Minimum effective dose of folic acid for food fortification to prevent neural-tube defects

• Published in: The Lancet (British edition) Vol. 350; no. 9092; pp. 1666 - 1669
• Main Authors: Daly, Sean, Mills, James L, Molloy, Anne M, Conley, Mary, Lee, Young J, Kirke, Peadar N, Weir, Donald G, Scott, John M
• Format: Journal Article
• Language: English
• Published: London Elsevier Ltd 06.12.1997; Lancet; Elsevier Limited
• Subjects: Adult; Biological and medical sciences; Birth defects; Clinical trials; Dietary supplements; Dose-Response Relationship, Drug; Double-Blind Method; Female; Folic acid; Folic Acid - administration & dosage; Folic Acid - blood; Food fortification; Food, Fortified; Fortified foods; Humans; Medical sciences; Miscellaneous; Neural Tube Defects - prevention & control; Neuropharmacology; Nutritional Requirements; Pharmacology. Drug treatments; Vitamin B; United States; North America; America; Human; Evaluation; Nervous system diseases; Vitamin; Red blood cell; Folic acid; Prevention; Randomization; Neural tube; Defect; Female; Pharmacokinetics; Profilometry; Public health; Comparative study
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(97)07247-4

Although a daily supplement of 400 μg folic acid has been shown to prevent neural-tube defects (NTD), most women do not take the recommended supplement. Thus, food fortification is to be introduced in the USA and is being considered in the UK. Because of safety concerns, the USA has chosen a level of fortification that will increase the average woman's intake by only 100 μg. 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 μg/ L have a very low risk of NTD, we undertook a randomised trial of several folic acid doses to find out how much is needed to reach this protective concentration. We screened 323 women. 172 with red-cell folate between 150 μg/L and 400 μg/L were invited to take part in the trial. 121 women were randomly assigned placebo or 100 μg, 200 μg, or 400 μg daily of additional folic acid. Compliance was monitored by having the women sign a dated sheet when taking the tablet. 95 women completed the 6-month study. There were significant increases in red-cell folate in all folic acid groups. The placebo group showed no significant change. The median incremental changes and median post-treatment concentrations were 67 μg/L (95% Cl 43-120) and 375 μg/L (354-444) in the 100 μg/day group, 130 μg/L (108-184) and 475 μg/L (432-503) in the 200 μg/day group, and 200 μg/L (125-312) and 571 μg/L (481-654) in the 400 μg/day group. A fortification programme that delivered 400 μg folic acid daily to women would protect against NTD, but at the expense of unnecessarily high exposure for many people. Delivery of 200 μg daily is also effective against NTD and safer for the general population. Based on projections from the positive folate balance in the group that received 100 μg daily, this dose taken continually, as it will be in fortified food, will also produce an important decrease in NTD.