June 24, 2020

expert reaction to study looking at embryo vitrification, neonatal outcomes and chance of pregnancy success

A study, published in the journal Human Reproduction, looked at embryo vitrification, neonatal outcomes and chance of pregnancy success.

Dr Gill Lockwood, Medical Director at Care Fertility Tamworth, said:

“This is an important study because it includes 25,000 patients, but it suffers from being both retrospective and covering a period of 6 ½ years during which much progress has been made worldwide with vitrification techniques.

“The reasons for the delay in the groups where thaw-transfer was not performed for more than 6 months are not explored; it could be that there were ‘uterine’ factors that needed to be investigated or treated.  Also the endometrial preparation methods (natural cycle or hormone controlled) could influence the outcome.  Several papers have suggested that ‘natural cycle’ could achieve higher implantation rates, but this is not suitable for older women who are more likely to have irregular cycles and were more likely to have a delayed transfer.  The ‘best’ embryos were vitrified on day 3 at the 8 cell cleavage stage and only the poor quality embryos were cultured to day 5 and vitrified as blastocysts.  Most clinicians would advocate culturing all embryos to blastocyst for vitrification as this gives a higher thaw survival rate.

“The paper also reports that ‘1 or 2’ embryos were transferred and this could influence the outcome in terms of implantation and live birth rate.

“There is no theoretical reason to believe that embryos vitrified at the temperature of liquid nitrogen can be impacted by the passage of a relatively short period of time.  Couples who have embryos cryopreserved because they are happily expecting the birth of their first successful embryo transfer should be reassured that there is a good prospect of a ‘frozen sibling’ arriving even if there is a delay of a year or more.  The advantage for women over 35 of storing supernumery embryos, which are literally ‘frozen in time’ at the age the woman was when the eggs were collected, far outweighs any possible reduction in success rates from extended storage.”

Dr Bassel Wattar, NIHR Academic Clinical Lecturer in Women’s Health, University of Warwick, said:

“This is a helpful study as it supports the overall safety of the embryo freezing technology and offers hope to many couples seeking fertility treatment with special needs.  It is showing high embryo survival rate as well as relatively low pregnancy complications with numbers consistent with the general population.

“Still, the evidence sought from this study should not be overstretched as it is prone to selection bias due to its retrospective observational nature.  This is especially evident when comparing the characteristics of the four groups for example where two thirds of women had tubal factor subfertiltiy, an unusually high number compared to the general subfertility population where it is usually a third.  Thus selection bias is an issue.

“Also there is risk of performance bias as I notice most women had 2 embryos transferred back (87% in group 1), which is not consistent with current evidence of transferring a single best embryo.

“The ultimate answer will arrive when we read the results of the awaited E-Freez trial (https://reproductive-health-journal.biomedcentral.com/articles/10.1186/s12978-019-0737-2).”

Dr Meenakshi Choudhary, Consultant Gynaecologist & Sub Specialist in Reproductive Medicine, Newcastle upon Tyne Hospitals NHS Trust, and Newcastle Fertility Centre at Life, said:

“The researchers should be commended for this as it is the largest study to date looking at length of storage of ‘snap frozen’ embryos in nearly 25,000 women undergoing their first embryo transfer after freeze all cycles.  However, the data is limited to 24 months storage period only.

“They address a crucial question ‘Does how long the embryos remain in frozen state affect chance of having a baby?’

“We need to first acknowledge and reassure women and couples considering frozen embryo transfers that it did not show any adverse outcomes in the babies born.

“Although the study reports almost halving of live birth chances if the embryos were frozen for 1-2 years compared to less than 3 months in storage, one need to take into account that less than 2.5% i.e. 566 women of the large study belonged to this 1-2 year storage group vs 11,000+ women in the less than 3 month period.

“In the UK and in many countries across the globe, clinics are moving toward blastocyst transfer.  However in this retrospective study, over 90% embryo transfers done were of cleavage stage embryos when the embryo is up to 3 days old.  One need to exercise caution to extrapolate this for blastocyst stage outcomes as only 54 blastocyst transfers took place in women with extended storage of 12-24 months.

“Based on the study, it seems the main reason why the age of women were much older in extended storage group (35 years vs 30 years in first group) was the batching of embryos by conducting multiple egg collection cycles to freeze adequate number of embryos before embarking on to embryo transfer cycle.  Although they tried to mitigate the age difference by doing a subgroup analysis in younger women under 36 years of age, the study does not report the cause for delayed first embryo transfer, number of cycles required for these women, their egg and embryo quality and the number of frozen embryos for this subgroup.

