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Original Investigation
December 10, 2019

Association Between Fertility Treatment and Cancer Risk in Children

Author Affiliations
  • 1Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark
  • 2Statistics and Pharmacoepidemiology, Danish Cancer Society Research Center, Copenhagen, Denmark
  • 3Childhood Cancer Research Group, Danish Cancer Society Research Center, Copenhagen, Denmark
  • 4Department of Clinical Medicine, Faculty of Health, Aarhus University and University Hospital, Aarhus, Denmark
  • 5Department of Pediatrics and Adolescent Medicine, Juliane Marie Centre, Rigshospitalet, Copenhagen, Denmark
  • 6Institute of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
  • 7Department of Gynecology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
JAMA. 2019;322(22):2203-2210. doi:10.1001/jama.2019.18037
Key Points

Question  Are children born after the use of specific fertility drugs and assisted reproductive technology at an increased risk of cancer?

Findings  In this retrospective cohort study that included 1 085 172 children born in Denmark, the risk of childhood cancer for those born after the use of frozen embryo transfer compared with children born to fertile women was significantly increased (44.4 vs 17.5 per 100 000 person-years, respectively; hazard ratio, 2.43). There was no significant increase in risk associated with use of other assisted reproductive technology, including in vitro fertilization, intracytoplasmic sperm injection, or hormonal treatment.

Meaning  Use of frozen embryo transfer was associated with a small but statistically significant increased risk for childhood cancer.

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.

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