Improved IVF results following the transfer of mitochondria from egg precursor cells: an ESHRE SIG Stem Cells opinion

An opinion statement from ESHRE's Special Interest Group Stem Cells on a technique of energising oocytes with mitochondria from autologous "egg precursor cells" has expressed some concerns with the first published report of "global patient experience" and advises caution when interpreting the results of the study.(1)

The technique, presented as the "Augment" treatment, is said in the report to be a proprietary technology demonstrating that the addition of mitochondria to oocytes during IVF "is safe, improves embryo quality, and increases the success of IVF". The source of the mitochondria is reported to be egg precursor cells found in the patient's ovarian cortex. 

The report, which was published in August 2015 in the open access Journal of Fertilization: In Vitro, IVF-Worldwide, Reproductive Medicine, Genetics & Stem Cell Biology, describes treatment in two series of poor prognosis patients at two centres, one in Canada and one in Dubai. Based on their results, the authors describe the treatment as "the latest major innovation" in ART.

Prior to the publication, some details of the technique were reported at a company symposium held during ESHRE's latest Annual Meeting (but without ESHRE's involvement). First author Dr Michael Fakih there described a "five-fold" increase in clinical pregnancy rate in 59 women with poor egg quality and previously poor IVF results.(2) Birth of the first baby following application of the Augment technique - described as a "breakthrough IVF treatment" - was also reported in exclusive detail in Time magazine in May. New Scientist described the birth as "the first stem cell baby".

The opinion from the SIG Stem Cells expresses concerns about support for statements from certain references, sources of potential bias in the studies' methodologies, and reasons for caution in the lack of any evidence of a direct beneficial effect of transferring mitochondria from egg precursor cells on embryonic development, even in animals. The Special Interest Group also notes that there is still controversy even over the existence of egg precursor cells in adults. 

The manufacturer's website advises that Augment is only available "in certain IVF clinics in select international countries", and not in the USA.

Click here to read the full statement of the ESHRE SIG Stem Cells.

1. Fakih MH, Shmoury MEl, Szeptycki J, et al. The AUGMENTSM Treatment: Physician Reported Outcomes of the Initial Global Patient Experience. JFIV Reprod Med Genet 2015; 3: 154. doi:10.4172/2375-4508.1000154.
2. See http://ir.ovascience.com/phoenix.zhtml?c=251343&p=irol-newsArticle&ID=2060028 


Howard Jones, 1910-2015

It was with great sadness that ESHRE learned of the death of Howard Jones. He was 104 years old and a pioneer of IVF in the USA in much the same way as his friend and colleague Robert Edwards was in Britain. 

However, Howard, with his wife Georgeanna, did not begin their IVF programme until 1980. Following 'retirement' from Johns Hopkins in Baltimore in 1978, they were moving to a new division of reproductive endocrinology at the Eastern Virginia Medical School in Norfolk, Virginia, on the very day of Louise Brown’s birth in England. Invited to comment on the news by a local journalist, and asked what it would take to have a test-tube baby in the USA, Howard replied in his characteristic laconic way, 'Just a little money'. That proved enough to set the Norfolk programme in motion and, after a frustrating year pursuing pregnancies in a natural cycle, Norfolk finally achieved its first success in its 13th patient to receive gonadotrophins. Delivery by Cesarean section followed on 28th December 1981.

Howard and Georgeanna were frequent and welcome visitors to ESHRE's annual meetings, and in 1998 in Gothenburg were jointly awarded honorary membership of ESHRE. Like Bob Edwards, Howard was ever sensitive to the ethical issues raised by assisted reproduction, and their initial work in Norfolk had been delayed by public protest. Howard was a founding father of the ASRM's ethics committee and, even at the age of 102, self-published a book on the religious, legal and bioethical implications of ART for defining 'personhood'. His last book appeared just a few months ago, a memoir of the early days of IVF in the USA.

