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.
PMID 36048761 36048761 DOI 10.1371/journal.pmed.1004078 10.1371/journal.pmed.1004078 Sargisian et al. 2022, Sargisian 2022
Cite this article
Sargisian, N., Lannering, B., Petzold, M., Opdahl, S., Gissler, M., Pinborg, A., Henningsen, A. A., Tiitinen, A., Romundstad, L. B., Spangmose, A. L., Bergh, C., & Wennerholm, U. B. (2022). Cancer in children born after frozen-thawed embryo transfer: A cohort study.. PLoS medicine, 19(9), e1004078. https://doi.org/10.1371/journal.pmed.1004078
Sargisian N, Lannering B, Petzold M, Opdahl S, Gissler M, Pinborg A, Henningsen AA, Tiitinen A, Romundstad LB, Spangmose AL, Bergh C, Wennerholm UB. Cancer in children born after frozen-thawed embryo transfer: A cohort study.. PLoS medicine. 2022;19(9):e1004078. doi:10.1371/journal.pmed.1004078
Increasing numbers of children are conceived using infertility treatment; concerns remain about potential effects on child neurodevelopment. To evaluate whether infertility treatment is associated with child neurodevelopment and whether such an association may be attributable to underlying subfecundity. DESIGN, SETTING, This cohort study was conducted among mother-child dyads in the National Institutes of Health Environmental Influences on Child Health Outcomes (ECHO) Cohort, with infants conceived between 1998 and 2022. Associations of subfecundity and infertility treatment with neurodevelopmental outcomes were assessed among children ages 2 to 10 years. Data were analyzed from May 14, 2025, to March 31, 2026. Subfecundity was defined as prior consultation for, treatment of, or diagnosis of infertility for either partner; at least 2 prior miscarriages; or ever having had unprotected heterosexual intercourse for 12 months without conceiving. Infertility treatment was categorized as in vitro fertilization (IVF) or non-IVF treatment. Harmonized caregiver responses to the Strengths and Difficulties Questionnaire and the Child Behavior Checklist yielded continuous raw scores for externalizing and internalizing problems. The total raw Social Responsiveness Scale (SRS) score quantified autism-like symptoms. Caregivers reported physician diagnosis of autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). Among 15 382 mother-infant dyads, there were 14 191 unique maternal participants (mean [SD] age at delivery, 30.9 [5.33] years; 8780 parous participants [57.1%]). ASD and ADHD were diagnosed in 876 offspring (7.6%) and 819 offspring (7.1%), respectively. In generalized linear models, subfecundity was associated with higher externalizing problem and SRS scores among all pregnancies (externalizing problems: b = 0.47 [95% CI, 0.14-0.81]; SRS score: b = 1.08 [95% CI, 0.01-2.14]) and when restricted to natural conceptions (externalizing problems: b = 0.45 [95% CI, 0.07-0.83]; SRS score: b = 1.12 [95% CI, -0.09 to 2.34]). Offspring of parents with subfecundity had higher odds of ASD (overall: odds ratio [OR], 1.27 [95% CI, 1.03-1.57]; natural conceptions: OR, 1.31 [95% CI, 1.04-1.64]). Children conceived via non-IVF treatment had higher odds of ADHD compared with those conceived via natural conception with subfecundity (OR, 1.77 [95% CI, 1.16-2.68]) or without subfecundity (OR, 1.54 [95% CI, 1.05-2.25]). There were no significant associations for IVF treatment. In this large US cohort study, subfecundity was associated with elevated scores for caregiver-reported symptoms of behavioral problems and higher odds of ASD diagnosis, independent of infertility treatment. Non-IVF treatment was associated with ADHD, warranting further research into specific indications for treatment that may increase risk of offspring neurodevelopmental problems.
Hart RJ et al., 2022·Front Reprod Health·
Open Access
It is well established that there are increased pregnancy-related complications for a woman who conceives through assisted reproductive treatment (ART). Furthermore, it is known that the risk to the child born is greater, believed to be related to prematurity and growth restriction. Studies have also reported epigenetic changes in the DNA of offspring conceived through ART. In addition, it is believed that they have a greater risk of congenital malformations, although some of these risks may relate to underlying infertility, rather than the ART treatment per se. As a result, it may be expected that there is a greater risk to the longer-term health of the child who is born from ART; however, evidence about the long-term health of children conceived through ART is reassuring. Even though, it is recognised that many of the studies in this field come with limitations. Low numbers of participants is one of the major limitations, which makes subgroup analyses for diverse types of ART, or diverse types of infertility, not feasible. Furthermore, studies are often limited by short follow-up periods because of the difficulty and costs involved in longitudinal study designs. In addition, the rapid changes over time in ART limit the generalisability and significance of long-term findings. Well-designed studies investigating the long-term health outcomes of ART-conceived offspring and the potential influences of various aspects of the ART procedure, as well as studies of the potential underlying epigenetic mechanisms, are imperative. Furthermore, conclusions from childhood hospitalisation data from the United Kingdom, the long-term follow-up and quality of life study from researchers in Melbourne, and the data published from the Western Australian Growing Up Healthy Study will go a long way to help reassure current and prospective parents who may require ART to conceive.
To assess infant (<1 year) and childhood (1-18 years) mortality in singletons conceived through assisted reproductive techniques (ART) versus naturally conceived singletons.
Nationwide prospective study.
Sweden. PATIENT(S): All singleton liveborn infants born from 1983 to 2012 in Sweden identified using the Medical Birth Register (N = 2,847,108), of whom 43,506 were conceived through ART treatments including in vitro fertilization with and without intracytoplasmic sperm injection. INTERVENTION(S): None. MAIN OUTCOME MEASURES(S): Infant (<1 year) and childhood (1-18 years) mortality. RESULT(S): Data on ART treatment and covariates were retrieved from population-based registers using the unique personal identity number assigned to all permanent residents in Sweden. Cox proportional hazards models estimated the hazard ratios (HRs) with 95% confidence intervals (CIs) as measures of association between ART treatments and death. The analyses were adjusted for maternal characteristics, infertility, child sex, and birth cohort and were restricted to individuals with complete information on covariates for fully adjusted analysis. Compared with naturally conceived singletons, higher infant mortality risks were seen in infants conceived through ART (adjusted HR 1.45; 95% CI, 1.19-1.77), especially after transfer of cryopreserved embryos (adjusted HR 2.30; 95% CI, 1.46-3.64). Early neonatal mortality risk (deaths during the first week) was increased in children born after transfer of blastocysts (HR 2.40; 95% CI, 1.05-5.48). No increased mortality risk was observed between the ages of 1 and 18 years. CONCLUSION(S): Singletons conceived through ART had an increased risk of infant mortality from birth up to 1 year of life, predominantly in the early neonatal period and in pregnancies after transfer of frozen and thawed embryos.