DEMOSTREMOS.ES
Cancer predisposition in children born after Frozen Embryo Transfer (FET)
Recently a very disturbing research on the cancer risk in children born after Frozen Embryo Transfer appeared. It is not just a single research study, but a whole body of evidence suggesting a strong likelihood of a lifelong cancer predisposition for future child if one uses Frozen Embryo Transfer (FET).
The magnitude of possible cancer predisposition is comparable to living in a severely radiation-polluted area [8], illustrating its significance. Here's the evidence:
First, there is strong statistical epidemiological evidence (1)(2), showing an elevated cancer risk of 1.28 in children after FET compared to fresh embryo transfer in a meta-research comprising all available papers up to 2020 (25,563 FET children) and a risk of 1.56 (FET vs fresh) in the latest research of 2022 on 22,630 FET children. So, we can consider the average risk to be about 1.42 (48,193 children) based on all available data for now. Despite the low absolute number of cancer cases in this research, the fact that the results are statistically significant and adjustments for known childhood cancer factors have been made, makes these results quite reliable. The probability of getting them by chance is very low, especially considering that there is not a single research study with the opposite conclusion and the fact that the effect sizes are very close to each other in different papers.Moreover, comparisons are between frozen and fresh embryo transfers within IVF, not with the general population, ruling out infertility-related health conditions as a confounding factor.
To put this risk in context, consider the comparison with living in severely radiation-polluted areas. According to the study 'Background Ionizing Radiation and the Risk of Childhood Cancer' (8), areas with over 200 nSv/hr background radiation see a 1.64 times higher cancer risk compared to less polluted areas. This frightening parallel shows that, even in case we agree that the risk from FET is currently only suspected, its potential magnitude - nearly matching the risk from high radiation exposure - is deeply concerning.
In our research, we found a study seemingly showing no cancer risk difference between frozen and fresh embryo transfers (9). However, a closer look reveals it actually concerns oocyte cryopreservation, a detail clarified in the study’s supplementary tables. Indeed, the research on oocyte cryopreservation shows no statistical difference in childhood cancer risk with fresh embryo transfer, which again points to genetic damage caused by embryo cryopreservation (because in the case of oocyte cryopreservation, half of the genetic material, the sperm, is intact, not cryopreserved, which gives the embryo the undamaged set of genetic material).)
To test this hypothesis, we need to look for biological evidence of genetic damage. It turns out, there are indeed at least two proven biological mechanisms explaining how vitrification can lead to cancer predisposition (shown in oocytes and embryos):
- DNA damage caused by vitrification ("Effect of oocyte vitrification on DNA damage in metaphase II oocytes and the resulting preimplantation embryos" by Haoya Chang (2019) (3), "The effect of cryopreservation on DNA damage, gene expression, and protein abundance in vertebrates" by Chiahsin Lin (2016) (4), "Increase in DNA fragmentation and apoptosis-related gene expression in frozen-thawed (vitrified) bovine blastocysts" by Sae Young Park (2006)(5), and many others).
- Vitrification interferes with epigenetics. (Arturo Reyes Palomares(2022)(6) "Update on the Epigenomic Implication of Embryo Cryopreservation Methods Applied in Assisted Reproductive Technologies With Potential Long-Term Health Effects". Moulavi F et al. (2021) (7) "Vitrification may interfere with the critical stages of epigenetic reprogramming during preimplantation embryo development", and many others).
So, of course, we still can suppose that: It is possible that statistical evidence alone could just be a data artifact or statistical glitch, The biological evidence alone could have an alternative explanation as well (the damage may exist but be insufficient to cause serious problems). But it is very hard to dismiss these two pieces of evidence together. Consider it like a judge in court: individually, each piece of evidence might raise questions, but together, they form an undeniable conclusion. It's like having both fingerprints at the crime scene and a credible witness testimony – each supports the other, making the case much stronger. In our case, the combined statistical and biological evidence compels us to acknowledge the significant risk. So, the childhood cancer risk is, most likely, indeed elevated by 40-50 percent in FET-born children.
Absolute risk. Here there are two possibilities:
- If this damage influences the specific causes of childhood cancer, we are talking about only the childhood cancer risk. So a 40-50 percent increase in relative risk translates indeed to a negligible increase in absolute cancer risk and poses no problem.
- But, here is a main concern: if this damage influences some general anti-cancer abilities of the human body or other general cancer-inducing factors, and that is how it increases childhood cancer risk, this is a disaster. That means it increases by 40 percent the lifetime cancer risk, which is an enormous effect and overlaps pretty much all possible lifestyle choices to minimize cancer risk during life. As we mentioned beforre, it is comparable to severe childhood radiation exposure effect. How parents will teach their child to make choices maximizing life expectancy, always rely only on evidence, calculate probabilities to make decisions, knowing that they deliberately increased their cancer risk by 40 percent in the first place?
That is awful starting position for future child, isn't it?
References:
(1)The association between fertility treatments and the incidence of paediatric cancer: A systematic review and meta-analysis. European Journal of Cancer. VOLUME 138, P133-148, OCTOBER 01, 2020.
https://www.ejcancer.com/article/S0959-8049(20)30419-6/abstract
(2)Cancer in children born after frozen-thawed embryo transfer: A cohort study. PLoS Med. 2022 Sep; 19(9): e1004078.
https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004078
(3). Effect of oocyte vitrification on DNA damage in metaphase II oocytes and the resulting preimplantation embryos. Mol Reprod Dev. 2019 Nov;86(11):1603-1614. doi: 10.1002/mrd.23247. Epub 2019 Aug 13. https://pubmed.ncbi.nlm.nih.gov/31408251/
(4).The effect of cryopreservation on DNA damage, gene expression and protein abundance in vertebrate Chiahsin Lin &Sujune Tsai 2016 https://www.tandfonline.com/doi/full/10.4081/ijas.2012.e21
(5).Increase in DNA fragmentation and apoptosis-related gene expression in frozen-thawed bovine blastocysts. Zygote. 2006 May;14(2):125-31. doi: 10.1017/S0967199406003649. https://pubmed.ncbi.nlm.nih.gov/16719948/
(6).Update on the Epigenomic Implication of Embryo Cryopreservation Methods Applied in Assisted Reproductive Technologies With Potential Long-Term Health Effects. Front. Cell Dev. Biol., 28 April 2022.
(7).Oocyte vitrification induces loss of DNA methylation and histone acetylation in the resulting embryos derived using ICSI in dromedary camel. Zygote. 2021 Oct;29(5):383-392. doi: 10.1017/S0967199421000150. Epub 2021 Mar 18. https://pubmed.ncbi.nlm.nih.gov/33731239/
[8]Background Ionizing Radiation and the Risk of Childhood Cancer: A Census-Based Nationwide Cohort Study. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4455589/
(9)Association of In Vitro Fertilization With Childhood Cancer in the United States'' Logan G Spector. https://pubmed.ncbi.nlm.nih.gov/30933244/
