Three clinical questions for Helsinki

As the curtain rises on yet another record-breaking ESHRE Annual Meeting, what answers might we expect – beyond a definite maybe – to three clinical questions among many still hovering indecisively over evidence-based fertility treatment?

  1. An itch or a scratch? Is endometrial injury worth it?

A 2012 Cochrane review of endometrial injury prior to IVF found insufficient evidence for any effect, but did advise “not to perform endometrial injury on the day of oocyte retrieval because it appears to significantly reduce clinical and ongoing pregnancy rates”.(1) Now, a second Cochrane review (presented this week as a poster) has evaluated endometrial scratch in IUI and suggests that it may well be beneficial, although again the quality of the evidence is deemed “very low”.(2) Following analysis, endometrial scratching appeared to increase the chance of pregnancy and live birth compared to no or sham procedure; the difference in outcome was statistically significant and appeared to roughly double the chance of live birth compared to no intervention (RR 2.22)

  1. Can PGS ever fulfil its promise?

The deficiencies of early technology PGS were apparently overcome by the introduction of complete chromsome screening, supported by small randomsied trials and the will of many for it to succeed. Next generation sequencing, whose validation as a chromosome screening technology is described on Monday by Peter Coleman in the exchange lecture of ESHRE and the Fertility Society of Australia, now presents a genomic approach whose accuracy rises and cost declines. Yet according to Elpida Fragouli from Reprogenetics UK and the University of Oxford’s Nuffield Department of Obstetrics and Gynaecology, around one-third of these chromosomally normal embryos fail to implant after transfer. Now, a new approach to embryo assessment based on the quantification of mitochondrial DNA found in the trophectoderm cells of a blastocyst sheds light on why so many of these apparently healthy embryos are actually not viable.(3) And it’s this approach in combination with aneuploidy screening which may now represent the most accurate and predictive measure of embryo viability we have ever had – and with it the great potential for improving IVF outcome.

Results from a prospective study of 280 chromosomally normal blastocysts to be presented by Dr Fragouli on Monday afternoon show that, of the 111 single blastocyst transfers whose outcome was so far known, 78 (70%) led to ongoing pregnancies, and every single one of them (100%) had levels of mitochondrial DNA known to be normal. The remaining 33 blastocysts failed to implant, and eight of these (24%) had unusually high levels of mitochondrial DNA. “The results confirm that embryos with elevated levels of mitochondrial DNA rarely implant,” said Dr Fragouli, who described her results as “very robust”.

With such accuracy, could this combination of tests be the holy grail of embryology, and the key to the embryo destined to implant?

  1. Will freeze-all favour all?

The freeze-all protocol in IVF remains well established in a segmentation strategy for OHSS rescue and prevention, but little more than an anecdotal hope in routine IVF. Prospective trials are few to non-existent, and one of them, Alfatoonian et al, was even withdrawn by its publisher three years after publication. A study to be presented on Wednesday from data analysed retrospectively from 12 centres and more than 16,000 treatment cycles in the USA suggests that freeze-all protocols are indeed associated with significantly improved IVF outcomes – especially in women over 35 (46% freeze-all vs 33% fresh).(4) There was also a benefit found in patients with elevated progesterone levels prior to egg retrieval – and this was evident whether they were younger than 35 (47% freeze-all vs 38% fresh) or older than 35 (45% freeze-all vs 30% fresh).

However, a linkage study based on the HFEA database of IVF cycles performed in the UK between 2003 and 2010 found that, while cumulative live-birth rates were equivalent after an initial eSET or DET in women under 37, there were fewer infants born to all women having repeated SET. This, say the investigators, ” suggests that the efficacy of embryo freezing may have been overestimated”.(5)

The theoretical case for freeze-all as a routine protocol in IVF remains based on a fear that ovarian stimulation has a deleterious effect on endometrial receptivity, and on the hope that transfer in a subsequent natural cycle may be more efficient. Only large RCTs will confirm, and at least two are ongoing, one – E-Freeze – under the direction of the UK’s National Institute for Health Research and due to report in 2020, and a Dutch multicentre trial – Freeze All – under the direction of the Netherlands Organisation for Health research and Development and due to complete in 2019.

Simon Brown, Editor of Focus on Reproduction

 1. Nastri CO, Gibreel A, Raine-Fenning N, et al. Endometrial injury in women undergoing assisted reproductive techniques. Cochrane Database Syst Rev. 2012; 7: CD009517.
2. Poster P-287, Endometrial scratching for pregnancy following sexual intercourse or intrauterine insemination (IUI): a Cochrane systematic review and meta-analysis.
3. Presentation O-059, Monday 4 July 2016, 16.15
Clinical implications of mitochondrial DNA quantification on pregnancy outcomes: a blinded prospective non-selection study
4.Presentation O-239, Wednesday 6 July 2016, 11.30
Multi-center study demonstrates freeze-all IVF protocols are correlated with higher ongoing pregnancy rates in women of advanced maternal age
5. Presentation o-123, Tuesday 5 July 2016, 10.00 Fewer live-births with repeated single embryo transfer as compared to initial double embryo transfer; time to question the efficacy of embryo cryopreservation?

 

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