Elsevier

The Lancet

Volume 358, Issue 9298, 15 December 2001, Pages 2069-2073
The Lancet

Public Health
Quantifying the effect of folic acid

https://doi.org/10.1016/S0140-6736(01)07104-5Get rights and content

Summary

Background

Folic acid is known to prevent neural-tube defects (NTDs) but the size of the effect for a given dose is unclear. We aimed to quantify such an effect.

Methods

We used published data from 13 studies of folic acid supplementation on serum folate concentrations and results from a large cohort study of the risk of NTDs according to serum folate, to measure the preventive effect of specified increases in intake of folic acid.

Findings

Serum folate concentrations increase by 0·94 ng/mL (95% Cl 0·77–1·10) for every 0·1 mg/day increase in folic acid intake in women aged 20–35 years, and about double that in people aged 40–65. Every doubling of serum folate concentration roughly halves the risk of an NTD. These two effects can be combined to predict the reduction in risk according to intake of extra folic acid and background serum folate concentration. Such results predict that the preventive effect is greater in women with low serum folate than in those with higher concentrations. The results have also been used to predict direct observations from large randomised trials and the effect of food fortification. From a typical western background serum folate of 5 ng/mL, about 0·2 mg/day (the US level of folic acid fortification) would be expected to reduce NTDs by about 20%; a similar effect can be expected from the current British recommendation (0·24 mg/day). An increase of 0·4 mg/day would reduce risk by about 36%, of 1 mg/day by 57%, and taking a 5-mg tablet daily would reduce risk by about 85%.

Interpretation

Folic acid fortification levels should be increased. Additionally women planning a pregnancy should take 5 mg folic acid tablets daily, instead of the 0·4 mg dose presently recommended.

Introduction

The risk of having a neural-tube defect (NTD) pregnancy can be reduced by raising folic acid consumption around the time of conception,1, 2, 3 but, the the size of the reduction for a given increase in folic acid intake is uncertain. This information is needed to decide what dose of folic acid to recommend for women planning a pregnancy, and the amount of folic acid with which to fortify flour. Fortification is needed because many pregnancies are unplanned. Unfortunately, data on the effect of folic acid by dose are few. Of the four randomised trials1, 4, 5, 6 assessing prevention of NTDs, only the MRC Vitamin Study1 had sufficient cases to estimate the magnitude of the effect of a specific dose of folic acid, and the dose tested in this trial (4 mg/day) was high. Other published studies are not suitable for quantifying the effect of folic acid because of selection bias, uncertainty about the dose of folic acid used, uncertainty as to whether folic acid was always taken before conception, or because background concentrations of blood folate were not measured.

Here, we use an alternative approach. To specify the dose-response relation between folic acid intake and risk of NTD according to background blood folate concentrations, we used published data on the effect of increasing folic acid intake on serum folate concentrations and on the relation between these concentrations and risk of having an NTD during pregnancy. We then assessed how well the derived model predicted direct observations.

Section snippets

Methods

To assess the relation between folic acid supplementation and plasma or serum folate concentration (taken to be equivalent so serum folate will be used for both), we identified published trials in which folic acid was administered in doses of up to 1 mg/day, and which measured the resultant change in serum folate.7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 We identified the trials from Medline (from 1965 to 2000, Medline subject headings: folic acid with administration and dosage; and

Results

We identified 14 studies that reported the effect of specified doses of folic acid up to 1 mg/day on serum folate (table 1). In six studies (nine treatment groups) the mean age ranged between 20 and 35 years, and 99% (375 of 379) of participants were women, so these trials mostly recruited women of childbearing age. In the other eight studies (17 treatment groups), the participants were older (mean age between 40 and 65 years) and only 29% (127 of 438) were women. The folic acid supplement was

Discussion

Our analyses show that the rise in serum folate associated with an increase in intake of folic acid over the range of doses considered is additive, whereas the relation between change in serum folate and change in NTD risk is proportional. Because a given increment in the dose of folic acid produces a constant absolute increase in blood concentration, the proportional increase in blood concentration will be less with a high starting value than with low values, so the proportional reduction in

References (42)

  • NJ Wald et al.

    Folic acid food fortification to prevent neural tube defects

    Lancet

    (1998)
  • JM Lawrence et al.

    Trends in serum folate after food fortification

    Lancet

    (1999)
  • RW Smithells et al.

    Further experience of vitamin supplementation for prevention of neural tube defect recurrences

    Lancet

    (1983)
  • NJ Wald et al.

    Folic acid, pernicious anaemia and the prevention of neural tube defects

    Lancet

    (1994)
  • N Wald et al.

    Prevention of neural tube defects: results of the MRC Vitamin Study

    Lancet

    (1991)
  • LD Botto et al.

    Neural-tube defects

    N Engl J Med

    (1999)
  • N Wald

    Folic acid and the prevention of neural tube defects: maternal nutrition and pregnancy outcome

    Ann NY Acad Sci

    (1993)
  • AE Czeizel et al.

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

    N Engl J Med

    (1992)
  • KM Laurence et al.

    Increased risk of recurrence of pregnancies complicated by fetal neural tube defects in mothers receiving poor diets, and possible benefit of dietary counselling

    BMJ

    (1980)
  • PN Kirke et al.

    A randomised trial of low dose folic acid to prevent neural tube defects

    Arch Dis Child

    (1992)
  • J Dierkes et al.

    Folic acid and vitamin B6 supplementation and plasma homocysteine concentrations in healthy young women

    Int J Vit Nutr Res

    (1998)
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