29 November 2016
"Add-on" treatments in IVF
An "analysis" reported in the British Medical Journal and commissioned for a BBC documentary concludes that the "benefits" derived from most of 27 add-on interventions offered by UK fertility clinics and "claimed to improve fertility outcomes" are not supported by robust evidence.(1) Only 11 were recommended by NICE guidelines and the investigators found evidence of benefit in only five (blastocyst culture, endometrial scratch, adherence compounds, oral antioxidants, and IUI in a natural cycle).
ESHRE's position on additional interventions in IVF is clear - that new technologies and approaches should not be introduced into a clinical setting without appropriate development and evidence demonstrating safety and benefit to the patient.(2) The treatment of infertility is a fast-moving field, with new scientific developments under constant evaluation. ESHRE supports the view that fertility patients should always be given full information on any treatment offered, including its risks and side effects. Patient consent to treatment should always be informed and based on the best evidence available.
1. Heneghan C, Spencer EA, Bobrovitz N, et al. Lack of evidence for interventions offered in UK fertility centres. BMJ 2016; 355: i6295. doi: 10.1136/bmj.i6295.
2. Harper J, Magli MC, Lundin K, et al. When and how should new technology be introduced into the IVF laboratory? Hum Reprod 2012; 27: 303-313.
19 October 2016
The full cycle of germline development in the lab
Scientists in Japan, who for the first time have used pluripotent stem cells to reconstitute the full female germline cycle in a mouse model, say the work "will provide a platform for elucidating the molecular mechanisms underlying totipotency and the production of oocytes of other mammalian species in culture".
The studies were published as a letter to Nature from the group of Katsuhiko Hayashi, a stem cell biologist at Kyushu University in Japan.(1) The report describes the series of studies which, via the generation of mature mouse oocytes in culture from embryonic stem cells and from iPS cells, culminated in the transfer of lab-created embryos and the birth of healthy mouse pups.
In earlier work, Hayashi and colleagues generated healthy mouse pups by maturing fibroblast-derived oocytes inside the mouse mother. In this new work the maturation took place entirely (and remarkably) in a laboratory dish, suggesting that "the platform", as Hayashi describes it in Nature, might one day be applicable in humans.
The group was also able to derive new embryonic stem cell lines from the blastocysts generated from the lab-made oocytes. That recreates, they note, a full cycle of female germ cell development in the lab.
Bjorn Heindryckx, Co-ordinator of ESHRE's SIG Stem Cells, notes that, although the in vitro-generated oocytes appeared relatively normal and functional when compared with in vivo oocytes, post-implantation efficiency, an important parameter of human ART, was significantly reduced in the in vitro oocytes (3.5% vs 61.7%). "This is a big difference," said Heindryckx, "and warrants further investigation."
"But this is still very important work," he emphasised. "Great progress, a fantastic paper, and a very impressive series of experiments - transcriptomics, functional analysis, genomics, stem cell derivation, and different cell types."
1. Hikable O, Hamazaki N, Nagamatsu G, et al. Reconstitution in vitro of the entire cycle of the mouse female germ line. Nature 2016; doi:10.1038/nature20104 .
12 October 2016
A single code to improve the traceability of donors’ tissues and cells in Europe
The European Directive on Tissue and Cells which defines European-wide standards for donated tissues and cells such as reproductive cells has been amended.
The new version of the legislation introduces the Single European Code (SEC), a unique identifier for tissues and cells, to improve the traceability and provide relevant information on the donated tissues and cells across the EU. The SEG is a simple code composed of two parts: a section about the donation and a section about the donated product. Following the Directive, the 2800 authorised tissue establishments active in the European Union will have to attach a SEG to all tissues and cells distributed for clinical application.
A web-based platform has been developed to support healthcare professionals and national competent authorities and allow them to trace all tissues and cells donated in the EU.
The new directive should be implemented in all EU Member States by 29 April 2017.
More information on the European Commission website >
Read the press release of the European Commission.
15 September 2016
ESHRE congratulates Lithuania on new ART legislation
Lithuanian President Dalia Grybauskaite’s veto of restrictive regulations in reproductive medicine was supported by the Lithuanian Parliament on Saturday 10th September 2016. The vote also introduced a new ART legislation, which opens the access to fertility treatment for Lithuanian families.
ESHRE had formally expressed its support to Lithuanian medical specialists and to the President in her veto. As proposed, the changes to Lithuania's regulation of IVF and other fertility treatments would have applied restrictions likely to limit access to treatments and even jeopardised patient safety. The new legislation passed along with the veto now allows state-funded IVF, the freezing of embryos, PGD for the identification and prevention of genetic defects in the embryos of at-risk couples and gamete donation.
