNetherlands, and are committed to using nodose higher than 225 IU.

So if dose has no effect on the number ofgood quality blastocysts, what does? Age,chromosomes?Well, here we enter a very enigmatic area. Ifyou have ten eggs how many of these eggs arechromosomally competent? We can guess theanswer in different age groups, but who hasthe evidence? We don’t know how large thevariation in euploidy rates is in women of thesame age group. So if you have ten eggs at age35, how large is the variation in the numberof normal embryos? It could be one normalblastocyst to five normal blastocysts, ormaybe ten in rare cases.

So are you a believer in screening embryos? I’ve been following this discussion for manyyears. And I personally conclude that we havefailed to deliver the proper evidence thatroutine comprehensive chromosome

PROUST QUESTIONNAIRE*Your greatest personal strength?

Connecting with others

What trait do you dislike in others?Stubbornness and an inability to accept newideas

What’s your greatest extravagence?A sailing boat used mainly for day trips

Who do you most admire?Barack Obama

What quality do you most admire inothers?A focus on ambition

Which words do you most overuse?Winners have a plan, losers have excuses(ask my kids)

What do you most value in friends?Openness and support

If not the Netherlands, where wouldyou most like to live?Italy

What book are youreading now?The Girl on the Train byPaula Hawkins

Where did you spendyour latest vacation?Peru

What is your favorite pastime?Sailing and biking

And your favourite writer?A F Th van der Heijen

The last film you saw?La Famille Bélier

Your favouritecomposer?Rachmaninov

Beer or champagne?Champagne

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


tudies now indicate that individualised ovarianstimulation programmes in modern ARTpractice can produce cohorts of mature oocytesable to yield cumulative live birth rates above40% after fertilisation in vitro. However, the

picture is not all sunshine and rainbows. There is asubstantial proportion of infertile patients who declineconventional ‘hormone driven’ IVF and seekalternative approaches. They may consider IVF as toocumbersome - the need for frequent monitoring ofovarian stimulation or because of hormonal sideeffects. These side effects range from abdominaldiscomfort and emotional disturbance to full-blownovarian hyperstimulation syndrome (OHSS).

Some patients have a narrow window of optimalovarian response to gonadotrophins, either because ofa non-linear dose-response, as observed in patientswith polycystic ovary syndrome (PCOS), or because ofpremature luteinisation leading to endometrialadvancement. Others may find it hard to combinefertility treatment with everyday life and struggle tocommute between home, work and the fertility centre.Some may live in rural areas and have to travel longdistances, or may face hours of dense traffic inmetropolitan areas.

Any or all of the above may be reasons for IVF’s lackof appeal, or may lead to treatment termination beforea successful pregnancy is achieved.1 Some patients willprefer an alternative simplified, low-burden ART.However, whether they would accept this at a cost, or

with a lower chance of pregnancy, is currentlyunknown.

Current status of IVMOocyte in vitro maturation (IVM) has been proposedas one alternative to conventional IVF, and, because ofits reduced hormonal burden for the patient, has beendescribed as a ‘patient-friendly’ treatment. But howdid IVM evolve and what is its current status inhuman reproduction?

IVM is a fertility treatment which obviates the needfor ovarian stimulation with gonadotrophins toproduce mature oocytes ready for fertilisation. The

COVER STORY

A shift at last from hype to hope

Following Europe’s first IVM live birth in Brussels,programme leader Michel De Vos argues that it’s now time

‘to embrace IVM’ as a useful approach in modern ART.

S

Immature oocytes from antralfollicles after minimal or no

gonadotrophin administration

The maturityof in vitromaturation


concept that immature human oocytes can resumemeiosis spontaneously and reach metaphase II within36 hours was acknowledged 50 years ago by RobertEdwards, who remained an advocate of IVMthroughout his entire career.2 Indeed, the historicalobservation of Edwards and others that approximately50% of human oocytes, when removed from theirfollicular environment, reach metaphase IIspontaneously is still valid and constitutes the basis ofoocyte maturation in vitro as we apply it today.

So it is disappointing to realise that maturation ratesof oocytes incubated in currently available IVMsystems registered for clinical use have not reallyevolved since those early experiments of Edwards backin the sixties, and low maturation rates are still a majorobstacle to the efficiency of IVM.

In contrast, the technology of hormone-driven ARThas seen tremendous advances in the past decades,fuelled by the development of pharmaceuticalcompounds to produce high quality oocytes followingovarian stimulation. The development of stimulationprotocols has led to major improvements inconventional hormone-driven ART results since thebeginning of the nineties. Similarly, GnRH antagonistprotocols with GnRH agonist trigger and efficientvitrification systems have seen an overall reduction inthe incidence of OHSS in high responders. Thus, alack of incentive to develop alternative methods toART has been one major impediment to the progressof IVM.

However, it would be unfair to say that IVM is anorphan technology and neglected by the scientificcommunity. For IVM is widely applied in animalbreeding, where maturation rates after IVM appear tobe much higher than in human IVM; indeed, yearlycattle embryo production using IVM has beenestimated to exceed 500,000. Furthermore, IVM hasattracted enormous interest from reproductivebiologists keen to unravel the complexity of humanoocyte maturation and translate the physiologicalprocess to the in-vitro setting. Finally, the improvedsuccess rates of IVM treatment in patients withPCO/PCOS reported by some groups and thesuccesful use of IVM in fertility preservationprogrammes have fuelled renewed interest in thistechnology.3,4

How it worksStrictly speaking, IVM involves the aspiration ofimmature oocytes from antral follicles after minimal

or no exogenous gonadotrophin administration.Oocyte collection is typically performed from folliclesof up to 12 mm and selection of a single dominantfollicle is avoided to prevent any negative impact ondevelopment of subordinate follicles.

Oocyte maturation rates in vitro are generally lowerthan maturation rates of oocytes retrieved in aconventional IVF programme after administration ofan ovulation trigger, suggesting that a considerableproportion of immature oocytes from small antralfollicles are still meiotically incompetent and wouldhave required more time within their follicularenvironment to accomplish physiological nuclear andcytoplasmic maturation.

Higher oocyte maturation rates can be obtainedwhen a bolus of hCG is administered, typically 36-38hours before oocyte retrieval. In these cases, meioticresumption is initiated in vivo and a proportion ofoocytes are found to have reached metaphase II at thetime of oocyte retrieval - they are oocytes which havethus completed meiosis in vivo and can readily beinseminated. As such, the hCG triggered IVM systemmay represent a semantical contradiction, but it isapplied more often than the ‘pure’ non-hCG triggeredsystem, where all oocytes are at GV stage at the time ofegg collection. Nevertheless, there is ongoing debate asto the most efficient clinical and laboratory protocolfor patients undergoing IVM.

