Meta‐analysis of cancer incidence in folic acid supplementation trials

Abstract

It has been suggested by several research groups that folate is procarcinogenic. Data in the 1940s of folate supplementation indicated that it enhanced the proliferation of cancer cells. Folate is a unique vitamin because its coenzymes are required for de novo adenine, guanine, and thymine nucleotide biosynthesis; therefore, it is essential for DNA synthesis and repair, and RNA synthesis, and structurally related folate analogs, such as methotrexate, are used as anticancer agents. Using a meta‐analysis weighted for the duration of folic acid (FA, pteroylglutamic acid) supplementation, we analyzed the cancer incidence of 5 published large prospective FA supplementation trials that lasted 1 year or more involving men and women. These articles were selected from over 1,100 identified by a PubMed search that was done in June 2009, and skin cancer was excluded by the original investigators or by us. Our data suggest that cancer incidence was higher in the FA supplemented groups than the non‐FA supplemented groups (relative risk = 1.26 [95% confidence interval: 1.05–1.51]). FA supplementation trials should be performed with careful monitoring of cancer incidence by investigators, and funding agencies should provide long‐term support. In the US, solid monitoring systems to detect side effects, such as increased cancer risk, should have been established before the food FA fortification mandate.