The etiology of childhood neuroblastoma remains largely unknown. In this systematic review and meta-analysis, we summarized and quantitatively synthesized published evidence on the association of maternal modifiable lifestyle factors with neuroblastoma risk in the offspring. We searched MEDLINE up to December 31, 2020 for eligible studies assessing the association of maternal smoking, alcohol consumption and nutritional supplementation during pregnancy with childhood (0–14 years) neuroblastoma risk. Random-effects models were run, and summary odds ratios (OR) and 95% confidence intervals (95% CI) on the relevant associations were calculated, including estimates derived from primary data (n = 103 cases and n = 103 controls) of the Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST) case control study (2009–2017) in Greece. Twenty-one eligible studies amounting 5163 cases participating in both case-control and cohort/linkage studies were included in the meta-analysis. Maternal smoking and alcohol consumption were not statistically significantly associated with neuroblastoma risk (summary OR smoking : 1.08, 95% CI: 0.96–1.22, I 2 =12.0%, n = 17 studies; summary OR alcohol : 1.01, 95% CI: 0.82–1.18, I 2 =0.0%, n = 8 studies). By contrast, maternal vitamin intake during pregnancy was associated with significantly lower neuroblastoma risk (summary OR: 0.57, 95% CI: 0.34–0.95, I 2 =58.9%, n = 4 studies). The results of the largest to-date meta-analysis point to an inverse association between vitamin intake during pregnancy and childhood neuroblastoma risk. Future longitudinal studies are needed to confirm and further specify these associations as to guide preventive efforts on modifiable maternal risk factors of childhood neuroblastoma.
- • An inverse association was found between vitamin intake during pregnancy and neuroblastoma risk.
- • There is also evidence for a modest positive association with maternal smoking during pregnancy.
- • Ongoing research is needed to guide preventive efforts on modifiable risk factors of neuroblastoma.
Neuroblastoma is the most commonly diagnosed extra-cranial solid tumor of infancy and childhood accounting for 8–10% of all pediatric (0–14 years) tumors, and for approximately 15% of cancer-related pediatric mortality . The tumor is characterized by a wide range of histopathologic features and a highly heterogeneous clinical phenotype. Despite advances in survival of neuroblastoma over the last decades , its etiology remains largely unknown.
Several genetic factors have been studied as potential risk factors of childhood neuroblastoma. Among these, the presence of mutations in the paired-like homeobox 2B ( PHOX2B ) gene and in the anaplastic lymphoma kinase ( ALK ) gene have been associated with increased risk for neuroblastoma . However, these genetic alterations account only for a small proportion of neuroblastic cases. Thus, over the last decades, several studies have focused on the effect of modifiable maternal characteristics, such as smoking, alcohol consumption and nutritional supplementation on the risk of childhood neuroblastoma . A recent meta-analysis (n = 14 studies) examining the associations of maternal smoking and alcohol consumption with the risk of neuroblastoma found a positive association with smoking [summary odds ratio (OR): 1.10, 95% confidence intervals (95% CI): 1.00–1.30] . Maternal use of vitamins and folic acid supplementation has been extensively associated with reduced risk of numerous birth defects and childhood malignancies, such as leukemia and central nervous system (CNS) tumors . A meta-analysis of two studies reported a sizable reduction in the OR of neuroblastoma in children with prenatal exposure to multivitamins (OR: 0.53, 95% CI: 0.43–0.68) with significant heterogeneity (p = 0.02) ; overall, evidence on the effect of nutritional supplementation on childhood neuroblastoma risk remains so far inconclusive due to limited number of studies.
We used primary incident data on childhood (0–14 years) neuroblastoma cases and matched controls derived from the Nationwide Registry of Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST) case-control study in Greece (2009–2017) to examine the association of modifiable maternal life-style factors, namely smoking, alcohol consumption and nutritional supplementation during pregnancy with the risk of neuroblastoma in the offspring. Thereafter, we systematically reviewed and meta-analyzed published evidence on the above associations including the results of the NARECHEM-ST study.