Because of the lower maturation rate and lowerdevelopmental potential of in vitro matured oocytesretrieved from antral follicles - at least using registeredIVM media - IVM is currently not a suitable optionfor every patient requiring IVF. Thus, the cornerstoneof an efficient IVM programme is proper patientselection - and it seems that women with polycystic

Patient selection criteria for IVM

Robert Edwards remained an advocateof IVM throughout his career. Hisobservation that approximately 50% ofhuman oocytes, when removed fromtheir follicular environment, reachmetaphase II spontaneously is stillvalid and the basis of oocytematuration today.


ovaries (PCO-like ovaries and women with PCOS) arethe best candidates for IVM. They yield sufficientlyhigh numbers of immature oocytes to compensate forthe inherently lower efficiency of IVM compared tostandard IVF.5 Serum concentration of AMH, abiomarker which correlates well with the severity ofthe PCOS phenotype, is a strong predictor of thenumber of immature oocytes retrieved by follicleaspiration, and, by proxy of oocyte number, AMHcorrelates with the probability of pregnancy afterIVM.5

There may be a learning curve for egg collectionsfrom small antral follicles, and closed-circuit needleflushing systems have been developed to avoid bloodclots in the aspirated follicular fluid, although theoptimal technique of immature oocyte collection fromantral follicles requires further study.6

What’s driving IVM today?However, despite its lower efficiency than standardIVF, a number of fertility clinics have continued to useIVM for several years, for a variety of reasons - toavoid OHSS, to circumvent local regulations on thenumber of oocytes that could be fertilised in vitro, andto reduce costs related to gonadotrophins. And eventhough OHSS has almost become extinct after theintroduction of GnRH agonist triggering and electiveembryo cryopreservation, interest in IVM as aminimal-burden alternative has not disappeared. Anumber of key developments can be identified asmajor drivers of this interest:

1. Favourable clinical outcomesAthough the patient series are small, live birth rates of40% and higher in patients with polycystic ovarieshave been reported from Western Australia.7 Keyelements contributing to the success of this non-hCGtriggered IVM protocol include FSH priming andblastocyst culture. However, in comparison withconventional IVF, IVM has not been able to generatean equal amount of blastocysts, although theimplantation rate per embryo appears similar in bothapproaches. One could therefore state that IVM is aless wasteful system in terms of embryo production

than conventional ART.We launched an IVM programmme at our centre in

Brussels in 2010. It was embedded within a researchproject aimed at improving IVM outcomes throughmodification of the clinical approach and culturesystem. Our initial results in patients with polycysticovaries were disappointing, but, contrary to whathappened in a number of pioneering IVM centres, wedid not abandon the programme. First, we learnt thattransfer of warmed IVM embryos after vitrificationthree days after ICSI performed better than freshembryo transfer. Second, we reduced the IVMincubation period from 40 to 30 hours and appliedextended embryo culture to the blastocyst stage in asubset of patients. By doing so, consistently goodclinical outcomes were obtained, comparable withthose published by the Australian group. Nevertheless,sufficiently powered clinical trials investigating thetrue potential of current IVM systems compared withconventional IVF are still lacking.

2. Reassuring safety scores of IVM systemsAt both a cytogenetic and epigenetic level, in vitromatured oocytes and embryos generated after IVM donot carry more chromosomal or methylation defects.8Data from these studies mitigate concerns withefficiency and safety of IVM technology (as proposedby the ASRM and SART), although follow-up ofchildren born after IVM remains mandatory.9 Previousstudies had shown abnormal methylation in oocytesafter IVM, but the immature oocytes used in thesestudies were derived from conventional IVF cycles andhad failed to complete meiosis after an ovulationtrigger. There is now compelling evidence thatattempts to ‘rescue’ these immature oocytes are notrecommended, as they have a high prevalence of DNAdamage, and embryonic development is grosslycompromised.10

3. In fertility preservation for cancer patientsImmature oocytes can be obtained from antral folliclesin the follicular and luteal phase of the cycle whenthere is not enough time to stimulate the ovaries andharvest mature oocytes. Oocytes can even be retrievedfrom extracorporeal ovarian tissue, matured in vitro,

MICHEL DE VOS: ‘A LACKOF INCENTIVE TODEVELOP ALTERNATIVEMETHODS TO ART HASBEEN ONE MAJORIMPEDIMENT TO THEPROGRESS OF IVM.

Current clinical protocol of IVM in Brussels.


fertilised - and result in live births.11 This combinedapplication of fertility preservation methods mayincrease hope of delayed childbearing to young cancerpatients who undergo ovarian cortex cryopreservationbefore gonadotoxic treatment.

4. IVM of oocytes can be a last resort in infertilepatients who have consistently high circulating levelsof FSH and a normal antral follicle count with antralfollicles unresponsive to FSH.

Although IVM research has not yet revolutionisedIVM systems in the clinical setting, improved IVMsystems are under way. Lessons have been learnt fromexperiments in animal models, where modulation ofthe maturation process in vitro through cAMP-mediated systems or the addition of oocyte growthfactors, such as Growth differentiation factor 9 (GDF9)and bone morphogenetic protein 15 (BMP15), canresult in substantially higher numbers of blastocysts.However, progress is slow, partly because of licensingand regulatory hurdles required in the development ofculture media.

Nevertheless, it’s my belief that the time has nowcome to embrace IVM as a useful additional tool inmodern ART practice. IVM requires no majormodifications in the ART laboratory; however, becauseof the complexity of physiological oocyte maturation,our current IVM systems, which are not physiological,do require further refinement. The promisingly goodclinical outcomes obtained in some pioneering IVMcentres, after proper patient selection, illustrate howIVM has the potential to grow to full maturity in thefuture.

References1. Gameiro S, Boivin J, Peronace L, Verhaak CM. Why dopatients discontinue fertility treatment? A systematic reviewof reasons and predictors of discontinuation in fertilitytreatment. Hum Reprod Update 2012; 18: 652–669.2. Edwards RG. Are minimal stimulation IVF and IVM set toreplace routine IVF? Reprod Biomed Online 2007; 14:267–270. 3. Junk SM, Yeap D. Improved implantation and ongoingpregnancy rates after single-embryo transfer with anoptimized protocol for in vitro oocyte maturation in womenwith polycystic ovaries and polycystic ovary syndrome. FertilSteril 2012; 98: 888-892.4. Grynberg M, Poulain M, Le Parco S, et al. Similar in vitromaturation rates of oocytes retrieved during the follicular orluteal phase offers flexible options for urgent fertilitypreservation in breast cancer patients, Human Reprod. Inpress.5. Guzman L, Ortega-Hrepich C, Polyzos NP, et al. Aprediction model to select PCOS patients suitable for IVMtreatment based on anti-Mullerian hormone and antralfollicle count. Human Reprod 2013; 28: 1261–1266. 6. Rose BI, Laky D. A comparison of the Cook single lumenimmature ovum IVM needle to the Steiner-Tan pseudodouble lumen flushing needle for oocyte retrieval for IVM. JAssist Reprod Genetics 2013; 30: 855–860. 7 Walls ML, Hunter T, Ryan JP, et al. In vitro maturation as analternative to standard in vitro fertilization for patientsdiagnosed with polycystic ovaries: a comparative analysis offresh, frozen and cumulative cycle outcomes. Human Reprod2015; 30: 88-96.8. Spits C, Guzman L, Mertzanidou A, et al. Chromosomeconstitution of human embryos generated after in vitromaturation including 3-isobutyl-1-methylxanthine in theoocyte collection medium. Hum Reprod 2015; 30: 653-663.9. The Practice Committees of the American Society forReproductive Medicine and the Society for AssistedReproductive Technology. In vitro maturation: a committeeopinion. Fertil Steril 2013; 99: 663-666.10. Coticchio G, Dal Canto M, Guglielmo M-C, et al. Double-strand DNA breaks and repair response in human immatureoocytes and their relevance to meiotic resumption. J AssistReprod Genetics 2015; 32: 1509-1516.11. Segers I, Mateizel I, Van Moer E, et al. In vitro maturation(IVM) of oocytes recovered from ovariectomy specimens inthe laboratory: a promising “ex vivo” method of oocytecryopreservation resulting in the first report of an ongoingpregnancy in Europe. J Assist Reprod Genetics 2015; 32:1221–1231.

