Parental and childhood exposures and the risk of retinoblastoma, hepatoblastoma, and germ cell, bone, and soft tissue tumors in children: a systematic review and meta-analysis.
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INTRODUCTION: Retinoblastoma, hepatoblastoma, germ cell tumors, bone tumors, and soft tissue tumors are rare types of childhood cancer. Identifying modifiable risk factors is essential to inform primary prevention. This review aimed to systematically examine literature and synthesize risk factors for childhood rare cancers. METHODS: PubMed, Web of Science, and Embase databases were searched using lists of keywords and MeSH terms related to parental and childhood exposures. Studies were included if they were case-control or cohort studies of children under the age of 20 years at diagnosis and reported relative risks (RRs) with 95% confidence intervals (95% CIs). Pooled effect sizes (ES) and CIs for risk factors were estimated using random-effects models. RESULTS: A total of 75 eligible articles from Asia, Europe, Latin America, North America, and Oceania reported cases of rare childhood cancers diagnosed between 1953 and 2021. Birth weight <2,500 g was associated with hepatoblastoma (ES 3.33, 95% CI 1.30-8.54) with considerable heterogeneity across studies. A borderline association was observed for retinoblastoma (ES 1.27, 95% CI 0.99-1.63), while the estimate for germ cell tumors was elevated, albeit with a wide CI (ES 1.20, 95% CI 0.80-1.80). No association was observed for bone tumors or soft tissue tumors. Small for gestation age was associated with hepatoblastoma (ES 1.76, 95% CI 1.28-2.43). Birth weight >4,000 g was not associated with any of the studied cancer types. Assisted reproductive technology (ES 2.82, 95% CI 1.82-4.39), Caesarean section (ES 1.47, 95% CI 1.20-1.79), and parental age >35 years (mothers ES 1.97, 95% CI 1.45-2.68; fathers ES 1.33, 95% CI 0.99-1.79) were observed to be associated with hepatoblastoma. Paternal smoking during preconception/pregnancy was associated with an increased risk of hepatoblastoma (ES = 1.58, 95% CI 1.18-2.12). Paternal occupational exposure to pesticides during preconception/pregnancy was associated with an increased risk of retinoblastoma (ES = 1.55, 95% CI 1.09-2.21). For some other exposures, we found several raised ES but with very wide CIs. DISCUSSION: We identified only a few modifiable risk factors for certain childhood cancers, notably paternal smoking for hepatoblastoma and paternal occupational exposure to pesticides for retinoblastoma. Larger studies for rare childhood cancers are needed, with international collaboration to increase sample sizes.