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

Abstract

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. 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 μg (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. 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) μg or placebo (n = 47) for 40 wk. RBC folate was measured at baseline and at 6, 12, 29, and 40 wk. 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. 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.