Europe’s first live birth in Brussels


While we are finalising the first reportfrom our European oocytecryopreservation survey - to which weare now adding ovarian tissuecryopreservation - we successfullyorganised the ESHRE postgraduatecourse in October at the ASRM annualmeeting in Baltimore. The topical subjectwas the pros and cons of oocyte cryopreservationversus embryo freezing.

We had 150 in attendance, and our speakers includedembryologists Laura Rienzi and Cristina Magli onscience and practice in the lab, followed by clinicaloutcomes and sociocultural and ethico-legalconsiderations from Professor Siladitya Bhattacharyaand myself.

This was a very well attended course, with manyquestions asked. With vitrification now established asthe favoured cryopreservation method in many partsof the world, the practical message from Laura was‘keep it simple and keep it fast’ - and do not disturb thecells, whether oocytes or embryos, by addingcomponents or extra steps to protocol. She concludedthat vitrification best maintains the oocyte’scompetence to develop in vitro and is most effective forimproving clinical results, and that evidence isaccumulating that the outcome and safety of oocytecryopreservation are similar to embryo freezing .

Cristina discussed the value of genetic diagnosis andscreening for both the oocyte and embryo. Shereported that the chromosome analysis of oocytes hasrevealed that more net errors in aneuploid zygotesoccur in meiosis II and that premature chromatid

separation is the prevalent form of errorsat meiosis I. The chromosome analysis ofembryos has revealed high levels ofmosaicism at the cleavage stage, which,she said, can cause misdiagnosis, andlow levels of mosaicism at the blastocyststage. However, in regularly developing

embryos, biopsy at previous stages ishighly predictive of the blastocyst’s chromosomecondition. Cristina also reviewed her own group’swork on the analysis of blastocyst fluid as a marker ofviability.

Siladitya Bhattacharya outlined the value of meta-analysis, and how the removal of one study maychange the final picture. Going back to the originaldata and not taking any meta-analyses for granted wasa valuable tip. On the question of outcome, heconcluded from the data that frozen-thawed embryotransfer lowers the risk of preterm babies, increasesmaternal safety but could be associated with large-for-gestational age offspring - whilst the pregnancy rate inpoor prognosis women was unclear.

The debate about freezing oocytes for non-medicalindications was very energetic, as was the discussionon what medical reasons other than the classicalcancer indications might be considered for oocytecryopreservation, such as Turner’s mosaics orendometriosis. Nevertheless, when asked if they wouldadvise their daughter to cryopreserve oocytes, or evenconsider oocyte cryopreservation themselves, mostwomen (and men) in the audience were positive aboutthe technique. Despite the enthusiasm, the discussionemphasised that we still have an ethical imperative togather data on the efficiency of oocytecryopreservation in non-medical indications, and tofollow up the offspring born to ensure that thetechnique does not affect the ‘welfare’ of the futurechild. Such discussion underlined the importance ofour own ESHRE study, a prospective full datagathering with eventual use and success ratespresented according to indication and patient age.

Plans for HelsinkiOur precongress course for this year’s AnnualMeeting, organised with the SIGs Early Pregnancy andEthics & Law, is titled What happens in utero lasts alifetime: A multi-disciplinary approach toimproving preconception and early pregnancy care.Full details are on the ESHRE website and, with suchmultidisciplined interest, early registration isrecommended.

Françoise ShenfieldCo-ordinator SIG Sociocultural

aspects of (in)fertility

SIG’s precongress course proves popular at ASRMUS audience largely committed to oocyte cryopreservation for non-medical reasons

Speakers at the ESHRE precongress course at this year’s ASRM annualmeeting; from left, Siladitya Bhattacharya, Françoise Shenfield,

Laura Rienzi and Cristina Magli.

SIG SOCIOCULTURAL ASPECTS 0F (IN)FERTILTY

Françoise Shenfield (GB), Co-ordinatorPaul Devroey (BE), DeputyAnna Pia Ferraretti (IT), DeputyVirginie Rozée (FR), Junior Deputy

STEERING COMMITTEE


SIG ENDOMETRIOSIS & ENDOMETRIUM

The EndoKey projectOur ESHRE guideline on themanagement of women withendometriosis aimed to improveendometriosis care in Europeanhospitals by providingrecommendations based on evidenceand good clinical practice (there were83 recommendations in total).1

Unfortunately, however, guidelinedevelopment is not automaticallyfollowed by healthcare improvementin practice. We have thus felt a needto gain insight into the application ofthe new guideline in the managementof women with endometriosis ineveryday practice (ie, actual clinicalcare) and the potential barriers toguideline adherence. By measuringand monitoring actual care, ‘qualityindictors’ can help to better implementthe guideline in European hospitals.

The EndoKey group (led bySchleedoorn, Nelen, Dunselman and

Vermeulen) have taken the first steps in thedevelopment of quality indicators by selecting acompact set of recommendations on which to focus,ie, ‘key recommendations’. Using a basic RAND Delphimethod, the group is now systematically selecting keyrecommendations from the ESHRE guideline with thesupport of an international expert panel of bothpatients and professionals.

Collaboration with the the European Society forGynaecological Endoscopy The Chair of the Endometriosis GuidelineDevelopment Group and the President of theEuropean Society for Gynaecological Endoscopy(ESGE) have begun a project to develop a jointguideline on the surgical management ofendometriosis. The goals of the project were discussedat two meetings last year, with representatives ofESHRE (Saridogan, Grimbizis, Vermeulen,Dunselman) and ESGE (De Wilde, Keckstein, Tanos,Ulrich). It was agreed that the aim should not be torewrite existing guidelines (the ESHRE and Germanendometriosis guidelines) but to provide guidance onhow endometriosis surgery should be performed.During the course of the project surgical techniqueswill be discussed in detail, making use of a videolibrary of the most common surgical procedures basedon recommendations of the ESHRE and Germanendometriosis guidelines. In the final version thevideo clips will be accompanied by written and spokencommentary. The first clip will cover the surgicalmanagement of ovarian endometriomas. The nextmeeting of the taskforce will be in Leuven on 9 April.

From guideline to implementation in clinical practiceEuropean Commission fundsresearch on endometriosisA multidisciplinary team ofresearchers from Germany, Scotland,Sweden, Argentina and Chile hasreceived a EU Horizon 2020 grant forendometriosis research. TheMOMENDO project will support an

exchange programme to explore currentconcepts of disease aetiology, including work on adultstem cells, microRNAs, iron-induced inflammatoryresponses, and novel endocrine approaches. The aim isa deeper understanding of the molecular mechanismsbehind the inflammatory pain associated withendometriosis and the persistent growth of lesions. Bycombining non-academic and clinical partners, theconsortium plans to translate these findings into noveltherapeutic approaches. For more information pleasecontact [email protected].

James Lind Alliance Endometriosis Priority SettingPartnershipA group of UK endometriosis researchers haveestablished a James Lind Alliance (JLA) PrioritySetting Partnership to conduct a national survey inGreat Britain and Ireland to identify endometriosisresearch questions that are important to patients, theircarers and professionals with clinical experience ofendometriosis. The JLA is a non-profit organisationfunded by the National Institute of Health Research(NIHR) in the UK. It provides a ‘tried-and-tested’, fairand rigorous process to help patients and clinicianswork together to agree on the most important researchquestions in a particular area (in this case,endometriosis), in order to influence the prioritisationof future research in that area. The project has beenformally endorsed by the World EndometriosisResearch Foundation. For more information pleasecontact [email protected].

