Elsevier

The Lancet

Volume 350, Issue 9092, 6 December 1997, Pages 1666-1669
The Lancet

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

https://doi.org/10.1016/S0140-6736(97)07247-4Get rights and content

Summary

Background

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.

Methods

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.

Findings

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.

Interpretation

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.

Introduction

Folic acid has been shown to prevent neural-tube defects (NTD) if taken during the periconceptional period1, 2 Government initiatives designed to implement these findings have suggested an increase in intake of 400 μg/day3, 4 Compliance with these recommendations has been poor.5 Consequently, many experts believe that primary prevention will be possible only through food fortification;6 however, this issue is hotly debated. In the USA, 140 μg folic acid will be added to every 100 g grain from Jan 1, 1998. This action should deliver an average increase of 100 μg per day, based on dietary modelling and on the assumption of equal bioavailability.7 This dose will almost certainly not mask pernicious anaemia,8 but it could be too low to prevent NTD. A decision as to whether food should be fortified with folic acid, and if so at what level, is awaited in the UK.

The difficulty with any fortification programme is that people who have low intakes of the fortified food must consume sufficient folic acid to benefit, whereas those who have high intakes must not receive a potentially harmful dose. Delivery of a dose of 400 μg/day to women of reproductive age would result in a substantial proportion of the population, including elderly people, being exposed to levels of folic acid in the milligram range—amounts that may mask pernicious anaemia.9

One critical piece of information is missing. What is the minimum dose of folic acid that will prevent NTD? The answer to this question cannot be obtained easily. Further trials with lower doses of folic acid and the occurrence of an NTD as the primary endpoint would be unethical, because women given lower doses might have affected children. Moreover, a food fortification trial would require a very large population, and a suitable control group could be difficult to identify. An alternative approach is to use an endpoint that can be related to the occurrence of NTD—namely, red-cell folate. A relation between folate status as determined by this measurement and the risk of NTD has been established10 and is accepted11

Previous work has shown an inverse relation between the risk of an NTD and maternal red-cell folate10 At values below 150 μg/L, the risk of an NTD was 6-6 per 1000 births, whereas when red-cell folate was greater than 400 μg/L the risk of an NTD was only 0-8 per 1000 births. The overall population risk was 1-9 per 1000 births. Thus, if the average value of red-cell folate in the population could be increased such that all pregnant women had values above 400 μg/L, the risk of NTD could be reduced by almost 60%. The risk of NTD can, therefore, be estimated by measurement of maternal red-cell folate. The effect of various levels of fortification on red-cell-folate status can be assessed, which will allow a systematic appraisal of the effect of such doses on NTD risk.

We undertook a randomised trial of several doses of folic acid to find out much folic acid a food fortification programme would have to deliver to produce concentrations of red-cell folate known to protect against NTD.

Section snippets

Methods

All female employees at the Coombe Women's Hospital, Dublin, Ireland, were invited to have measurements of red-cell folate (screening sample). Women with values between 150 μg/L and 400 μg/L were eligible and were asked to take part in the trial. Those with values below 150 μg/L were judged clinically deficient. Although these women would be at high risk of NTD and would require a greater increase in red-cell folate to reach 400 μg/L, ethically, we could not include them in the trial. They were

Results

323 women were screened (figure). 14 (4·3%) had values of red-cell folate below 150 μg/L and 137 (42·4%) had values above 400 μg/L. Of the 172 (53·3%) women eligible to take part in the trial, 51 (29·7%) decided not to participate. 31 were changing employment (22 of whom were recently qualified midwives), eight refused consent, six were planning pregnancy, three had current disease, two were pregnant, and one had had a baby with an NTD. Red-cell-folate values were significantly lower among

Discussion

The current recommendations to prevent NTD require women to take an additional 400 μg folic acid per day. These recommendations were based mainly on a non-randomised trial14 and several case-control studies.15, 16 The randomised controlled trials that showed a benefit in prevention of NTD used 800 μg folic acid daily to prevent occurrences2 and 4000 μg folic acid daily to prevent recurrences.1 Current recommendations designed to reduce the incidence of NTD have been ineffective because of lack

References (16)

  • Prevention of neural tube defects: results of the Medical Research Council Vitamin Study

    Lancet

    (1991)
  • AE Czeizel et al.

    Prevention of the first occurrence of neural tube defects by periconceptional vitamin supplementation

    N Engl J Med

    (1992)
  • Folic acid and the prevention of neural tube defect

    (1992)
  • Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects

    Morbid Mortal Weekly Rep

    (1992)
  • NAC Clark et al.

    Compliance with the Department of Health recommendations: routine folate prophylaxis to prevent fetal neural tube defects

    Br J Obstet Gynaecol

    (1994)
  • C Wald et al.

    Folic acid and the prevention of neural tube defects

    BMJ

    (1995)
  • GregoryJF

    Bioavailability of folate

    Eur J Clin Nutr

    (1997)
  • Food additives permitted for direct addition to food for human consumption; folic acid (folacin)

    Federal Register

    (1993)
There are more references available in the full text version of this article.

Cited by (253)

  • Vitamin D as a modifier of genomic function and phenotypic expression during pregnancy

    2023, Feldman and Pike's Vitamin D: Volume One: Biochemistry, Physiology and Diagnostics
  • Pregnancy: Prevention of neural tube defects

    2023, Encyclopedia of Human Nutrition: Volume 1-4, Fourth Edition
  • Degradation of vitamins

    2020, Chemical Changes During Processing and Storage of Foods: Implications for Food Quality and Human Health
  • Flour fortification and the prevention of neural tube defects (NTDs)

    2019, Flour and Breads and Their Fortification in Health and Disease Prevention
View all citing articles on Scopus
View full text