ESHRE therefore congratulates Lithuania on their new IVF legislation which complies with the modern medical standards and good practice in the field, makes IVF widely accessible to families and ensures safe and successful fertility treatment.
Dr Kersti Lundin, Chairman of ESHRE said “ More than 6,5 million babies in the world were born thanks to IVF since 1978. IVF has become a widespread treatment, that can be safely provided to sub-fertile and infertile patients. However national ART legislations have a huge influence on the safety and efficiency of the treatment, as well as on family rights. It is therefore up to the governments to adopt legislations that ensure these rights are respected and that safe treatments are provided. We are pleased with the recent legislative developments in Lithuania and warmly welcome the adoption of this new regulation which paves the way of a state-funded IVF. We hope that other European countries can follow this path.”
ESHRE will continue to express its full commitment to all countries for the safe and accessible treatment of infertility, to protect family rights as upheld by the World Health Organization and European Union and oppose to any statutory developments which limit both family rights and access to safe services.
20 June 2016
ESHRE supports opposition to proposed ART changes in Poland
ESHRE has expressed its full support to the Polish Gynecological Society and Polish Society for Reproductive Medicine and Embryology in their opposition to legislative changes proposed in the treatment of infertility. As proposed, the changes would in effect reverse legislation introduced by the former coalition government and apply restrictions likely to limit access to fertility treatments and limit the practice of ART. Among the proposed changes are a limit of one on the number of occytes for fertilisation and a ban on embryo freezing.
In 2013 the Polish Ministry of Health introduced a three-year IVF reimbursement programme. This so far has involved around 17,000 couples and seen the birth of 5200 children, a delivery rate of 34%. Now, however, following parliamentary elections in 2015 and the formation of a new conservative government, the IVF reimbursement programme has already been discontinued and proposals put in place for a new round of restrictive legislation.
If approved, such legislation would consign Poland to its former status, when it stood alone as the only major European country without any statutory support for ART. When similar restrictive legislation was introduced in Italy in 2004, it was seen as a denial of family rights and challenged - successfully - in the constitutional courts. Indeed, all the restrictive components of Italy's Law 40 have now been dismantled by the Italian courts.
At the time ESHRE expressed its full and continuing commitment to the wide application of safe fertility treatments in Italy, and does so now in Poland. ESHRE has given its support to the Polish societies in their efforts to maintain good practice in the treatment of infertility in Poland, and remains opposed to any statutory developments which limit both family rights and access to services.
* Former ESHRE chairmen Juha Tapanainen and Luca Gianaroli spoke at a press conference at the Polish Parliament in June in protest at the proposals, which can be seen at http://www.sejm.gov.pl/sejm8.nsf/transmisje_arch.xsp?unid=519E35970C2E3F40C1257FCD00290F73
20 June 2016
Record impact factor for Human Reproduction Update
ESHRE's review journal Human Reproduction Update, for many years the leading title in the citation categories of Reproductive Biology and O&G, has seen its impact factor rise from 10.165 to 11.194 in the latest journal analysis released in June. This is the highest recorded impact factor ever in these two categories.
Both of ESHRE’s other two titles also increased their
impact factor from last year. Molecular Human Reproduction rose from 3.747 to 3.943, and ESHRE's flagship title Human Reproduction confirmed its high-ranking status with a rise from 4.569 to 4.621.
"This is another important step towards an impact factor of 5 for Human Reproduction," said editor-in-chief Hans Evers. "For a journal with almost exclusively original scientific articles, this is indeed a proud achievement."
All three ESHRE journals now rank in the top ten titles in O&G, with two titles, Human Reproduction and Update, securely placed within the top four. Fertility & Sterility, with an impact factor of 4.426, fell back slightly from its score of 4.59 last year.
According to Thomson Reuters, owners of the Journal Citation Reports, the impact factor is a measure of the frequency with which the "average article" in a journal has been cited in a specified period. It is calculated by dividing the number of current year citations to the source items published in that journal during the previous two years. The latest impact factors, for 2015, thus relate to all citable papers published in 2013-14. Despite emerging alternative metrics, impact factors remain the most reliable measure of journal quality.
Some of the highly cited papers contributing to the growing success of all three ESHRE journals can be read here.
9 May 2016
In vitro embryo development through the early post implantation stages
A new technique allowing embryos to develop in vitro beyond the implantation stage has been reported simultaneously by two research groups - from Cambridge, UK, and Harvard, USA.(1,2) The technique, which for the first time will allow analysis of key stages of human embryo development up to the agreed 14-day post-fertilisation limit, demonstrates the remarkable self-organising capacity of human blastocysts, which so far has been quite unseen and unknown. However, this same reorganisation of the embryo, which normally takes place during the early post-implantation phase, has now been achieved in the laboratory and thus presents a unique opportunity to better understand human development during these early crucial stages.
