Public HealthQuantifying the effect of folic acid
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)
- et al.
Low-dose folic acid supplementation decreases plasma homocysteine concentrations: a randomised trial
Am J Clin Nutr
(1999) - et al.
Fortification with low amounts of folic acid makes a significant difference in folate status in young women: implications for the prevention of neural tube defects
Am J Clin Nutr
(1999) - et al.
Effects of folic acid and combinations of folic acid and vitamin B-12 on plasma homocysteine concentrations in healthy young women
Am J Clin Nutr
(1998) - et al.
Reduction of homocysteine levels in coronary artery disease by low-dose folic acid combined with vitamins B6 and B12
Am J Cardiol
(1999) - et al.
Enhancement of the antidepressant action of fluoxetine by folic acid: a randomised, placebo controlled trial
J Affect Disord
(2000) - et al.
Dietary strategies for lowering homocysteine concentrations
Am J Clin Nutr
(2000) - et al.
Combination of low-dose folic acid and pyridoxine for treatment of hyperhomocysteinaemia in patients with premature arterial disease and their relatives
Atherosclerosis
(1999) - et al.
Effect of increasing dietary folate on red-cell folate: implications for prevention of neural tube defects
Lancet
(1996) - et al.
Vitamin B-12, vitamin B-6, and folate nutritional status in men with hyperhomocysteinemia
Am J Clin Nutr
(1993) - et al.
Vitamin requirements for the treatment of hypercysteinemia in humans
J Nutr
(1994)