Look forward to 2016: mark your agenda!The new year will start with a SIGEE Campus meetingin Istanbul in February (26-28 inclusive), a jointventure with the Turkish Society of Endometriosis andAdenomyosis. The meeting will debate and discusscontroversies in the diagnosis and management ofendometriosis and adenomyosis. Our activities willcontinue with our yearly precongress course inHelsinki (3 July) on the medical treatment options forendometriosis, ranging from basic, throughtranslational to late preclinical and clinical subjects.

Andrew HorneCo-ordinator SIG Endometriosis and Endometrium

1. See https://www.eshre.eu/Guidelines-and-Legal/Guidelines/Endometriosis-guideline/Guideline-on-the-management-of-women-with-endometriosis.aspx.

STEERING COMMITTEEAndrew Horne (GB), Co-ordinatorCarla Tomassetti (BE), DeputyAndrea Romano (NL), DeputyAntonio Simone Lagana (IT), Junior DeputyGerard Dunselman (NL), Past Co-ordinator


Founded in 2002, the SIG SQART hasa long history of active participationin ESHRE and, with a new steeringcommittee in place, has recentlyreaffirmed its continuing mission. SQART is involved in many aspects ofART and still contributes to SETpolicies and preventive measures forOHSS in an environment of fastdeveloping technologies. On this fast lane to thefuture, SQART is present at the intersection ofscientific design and clinical implementation - as isevident in the subjects of our upcoming events.

Back to the future of ARTAlongside the SIGs Ethics & Law and Stem Cells, weare organising two upcoming events that return to thefuture of ART. These will cover standard treatmentssuch as ultrasound but will also move forward toinnovative experimental treatments. We thus warmlyinvite you to our precongress course in Helsinki, whichis organised with the SIG Stem Cells on 3 July andtitled ART in 2020: the next frontier. All the topicsfeatured - stem cell therapies, the manipulation ofgametes, uterine transplantation - are all experimentalbut still attract much interest. And it’s fair to say that,in our progress to overcome mitochondrial and otherdiseases, the use of nuclear transfer or ‘next generation’gametes is no longer fiction.

Although such advances are scientific, they must stillbe considered from a safety and ethical point of view:they all SEEM okay, but are they really okay? So join usin Amsterdam for an ESHRE Campus course at thecutting edge of the future of ART: Novel gametemanipulation technologies in ART: SEEM (safety,ethical, efficient, moral) okay? on 22-23 September.

The SIG SQART is also in the process of organising a

Campus course on oncofertility inwomen. Some central questions -when to preserve gametes or gonadaltissue and in which patients - are still amatter of debate. More details will besoon available on the ESHRE website.

To help us plan future SQARTevents, we’d be grateful if you could

complete the questionnaire accessibleon the ESHRE website (https://www.eshre.eu/sqart/questionnaire) and tell us your ideas, so that futureSQART events will be best tailored to suit your needs.We hope to hear from you soon.

Arianna D’Angelo Co-ordinator SIG SQART

Kelly Tilleman, Deputy

Guidelines for quality and safetyESHRE began its investment in guidelines in 2009with a manual for guideline development andrecruitment of a research specialist. Five years later, theESHRE guidelines programme is firmly establishedand has resulted in three published clinical guidelines -on the management of women with endometriosis andpremature ovarian insufficiency, and on routinepsychosocial care in infertility and assistedreproduction. An update of the revised guidelines forgood practice in IVF laboratories has been completed.

More exciting projects are planned for 2016. First, amultidisciplinary guideline group is working on thedevelopment of a guideline on recurrent miscarriage(working title), which will include recommendationson the diagnosis of underlying conditions and on thevarious treatment options for couples after multiplemiscarriages.

ESHRE will also focus more on the disseminationand implementation of its guidelines, whose final aimis acceptance in clinical practice and the improvementof care of patients with infertility. So this year moreemphasis will be placed on the development of tools tohelp clinicians implement the ESHRE guidelines intheir local practice, on the development of patientinformation, and on the evaluation of impact.

Finally this year a topic for the next ESHREguideline must be selected. Do you have any idea of asubject in need of a European guideline? Do you havea strong opinion on a certain topic that should beaddressed in an ESHRE guideline, a subject with highvariability in care and/or high potential forimprovement of care? Please [email protected] or the Co-ordinator of theappropriate SIG. Your idea may well be the start of anew exciting guideline project.

Nathalie VermeulenESHRE Research Specialist

SIG SAFETY AND QUALITY IN ART

The safety of new technological developmentsSTEERING COMMITTEE

Arianna D’Angelo (GB), Co-ordinatorKelly Tilleman (BE), Deputy Ioana Rugescu (RO), DeputyZdravka Veleva (FI), Junior DeputyWillianne Nelen (NL), Past Co-ordinator

The SIG SQART steering committee at its business meeting in November.Left to right, Kelly Tilleman, Willianne Nelen, Ioana Rugescu, Zdravka

Veleva, Arianna D’Angelo

Answer ourquestionnaire viathe QR above orSIG SQART page

on the ESHREwebsite, and help

us plan futureevents.

SIG REPRODUCTIVE GENETICS

Highlights of 2015 in reproductive genetics

Thirty-eight years after the first IVFbaby, ‘success’ remains a majorchallenge in reproductive medicine,with two-thirds of IVF cycles stillending in failure. Some of theoutstanding papers described belowwill likely be the basis of novelmethodologies to select gametesand embryos with the best qualityand developmental capacity. Their common theme isthat they make use of combinations of newtechnologies in molecular, imaging and geneticanalysis to study the human oocyte and embryo.

In the context of embryo selection for IVF, Capalboet al investigated the microRNAs secreted intoblastocyst culture media and identified somemicroRNAs differentially expressed in subsequentlyimplanted versus non-implanted blastocysts, thoughfurther work is required to explore their use asbiomarkers of implantation potential.1

Aneuploidy in early human development is still ahot topic in our field, particularly the search forpredictive markers and a better understanding of themechanisms behind chromosome abnormalities. Onerecent development in analysing the genetic content ofembryos and predicting implantation potential is theuse of blastocoel fluid as a source material. Theprediction of aneuploidy was achieved by peptidedetection and quantification in the blastocoel cavity ofhuman preimplantation embryos.2 This showed that itmight be possible to identify aneuploid embryos basedon the levels of GAPDH and the detection of histoneH2A proteins. On the other hand, aCGH on amplifiedDNA from the blastocoel fluid indicated karyotypicdiscordance when compared to aCGH of theremaining ICM-TE sample. This study, althoughshowing that the diagnostic accuracy of blastocoelfluid aCGH is unacceptable for clinical use, didsuggest a mechanism that marginalises aneuploidnuclei into the blastocyst cavity.3

Another recent study supports the notion thatembryo development is strongly influenced bymaternal factors and may be determined even beforemajor embryonic gene activation.4 From this study itappears that the chromosomal status of an embryomay be predicted by a 12-gene transcriptomicsignature. Furthermore, the study presents evidencefor a correlation between the kinetics of early embryodevelopment and gene expression that might be usedto develop special algorithms for predictingdevelopment to the blastocyst stage or for time-lapsewith chromosomal analysis to identify cell cycle andfragmentation parameters diagnostic of ploidy, in linewith previously published work of others.

