Assisted Reproductive Technology and Risk of Childhood Cancer Among the Offspring of Parents With Infertility: Systematic Review and Meta-Analysis.

Background: The relationship between assisted reproductive technology (ART) and childhood cancer risk has been widely debated. Previous meta-analyses did not adequately account for the impact of infertility, and this study addresses this gap. Objective: Our primary objective was to assess the relative risk (RR) of childhood cancer in infertile populations using ART versus non-ART offspring, with a secondary focus on comparing frozen embryo transfer (FET) and fresh embryo transfer (fresh-ET). Methods: A literature review was conducted through PubMed, Embase, Cochrane, and Web of Science, with a cutoff date of July 10, 2024. The study was registered with the International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY 202470119). Inclusion criteria were based on the PICOS (Population, Intervention, Comparison, Outcomes, and Study Design) framework: infertile or subfertile couples (population), ART interventions (in vitro fertilization [IVF], intracytoplasmic sperm injection [ICSI], FET, and fresh-ET), non-ART comparison, and childhood cancer risk outcomes. Data abstraction focused on the primary exposures (ART vs non-ART and FET vs fresh-ET) and outcomes (childhood cancer risk). The risk of bias was assessed using the Newcastle-Ottawa Quality Assessment Scale, and the evidence quality was evaluated with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Pooled estimates and 95% CIs were calculated using random effects models. Results: A total of 18 studies were included, published between 2000 and 2024, consisting of 14 (78%) cohort studies and 4 (22%) case-control studies, all of which were of moderate to high quality. The cohort studies had follow-up periods ranging from 3 to 18 years. Compared with non-ART conception, ART conception was not significantly associated with an increased risk of childhood overall cancer (RR 0.95, 95% CI 0.71-1.27; GRADE quality: low to moderate). Subgroup analyses of IVF (RR 0.86, 95% CI 0.59-1.25), ICSI (RR 0.76, 95% CI 0.26-2.2), FET (RR 0.98, 95% CI 0.54-1.76), and fresh-ET (RR 0.75, 95% CI 0.49-1.15) showed similar findings. No significant differences were found for specific childhood cancers, including leukemia (RR 0.99, 95% CI 0.79-1.24), lymphoma (RR 1.22, 95% CI 0.64-2.34), brain cancer (RR 1.22, 95% CI 0.73-2.05), embryonal tumors (RR 1, 95% CI 0.63-1.58), retinoblastoma (RR 1.3, 95% CI 0.73-2.31), and neuroblastoma (RR 1.02, 95% CI 0.48-2.16). Additionally, no significant difference was observed in a head-to-head comparison of FET versus fresh-ET (RR 0.99, 95% CI 0.86-1.14; GRADE quality: moderate). Conclusions: In conclusion, this study found no significant difference in the risk of childhood cancer between offspring conceived through ART and those conceived through non-ART treatments (such as fertility drugs or intrauterine insemination) in infertile populations. While infertility treatments may elevate baseline risks, our findings suggest that whether individuals with infertility conceive using ART or non-ART methods, their offspring do not face a significantly higher risk of childhood cancer. Further research, especially comparing infertile populations who conceive naturally, is needed to better understand potential long-term health outcomes.