December 10, 2019

expert reaction to frozen embryo transfer IVF and childhood cancer risk

Research, published in JAMA, reports that children born through IVF have an elevated risk of childhood cancer.

Richard Kennedy, Medical Director, Birmingham & Solihull Local Maternity System; and Honorary Consultant Obstetrician and Gynaecologist, Birmingham Women’s and Children’s Hospital, Birmingham Women’s and Children’s NHS Foundation Trust, said:

“Freezing of embryos and their replacement after thawing is increasingly common practice in assisted conception treatment. This enables one embryo to be replaced at a time following IVF treatment in which a number of embryos are created simultaneously. This large study of over 1 million children born in Denmark dating back to 1996 has shown an association between cancer in children who were conceived following replacement of thawed frozen embryos. The overall risk is however small. Following natural conception the risk of childhood cancer is approximately 2/1000 and following frozen embryo replacement in this study rises to slightly more than 4 per 1000. Deriving associations between childhood cancer and infertility treatment is made difficult by the rare occurrence of such cancers, the possible effect of the underlying causes of infertility and the changes in treatment techniques over time. Many millions of healthy children have been born following infertility treatment and couples and women planning to conceive in this way should be assured that the overall risk to a child developing childhood cancer is only slightly increased.”

Dr Yacoub Khalaf, Honorary Professor at King’s College London, said:

“This is yet another study that reports an association between IVF and increased risk of childhood cancer. Whilst it is clear that association does not necessarily mean causation,  a hazard ratio of 2.5 sounds disturbing but it should be emphasised that the rarity of such occurrence puts these hazards in perspective.

“The number of children born following frozen cycles was too small (3356) for these kinds of studies where it is usually so difficult to account for the many confounding variables that could influence this relatively rare risk. The authors acknowledged the weaknesses of their study.

“Furthermore, during the period of the study 1996-2012, embryos used for transfer used to be mainly the surplus embryos (which are usually of inferior quality) after fresh embryo transfer. Whether the results can be extrapolated to current practice where it is  becoming common for  all embryos to be electively frozen for safety considerations, and transferred later.  

“Previous studies quoted 1.9 in 10,000. So if the hazard ratio is correct, the risk of childhood cancer would be 1 in 2000 at worst, which although serious, is considered rare. Embryo freezing is becoming very common and transferring frozen embryos has been suggested to be in some circumstances more successful than transferring fresh embryos. The repercussions of such a study could include putting patients off this option, perhaps prematurely,  as a cause and effect has not been, and may not be easily, established.”

Dr Mina Alikani, Senior Director of Northwell Health Fertility Laboratories, New York City and Dr Jacques Cohen, Director of The ART Institute of Washington, said:

“This is an important follow-up study that raises questions about the meaning of statistical significance, given the numerator of 14 affected children in a very large group of over a million subjects.

“Explaining and agreeing on outcome trends is very complicated in the field of assisted reproduction where there are over 200 confounders, and the majority is related to laboratory technology.  Confounders were disproportionately analyzed in this study. National registries often do not have the level of detail. 

“Almost all aspects of freezing technology and embryo culture have changed since the study period. Importantly freezing technology has significantly improved, particularly embryo survival rates. The question is what message patients and reproductive specialists should take home from this study other than disclosure of the study’s existence?”

Dr Alasdair Rankin, Director of Research and Policy at the blood cancer charity Bloodwise, said:

“It’s important for parents who had this particular form of fertility treatment not to worry unduly about these findings. This is particularly important when you consider that for women and young people who have cancer and want to have children in future, freezing embryos before treatment is often the only choice available to them.

“While a doubling of relative risk sounds scary, childhood cancers are thankfully very rare, so the absolute risk is still low. The risk of cancer increased from around one in 480 to one in 240 for children born using frozen embryo transfer.

“Although this study looks at over a million births, the number of children born from frozen embryos in this study was relatively small, and the total number of children in this group with cancer was very small. Leukaemia accounted for five of the 14 cases of cancer, but leukaemia is the most common form of cancer in children so this is not surprising.”

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

“As the proportion of babies born worldwide following assisted conception techniques like IVF and ICSI continues to grow, this interesting study from Denmark, where nearly one in ten babies are the result of IVF treatment, finds that there is apparently a small increased risk of a diagnosis of childhood cancer in babies born following frozen embryo transfer.

“Fortunately, childhood cancer is very rare (less than one case per 10 000 births) so with even a doubling of a tiny number it still remains rare, much rarer than illnesses caused by genetic problems which affect 2% of of all pregnancies. Paternal smoking has also been shown to almost double childhood cancer rates in spontaneous conceptions.

“Modern freezing techniques like vitrification (‘flash freezing’) are biologically very different than the ‘slow freezing’ techniques which were used for most of the period that this study covers.

The ability to freeze embryos has offered two substantial benefits for couples with fertility problems in that it has effectively removed the risk of Ovarian Hyper Stimulation Syndrome (OHSS) and allowed babies to born ‘one at a time’ and avoid the risk of prematurity associated with multiple births. Embryo freezing also ‘freezes in time’ the mother’s age at the point at which the embryos were created and offers the chance of later pregnancies without having to go through repeated ‘fresh’ treatment cycles.