An alternative avenue has beenexplored by the group of Fragouli andWells. In a recent study they identifiedan association between mitochondrialDNA, aneuploidy and the ability of anembryo to implant in the uterus.5 Theauthors observed that the quantity ofmtDNA in biopsied trophectoderm

cells was significantly higher inblastocysts from older versus younger women, as wellas in aneuploid versus euploid blastocysts, independentof age, while the mtDNA levels were lower inblastocysts capable of establishing a clinical pregnancythan in those failing to implant after transfer. Theauthors also established a mtDNA quantity thresholdabove which implantation failure was 100% andproposed that assessment of mtDNA could represent anovel biomarker of embryo viability, forming the basisof a simple and inexpensive clinical test with potentialvalue for IVF treatment. Results from ensuing similarstudies have also proved encouraging.6

The use of array technologies to detect andunderstand aneuploidy in embryos and gametesremains a major focus, and a study of aneuploidy byaCGH in pooled first and second PBs shows thatmeiotic separation errors in oocytes can effectively bedetected in this way.7 When employed in embryoselection this approach may increase live birth rate in aPGS versus control group of patients with repeatedimplantation failure or of advanced maternal age.

Overall, PGS with the use of comprehensivechromosome screening technology assists embryoselection, but results from several ongoing RCTs arestill expected to clarify its use for different patientgroups and embryo biopsy stages. In the meantime,several studies have focused on validating and applyingnext-generation sequencing (NGS) as a new platform,which has so far proved highly concordant withaCGH.8 NGS may allow the simultaneous diagnosis ofsingle gene disorders and aneuploidy and may have thepotential to provide more detailed insight into otheraspects of embryo viability.

From a mechanistic point of view, a striking newdiscovery was made studying chromosomalconstitution and chromosome-specific recombinationrate and distribution in single oocytes.9 This not onlysupported data from trisomy screening showing thatchromosome segregation in meiosis I is greatly affectedby recombination, which subsequently affectssegregation in meiosis II, but also that a majorityexhibit equational separation of chromatids in meiosisI and reductional division at meiosis II, much differentfrom all common mechanisms which prevail in meiosisof most eukaryotes. This study firmly establishes the


The goal remains identifying gametes and embryos with development potential

STEERING COMMITTEEClaudia Spits (BE), Co-ordinatorTania Milachich (BG), DeputyGeorgia Kakourou (GR), DeputySigne Altmäe (EE), Junior DeputyUrsula Eichenlaub-Ritter (DE), Past Co-ordinator


fact that meiotic errors significantly contributeto aneuploid conceptions, and enhances ourunderstanding of the origin of aneuploidy andthe chromosomal constitution of the oocyte andits corresponding polar bodies. The implicationsremain to be determined, but the knowledge issignificant considering, for example, thattransplantation of any of the products of femalemeiosis between oocytes has been proposed fortreatment of mitochondrial disease. Complexaneuploidies of mitotic origin were alsoextensively investigated in another study,providing an additional explanation to the limitationsof human fertility.10

The field of fertility genetics has also been yieldinginteresting results. For instance, McCoy et al recentlypublished a genome-wide association study ofaneuploidy risk in patients undergoing PGS.11 Theygenotyped the embryos and compared them to theparental DNA using SNP microarrays, and identifiedthe rs2305957 SNP as a polymorphism associatedwith high rates of embryonic mitotic errors. The polo-like kinase 4 (PLK4) gene, involved in cell cycle andcytoskeletal regulation, is tightly linked with thisvariant and was thus identified as a candidate geneinvolved in mitotic errors in preimplantation.

On the methodological front, several novelexperimental approaches are revolutionising geneticsresearch and are promising to shed light not only onthe identification of novel genes, but also in thetreatment of disease. One experimental approach toidentify genes in female meiosis and fertility wasreported by Pfender et al.12 It involves themicroinjection of small interfering RNAs into smallfollicle-enclosed mouse oocytes to block expression ofdistinct, still unknown meiotic genes during folliclegrowth and oocyte maturation. The assessment of theimpact of this in vitro knockdown by quantitative liveimaging of the oocytes helped identify a number ofnew genes implicated in meiosis and to provide newinformation on causes of chromosome segregationerrors and risk factors of anaphase lagging inoogenesis.

Another of these exciting methods is RNA-guidedgenome editing for genetic research.13 This methodhas also opened new perspectives to eliminatemutations, model human disease in primates, orprevent disease in transgenic mouse models. However,the safety, benefit and particularly the ethical and legalimplications of germline editing still need to beassessed, as recently addressed by editorials in NatureMedicine and in meetings of concerned scientists.14,15

Certainly, for the time being the reproducibility andvalidity of all novel methods and studies must bemore extensively tested, while the rapid developmentsin reproductive genetics promise new excitingfindings in the near future - to improve assistedreproduction and understand the basics of gamete andembryo development and quality.

Future SIG activitiesThis year we are looking forward to two Campusworkshops, Oocyte maturation, from basics toclinic to be held in March in Brussels, and Allabout preconception, preimplantation andprenatal testing in April in Maastricht, asalready described in the previous issue of Focuson Reproduction. Finally, our precongress coursein Helsinki will focus on Genetics andepigenetics behind subfertility andreproductive system disease. We hope towelcome you to this exciting course.

Georgia KakourouDeputy, SIG Reproductive Genetics

1. Capalbo A, Ubaldi FM, Cimadomo D, et al. MicroRNAs inspent blastocyst culture medium are derived fromtrophectoderm cells and can be explored for human embryoreproductive competence assessment. Fertil Steril 2015; pii:S0015-0282(15)01931-7.2. Poli M, Ori A, Child T, et al. Characterization andquantification of proteins secreted by single human embryosprior to implantation. EMBO Mol Med. 2015; 7:1465-1479.3. Tobler KJ, Zhao Y, Ross R, et al. Blastocoel fluid fromdifferentiated blastocysts harbors embryonic genomicmaterial capable of a whole-genome deoxyribonucleic acidamplification and comprehensive chromosome microarrayanalysis. Fertil Steril 2015; 104: 418-425. 4. Vera-Rodriguez M, Chavez SL, Rubio C, et al. Predictionmodel for aneuploidy in early human embryo developmentrevealed by single-cell analysis. Nat Commun 2015; 6: 7601. 5. Fragouli E, Spath K, Alfarawati S, et al. Altered levels ofmitochondrial DNA are associated with female age,aneuploidy, and provide an independent measure ofembryonic implantation potential. PLoS Genet 2015; 11:e1005241.6. Diez-Juan A, Rubio C, Marin C, et al. Mitochondrial DNAcontent as a viability score in human euploid embryos: less isbetter. Fertil Steril 2015; 104: 534-541.7. Feichtinger M, Stopp T, Göbl C, et al. Increasing live birthrate by preimplantation genetic screening of pooled polarbodies using array comparative genomic hybridization. PLoSOne 2015 Jul 15; 10(7): e0133334.8. Zheng H, Jin H, Liu L, et al. Application of next-generationsequencing for 24-chromosome aneuploidy screening ofhuman preimplantation embryos. Mol Cytogenet 2015; 8: 38.9. Ottolini CS, Newnham LJ, Capalbo A, et al. Genome-widemaps of recombination and chromosome segregation inhuman oocytes and embryos show selection for maternalrecombination rates. Nat Genet 2015; 47: 727-735.10. McCoy RC, Demko ZP, Ryan A, et al. Evidence ofselection against complex mitotic-origin aneuploidy duringpreimplantation development. PLOS Genet 2015 Oct 22;11(10):e1005601.11. McCoy RC, Demko Z, Ryan A, et al. Common variantsspanning PLK4 are associated with mitotic-origin aneuploidyin human embryos. Science 2015; 348: 235-238.12. Pfender S, Kuznetsov V, Pasternak M, et al. Live imagingRNAi screen reveals genes essential for meiosis in mammalianoocytes. Nature 2015; 524: 239-242.13. Singh P, Schimenti JC, Bolcun-Filas E. A mousegeneticist's practical guide to CRISPR applications. Genetics2015; 199: 1-15.14. Germline editing. Nat Med 2015; 21: 295.15. Baltimore D, Berg P, Botchan M, et al. Biotechnology. Aprudent path forward for genomic engineering and germlinegene modification. Science 2015; 348:36-38.