Today, the eponymous Jones Institute for Reproductive Medicine in Norfolk is named in honour of Howard and Georgeanna. Together, they demonstrated the validity of ovarian stimulation with hMG in what would become the forerunner of today's universal low dose protocols.

Record impact factor for Human Reproduction Update

For the first time ever a journal from the citation categories of Reproductive Biology and O&G has achieved a double-digit impact factor. Human Reproduction Update, for many years the leading title in both categories, has now seen its impact factor rise from 8.657 to 10.165 in the latest citation analysis released in June. 

Another of ESHRE’s three titles also increased its impact factor from last year. Molecular Human Reproduction rose from 3.483 to 3.747, which included for the first time listing in the category of O&G. ESHRE's flagship title Human Reproduction confirmed its high-ranking status with an impact factor of 4.569, a figure very similar to that achieved in 2014. 

"The new impact factor for Human Reproduction Update fulfils the dream of any journal in the field of O&G," said its Editor-in-Chief Felice Petraglia. ‘It's a truly historical achievement." 

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 2014, thus relate to all citable papers published in 2012-13. Despite emerging alternative metrics, impact factors remain the most reliable measure of journal quality.

* To mark the ESHRE journals' first, third and fourth ranking in Reproductive Biology, and Update's outstanding achievements in O&G, the journals' publisher OUP has made the five most highly cited papers in each title free to read online. 

Find out more here

Swiss referendum voters in support of PGD
Switzerland voted on 14 June to allow PGD for the detection of single gene disorders and PGS for detecting aneuploidy in IVF embryos. The referendum vote - with 62% in support of PGD and PGS - would effectively amend the existing constitution to include the two previously outlawed procedures. With successful challenges to anti-PGD legislation in Italy and Austria, Switzerland in maintaining its ban was looking increasingly isolated in Europe.  

The referendum will also kick out restrictions on the number of embryos generated in an IVF cycle, which have so far been limited to those that "can be immediately implanted". The vote, if confirmed and incorporated into the constitution, will now make embryo freezing legal and encourage single embryo transfer. 

Commenting on the developments, Dr Edith Coonen, Chair of ESHRE'sPGD Consortium said: "It's great news for Swiss people, because it provides another reproductive option for those who need it in their trusted home environment and without having to go abroad. The vote indicates broad public support, and in professional support the PGD Consortium is committed to the exchange of knowledge and promotion of best practice." 

Calls for a ban on genome engineering in reproductive cells

In advance of studies thought to involve the modification of DNA in human embryos, experts in genome-editing technology have called for a moratorium in any research which aims to modify the human germline. Describing such work as "dangerous and ethically unacceptable", they write: " 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."

They add that genomic editing of human non-reproductive cells - using the same basic 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 — in which the genetic correction would last the lifetimes of the modified cells and their progeny — could provide a once-and-for-all curative treatment for patients with some types of genetic disease.

Thus, according to an accompanying editorial in Nature, these gene-editing tools are being used to develop therapies to correct genetic defects in people (such as by editing white blood cells). Researchers "fear that attempts to produce ‘designer babies’ by applying the methods to embryos will create a backlash against all use of the technology."

A report recently published in MIT Technology Review described experiments in animals in which the genomes of pigs and cattle had been modified to incorporate useful genes and remove the bad ones using a genome editing technology known as CRISPR-Cas9.(2)

Most countries, including the EU but not the USA (where government approval is required), have banned germline engineering, mainly because the genetic changes created by germline editing would be passed on to future generations.

1. Lanphier E, Urnov F, Haecker SE. Don't edit the human germ line. Nature 2015; 519: 410-411.
2. Regalado A. Engineering the perfect baby. MIT Technology Review, 5 March 2015.