“There is evidence that the birthweight of babies born from frozen cycles is higher than with fresh IVF and closer to that of babies conceived naturally. As low birthweight can be associated with health problems in later life, frozen transfer cycles may offer lifetime health benefits.

Ensuring that fertility patients have up to date information about all aspects of the treatments offered, including any increased risks, remains central to good practice.”

Prof Alastair Sutcliffe, Professor of General Paediatrics, University College London (UCL), said:

“The researchers in Denmark have compared cancer diagnosis in children born after their parents have had fertility treatments to conceive versus the other children born in Denmark.

“They have found an increased risk of cancer in children after cryopreservation but not other types of treatment. This could be a random chance finding in view of multiple comparisons as the alleged risk or hazard ratio has a wide confidence interval from 1.4 to the middle risk of 2.4. This is important as it does not convincingly show a higher risk of cancer in these children – the numbers of children inevitably are small as fortunately childhood cancer is a rare outcome. Furthermore, the cancers suggested from the Danish study do not appear to have any link to the known risk of cancers after freezing due to imprinting disorders such as Beckwith Weideman syndrome. Again, inferences that this may be a random chance finding.

“Hazard ratio is a relative effect and tells us nothing about absolute risk which will be very small.

“Existing evidence does not suggest an increased risk of cancers as a whole after any form of IVF, but monitoring is important. Embryo freeze thawing is more and more de rigueur due to the need to reduce twins, threes, fours or more, by single embryo replacement. Ironically twinning itself is associated with increased cancer risk, thus if this paper’s findings are valid (I am evidently skeptical) it would be of concern.

“There is at present an ongoing study involving Australia, Scandinavia and the UK to attempt to address such risks with a population of 100 million as opposed to Denmark’s 5.5 million so at that point a more accurate estimate of risk will be made available from cryopreservation or any other method of conceiving with assisted conception”

Prof Daniel Brison, Honorary Professor of Clinical Embryology and Stem Cell Biology; Scientific Director of the Department of Reproductive Medicine, University of Manchester, said:

“This is a large and carefully analysed study and the association reported between frozen embryo transfer and cancer in children deserves further research.  However, the results presented here should not alarm couples undergoing frozen embryo transfer or children born from this technique.  The number of cancer cases reported was very small, only 14 in total, and so the possibility that this has occurred by chance or due to some other unknown factor is high.  Or as the authors correctly point out, “the findings should be considered exploratory”.  

“Frozen embryo transfer has been used for decades in animal species and in human clinical ART and there is no known mechanism by which the freezing process might cause cancer.  Frozen embryo transfers are also associated with potential health advantages such as birthweight and early child growth patterns which are closer to naturally conceived children, as shown in the largest ever study of its type in the UK last year. However, the association reported here should certainly prompt researchers to investigate and optimise the processes for freezing gametes and embryos.”

Prof Abha Maheshwari, Consultant in Reproductive Medicine, Honorary Professor and Director & Person Responsible at Aberdeen Fertility Centre, University of Aberdeen, said:

“This is a great paper, congratulations to the authors. It raises some concern about frozen embryo transfer but as authors rightly mentioned in the limitations, absolute numbers are very small not only of childhood cancers but for children born with frozen embryo transfer in this study.  In absolute numbers: 2 in 500 babies resulting from frozen embryo transfer and 1 in 500 resulting from fresh embryo transfer has had a diagnosis of cancer in this report. The data need replication from other parts of the world.

“It should also be noted that the time period that relates to this study (1995- 2015) – older method of freezing was used. Freezing techniques have improved so much in recent years, so this may not apply with newer techniques. More data is awaited, and we should continue to collect and follow up children born from these technologies.

“There is no reason to panic but what it highlights is that we need more data on frozen embryo transfer and should be cautious in using it for all unless there is a clinical indication such as ovarian hyperstimulation.  There are benefits from frozen embryo transfer as it almost eliminates risks of ovarian hyperstimulation and reduces risk of small for gestational age babies.

“There are pros and cons with frozen transfers, and they have to be taken in consideration with individualised decisions made for each case rather than a blanket policy of freeze all for all, until more data is available.”

‘Association Between Fertility Treatment and Cancer Risk in Children’ by Marie Hargreave et al. was published in JAMA at 16:00 UK time on Tuesday 10th December. 

DOI: 10.1001/jama.2019.18037

Declared interests

Richard Kennedy: I have no conflicts to declare

Dr Alasdair Rankin: No interests to declare.

Dr Gill Lockwood: I don’t have any declarations of interest

Prof Alastair Sutcliffe: I have no conflict of interest

Prof Daniel Brison: I hold funding from the UK NIHR for research into oocyte and embryo freezing.

Prof Abha Maheshwari:  I am chief investigator for UK for randomised trial ( E-Freeze) comparing fresh versus frozen embryo transfer

None others received.