Fresh and Frozen Embryo Transfers May Increase Risk of Childhood Leukemia

While overall cancer risk was no different for children born after fertility treatments compared with those naturally conceived, frozen or fresh embryo transfer did appear to increase risk of leukemia, according to a French cohort study.

Among more than 8.5 million children, the overall risk of cancer did not differ between those conceived naturally and those born after fresh embryo transfer (HR 1.12, 95% CI 0.96-1.31), frozen embryo transfer (HR 1.02, 95% CI 0.78-1.32), or artificial insemination (HR 1.09, 95% CI 0.86-1.38), reported Paula Rios, MD, PhD, of the French National Agency for Medicines and Health Products Safety in Saint-Denis, France, and colleagues.

However, the risk of acute lymphoblastic leukemia (ALL) was higher among children born after frozen embryo transfer (HR 1.61, 95% CI 1.04-2.50), for a risk difference of 23.2 per million person-years compared with children conceived naturally, they wrote in JAMA Network Open.

In addition, among children born from 2010 to 2015, the risk of leukemia was higher among those born after fresh embryo transfer (HR 1.42, 95% CI 1.06-1.92), for an adjusted risk difference of 19.7 per million person-years.

"This risk, although resulting in a limited number of cases, needs to be monitored in view of the continuous increase in the use of ART [assisted reproductive technologies]," Rios and colleagues wrote.

Among previous studies with 100,000 or more ART-exposed children, there was no increase in overall cancer risk observed, with the exception of one study that reported a "marginal association" with ART. However, positive associations have been documented across studies of specific cancer types, Rios and colleagues said, though these studies "were based on limited numbers of case patients exposed to each ART modality."

In an invited commentary, Marie Hargreave, PhD, of the Danish Cancer Institute in Copenhagen, noted that "use of ART has been linked with several detrimental perinatal outcomes among children, including preterm birth and congenital malformations; disturbingly, several high-quality studies and systematic reviews have reported increased cancer risk among children born after fertility treatment."

A 2019 Danish study of children born after frozen embryo transfer by Hargreave and colleagues and a 2020 study of babies with birth defects born after in vitro fertilization both showed a heightened risk of childhood cancers. However, a Dutch study showed that children conceived via ART methods were at no greater risk of cancer compared with those born to subfertile mothers who did not use ART.

For this study, Rios and colleagues used data from the French National Mother-Child Register (EPI-MERES) for all children born alive in France from January 2010 through December 2021.

The study sample included 8,526,306 children with a mean age of 6.4 years. About half were boys, 96.4% were singletons, 12.1% were small for gestational age at birth, and 3.1% were born with a congenital malformation. In all, 3.1% of the children were born following medically assisted reproduction, including 1.6% after fresh embryo transfer, 0.8% after frozen embryo transfer, and 0.7% after artificial insemination.

A total of 9,256 case patients with cancer were identified over a median follow-up of 6.7 years, with 165, 57, and 70 born after fresh embryo transfer, frozen embryo transfer, and artificial insemination, respectively.

Patients with cancer diagnoses were more likely to be born preterm, be large for gestational age, and have been diagnosed with congenital malformations compared with children without cancer.

Leukemia was the most common cancer diagnosed, accounting for 29.4% of total cases, and ALL accounted for 79.1% of leukemia cases.

Among the patients diagnosed with leukemia, 2,635 were conceived naturally, 52 were born after fresh embryo transfer, 23 were born after frozen embryo transfer, and 19 were born after artificial insemination. Among the patients diagnosed with ALL, 2,083 were conceived naturally, 39 were born after fresh embryo transfer, 20 were born after frozen embryo transfer, and 16 were born after artificial insemination.

While the number of births following fresh embryo transfers declined beginning in 2014, the number of children born following frozen embryo transfers grew over the study period. The number of yearly births after artificial insemination was stable over the study period, the authors noted.

Hargreave noted that the study authors "rightly raised the concern that it is unknown whether the increased leukemia risk observed in their study may, in fact, be attributable to factors related to the underlying infertility rather than the fertility treatment. Nevertheless, other high-quality studies with information on maternal infertility have reported increased cancer risk among children born after ART, even when using a reference group of children born to mothers with fertility problems who did not use ART."

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