Pre- and postfortification intake of folate and risk of colorectal cancer in a large prospective cohort study in the United States

Am J Clin Nutr. 2011 Oct;94(4):1053-62. doi: 10.3945/ajcn.110.002659. Epub 2011 Aug 3.


Background: A higher folate intake is associated with a decreased colorectal cancer risk in observational studies, but recent evidence suggests that excessive folate supplementation may increase colorectal cancer risk in some individuals. Therefore, mandatory folic acid fortification of grain products in the United States may have unintended negative consequences.

Objective: We examined the association between folate intake and colorectal cancer risk, including 8.5 y of postfortification follow-up.

Design: We examined the association between folate intake and colorectal cancer in the NIH-AARP Diet and Health Study-a US cohort study of 525,488 individuals aged 50-71 y initiated in 1995-1996. Dietary, supplemental, and total folate intakes were calculated for the pre- and postfortification periods (before and after 1 July 1997) based on a baseline food-frequency questionnaire. HRs and 95% CIs were calculated by using multivariable Cox proportional hazards regression models.

Results: During follow-up through 31 December 2006 (mean follow-up: 9.1 y), 7212 incident colorectal cancer cases were identified. In the postfortification analysis (6484 cases), a higher total folate intake was associated with a decreased colorectal cancer risk (HR for ≥900 compared with <200 μg/d: 0.70; 95% CI: 0.58, 0.84). The highest intakes specifically from supplements (HR: 0.82; 95% CI: 0.72, 0.92) or from diet (HR: 0.81; 95% CI: 0.67, 0.97) were also protective. The pattern of associations was similar for the prefortification period, and no significant differences between time periods were observed.

Conclusions: In this large prospective cohort study that included 8.5 y of postfortification follow-up, folate intake was associated with a decreased colorectal cancer risk. Given that the adenoma-carcinoma sequence may take ≥10 y, additional follow-up time is needed to fully examine the effect of folic acid fortification.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Aged
  • Cohort Studies
  • Colorectal Neoplasms / epidemiology*
  • Colorectal Neoplasms / prevention & control
  • Diet
  • Dietary Supplements
  • Edible Grain / chemistry
  • Folic Acid / administration & dosage*
  • Folic Acid / adverse effects
  • Follow-Up Studies
  • Food, Fortified* / adverse effects
  • Humans
  • Incidence
  • Legislation, Food
  • Male
  • Middle Aged
  • Proportional Hazards Models
  • Prospective Studies
  • Registries
  • Risk
  • Surveys and Questionnaires
  • United States / epidemiology


  • Folic Acid