Georgia Kakorou,SIG Deputy,

describes‘outstandingpapers of the

year’.

SIG REPRODUCTIVE ENDOCRINOLOGY

POI guideline now approved and availableLooking back on 2015, we can feelvery happy and a little proud aboutwhat has been achieved. First, anESHRE guideline on the Managementof women with premature ovarianinsufficiency was published on theESHRE website in December(https://www.eshre.eu/guideline/POI).This evidence-based guideline waswritten by the development group chaired by LisaWebber and Melanie Davies (co-chair until December2014). A summary paper for Human Reproductionand a patient version will be published in 2016. Also,a very well designed workshop on Old and new inreproductive endocrinology took place in Helsinkiin April and our precongress course in Lisbon onRecurrent implantation failure was the bestattended at last year’s annual meeting!

Upcoming eventsWith two new crew members aboard, PeterHumaidan and George Lainas, our SteeringCommittee looks ahead to the year 2016 withhigh expectations. These will comprise aCampus workshop on 8-9 April in Istanbul onthe Multifaceted challenge of femalereproductive ageing, with focus on the

physiology of the ageing process andthe management of couples with age-related fertility decline.

In addition, a joint workshop withthe SIG Reproductive Surgery has alsobeen planned for Thessaloniki on 5-6May on Surgery in reproductivemedicine: benefits and limits. Topics

will include PCOS, endometriosis, tubaldisease and fibroids. Later the Annual Meeting inHelsinki in July (on mid-summer night) will feature avery attractive pre-congress course dedicated toManaging the difficult IVF patient: facts andfiction. This will offer participants an insight intoworking with the older IVF patient, the medicallycomplicated, the fat and the thin, and the patient with

a co-morbidity such as endometriosis and uterinecavity distortion.

This will also see the presentation of two largeIVF trials on dosage and individualisation ofovarian stimulation. With the likelihood of newevidence, these trials may yet be the kick off fordeveloping an ESHRE guideline on ovarianstimulation protocols for IVF/ICSI. It will be anextensive work package and the SIG RE is nowconsidering a guideline group for OS-ART.

Frank BroekmansCo-ordinator SIG Reproductive Endocrinology


STEERING COMMITTEEFrank J. Broekmans (NL), Co-ordinatorDaniela Romualdi (IT), Deputy Peter Humaidan (DK), DeputyGeorge Lainas (GB), Junior DeputyEfstratios Kolibianakis (GR), Past Coordinator

SIG ETHICS & LAW

ESHRE/FIGO meeting on ethics of human reproduction and healthA successful third joint meeting of theEthics Committee of FIGO(International Federation ofGynecology and Obstetrics) andESHRE’s SIG Ethics & Law was held atlast year’s FIGO world conference inVancouver in October. The meeting wasjointly chaired by Veerle Provoost, PastCo-ordinator of the SIG Ethics & Law, and BernardDickens, chair of FIGO’s Ethics Committee.

The plan was to have five presentations on topics ofmutual interest: two from each society and a furtherone by Françoise Shenfield, who is active in bothorganisations. She was due to speak on the ethics ofoocyte cryopreservation, the subject of an imminentreport by the SIG Sociocultural aspects of infertility.However, due to illness she was unfortunately unableto join in.

The session therefore went ahead with four talks.For ESHRE, Wybo Dondorp, associate professor of

Bioethics at Maastricht University,reviewed the ethical aspects of expandeduniversal carrier screening for recessivediseases, while Veerle Provoost discussedthe findings and policy implications ofqualitative research into couples’decisions on embryo disposition. For

FIGO, presentations were given by DuruShah, gynaecologist and past honorary professor ofObstetrics & Gynaecology in Mumbai on the ethicalchallenge of adolescent pregnancies and by JoannaCain, professor of O&G at the University ofMassachusetts, on the use and limits of conscientiousobjection in medical practice. The upside of the lowernumber of talks was more time for fruitful discussionwith the audience and among the members of thepanel.

Wybo DondorpFormer Co-ordinator, SIG Ethics & Law

STEERING COMMITTEEGuido Pennings (BE), Co-ordinatorGuido De Wert (NL), Deputy Lucy Frith (GB), DeputyVeerle Provoost (BE)), Past Co-ordinator


SIG PSYCHOLOGY & COUNSELLING

Almost 1000 guideline downloads since AprilThese are exciting and busy timesfor the SIG Psychology &Counselling. Our precongresscourse in Lisbon was on cross-cultural issues in infertility, themeaning of parenthood and theexperience of infertility treatment.We learned more about how culturalcharacteristics can play an importantrole in shaping infertility both within and outsideEurope.

We also found out more about the perception offertility among mental health professionals. Indeed,an online survey of ESHRE members revealed thatthere is a positive perception of psychologists andcounsellors in fertility care. However, there is also alack of awareness about the different roles theyperform, both with patients and their colleagues in aninterdisciplinary context.

Guideline downloadsOur ESHRE guideline on Routine psychosocial care ininfertility and medically assisted reproduction - Aguide for fertility staff was published in April last yearand has been attracting much attention, with 962downloads of the document since then. The majorityof downloads were by clinicians (30%), psychologists(17.3%) and embryologists (15.9%). The mostfrequent reasons for downloading wereimplementation or to learn more (64%).

We are quite satisfied to see how the guidelines havebeen disseminated so far and how professionals seem

interested in knowing more aboutthem and their implementation.

Campus meetingsWe joined the SIG Endometriosis andEndometrium to organise our latestCampus meeting on Sexualfunctioning in women dealing with

infertility and/or endometriosis. Themeeting delivered an update on the interrelationshipbetween sexual function, infertility and endometriosis,which encouraged discussion of important topicsrelated to sexual health which are difficult to managein clinical practice.

This year, as noted below, we are joining forces withfour other ESHRE SIGs in the May Campus workshopon fertility preservation in boys. The meeting will havea strong emphasis on the psychological challenges forpatients and their parents.

Our next precongress course, Complex cases ininfertility counselling: Discovering new territories,implementing new techniques and creating new

conversations to be held in Helsinki willconsider new techniques for complex cases(with expected results) and how we can managetheir arising legal, ethical, medical andpsychosocial issues. We will also have theopportunity to learn more about sexualdysfunction in infertile couples and fertilityassessment and counseling.

Juliana PedroJunior Deputy, 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

Five ESHRE SIGs join forces for fertility preservation Campus


SIG REPRODUCTIVE SURGERY

SIG EMBRYOLOGY

Following the Annual Meeting inLisbon, we held a very well attendedCampus workshop in Leuven inOctober. This was the last workshopfollowing this frequently repeatedprogramme and now for 2016 a totallyrenewed programme will be proposed incooperation with Liege University.Thanks are due to Michelle Nisolle,Deputy of our SIG, and Stephan Gordts and his teamwho have been able to develop this advanced course(with work on cadavres) as a complement to theLeuven workshops.

