Environmental Risk Factors of Childhood Lymphoma: A Systematic Review and Meta-Analysis
Authors: Dolatkhah Roya , Onyije Felix M. , Bouaoun Liacine , Olsson Ann , Schüz Joachim 
Published: December 2024

Background
Previous studies investigating risk factors for childhood lymphoma have shown inconsistent results. This systematic review and meta-analysis aimed to synthesize the available evidence on the risk of childhood lymphoma and its subtypes Non-Hodgkin's Lymphoma (NHL) and Hodgkin's Lymphoma (HL) for various potential and modifiable risk factors and to provide meta effect sizes .
Methods
Peer-reviewed scientific articles were identified, retrieved and screened through PubMed, Web of Science (WOS) and EMBASE databases and included studies that
1) were case-control or cohort studies and provided Relative Risk (RR) estimates (such as Odds Ratio (OR)), Hazard Ratio (HR), Standardized Mortality Ratio (SMR), Mortality Rate Ratio (MRR), Standard Incidence Ratio (SIR) or Incidence Rate (IRR)) with 95% confidence intervals (CI),
2) reported effect estimates for specific exposure time window: pre-conceptional, prenatal or postnatal, and
3) reported lymphoma risks for children under 20 years of age at diagnosis were assessed using the Joanna Briggs Institute critical appraisal (JBI) tools.
A total of 69 studies (35 case-control studies and 34 cohort studies including nested or registry-based case-control studies) were included. After assessing articles for quality using the JBI tool, case-control studies achieved a higher mean score (86.6%) compared to cohort studies (73.6%). Meta-analyses with the random effects model were performed overall and separately by study design and reported using pooled effect sizes (ES) with corresponding 95% CIs.
Results
In the case-control studies, younger maternal age (≤25 years) was associated with a higher risk of HL (ES=1.81; 95%CI: 1.25-2.63) and lymphoma (ES=1.48; 95%CI: 1.17-1.86), while in the combined analysis, children with younger fathers (&lt;=25 years) had a lower risk of developing lymphoma (ES=0.79; 95%CI: 0.65-0.96). Parental smoking before and during pregnancy was associated with a higher risk of NHL and lymphoma, while in case-control studies, NHL risk was associated with prenatal maternal (ES=1.43; 95%CI:1.08-1.88) and paternal (ES=1.56; 95%CI:1.09-2.24) smoking of 1-10 cigarettes per day. Maternal prenatal insecticide (ES=1.97; 95%CI:1.42-2.73) and pesticide (ES=1.67; 95%CI=1.21-2.32) exposure were associated with a higher risk of NHL and lymphoma, respectively, in case-control studies. In the combined analysis, breastfeeding for ≤6 months was associated with a higher risk of NHL (n=7, ES=1.34;95%CI:1.04-1.74), and lymphoma (ES=1.39;95%CI:0.99-1.97). Gestational age, gestational size, caesarean section, and low birthweight (&lt;2,500 gram) were not associated with childhood lymphoma, based on few cohort studies. Moderate heterogeneity was observed for short gestational age (&lt;37 weeks) and low birthweight (&lt;2,500 gram), and substantial heterogeneity for small gestational age. Only birthweight was investigated in both cohort and case-control studies, where high birthweight (&gt;4,000 gram) resulted in an elevated meta effect size for 2 cohort studies with low heterogeneity, while a reduced meta effect size for 2 case-control studies with no heterogeneity.
Conclusion
Although there was a limitation in the number of studies assessing childhood lymphoma risk, the findings of the current study provided information on the association between modifiable risk factors, such as parental smoking and maternal prenatal exposure to pesticides and insecticides, and the risk of childhood lymphoma and its subtypes. While there are inherent biases in observational studies that may have influenced our findings, they should therefore be interpreted with caution.
Keywords
Lymphoma; Children; Exposure; Aetiology