A large cohort study from the Nordic countries has found that children born after FET had a higher risk of childhood cancer than children born after fresh embryo transfer and spontaneous conception, while no increased risk was found after any form of ART collectively. The authors urge caution in interpreting the results.
A new study of almost 8 million children in Nordic countries raises the possibility that children (up to the age of 18) born after frozen embryo transfer may have a higher risk of cancer than children born naturally or after fresh ART.(1) The study, from the CoNARTaS (Committee of Nordic ART and Safety) cohort, analysed the registry data of 7,944,248 children in Denmark, Finland, Norway and Sweden, of whom 171,744 were born after ART (2.2%) and 7,772,474 conceived spontaneously. Of those born after ART, 22,630 were born after FET. The registry figures represented all children born between 1994 and 2014 in Denmark, 1990 and 2014 in Finland, 1984 and 2015 in Norway, and 1985 and 2015 in Sweden. The births were cross-linked to any cancer (or cancer groups) in national health registries.
Results showed that children born after FET were at higher risk of cancer than children born after fresh embryo transfer and spontaneous conception (incidence rate 30.1/100,000 person-years vs 18.8/100,000 and 16.7/100,000). However, when analysed as a single ART group (fresh and frozen ET), the use of any type of ART did not reveal any increased risk of cancer over spontaneous conception. The most common types of cancer seen in the study were leukemia and tumours of the central nervous system.
The study authors stress that their findings should be interpreted with caution; although the study was large, the number of children born after FET who later developed cancer was low (48 cases), and this, they suggest, could limit the statistical strength of the analysis. Principal study authors Ulla-Britt Wennerholm and Christina Bergh noted in a press statement that, while ‘the individual risk was low’, its impact at a population level ‘may have an impact due to the huge increase in frozen cycles after assisted reproduction’. They emphasised that ‘no increase in cancer was found among children born after assisted reproduction techniques overall’.
Nevertheless, the authors describe their estimates as ‘robust’, which changed only marginally after adjustment for relevant confounders – and which reassuringly confirm other large-scale registry studies (including from the CoNARTaS group) which also found no increased risk in any childhood cancers after any ART.(2,3)
Why FET should be associated with any possible higher risk ‘is not known’, state the authors, adding: ‘Each childhood cancer type has its own risk factor profile, but many childhood cancers are thought to derive from embryonic accidents and originate in utero.’ Higher birth weight, for example, has been associated with a higher childhood cancer risk, or changes in epigenetics dependent on the use of different ARTs. Several registry studies and systematic reviews have found a lower risk of preterm birth and low birth weight in FET infants than in those following fresh embryo transfer - but a higher risk of high birth weight and macrosomia in FET infants.
The authors further raise the possibility of some effect of embryo selection. Indeed, many FET cycles during this long study period would have taken place after a failed fresh transfer cycle – thereby implying that the best embryo was used for fresh transfer, with selection of a poorer quality embryo in the frozen cohort. However, the authors point out that only good quality embryos were frozen, while in the fresh group embryos of less quality were also transferred. Further, the number of blastocyst transfers was higher in the FET group. Thus, with absence of any corroborating evidence, the authors were unable to support the possibility of any embryo selection effect.
Nevertheless, and despite the absence of an explanation, the results clearly indicated that children born after FET did indeed have a higher risk of childhood cancer than children born after fresh ET and spontaneous conception. But the actual cancer case numbers were low, and the authors urge caution in interpretation. It might also be noted that the protocols and technologies of embryo freezing have changed considerably since the mid-1980s, when the first of the registry data was collected for this study.
So what might the results mean for clinics and their patients? Christina Bergh told Focus on Reproduction: ‘For clinics it means that some concerns may be raised considering the huge increase in FET, particularly freeze-all strategies without clear medical indications.
For patients it means that we now have a better view on long-term risks, such as cancer, after ART and FET - but that those risks, although higher after FET, are low at an individual level.’
1. Sargisian N, Lannering B, Petzoid M, et al. Cancer in children born after frozen-thawed embryo transfer: A cohort study. PLoS Med 2022; 19(9): e1004078. doi.org/10.1371/journal. pmed.1004078
2. Sundh KJ, Henningsen AK, Kallen K, et al. Cancer in children and young adults born after assisted reproductive technology: a Nordic cohort study from the Committee of Nordic ART and Safety (CoNARTaS). Hum Reprod 2014; 29: 2050–2057.
3. Williams CL, Bunch KJ, Stiller CA, et al. Cancer risk among children born after assisted conception. N Engl J Med 2013; 369: 1819–1827.
doi.org/10.1056/ NEJMoa1301675 PMID: 24195549