Increased risk of certain cancers for children conceived from frozen embryos

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When frozen embryos are used during in vitro fertilization (IVF), the resulting children have a slightly higher risk than other kids for certain types of cancer, Channel News Asia reports evidence from Denmark suggests. Analysing health records of more than a million Danish children, researchers found that babies conceived through assisted reproduction involving frozen embryo transfer were more than twice as likely to develop childhood cancer, particularly leukaemia and neuroblastoma, a type of brain cancer, according to the research.

"We did not find increased risks with other types of fertility treatments," said study leader Marie Hargreave of The Danish Cancer Society Research Centre, in Cophenhagen. Hargreave called for more research to validate her group's findings. Moreover, "it is important to stress the fact that the increased risk is very small for the individual as childhood cancer is very rare," she is quoted in the report as saying.

Denmark has one of the highest rates of assisted reproduction technology in the world. In 2018, 9.8% of newborns there had been conceived with fertility treatments, the researchers note in their report. To see whether techniques used in assisted reproduction might elevate cancer risk in children, Hargreave's team turned to national registries of births, deaths and medical records. The analysis found the incidence of childhood cancer among children born to women with no fertility issues was 17.5 per 100,000. For children born as a result of frozen embryo transfer, the incidence was 44.4 per 100,000, which translated to a 2.43-fold higher risk.

There were no other statistically-meaningful increases in cancer risk for children conceived through any other assisted-reproduction techniques. Overall there had been 341 childhood cancer cases during the time period studied: 1 January, 1996 through 31 December, 2012.

The new study has looked at an important question, said Dr Alan B Cooperman, director of the division of reproductive endocrinology and infertility at the Mount Sinai Health System in New York City. But because the study looks only at an association, "it is not clear whether the finding is related to the procedure itself or the patients who needed the procedure," Cooperman said in an email. Beyond that, "any time a rare event is studied in a large retrospective study, the statistical precision to make accurate conclusions is limited."

With that said, "prospective parents can be reassured that in 12.2m 'person-years' of follow-up, that childhood cancer was diagnosed in less than 0.01per cent of children, regardless of whether or not IVF was used for conception," Cooperman noted in the report.

With frozen embryo transfers becoming more and more common, it will be important to see more studies on this topic, said Dr Sunita Katari, an assistant professor at the Magee Centre for Fertility & Reproductive Endocrinology at the UPMC Magee-Women’s Hospital in Pittsburgh, Pennsylvania. "It's something that really needs more investigation and larger studies from different countries," Katari said. It would also be helpful to have information "on the actual diagnosis of individuals going through fertility treatments in this study," Katari said.

Abstract
Importance: An increasing number of children worldwide are born after the use of fertility treatment, although it remains unclear whether the treatment affects the risk of childhood cancer and whether any associations observed are due to the use of specific drugs, the use of specific procedures, or the underlying infertility.
Objective: To examine the association between different types of fertility treatments and cancer risk in children.
Design, Setting, and Participants: A retrospective cohort study based on Danish population-based registry data and the Danish Infertility Cohort (individual record linkage) that included 1 085 172 children born in Denmark between January 1, 1996, and December 31, 2012, linked with parental information. There were a total of 2217 children diagnosed with cancer (follow-up occurred during 1996-2015).

Exposures Maternal fertility treatment during the index pregnancy, including the use of fertility drugs (clomiphene [n = 33 835], gonadotropins [n = 57 136], gonadotropin-releasing hormone analogs [n = 38 653], human chorionic gonadotropin [n = 68 181], progesterone [n = 41 628], and estrogen [n = 16 948]) and assisted reproductive technology (in vitro fertilization [n = 19 448], intracytoplasmic sperm injection [n = 13 417], and frozen embryo transfer [n = 3356]). Each exposure was examined separately and compared with children born to fertile women.
Main Outcomes and Measures: Hazard ratios and incidence rate differences for childhood cancer.

Results: After 12.2 million person-years of follow-up (mean, 11.3 years), the incidence rate of childhood cancer was 17.5 per 100 000 for children born to fertile women (n = 910 291) and 44.4 per 100 000 for children born after the use of frozen embryo transfer (n = 3356). Compared with children born to fertile women, the use of frozen embryo transfer was associated with an elevated risk of childhood cancer (14 cancer cases; hazard ratio, 2.43 [95% CI, 1.44 to 4.11]; incidence rate difference, 26.9 [95% CI, 2.8 to 51.0] per 100 000), mainly due to an increased risk of leukemia (5 cancer cases; incidence rate, 14.4 per 100 000; hazard ratio, 2.87 [95% CI, 1.19 to 6.93]; incidence rate difference, 10.1 [95% CI, −4.0 to 24.2] per 100 000) and sympathetic nervous system tumors (<5 cancer cases; hazard ratio, 7.82 [95% CI, 2.47 to 24.70]). There were no statistically significant associations with the use of the other types of fertility treatment examined.
Conclusions and Relevance: Among children born in Denmark, the use of frozen embryo transfer, compared with children born to fertile women, was associated with a small but statistically significant increased risk of childhood cancer; this association was not found for the use of other types of fertility treatment examined.

Authors
Marie Hargreave; Allan Jensen; Merete Kjær Hansen; Christian Dehlendorff; Jeanette Falck Winther; Kjeld Schmiegelow; Susanne K Kjær

Channel News Asia report

JAMA abstract

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