Kids Born From Frozen Embryos May Have Increased Cancer Risk

Children born after frozen-thawed embryo transfer (FET) may have a higher risk of cancer than children born through fresh embryo transfer or spontaneous conception, a large-registry study suggests.

The results, however, “should be interpreted cautiously,” the authors note, given the low number of cancer cases reported among children born using FET.

Still, the findings do “raise concerns considering the increasing use of FET, in particular freeze-all strategies without clear medical indications,” the authors conclude.

The study was published online in PLOS Medicine.

The number of children born after FET has increased globally and even exceeds the number of those born after fresh embryo transfer in many countries. In the US, for instance, the FET rate has doubled since 2015; FETs constituted almost 80% of all embryo transfers using assisted reproductive technology (ART) without a donor in 2019.

Despite the benefits associated with FET, which include improved embryo survival and higher live birth rates, some previous research has hinted at a higher risk of childhood cancer in this population.

In the current study, researchers from the University of Gothenburg, Sweden, wanted to better under the risk of childhood cancer following FET. The investigators analyzed data from 171,774 children born via ART, including 22,630 born after FET, as well as roughly 7.7 million children born after spontaneous conception in Denmark, Finland, Norway, and Sweden.

After a mean follow-up of about 10 years, the incidence rate of cancer diagnosed before age 18 years was 16.7 per 100,000 person-years for children born after spontaneous conception (16,184 cases) and 19.3 per 100,000 person-years for children born after ART (329 cases).

The researchers found no increased risk of cancer before age 18 years in the group of children conceived via ART compared with those conceived spontaneously.

However, children born after FET had a significantly higher risk of cancer compared with children born after fresh embryo transfer (adjusted hazard ratio [aHR], 1.59) and spontaneous conception (aHR, 1.65). Specifically with regard to ART, the incidence rate for those born after FET was 30.1 per 100,000 person-years — 48 total cases — compared with 18.8 per 1000,000 person-years after fresh embryo transfer.

Adjusting for macrosomia, birth weight, or major birth defects only influenced the association marginally.

For specific cancer types, children born after FET had more than a twofold higher risk for leukemia in comparison with those born after fresh embryo transfer (aHR, 2.25) and spontaneous conception (aHR, 2.22).

Still, the authors say these results should be interpreted “cautiously,” given the small number of children diagnosed with cancer after FET. The researchers also acknowledge that they do not know why children born after FET would face a higher risk of cancer.

These findings, however, do align with those from a 2019 Dutch population-based study. In the Dutch study, which included more than 24,000 ART-conceived children and over 23,000 naturally conceived children, the risk of cancer after ART was not higher overall, but it was greater when only those conceived after FET were considered (aHR 1.80); this increased risk, however, was not statistically significant.

“Since the use of FET is substantially increasing, it is important to tease out whether the increased cancer risk is a true risk increase due to the ART procedures using FET, or due to chance or confounding by other factors,” authors of the 2019 Dutch study, Mandy Spaan, PhD, and Flora E. van Leeuwen, PhD, told Medscape Medical News.

“But, as childhood cancer is (fortunately) a rare disease, it is very difficult to study this research question among ART children due to limited numbers,” said Spaan and van Leeuwen, who are with the Netherlands Cancer Institute.

Given this, the two experts call for additional large population-based cohort studies to investigate the risk of cancer after ART, especially FET, and for a subsequent analysis that pools these data. They hope this strategy “will lead to reliable estimates” and provide information on the risks of FET in comparison with approaches that involve fresh embryos.

The current study had no commercial funding. The study authors as well as Spaan and van Leeuwen have disclosed no relevant financial relationships.

PLoS Med. Published online September 1, 2022. Full text

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