Both groups working in parallel established a system for the in vitro culture of human embryos and, using this technique, followed the development of the embryos up to day 13 - to a point just before the 14-day internationally (and legally) agreed limit for embryo research. Immediately following "implantation", the three cell types that comprise the blastocyst are seen to reorganise into a new configuration.
"The stem cells in the epiblast that will form the future body have the remarkable ability to self-organise themselves and create a cavity that represent the basic structure of the early post-implantation human embryo," Professor Zernicka-Goetz, leader of the Cambridge group and an author on both papers. said in a press release. "Without this cavity, it would be impossible for the embryo to develop further as it is the basis for its future development. It is also a mechanism that we can study using human embryonic stem cells."
Comment on the study has not only raised the prospect of a better understanding of implantation in IVF, but also the applicability of the 14-day rule for embryo research. A commentary in the journal Nature, in which one of the reports appeared, forecast that such studies of human development in vitro "are on a collision course with an international policy that limits embryo research to the first two weeks of development".(3) At ESHRE's Annual Meeting in 2015, Dutch bioethicist Guido De Wert, a former co-ordinator of ESHRE's Task Force Ethics & Law, argued that it was now time to reconsider the 14-day time limit for embryo research, arguing that the "existing consensus reflects the will of policy-makers to draw a line somewhere rather than a shared understanding of why this should be at 14 days instead of another developmental stage".(4)
1. Deglincerti A, Croft GF, Pietila LN, et al. Self-organization of the in vitro attached human embryo. Nature 2016; doi: 10.1038/nature17948.
2. Shahbazi MN, Jedrusik A, Vuoristo S, et al. Self-organisation of the human embryo in the absence of maternal tissues. Nature Cell Biology 2016; DOI: 10.1038/ncb3347
3. Hyun I, Wilkerson A, Johnston J. Revisit the 14-day rule. Nature 2016; 583: 169-171.
4. De Wert G, Dondorp WJ. Time to reconsider the time limit for human embryo research? ESHRE Annual Meeting 2015; O-246.
1 March 2016
Functional gametes in vitro
In what appears to be a major step forward in the production of stem-cell derived gametes, scientists in China have reported the successful meiosis of primordial germ cells in the mouse to functional male gametes in vitro.(1) The scientists, from Nanjing Medical University, China, describe a process of complete in vitro meiosis, from primordial germ cell-like cells (derived from pluripotent embryonic stem cells) to the formation of male spermatid-like cells capable of producing viable fertile offspring via ICSI. So far, they write, the recapitulation of meiosis completely in vitro, a process unique to germ cells, "has remained a major obstacle" toward the production of functional stem-cell derived gametes.
The in vitro meiosis described was fully compliant with the gold standards of meiosis established in 2014, which included the correct erasure of imprints, synapsis, and recombination. According to reports, all other attempts to adequately control all the key stages of sex cell division according to these criteria had failed. In this case, the resulting embryos went on to full embryonic development and, following ICSI, produced fertile offspring that gave birth to the next generation.
"This unequivocally demonstrates the recapitulation of meiosis in a culture environment and proves the functionality of spermatids generated from pluripotent stem cells in vitro," the investigators reported. "Our findings could facilitate the generation of haploid human spermatids in vitro with the prospect of treating male infertility."
The achievements implicit in the report were universally greeted with excitement by scientists, although many lay press reports forecast the imminent redundancy of men. Chris Barratt, editor of ESHRE's Molecular Human Reproduction journal, said: "There have been numerous attempts and false dawns to developing a robust system for in vitro meiosis. A number of studies have been published that have subsequently been difficult to repeat, so this latest is a landmark study in that it has satisfied internationally agreed standards.”
1. Zhou Q, Wang M, Yuan Y, et al. Complete meiosis from embryonic stem cell-derived germ cells in vitro. cell Stem Cell 2016: DOI: http://dx.doi.org/10.1016/j.stem.2016.01.017
24 February 2016
HROpen: a fourth journal for ESHRE
Siladitya Bhattacharya, Professor of Reproductive Medicine at the University of Aberdeen, UK, will be the first Editor-in-Chief of ESHRE's new journal HROpen. His appointment, which was confirmed by ESHRE's Executive Committee following interviews in February, will be for a three-year term with opportunity for extension for a further three years.
