The results from this study provide a pattern, albeit weak, that is consistent with the a priori hypothesis that maternal vitamin supplementation during the perigestational period reduces the risk of GCTs. We observed some variation by histology but many of the observed inverse associations were modest and failed to reach statistical significance. Moreover, analyses evaluating the timing of vitamin exposure before and during pregnancy did not indicate any relationship to GCT risk.
One previous case-control study that included 105 pediatric GCTs cases and 639 controls reported no association with maternal vitamin use (OR=1.1; 95% CI 0.6-2.0) (16
). Case-control studies of several other childhood tumors have generally indicated that prenatal vitamin use and/or folate supplementation reduces risk. A recent review by Goh and Koren reported reduced risks of childhood cancers in association with maternal vitamin supplementation in 6/7 studies of brain tumors, 4/4 studies of acute lymphoblastic leukemia, 2/2 studies of neuroblastoma, and 1/1 study of retinoblastoma. Some of the reviewed studies suggested that vitamin supplemention during the periconception period specifically is associated with a reduction in risk (17
). However, we did not find any evidence for a relation between timing of maternal vitamin use and GCTs.
Molecular abnormalities in GCTs vary by sex, diagnosis age, and histologic subtype and include aneuploidy, chromosome abnormalities (most commonly involving 12p), and abnormal DNA methylation patterns (4
). Aberrant methylation patterns have commonly been detected in pediatric GCTs in several genes, including the imprinted genes IGF2 and H19, testis/cancer-associated genes, and tumor suppressor genes (4
). In addition, expression of the p40 protein of the long interspersed nucleotide element-1 (Line-1) transposable element, which is normally silenced through epigenetic mechanisms (18
), has been reported in pediatric malignant GCTS (9
). A biologically plausible hypothesis is that maternal vitamin deficiency during and around pregnancy alters GCT risk in offspring by affecting DNA methylation patterns in germ cells. The developmental time period may have increased susceptibility to DNA methylation errors because of the two major waves of epigenetic reprogramming that occur in the blastocyt and germ cells (12
A major strength of this study is the relatively larger number of subjects compared to previous studies. To our knowledge, only five previous case-control studies of childhood GCTs (case numbers ranging from 41-105) have investigated etiological factors in GCT development (16
). The size of our study also allowed for a more detailed examination than previous studies of the association between GCTs and etiologic factors by subject and tumor characteristics.
Our study had several limitations. Although our study included more cases than prior studies, all studies of this type of tumor, including ours, have limited statistical power to detect modest effect sizes. Another potential limitation is selection bias. Selection bias could have occurred if control participants were not a representative sample of the nondiseased population from which cases arose (15
). Given that the response rate among potential controls was 66% (23
) and more control than case mothers reported being of white race and having higher levels of education, characteristics associated with vitamin supplementation during pregnancy (24
), we cannot exclude that selection bias affected our risk estimates. In addition, recall bias, where a mother's ability to accurately recall her exposures during pregnancy depends on whether her child is a case or control, may lead to differential exposure misclassification and consequent bias in the risk estimate (15
In conclusion, these data are consistent with results from studies of other childhood cancers suggesting a reduced risk of malignancy in association with maternal vitamin supplementation. However, limitations regarding statistical power and biases that affect observational studies preclude firm conclusions.