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. 2022 Sep 1;19(9):e1004078.
doi: 10.1371/journal.pmed.1004078. eCollection 2022 Sep.

Cancer in children born after frozen-thawed embryo transfer: A cohort study

Nona Sargisian  1 , Birgitta Lannering  2 , Max Petzold  3 , Signe Opdahl  4 , Mika Gissler  5   6 , Anja Pinborg  7 , Anna-Karina Aaris Henningsen  7 , Aila Tiitinen  8 , Liv Bente Romundstad  9   10 , Anne Lærke Spangmose  7 , Christina Bergh  1 , Ulla-Britt Wennerholm  1
Affiliations

Cancer in children born after frozen-thawed embryo transfer: A cohort study

Nona Sargisian et al. PLoS Med. .

Abstract

Background: The aim was to investigate whether children born after assisted reproduction technology (ART), particularly after frozen-thawed embryo transfer (FET), are at higher risk of childhood cancer than children born after fresh embryo transfer and spontaneous conception.

Methods and findings: We performed a registry-based cohort study using data from the 4 Nordic countries: Denmark, Finland, Norway, and Sweden. The study included 7,944,248 children, out of whom 171,774 children were born after use of ART (2.2%) and 7,772,474 children were born after spontaneous conception, representing all children born between the years 1994 to 2014 in Denmark, 1990 to 2014 in Finland, 1984 to 2015 in Norway, and 1985 to 2015 in Sweden. Rates for any cancer and specific cancer groups in children born after each conception method were determined by cross-linking national ART registry data with national cancer and health data registries and population registries. We used Cox proportional hazards models to estimate the risk of any cancer, with age as the time scale. After a mean follow-up of 9.9 and 12.5 years, the incidence rate (IR) of cancer before age 18 years was 19.3/100,000 person-years for children born after ART (329 cases) and 16.7/100,000 person-years for children born after spontaneous conception (16,184 cases). Adjusted hazard ratio (aHR) was 1.08, 95% confidence interval (CI) 0.96 to 1.21, p = 0.18. Adjustment was performed for sex, plurality, year of birth, country of birth, maternal age at birth, and parity. Children born after FET had a higher risk of cancer (48 cases; IR 30.1/100,000 person-years) compared to both fresh embryo transfer (IR 18.8/100,000 person-years), aHR 1.59, 95% CI 1.15 to 2.20, p = 0.005, and spontaneous conception, aHR 1.65, 95% CI 1.24 to 2.19, p = 0.001. Adjustment either for macrosomia, birth weight, or major birth defects attenuated the association marginally. Higher risks of epithelial tumors and melanoma after any assisted reproductive method and of leukemia after FET were observed. The main limitation of this study is the small number of children with cancer in the FET group.

Conclusions: Children born after FET had a higher risk of childhood cancer than children born after fresh embryo transfer and spontaneous conception. The results should be interpreted cautiously based on the small number of children with cancer, but the findings raise concerns considering the increasing use of FET, in particular freeze-all strategies without clear medical indications.

Trial registration: Trial registration number: ISRCTN 11780826.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Proportional distribution of age at first cancer (any type) among spontaneously and ART-conceived children born in Denmark (1994–2014), Finland (1990–2014), Norway (1984–2015), and Sweden (1985–2015) and diagnosed with cancer before age 18 years.
ART, assisted reproduction technology.
Fig 2
Fig 2. Age-specific hazard rates of first cancer (any type) among spontaneously and ART-conceived children born in Denmark (1994–2014), Finland (1990–2014), Norway (1984–2015), and Sweden (1985–2015) and diagnosed with any cancer before age 18 years.
ART, assisted reproduction technology; CI, confidence interval.
Fig 3
Fig 3. Cumulative hazard of first cancer (any type) up to 18 years for spontaneously and ART-conceived children born in Denmark (1994–2014), Finland (1990–2014), Norway (1984–2015), and Sweden (1985–2015). Crude hazard ratio 1.13; 95% CI 1.01 to 1.26, p = 0.03.
ART, assisted reproduction technology; CI, confidence interval.
Fig 4
Fig 4. HRs with 95% CI for independent covariates including macrosomia for risk of cancer in children born after FET versus fresh embryo transfer.
CI, confidence interval; FET, frozen-thawed embryo transfer; HR, hazard ratio.
Fig 5
Fig 5. HRs with 95% CI for independent covariates including macrosomia for risk of cancer in children born after FET versus spontaneous conception.
CI, confidence interval; FET, frozen-thawed embryo transfer; HR, hazard ratio.
See this image and copyright information in PMC

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