Frozen embryo transfer is associated with higher rates of childhood cancer

A study has found that embryos that have been frozen and thawed are associated with slightly higher rates of leukemia and sympathetic nervous system tumours. We aren't sure why.

New treatments bring not only hope but uncertainty. Both in vitro fertilization (IVF), for instance, and intracytoplasmic sperm injection (ICSI) have had small but detectable unexpected effects. So, too, we now find, with frozen embryo transfer.

According to a paper out last Wednesday in JAMA, the Journal of the American Medical Association, which I summarize below, the good news is that the increased risk of childhood cancer is still low. The troubling news, however, is that there is an increase, and we are not entirely sure why.

The researchers gently speculate about what could be causing it. They mention the process of freezing and thawing embryos, the timing of the fertility drugs that are used, and the effects of cryoprotectants. 

Human embryos were first frozen in the mid-80s. During the freezing process, water is slowly drawn out of the cells and replaced with cryoprotectant chemicals, and during the thaw, that process is reversed. More recently, slow freezing has been replaced by rapid freezing, or vitrification, in which higher concentrations of cryoprotectants are typically used.

We have a duty to intensively study new medical technologies to make sure we understand the consequences. Detecting effects is not always easy. As in this case, it often involves collecting and analyzing a great deal of data. If you don't collect it, you can't analyze it. If it weren't for an extensive collection of interlinked registries, these findings may not have been possible. A shoutout to the Danish Medical Birth Registry, the Danish National Patient Register, the Danish National IVF Registry, the Danish National Prescription Registry, the Danish Infertility Cohort, and the Danish Cancer Registry.

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Frozen embryo transfer is associated with a small but significant increase in childhood cancer, according to Danish cancer researchers.

In the past 40 years, more than eight million children have been born as a result of assisted reproductive technology (ART). Researchers have long wondered whether such interventions carry health risks.

Marie Hargreave of the Danish Cancer Society Research Center, based in Copenhagen, and her colleagues looked at data relating to 1,085,172 children born in Denmark in the years 1996 through 2012. All residents of Denmark have a unique personal identification number. The researchers were able to link individual children to individual mothers, whose health data had been captured by multiple national registers. Information in the registers includes whether a woman had had problems with infertility, what treatment she underwent, and what drugs she'd been prescribed.

Childhood cancer is rare. Nonetheless, during the study period, 2217 children were diagnosed with it. 

The researchers evaluated risk of cancer by examining the mother's history of fertility problems and her use of fertility drugs and treatments during this pregnancy. They specifically looked at whether the mother had undergone in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), and frozen embryo transfer, among other things, and they investigated the exposures separately.

Hargreave and her colleagues found no statistically significant association between use of fertility drugs, the use of fertility treatment in general, or the use of IVF or ICSI in particular and cancer, when compared to fertile women. But they did find a statistically significant association between use of frozen embryos and cancer. Specifically, children who had been born after frozen embryo transfer had higher rates of leukemia and sympathetic nervous system tumours. 

This study cannot tell us why this is. But the researchers cite previous work in animals that found freezing and thawing can cause changes to how genes are expressed. They also point out that drug regimens used in frozen embryo transfer could play a role. Finally, they speculate that cryoprotectants, which have also been shown in animal studies to cause changes in gene expression, could be involved. 

The study is strong because the comprehensive registries mean they had data on almost everyone of interest. As well, details on precisely when things occurred was a matter or record, not recall.

Denmark has one of the highest rates of ART use in the world. In 2018, almost one in every ten babies born in the country was conceived with the help of assisted reproductive technology.

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