While the primary aim of HROpen is to broaden the editorial range of the ESHRE journals and provide a publication of high quality research beyond the traditional focus of infertility, it was also apparent that a truly modern journal should meet two criteria: open access and online publication. HROpen will fulfil both these requirements - and indeed will be the first open access journal in reproductive medicine. More and more funding organisations, as well as academic institutions, require open access publication, and hopes are that HROpen will offer a rapid and inexpensive means of publication to research groups throughout the world, with a wider scope than ESHRE's present titles.
"We believe we can reach out to a wider range of the scientific community this way," says ESHRE Chairman Kersti Lundin, "and that the format will open up new ways of communicating." Authors will incur no processing fees for the first three years of the journal's life, and expectations are that the first papers will be published online before the end of this year.
There were more than 20 eminent applicants for the post of Editor-in-Chief, a number of whom were short-listed and interviewed. Bhattacharya, who has earned an international reputation in health services research, randomised trials and the epidemiology of reproductive medicine, was a welcome appointment and ESHRE is confident that he will steer the new journal to a respected place alongside its three sister publications.
25 January 2016
Rapid developments in gene editing
A short report published on the ESHRE website in March last year noted calls for a moratorium on genome engineering in reproductive cells.(1) The calls were made in advance of studies on the modification of DNA in human embryos. One commentary urged: "In our view, genome editing in human embryos using current technologies could have unpredictable effects on future generations . . . Such research could be exploited for non-therapeutic modifications."(2)
Since then, the techniques of genome editing have moved on at remarkable speed, highlighted most recently with the application from a UK group for a research licence to use the gene editing system of CRISPR to identify and understand the single genes involved in early embryo development.(3) By using this technique the group (from the Francis Crick Institute in London) plans to knock out up to four genes in a fertilised oocyte while still at the single-cell stage to determine their role in early embryonic human development.
In December last year in Washington an international summit meeting on gene editing agreed that:(4)
* basic and preclinical research in the specific alteration of genetic sequences should proceed, subject to appropriate legal and ethical rules and oversight
* clinical use in somatic cells (in which the edited genomes will not be inherited by future generations) can be rigorously evaluated
* germline editing poses "many important issues" - such as the risks from inaccurate editing and implications for future generations - and thus "it would be irresponsible to proceed with any clinical use of germline editing unless and until the relevant safety and efficacy issues have been resolved
Genomic editing of human non-reproductive cells - using the same CRISPR technology - aims to repair or eliminate a mutation underlying a monogenic disease. The principle is that corrective changes to a number of cells carrying the mutation could provide a once-and-for-all curative treatment for patients with some types of genetic disease. In December US scientists reported that they had used CRISPR to remove part of a defective gene in mice with Duchenne muscular dystrophy, allowing the animals to make an essential muscle protein. The journal Science described this as "the first time CRISPR has been successfully delivered throughout the body to treat grown animals with a genetic disease".(5)
A recent policy forum in Science, which hailed the CRISPR technology as the scientific breakthrough of 2015, concluded that the socio-ethical and policy concerns surrounding gene editing remain "high, with countries, the scientific community and individuals divided on the issue".(6) The report analysed human embryo policies in 16 countries and found that some ban the practice outright, while others allow a degree of related basic research. In addition, there are countries such as the UK and China which permit research for reproductive purposes and where potential clinical applications are not explicitly outlawed. The report reiterates the Washington summit's conclusion that it would be irresponsible to proceed with the clinical application of germline editing until the relevant safety issues have been resolved.
A writing group including several members of ESHRE has evaluated the current status of genomic editing in the human germline and pluripotent stem cells. In a paper now submitted for publication the authors have identified numerous technical challenges and limitations associated with the CRISPR/Cas genomic editing system, which in the human germline will require more research. However, they conclude that these limitations should not lead to a generalised moratorium on the technique in human embryos, but rather encourage efforts to establish an international regulated framework making transparent research possible.
A discussion of the risks, advantages and possible applications of gene editing will be featured in an ESHRE workshop in September organised in Amsterdam by several of the Society's Special Interest Groups.(7)
1. See https://www.eshre.eu/Press-Room/ESHRE-News.aspx
2. Lanphier E, Urnov F, Haecker SE. Don't edit the human germ line. Nature 2015; 519: 410-411.
3. See http://www.sciencemag.org/news/2016/01/uk-researcher-details-proposal-crispr-editing-human-embryos
4. See http://www8.nationalacademies.org/onpinews/newsitem.aspx?RecordID=12032015a
5. See http://www.sciencemag.org/news/2015/12/crispr-helps-heal-mice-muscular-dystrophy
6. Isasi RM, Kielderman E, Knoppers BM. Editing policy to fit the genome? Science 2016; 351: 337-339