Upcoming eventsThis month (21-22 January) we will be running our

first meeting in Coventry on When issurgery the answer to early pregnancycomplications? followed just a weeklater (28-30 January) by a workshop inMilan on The impact of reproductivesurgery on cross-talk between theembryo and the endometrium.

These will be followed by ourprecongress course in Helsinki in July,

which this year will be about the Managmement ofmyomas in women wishing to preserve reproductivefunction.

We have also agreed that our precongress course inGeneva in 2017 will be on the management ofcomplications in reproductive surgery

In addition to these activities, we have made theassumption that a lot of subtle pelvic abnormalities(minimal endometriosis, minimal uterine pathology,subtle tubal lesions) are either not diagnosed or nottreated, which may often prevent many patients fromconceiving naturally. In the light of these assumptionsthe SIG RS is keen to launch a survey of the diagnosisand treatment of such abnormalities to assess theirimpact on fertility treatment and outcome. A proposalwill be made to all interested members over thecoming weeks, and we hope that a great number ofreproductive surgeons will respond positively.

Antoine WatrelotCo-ordinator SIG Reproductive Surgery

Subtle pelvic abnormalities: SIG survey to assess impact

Updated guidelines on good laboratory practice nearing completion

STEERING COMMITTEEAntoine Watrelot (FR), Co-ordinatorMichelle Nisolle (BE), DeputyRazvan Vladimir Socolov (RO), DeputyFilipa Beja Osório (PT), Junior DeputyTin-Chi Li (HK), Past Co-ordinator

Subtle tubal lesion: hydatid of Morgani on patent tube.How do such abnormalities affect fertility treatment?

Two major SIG Embryology activitiesare nearing completion – The revisedguidelines for good practice in IVFlaboratories and the digital Atlas ofembryology – while other projects arein development.

Oocyte maturation: from basic toclinic, to be held in Brussels 3-5March, will be one of two coursesplanned for 2016. An understanding ofoocyte maturation is needed not just to improve theclinical efficiency of IVM, but also for a moreobjective and specific definition of oocyte quality inART. The programme will cover the fundamentalprinciples of oocyte maturation, plus the translationaland clinical aspects of IVM, as well as its introductioninto an ART programme.

We will also support the Advanced training course

for embryologists and paramedicspromoted by the Paramedical Groupon 3-5 November in Gothenburg. Theprogramme will cover specific andpractical aspects of IVF, includingculture media composition, qualitycontrol, and cryopreservation - withhands-on training. A significant partof the course will cover the use of

statistics for correct data interpretation,study design, and manuscript preparation.

We are planning for early 2017 a third ESHRECampus From gametes to blastocysts – a continuousdialogue, a course extremely well received in the pastwhich will now be updated to include the latestdevelopments in gamete and embryo research.

Giovanni CoticchioCo-ordinator SIG Embryology

STEERING COMMITTEEGiovanni Coticchio (IT), Co-ordinatorSophie Debrock (BE), Deputy Susanna Apter (SE), DeputyDebbie Montjean (FR), Junior DeputyMaria José De los Santos (ES), Past Co-ordinator


TASK FORCE DEVELOPING COUNTRIES & INFERTILITY

The Arusha meeting of December 2007, jointlysponsored by ESHRE and the Genk Institute forFertility Technology, brought together 37 experts ofdifferent origin to assess the problem of childlessnessand infertility care in resource-poor countries.Medical, socio-cultural, ethical, economic and politicalissues on this topic were discussed.

The meeting was the opening initiative of ESHRE’sTask Force for Developing countries and infertility andtwo important goals were set: first, to make infertilitycare in developing countries an open ‘discussible’problem, and second, to develop methods to performART at a much lower cost. The latter would beachieved by simplifying ovarian stimulation protocolsand modifying IVF procedures such that IVFtreatment would be substantially cheaper.

A trial to examine the value and effectiveness of anew ‘simplified’ laboratory method began at the GenkInstitute for Fertility Technology in 2011. The firstresults of our prospective study were presented at the2013 ESHRE Annual Meeting in London, where resultsshowed that fertilisation and embryo implantationrates were similar to those reported by high resourceIVF programmes. The first baby was born on 17November 2012.1 With such reassuring results from

this simplified IVF method, we next aimed to startsimilar studies in different centres in resource-poorcountries.

Although demand for our project is immense,funding remains very difficult. International societies,NGOs and foundations show some interest, but this iswhere the story ends. All costs linked to the projectare now covered by The Walking Egg non-profitorganisation.2

In November the first Walking Egg centre in aresource-poor country was set-up in Accra, Ghana,with the support of the Pentecost Church. A teamfrom Ghana attended a one-week training course inGenk in February 2015 and in November the firstpatients were treated in a new centre in Accra.Jonathan van Blerkom and a team from Genk werepresent in Accra for the ten-day set-up.

The first cohort of patients were treated with acombination of tamoxifen, low-dose hMG if needed,indomethacin, 5000 IU hCG and intravaginalprogesterone in the luteal phase. Although ovarianresponse to tamoxifen was unexpectedly low, the

Eight years after assessingneed and opportunities indeveloping countries, thefirst low cost ‘WalkingEgg’ clinic opens in Ghana

The first Walking Egg IVF centre in Africa, November 2015.

November 2015,Jonathan VanBlerkom, left,examining fertilisedeggs from the firstcohort of patients,and the clinic’s firstembryo transfer.


fertilisation rate of the eggs retrieved was verygood and 12 embryo transfers could be performed.Results were not available at the time of writing.

Local clinicians and biologists have been trainedto perform the different procedures, and results ofthis were very reassuring for both parties. Thismonth, January 2016, a second Walking Egg centrewill be set up in Nairobi, Kenya.

Willem OmbeletCo-ordinator TF Developing countries and infertility

1. Van Blerkom J, Ombelet W, Klerkx E, et al. First birthswith a simplified culture system for clinical IVF and ET.Reprod Biomed Online 2014; 28: 310-320. 2. Ombelet W. Is global access to infertility care realistic?The Walking Egg Project. Reprod Biomed Online 2014;28: 267-272.

Trainees fromGhana andNairobi, Kenya,meeting in Genk,February 2015.

PGD CONSORTIUM

After the successful launch of theonline PGD database in Lisbon,the Steering Committee has nowworked out final details andimplemented some of thesuggestions put forward byparticipants. Thus, following aninitial test by Steering Committeemembers, the database is nowready for a second round oftesting, to which all PGDConsortium members will be invited. Provided thatno major problems are encountered, the database willfinally be brought into use and PGD data can beentered both retrospectively and prospectively fromthen on.

Working groupsOur working group for monitoring new technologiesin PGD, chaired by Martine DeRycke, has set up andrecently sent out a second survey to investigate thetake up rate and implementation of new technologiesin ART and genetic diagnostic labs. As soon as allresults have been collated, a manuscript will beprepared focusing on the comparison between theperiod covered by the first survey in 2013 and acomparable period in 2015 to provide insight intoreal-time trends in PGD or PGS.

