MINIMUM EFFECTIVE DOSE OF FOLIC-ACID FOR FOOD FORTIFICATION TO PREVENT NEURAL-TUBE DEFECTS

Background Although a daily supplement of 400 mu g folic acid has been shown to prevent neural-tube defects (NTD), most women do not take th e recommended supplement. Thus, food fortification is to be introduced in the USA and is being considered in the UK. Because of safety conce rns, the USA has chosen a level of fortification that will increase th e average woman's intake by only 100 mu g. Such an increase, although safe, may be ineffective; but a trial to assess its efficacy would be unethical. Because women with red-cell folate concentrations above 400 mu g/L have a very low risk of NTD, we undertook a randomised trial o f several folic acid doses to find out how much is needed to reach thi s protective concentration. Methods We screened 323 women. 172 with re d-cell folate between 150 mu g/L and 400 mu g/L were invited to take p art in the trial. 121 women were randomly assigned placebo or 100 mu g , 200 mu g, or 400 mu g daily of additional folic acid. Compliance was monitored by having the women sign a dated sheet when taking the tabl et. 95 women completed the 6-month study. Findings There were signific ant increases in red-cell folate in all folic acid groups. The placebo group showed no significant change. The median incremental changes an d median post-treatment concentrations were 67 mu g/L (95% CI 43-120) and 375 mu g/L (354-444) in the 100 mu g/day group, 130 mu g/L (108-18 4) and 475 mu g/L (432-503) in the 200 mu g/day group, and 200 mu g/L (125-312) and 571 mu g/L(481-654) in the 400 mu g/day group. Interpret ation A fortification programme that delivered 400 mu g folio acid dai ly to women would protect against NTD, but at the expense of unnecessa rily high exposure for many people. Delivery of 200 mu g daily is also effective against NTD and safer for the general population. Based on projections from the positive folate balance in the group that receive d 100 mu g daily, this dose taken continually, as it will be in fortif ied food, will also produce an important decrease in NTD.