Maternal lifestyle factors and risk of neuroblastoma in the offspring: A meta-analysis including Greek NARECHEM-ST primary data

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Introduction

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 12345 . 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 [6] , 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 [37] . 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 8910 . 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] [10] . 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 111213 . 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) [14] ; 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.