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

Nona Sargisian; Birgitta Lannering; Max Petzold; Signe Opdahl; Mika Gissler; Anja Pinborg; Anna-Karina Aaris Henningsen; Aila Tiitinen; Liv Bente Romundstad; Anne Lærke Spangmose; Christina Bergh; Ulla-Britt Wennerholm

doi:10.1371/journal.pmed.1004078

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

Sargisian N, Lannering B, Petzold M, Opdahl S, Gissler M, Pinborg A, Henningsen AA, Tiitinen A, Romundstad LB, Spangmose AL, Bergh C, Wennerholm UB

Published September 2022 PLoS medicine, 19(9), e1004078

DOI 10.1371/journal.pmed.1004078 PMID 36048761 PMC PMC9436139

RRM Academy Synopsis

Nordic children after frozen embryo transfer had higher cancer risk

In a registry cohort, frozen-thawed embryo transfer was associated with higher childhood cancer risk (adjusted hazard ratio 1.59 against fresh transfer). The cohort covered 7,944,248 Nordic children. Children conceived with any ART overall showed no clear difference from spontaneous conception.

Key Findings

Any ART against spontaneous conception: 329 cancers in the ART group, 19.3 against 16.7 per 100,000 person-years. Adjusted hazard ratio (aHR) 1.08, 95% CI 0.96 to 1.21, p = 0.18.
After FET there were 48 cancers, an incidence rate of 30.1 per 100,000 person-years, compared with 18.8 after fresh transfer: aHR 1.59, 95% CI 1.15 to 2.20, p = 0.005.
Against spontaneous conception, children born after FET had aHR 1.65 (95% CI 1.24 to 2.19, p = 0.001).
Leukemia after FET: 23 cases, 14.4 per 100,000 person-years, against 6.2 after fresh transfer. aHR 2.25, 95% CI 1.38 to 3.68.
Epithelial tumors and melanoma after ART: 22 cases, 1.3 per 100,000 person-years, against 0.8 after spontaneous conception (812 cases). aHR 1.89, 95% CI 1.20 to 2.97, p = 0.01.

Interpretation

The study is a registry-based cohort, so it reports associations. The authors name the small number of cancers in the FET group as the main limitation and write that the study cannot give a definite answer. They also state that residual confounding by genetics, parental preconception health and lifestyle cannot be excluded. Finland was left out of the FET analysis because its registry does not record ART method. The authors describe the absolute risk as low. The FET analysis covered children born in Denmark, Norway and Sweden, where most FET cycles followed a failed fresh cycle and freeze-all was hardly used.

RRM Context

IVF bypasses the reasons conception fails and leaves them untreated. The cohort adds long-term child-health data to the IVF record, with FET associated with a higher childhood cancer risk than fresh transfer in these Nordic registries. The authors write that the findings raise concerns given the growing use of FET. Restorative reproductive medicine evaluates and treats the cause of infertility, allowing conception without embryo freezing.

Our editorial summary of this paper, not the article's abstract.

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

ISRCTN 11780826.

Topics

Assisted Reproduction

Safety and Risks Long Term Child Outcomes

Assisted Reproduction › Safety and Risks › Long Term Child Outcomes

Nona Sargisian, Birgitta Lannering, Max Petzold, Signe Opdahl, Mika Gissler, Anja Pinborg, Anna-Karina Aaris Henningsen, Aila Tiitinen, Liv Bente Romundstad, Anne Lærke Spangmose, Christina Bergh, Ulla-Britt Wennerholm

N Sargisian, B Lannering, M Petzold, S Opdahl, M Gissler, A Pinborg, A Henningsen, A Tiitinen, L Romundstad, A Spangmose, C Bergh, U Wennerholm

PMID 36048761 36048761 DOI 10.1371/journal.pmed.1004078 10.1371/journal.pmed.1004078 Sargisian et al. 2022, Sargisian 2022

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

Nordic children after frozen embryo transfer had higher cancer risk

Key Findings

Interpretation

RRM Context

Abstract

Topics

By this author

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