Folic Acid Fortification Linked to Drop in Childhood Cancers

Yael Waknine

May 21, 2012

May 21, 2012 — The US Food and Drug Administration has mandated folic acid supplementation of enriched grain products since 1996. Now, investigators find the rates of some childhood cancers have decreased significantly after that timepoint compared with earlier years.

The effect is particularly strong among infants, according to an article published online May 21 in Pediatrics.

Using 1986 to 2008 data from the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) program, Amy M. Linabery, MS, PhD, from the University of Minnesota in Minneapolis, and colleagues examined incidence rates for various cancers in 8829 children diagnosed between birth and age 4.

When they compared the pre- and post-fortification periods (1986 to 1997 vs 1998 to 2008), they found a 20% decrease in the prevalence of Wilms tumor (WT; nephroblastoma), the most common form of pediatric kidney cancer (n = 231 vs 340; incidence rate ratio [IRR], 0.8; 95% confidence interval [CI], 0.68 - 0.95).

They also detected a 46% decline in the incidence of primitive neuroectodermal tumors in the post-fortification era compared with the 10 years prior (PNETs; n = 37 vs 77; IRR, 0.56; 95% CI, 0.37 - 0.84). PNETs are a rare condition with extremely low 5-year survival rates even after chemotherapy and radiation therapy.

The researchers also uncovered a slight decrease in the incidence of ependymoma, an intracranial tumor of the central nervous system between the 2 time periods (n = 65 vs 108; IRR, 0.70; 95% CI, 0.51 - 0.97).

"Folate is critical for embryonic development because of its contributions to DNA biosynthesis, cell proliferation, and DNA methylation," the authors explain.

No significant changes occurred in the rate of other tumors, including lymphoid and acute myeloid leukemia, astrocytoma, medulloblastoma, neuroblastoma, ganglioneuroblastoma, retinoblastoma, hepatoblastoma, rhabdomyosarcoma, and gonadal neoplasm (IRR range, 0.90 - 1.18), and the overall incidence of studied cancers remained consistent (IRR, 1.01; 95% CI, 0.96 - 1.06).

"These results provide support for a decrease in WT and possibly PNET incidence, but not other childhood cancers, after US folic acid fortification," the authors emphasize.

When the analysis was restricted to infants aged younger than 1 year at diagnosis, the effect was even greater for WT (IRR, 0.61; 95% CI, 0.40 - 0.90) and PNET (IRR, 0.30; 95% CI, 0.11 - 0.73, respectively), but the rate of acute myeloid leukemia rose (IRR, 1.51; 95% CI, 1.03 - 2.25).

Using regression models, the researchers determined that the annual incidence of WT in 0- to 4-year-olds increased by 2.2% from 1986 to 1997 (95% CI, -1.2% to 5.8%) but decreased significantly thereafter by 4% (95% CI, -7.3% to -0.6%; P < .05).

Likewise, a nonsignificant increase in PNET incidence from 1986 to 1993 (11.5%; 95% CI, -5.0% to 31.0%) was followed by a significant decrease of 7.4% (95% CI, -12.1% to -2.4%; P < .05).

Although no inflection point was identified in the ependymoma trend, annual incidence rate decreased significantly over the entire period from 1986 to 2008 (-2.7% per year; 95% CI, -4.5% to -0.9%).

In contrast, a positive trend was observed for hepatoblastoma over the study period (2.1%; 95% CI, 0.2% - 4%).

Does Folic Acid Supplementation Prevent Cancer?

According to the researchers, a causal relationship with folic acid cannot be inferred with this type of analysis because of such confounding factors as concomitant increases in preventive measures and decreases in harmful exposure.

However, the newly reported data are consistent with 2 ecologic studies from Canada, which also showed a decrease in WT after mandatory folate fortification.

Dr. Linabery and colleagues note that the preventive effects of folic acid may be underestimated in their current study because of opposing secular trends, such as an increase in birth weight, that may contribute to the risk for other cancers.

Potential mechanisms for the influence of folate deficiency on cancer development include a “catastrophic cycle” of DNA repair, resulting in chromosomal damage and malignancy; moreover, DNA hypomethylation may cause genetic instability or pro-oncogene activation.

"Although a relationship between in utero folic acid and risk of childhood cancers is biologically plausible, there is currently no direct evidence supporting a specific mechanism," the researchers write.

Limitations of the study include its ecologic nature as well as the low prevalence of childhood cancer, which limits its power of analysis.

"Alternative study designs, such as prenatal feeding experiments in animal models, are required to rule out other explanations, confirm causal relationships, and elucidate mechanisms," the authors conclude.

Research was supported by the National Institutes of Health and the Children’s Cancer Research Fund, Minneapolis, Minnesota. The authors have disclosed no relevant financial relationships.

Pediatrics. 2012;129:1125-1133. Abstract

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