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Am J Clin Nutr. 2019 Aug 10. pii: nqz160. doi: 10.1093/ajcn/nqz160. [Epub ahead of print]

Folic acid supplementation and risk of colorectal neoplasia during long-term follow-up of a randomized clinical trial.

Author information

Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
Department of Oncology, Georgetown University School of Medicine, Washington, DC, USA.
Department of Medicine, University of Colorado School of Medicine, Denver, CO, USA.
Department of Gastroenterology, Hepatology, and Nutrition, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Population Health Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Dalla Lana School of Public Health, University of Toronto, Ontario, Canada.
Department of Pathology, Fairview Southdale Hospital, Edina, MN, USA.
Department of Mathematics and Statistics, University of Vermont, Burlington, VT, USA.
Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.



The Aspirin/Folate Polyp Prevention Study previously found folic acid increased risk of advanced and multiple colorectal adenomas during a surveillance colonoscopy interval starting about 3 y after randomization.


We conducted secondary analyses to evaluate folic acid effects with additional follow-up after treatment was stopped.


In total, 1021 participants recently diagnosed with colorectal adenomas were randomly assigned to 1 mg/d of folic acid (n = 516) or placebo (n = 505), with or without aspirin, beginning 6 July 1994. The original 3-y treatment period was extended into a subsequent colonoscopy interval, but eventually stopped prematurely on 1 October 2004. With additional post-treatment follow-up, a total of 663 participants who extended treatment completed a second colonoscopic surveillance interval after the initial 3-y follow-up. In addition, 490 participants provided information regarding a subsequent surveillance colonoscopy occurring before completion of follow-up on 31 May 2012, including 325 who had agreed to extended treatment. Study endpoints included conventional adenomas, sessile serrated adenomas/polyps (SSA/Ps), or colorectal cancer, and RRs with 95% CIs were adjusted for baseline characteristics associated with availability of follow-up.


Among those who extended treatment, any colorectal neoplasia was found in 118 (36%) participants assigned to placebo and 146 (43%) assigned to folic acid during the second surveillance interval (RR: 1.21; 95% CI: 0.99, 1.47; P = 0.06). Increased risk of SSA/P with extended folic acid supplementation was statistically significant during the second surveillance interval (RR: 1.94; 95% CI: 1.02, 3.68; P = 0.04). There was no evidence of post-treatment effects for any colorectal neoplasia (RR: 1.01; 95% CI: 0.80, 1.28; P = 0.94), and the post-treatment effect for SSA/P was no longer statistically significant (RR: 1.38; 95% CI: 0.59, 3.19; P = 0.46).


Delayed treatment effects were not observed, but folic acid may increase SSA/P risk. This trial was registered at as NCT00272324.


clinical trial; colorectal adenoma; colorectal cancer; folic acid; sessile serrated adenoma/polyp


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