UK to allow mitochondrial donation

The UK is poised to become the world's first country to allow clinical trials of mitochondrial donation in couples known to be at high risk of passing on mitochondrial diseases to their children. The move follows a vote in the UK's lower Parliament (the House of Commons) which approved the measure by a considerable majority; if the measure now succeeds in passing the House of Lords and meeting the regulatory requirements of the HFEA, the first trials could begin towards the end of this year. The trials are likely to be at the Wellcome Trust Centre for Mitochondrial Research at Newcastle University, under the direction of Professor Doug Turnbull, which would need to apply for a research license from the HFEA. 

The possibilities of preventing the transmission of mitochondrial diseases (which are said to affect around 2500 women in Britain) has already been the subject of a favourable public consultation by the HFEA.

Two techniques have been explored so far: nuclear transfer from the intended parents' affected zygote to an enucleated donor zygote with healthy mitochondria; and maternal meiotic spindle transfer in which the meiotic spindle from the mother's affected oocyte is transferred to a healthy donor oocyte (whose spindle has been removed) before fertilisation with the partner's sperm. Both techniques involve genetically modifying a human oocyte, which is not currently permitted in any treatment in the UK.

The controversial issue, however, as demonstrated in the consultations and Parliamentary debates, is not the technique, but the ethics of gene modification - and the inevitability that in each of these techniques the healthy reconstructed embryo will contain the donor's mitochondria as well as the intended parents' own DNA. It was for this reason that the ever inventive British press dubbed the technique 'three-parent IVF' and rightly raised the question of future genetic inheritance in these families - even though the proportion of donor DNA in these embryos would be very small (around 0.2% of the total genetic material).

While ESHRE has made no formal statement on mitochondrial donation (or any contribution to the consultations), Anna Veiga, ESHRE's former Chairman and currently Scientific Director at Hospital Universitari Quiron Dexeus in Barcelona, said: 'After extensive scientific review and public consultation, the technique of mitochondrial donation will be ready for clinical application if approved by the UK's House of Lords. 

'This represents an important step in the prevention of mitochondrial disease and the possibility of reproduction with their own gametes for affected couples. The minor contribution from the donor’s mitochondria to the genetic constitution is not expected to cause any adverse outcome in the offspring. In my opinion, no major ethical concern arises in such cases, considering that oocyte donation is a frequently used alternative in affected couples. As in any other ART procedure, couples must receive complete and detailed information.'


If you are interested in this topic, you can also read the special issue of MHR: Basic Science of Reproductive Medicine "‘Mitochondria: their genome and their contribution to well-being and disease". The issue can be found here.

'Low' rates of ART complications found in analysis of US database

A study described as the first to quantify ART-associated patient risks in the USA has found that complication rates are "low", with "no concerning trends or patterns identified". The report was published in the Journal of the American Medical Association.(1)

The findings were based on data submitted to the Centers for Disease Control and Prevention National ART Surveillance System (NASS) for treatments between 2000 and 2011, a total of more than 1.1 million autologous cycles. Reported complications (defined as having been directly related to ART and occurring within 12 weeks of cycle initiation) included infection, haemorrhage requiring transfusion, moderate or severe ovarian hyperstimulation syndrome (OHSS), medication adverse event, anaesthetic complication, hospitalisation, patient death within 12 weeks of stimulation, and other complications.

As expected, the most common complication (without multiple pregnancy) was OHSS, occurring at a peak rate of 153.5/10,000 autologous cycles (1.53%), with hospitalisations peaking at 34.8/10,000 autologous cycles; rates of other complications remained below 10/10,000 cycles. Reported complications following donor cycles were less frequent; none showed a significant trend. 

Fifty-eight total deaths were reported (18 stimulation­related and 40 maternal deaths prior to infant birth). No donor deaths were reported.

However, the authors warn - as did experts speaking at a workshop of ESHRE's EIM Consotrium last year - that "underreporting of complications remains an inherent limitation of surveillance systems and must be considered when interpreting our findings". 

1. Kawwass JF, Kissin DM, Kulkarni AD, et al. Safety of Assisted Reproductive Technology in the United States, 2000-2011. JAMA 2015; 313: 88-90.