The working group on HLA, chaired by JanTraeger-Synodinos, has received input from 15centres reporting on more than 750 PGD-HLAcycles. This dataset will be a valuable source ofinformation for evaluating the clinical utility of

HLA-PGD, and to investigatethose aspects of PGD cycleswhich influence a positiveoutcome (birth of a geneticallysuitable donor-baby) andclinical outcomes of bonemarrow transplant from PGD-selected donors. Data are nowbeing cleaned and the resultswill be presented in Helsinki.

Upcoming eventsPGD and PGS are procedures at the crossroad ofclinical genetics and reproductive medicine. Therecan be no successful collaboration without crossfertilisation. Building on this idea, we have joinedforces with the European Society of Human Geneticsin organising a Campus course titled All aboutpreconception, preimplantation and prenatalgenetic testing, to be held in Maastricht, theNetherlands, from 13-15 April 2016. Information onthe programme, speakers, registration andaccommodation is availableon the ESHRE website.

A new chair will take over my role in the SteeringCommittee in Helsinki. As a result, there will be avacancy for a committee member and I would like toinvite all Consortium members who feel they cancontribute to the importance and scientific prosperityof the Consortium to come forward and send theirnomination to ESHRE’s Science Officer, VeerleGoossens.

Edith CoonenChair PGD Consortium

STEERING COMMITTEEEdith Coonen (NL), ChairSiobhan SenGupta (GB), Chair ElectMartine De Rycke (BE), MemberCéline Moutou (FR), MemberGeorgia Kokkali (GR), MemberJoanne Traeger-Synodinos (GR), Past Co-ordinatorVeerle Goossens (BE), Science manager

Final testing for new online database system


LAST WORD

publicly presented a method forcreating human sperm in vitro. Thisfollowed publication of a patentapplication in June (also announced bypress release) for a process of in vitrospermatogenesis from male germinaltissue ‘in a bioreactor’.1 At a pressconference in Lyon in September theresearchers said (according to pressreports) that the method took 20 yearsto refine, and may yet take several yearsbefore the quality of the sperm isconfirmed. The process involveddevelopment of a bioreactor using aviscous fluid made partly of substancesfound in mushrooms or in crustaceanshells resembling the fluid ofseminferous tubules.

As our report on page 12 indicates,the first details of energising oocyteswith mitochondria from oogonial stemcells have now been published and,apparently, exposed to peer review. Thepublished paper, which reports ‘globalpatient experience’ in two series of poorprognosis IVF patients in two treatmentcentres, was received by an open-accessjournal on 28 July and accepted forpublication on 7 August; the journal hasno formal impact factor (just a selfcalculated ‘unofficial’ IF of 1.0).

The in vitro spermatogenesis researchis yet to be peer reviewed and, while thesperm cells are said to appear normal, itis not known whether they are viable. Apress release issued on 17 Septemberwas accompanied by 37 imagesillustrating several stages of the process.Most experts asked by journalists tocomment on the press claims werecautious, and non-committal before

The rush to publish Medical journal or TV news?Peer review or public interest?

publication of any data. The Frenchdaily Le Monde quoted a Frenchclinician saying: ‘Nous attendons avecimpatience une publication scientifiquevalidée par les pairs.’

Press reports on both developmentsno doubt were a reflection of publicinterest. These were indeed attractivestories, both likely to stir public interestand each a step forward in reproductivescience with important public healthimplications. But one wonders why theresearchers took their findings first tothe press and not to peer review.

What both processes have in common,of course, is commercialisation, the onefrom a French start-up company calledKallistem, the other from a USorganisation called OvaScience, andpublicity (what the earnest promise ofmarketing would call ‘raisingawareness’) will inevitably have some ill-defined spin-offs.

For example, Kallistem announced ina press release in May last year that ‘itaims to raise funds to accelerate its plansfor growth and is also looking forpartners for its expansion into the US’.

The announcement seemed nothingmore than an appeal for partners to takeon the technology under licence.OvaScience explained in a press releasein late September that it expected to missits 2015 target of 1000 cycles but wouldcontinue ‘to enhance its commercialoperations’. There is more than asuspicion that these press initiatives -despite their public interest - are drivenmore by commerce than by science, andare more for investors than for clinicians.

Most scientific developments reportedin the press are, however, the result ofpress releases. For example, all the majorjournals (except the New England Journalof Medicine but including HumanReproduction) have their own well oiledpress operations, with press releasesissued under embargo with frequentregularity - even several every week byThe Lancet or JAMA. Their aim, ofcourse, is to promote the journal title, theimportance of the work, and ultimatelythe impact factor.

And ESHRE too, like most otherlearned societies, has a very active pressprogramme at its annual meeting in

There were two eye-catching developments in reproductive science last yearwhich were each apparently reported in the popular press before peer review ina medical journal. First, the birth of the world’s first ‘stem cell baby’ wasdescribed in exclusive detail in Time magazine in May following the oocytetransfer of mitochondria from the mother's ‘egg precursor cells’. A few weekslater a French start-up company working with a government lab in Lyon


The report of ‘global patient experience’ using a proprietarytechnique of energising oocytes with mitochondria waspublished in August in the open access Journal ofFertilization: In Vitro - IVF Worldwide, ReproductiveMedicine, Genetics & Stem Cell Biology.

which abstracts with news and scientificvalue are selected for press release. Thepress programme, ESHRE agrees,presents its members and their work asscientifically progressive, clinicallyhelpful and ethically responsible.

Most of these press releases, andespecially those issued by the medicaljournals, are based on scientific paperswhich have passed the test of peerreview to some extent, either forinclusion in a publication or at acongress.

At the other end of thiscommunications continuum lies thejournalist (and the boss), bombarded bya daily avalanche of ‘news’ via Twitter,e-mail, telephone informant and . . .press release. A specialist reporter on atop London newspaper will receivemore than 50 ‘tips’ a day for stories, andall must compete with each other forthe limited space available.

Most news editors will defend theirchoice of health stories more on thegrounds of public interest than ofscientific validity. They, therefore, claimto be the best judge of public interest. Ifit gets in the paper, gets on the TVnews, it must be in the public interest.So who could resist a sperm-in-the-labstory, or the first stem-cell baby? Yet isit right that such apparently importantdevelopments in reproductive science,with such huge implications, are madepublic without any evidence forprofessional assessment, without theopportunity for legitimate publicscrutiny?

Contrast this approach to publicityaccompanying the first live birthfollowing uterine transplantation, whichwas descibed in The Lancet in October2014 in a detailed report from theGothenburg group.2 Principal

always inhibit that most prized ofjournalists’ trophies, the exclusive.Indeed, the first word in the headline ofTime magazine’s report on the first eggprecursor cell baby was ‘Exclusive’.

But usually the press does get it right,and certainly the press usually has thebest idea of what will interest the publicand what’s in the public interest. Thetwo are not mutually inclusive, however,and an initial test of peer review maywell help mark the distinction betweenthese two commonly confusedpriorities.

Simon BrownFocus on Reproduction

1. See https://data.epo.org/publication-server/pdf-document?pn=2886644&ki=A1&cc=EP2. Brannstrom M, Johanneson L, BokstromN, et al. Livebirth after uterustransplantation. Lancet 2014; 385: 2352-2353.

investigator Mats Brannstrom hadmade it clear throughout the 15 years ofthis programme that case details(always anonymous) would only bedescribed in a scientific paper subject topeer review; and in this case the pressrelease came from The Lancet (not theinvestigators), and the press conferencein Gothenburg (plus YouTube video)came only after the Lancet publication.

The press, of course, doesn’t alwaysget it right, even with a press release toguide them. And a press release will

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

www.eshre.eu/campus

www.eshre.eu

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