Long-term effect of low-dose folic acid intake: Potential effect of mandatory fortification on the prevention of neural tube defects

Abstract

Background: Understanding the full effect of chronic low-dose folic acid is important in interpreting the effect of the mandatory folic acid fortification program in North America. Objective: We aimed to describe the rate of attainment and steady state (plateau) of red blood cell (RBC) folate in response to long-term intake of 140 lg (designed to mimic fortification) and 400 μg (recommended dose for the primary prevention of neural tube defects) folic acid/d in reproductive-aged women living in a country with minimal fortification. Design: On the basis of pharmacokinetics principles, it was recently proposed that a steady state should be reached after 40 wk. Thus, 144 women aged 18-40 y were randomly assigned to receive a daily folic acid supplement of 140 (n = 49) or 400 (n = 48) lg or placebo (n = 47) for 40 wk. RBC folate was measured at baseline and at 6, 12, 29, and 40 wk. Results: After 40 wk, RBC folate did not reach a plateau in either treatment group. Kinetic modeling of the data indicated that RBC folate would approximately double from 779 to 1356 nmol/L in response to 140 μg folic acid/d with only ≈50% of model-estimated steady state conditions achieved at 40 wk. An average RBC folate concentration of 1068 nmol/L after 12 wk of supplementation with 400 μg folic acid/d was readily achieved at 36 wk after continuous intake of 140 μg/d. Conclusion: Our model shows the considerable length of time required to attain the full effect of low-dose folic acid, which suggests that 140 μg folic acid/d could be as effective as 400 μg folic acid/d taken during the periconceptional period if given sufficient time. This trial is registered at www.anzctr.org.au as ACTRN12609000215224. © 2011 American Society for Nutrition.