Linabery A, Johnson K, Ross J. Childhood cancer incidence trends in association with US folic acid fortification (1986–2008). Pediatrics 2012;129(6):1125-1133.
Disease incidence data was collected from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program. The SEER program collects all cancer incidence data in 5 US states (Connecticut, Hawaii, Iowa, New Mexico, and Utah) as well as the metropolitan areas of Detroit, Seattle, San Francisco-Oakland, and Atlanta. These 9 registries make up about 9.5% of the US population.
The study looked at first diagnosis of cancer during 1986–2008 among children <5 years of age, looking both at total incidence of cancer and 14 categories of malignancy most likely to have prenatal origins. These included any leukemias, central nervous system tumors, ependymomas, astrocytomas, medullablastomas, primitive neuroectodermal tumors (PNET), neuroblastomas, ganglioneuroblastomas, retinoblastomas, nephroblastomas or Wilms tumor (WT), hepatoblastoma, rhabdomyosarcoma, and germ cell tumors. Incidence rates were compared for those estimated to be in utero before the mandate of folic acid fortification into enriched grain products (before 1996) and after fortification was mandatory (after 1998).
Between 1986 and 2008, 8,829 children between the ages of 0 and 4 were diagnosed with malignancies in the SEER areas, including 3,790 estimated to be in utero during the prefortification period and 3,299 estimated to be in utero during the postfortification period. Comparing pre- and postfortification periods, incidence rates were similar for all cancers combined (IRR=1.01, 95% CI: 0.96–1.06) and for most cancer types examined. However, incidence rates of Wilms tumor (nephroblastoma), primitive neuroectodermal tumors (PNETs), and ependymomas were significantly lower postfortification (IRRWT=0.80, 95% CI: 0.68–0.95; IRRPNET=0.56, 95% CI: 0.37–0.84; IRRependymoma=0.70, 95% CI: 0.51–0.97). When looking only at infants, there was a greater reduction in WT and PNETS (but not in ependymomas), while the rate of acute myeloid leukemia (AML) was increased (IRR=1.51, 95% CI:1.03–2.25).
Evidence from both observational and experimental research provides strong empirical support for a link between low folate levels and increased risk for malignancy.1,2,3 This current study provides further support that for specific malignancies (Wilms tumor, primitive neuroectodermal tumors), a decrease in incidence may be observed when folate is supplemented in the diet.
Two mechanisms have been suggested to explain the association between cancer incidence and folic acid deficiency.4 The first is that in a state of folate deficiency, there is decreased synthesis of the nucleotide thymine. In a state of deficiency, uracil will be inserted into the DNA instead. Repeated insertion of uracil can lead to defects in DNA repair resulting in chromosomal damage and ultimately, malignancy. The second relates to epigenetic effects, where folate deficiency reduces the availability of methyl donors, such as S-adenosylmethionine. This can lead to hypomethylation, which can cause genetic instability or cause protooncogene activation if the hypomethylation exists in the promoter region of a gene. It is important to note that high folate levels may also theoretically promote malignancy by silencing tumor suppressor genes via methylation of their promoter regions or by increasing cell proliferation due to greater production of nucleotide precursors.5
Ultimately, it appears that adequate presence of folate in the diet of pregnant woman is important for proper DNA functioning and to potentially reduce the risk of some childhood cancers in addition to its known benefit of reducing risk of spina bifida and other neural tube defects.
A causal relationship between folic acid intake and incidence of malignancy cannot be definitively inferred through this type of research. It is possible that the observed reductions in incidence may be due to other concurrent increases of other preventive factors, or due to a concurrent decrease in exposure to causative factors. One example of an additional preventive factor implemented around the same time was the 1992 recommendation that women of childbearing age take a prenatal vitamin with a minimum of 400 mcg of folic acid daily.6 Furthermore, prenatal folic acid exposure may reduce risk of malignancy through mechanisms that are only specific to WT and PNET, and therefore the trend may have no effect on or may, in fact, increase the risk of other types of childhood cancers. Finally, it is possible that cancer susceptibility and distribution in the 9.5% of the US population under surveillance in the SEER registries is not the same as in the US population as a whole.
There are still westernized countries that do not mandate folic acid fortification.7 This could provide an opportunity to compare rates of these malignancies in countries without fortification. For example, if rates of WT and or PNET were also decreasing in countries without fortification, that could suggest that there is an alternate cause for the trend observed in this study.
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- Bunin GR, Meadows AT, Emanuel BS, Buckley JD, Woods WG, Hammond GD. Pre- and postconception factors associated with sporadic heritable and nonheritable retinoblastoma. Cancer Res. 1989;49(20):5730-5735.
- Preston-Martin S, Pogoda JM, Mueller BA, et al. Prenatal vitamin supplementation and risk of childhood brain tumors. Int J Cancer Suppl. 1998;11:17-22.
- Kim YI. Folic acid supplementation and cancer risk: point. Cancer Epidemiol Biomarkers Prev. 2008;17(9):2220-2225.
- Duthie SJ. Folic acid deficiency and cancer: mechanisms of DNA instability. Br Med Bull. 1999;55(3):578-592.
- Ly A, Lee H, Chen J, et al. Effect of maternal and postweaning folic acid supplementation on mammary tumor risk in the offspring. Cancer Res. 2011;71(3):988-997.
- Centers for Disease Control. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep. 1992;41(RR-14):1-7.
- Wright AJ, Dainty JR, Finglas PM. Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK. Br J Nutr. 2007;98(4):667-675.