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