“A study led by me looking at 15 years of HFEA data on chance of a live birth after egg freezing was presented at the Fertility 2020 conference in Edinburgh.  We are seeing more and more patients seeking to preserve fertility for medical or social reasons.  We wanted to know what to tell them about the potential for success with egg freezing.  So we took the available data and found some significant results.  Our findings in that study suggested that although success rates using frozen eggs are on the rise, women seeking to preserve fertility should be made aware that freezing eggs is far from a guarantee that you will have a baby later with a likelihood of success as low as 1 in 5 chance of having a baby.  One of the limitations of our retrospective data study was that we could not look at effect of length of storage on the live birth chance.

“If there is a direct correlation of length of freezing and live birth chance based on this new study from China, it is vital that we look at its wider implications especially for storage beyond 2 years in elective fertility preservation as well as donor egg bank.

“With the ongoing campaign to extend the HFEA’s ten-year storage limit for social egg freezing, it is more crucial that we are able to help these women who have opted for this option as a reproductive choice to make a fully informed decision knowing what their chances are of having a live birth taking into account how long they keep their eggs in ice for.  But this will only be possible if we have that data ourselves to inform them.”

Prof Darren Griffin, Professor of Genetics, University of Kent, said:

“In general terms this well conducted study is good news for patients seeking fertility treatment.  We were already pretty sure that vitrification was safe, but this particular set of investigations adds much needed information to the literature.  A number of clinics now operate a “freeze-all” policy, which is exactly “as it says on the tin” – all embryos are vitrified and then first transferred in a later cycle.  The results reported here provide incredibly important background information for clinics operating a “freeze-all” strategy and for those who wish to do so in the future.

“The results on storage time and its relationship to clinical pregnancy/live birth rates need further scrutiny and may inspire further research into how storage conditions can be improved in the future.  It is reassuring to note that there was no statistically significant association between ectopic pregnancy, miscarriage, nor adverse neonatal outcomes.  As this was a single centre study, it would be interesting to learn what the experience of other centres are, with a view to multi-centre analyses being performed in the future.”

Prof Ying Cheong, Professor of Reproductive Medicine, University of Southampton, and Clinical Director, Complete Fertility Southampton, said:

“This is a retrospective study of just under 25,000 patients undergoing frozen embryo transfer after various timeframes of storage, from under 3 months up to 24 months.  Whilst the results suggested that the pregnancy rates decreased with increasing storage time, we need better controlled studies to be sure.  This is because the study suffers from many major drawbacks due to its retrospective nature, namely that the groupings under 1) diagnosis, 2) quality of embryos replaced, 3) single versus double embryo replacement and 4) early versus later developed embryos (blastocyst) replacement all varied significantly amongst the groups, which undoubtedly would have severely impact on the validity of the results.

“The findings unfortunately cannot be generalised as most IVF centres in the UK now freeze embryos at the blastocyst stage, but the blastocyst replacement rate in this study in the four groups was consistently under 10%, i.e., most embryos replaced were at the cleavage stage.  So, even if the limitations of the study design were overcome, the data would be more relevant to the effect of storage time after freezing of cleavage stage embryos rather than of blastocyst stage embryos, which is what most IVF centres use.”

Dr Ali Abbara, Clinical Senior Lecturer in Endocrinology, Imperial College London, said:

“This is a very large study, and the findings are interesting in that they suggest that embryos frozen for a longer duration of time could be less liable to result in pregnancy.

“However, it does appear that the groups of patients with the longer durations of frozen embryos also had a poorer prognosis with regards to the chance of pregnancy in any case, which could have an important bearing on the differences in pregnancy rates observed between the groups.

“Of course, if the duration of freezing is longer, women will be older at the time of having the embryos put back, but this did not appear to entirely explain the differences in prognostic factors between the groups.  For example, women were approximately one year older if their embryos were frozen for an extra 4 months and similarly in the other groups.

“The reason for the longer duration until the embryos were transferred in some women, especially those with poorer prognosis, was unclear.

“The researchers have attempted to statistically correct for the differences in the prognostic factors between the groups and report that the findings are similar even when analysed only in good prognosis patients.

“In order to really identify whether a longer duration of embryo freezing truly reduces the chance of pregnancy, it would be necessary to randomise women to different durations of embryo freezing so that the prognostic factors would be more similar between the groups, which would be a very challenging study to conduct.  So in the mean time, presenting the additional data in patients with similar prognosis would be of interest.”

‘The effect of storage time after vitrification on pregnancy and neonatal outcomes among 24 698 patients following the first embryo transfer cycles’ by Jianghui Li et al. was published in Human Reproduction at 00:05 UK time on Wednesday 24 June 2020.

DOI: 10.1093/humrep/deaa136

Declared interests

Dr Gill Lockwood: “I have no conflicts of interest.”

Prof Bassel Wattar: “None to declare”

Dr Meenakshi Choudhary: “No Conflict of Interest.”

Prof Darren Griffin: “No COI.”

Prof Ying Cheong: “Medical Director of Complete Fertility.”

None others received.