Grand Rounds

Are Children Born After use of ART and Fertility Drugs at a Higher Risk of Childhood Cancer?

BACKGROUND AND PURPOSE:

Associations between ART, fertility drugs, and cancer in offspring remain uncertain
- Where associations have been found, it is unclear if results are a result of the treatment plan or underlying infertility
Hargreave et al. (JAMA, 2019) investigated the association between different types of fertility treatments and cancer risk in children

Retrospective cohort study
Data sources
- Danish population-based registries and Danish Infertility Cohort (individual record linkage)
Participants
- Children born between 1996 to 2012 (linked with parental information)
Exposures: Maternal fertility treatment during the index pregnancy including
- Fertility drugs: Clomiphene | Gonadotropins | GnRH analogs | Human chorionic gonadotropin | Progesterone | Estrogen
- ART: IVF | ICSI | Frozen embryo transfer
Study design
- Cohort follow up through to 2015
- Each exposure was examined separately and compared with children born to fertile women
Primary outcomes
- Hazard ratio (HR) and incidence rate differences for childhood cancer

1,085,172 children included
- 2,217 children were diagnosed with cancer
- 12.2 million person-years of follow-up (mean, 11.3 years)
Use of frozen embryo transfer was associated with an elevated risk of childhood cancer (14 cancers) based on the following incidence rates of childhood cancer
- Fertile women (control): 17.5 per 100,000
- Frozen embryo: 44.4 per 100,000
- HR 2.43 (95% CI, 1.44 to 4.11) | Incidence rate difference 26.9 (95% CI, 2.8 to 51.0) per 100,000
Elevated risk for frozen embryo was mainly due to an increased risk of
- Leukemia (5 cancer cases)
  - Incidence rate, 14.4 per 100,000 | HR 2.87 (95% CI, 1.19 to 6.93) | Incidence rate difference 10.1 (95% CI, −4.0 to 24.2) per 100,000)
- Sympathetic nervous system tumors (<5 cases)
  - HR 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

Authors acknowledge important limitations including
- Rarity of childhood cancer cases
- Confounding was assessed, however not all confounders can be accounted for and one important confounder – infertility diagnosis – was not available
Slight increased risk of childhood cancer associated with use of frozen embryo transfer
No other associations found between childhood cancer and the use of other types of fertility treatment examined

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