Editorial
See corresponding article on page 11.
New insights on the lowest dose for mandatory folic acid fortification?1,2
Petra Verhoef
For more than a decade, there has been mandatory fortification
of flour with folic acid in the United States, Canada, and at least
50 other countries around the world, with the sole purpose of im-
proving folate status in women of childbearing age, thereby re-
ducing the incidence of neural tube defects (NTDs) in newborns
(1, 2). This strategy appears to have been effective, because the
incidence of NTDs in North America and several other devel-
oped countries has declined in the years after the introduction of
fortification (1, 3). The estimated average increase in intake of
folic acid after the introduction of mandatory fortification in
1998 was 0.150.25 mg/d (1, 4). In parallel, folate status in
all population segments in, for example, the United States
young, old, women, menwent up, and this is the crux of the
fortification matter: folic acid supplementation affects many in
the general population who may not necessarily benefit from it
(5). For example, some studies have shown an increased risk
of masking of vitamin B-12 deficiency in older adults. Even
though the so-called doctors delay may be a nonissue if ap-
propriate markers of vitamin B-12 are measured, the patients
delay may occur (6). Furthermore, there have been reports on
increased colorectal cancer risk as a consequence of folic acid
supplementation (7), but a meta-analysis of randomized con-
trolled trials of folic acid supplementation has not confirmed
these concerns (8).
This uncertainty about the safety of folic acid has left those
involved in advising and decision making on mandatory folic acid
fortification with several important questions:
1) Can we expose entire populations to a compound that may
prevent a rare, yet disruptive, medical condition in newborns?
2) Would we accept some risk, knowing that there would be
other health benefits for those other exposed segments of
the population?
3) Should we lower the fortification level, and what is then the
lowest dose of folic acid that can effectively reduce the in-
cidence of NTDs?
For difficult questions such as these, the fact that folic acid
lowers fasting concentrations of total homocysteinewhich, in
the late 1990s, was a frequently studied risk factor for cardiovas-
cular disease (9)was welcomed as a justification to increase
intake of folic acid in the general population. And although
doubt about the causal role of homocysteine or folate status in
the etiology of cardiovascular disease has grown (8), homocys-
teine is still considered a useful marker of the intracellular status
of the B-vitamins involved in the homocysteine-methionine
Am J Clin Nutr 2011;93:12. Printed in USA. 2011 American Society for Nutrition
metabolism, in particular folate (10). Even though folate concen-
trations increase linearly with increasing doses of folic acid, the
homocysteine concentration reaches a plateauie, it cannot be
lowered furtherwhen intakes of folic acid are increased. This
latter feature allows for the conduct of dose-finding studies to find
the lowest possible dose for a maximal homocysteine-lowering
effect (11).
In this issue of the Journal, Tighe et al (12) conducted a ran-
Downloaded from ajcn.nutrition.org by guest on June 11, 2016
domized, placebo-controlled, dose-finding trial with folic acid
in 101 patients with ischemic heart disease and 71 healthy vol-
unteers, with an average age of 64 y. The study took place in
Northern Ireland, where there is no mandatory fortification
with folic acid. The findings show that a folic acid supplement
of 0.2 mg/d can, if taken for 6 mo, effectively lower plasma total
homocysteine concentrations. Doses of 0.4 and 0.8 mg/d led to
a quicker drop in homocysteine concentrations than did a dose
of 0.2 mg/d, but these doses were not more effective in the long
run. When it comes to fortification of staple foods with folic
acid, this long-term effect is most relevant. Tighe et al (12)
proposed that previous dose-finding studies probably overesti-
mated the folic acid dose required for maximal homocysteine
lowering because the durations of treatment were too short.
In a post hoc analysis, the authors also found that the extent of
homocysteine lowering on folic acid supplementation was lowest
in those with low vitamin B-12 status at the start of the study. In
a population of older adults, vitamin B-12 status is indeed
expected to be a determinant of circulating homocysteine, next
to folate status (13), and it has also been shown that the com-
bination of folic acid and vitamin B-12 is (slightly) more effec-
tive in homocysteine lowering than is folic acid alone (14).
How does this study help in debates on whether to introduce
mandatory folic acid fortification in countries that have not done
so thus far or whether to lower the levels of fortification in those
countries that have fortification in place?
The study shows that long-term supplementation of 0.2 mg
folic acid/d, a dose quite similar to the current increase in in-
take induced by mandatory fortification (4), is as effective as
0.4-mg doses in lowering homocysteine concentrations. A
meta-analysis of previous dose-finding studies concluded that
0.8 mg/d was the optimal dose (15). However, considering the
1
From Unilever R&D Vlaardingen, Vlaardingen, Netherlands.
2
Address correspondence to P Verhoef, Unilever R&D Vlaardingen, Oliv-
ier van Noortlaan 120, 3133 AT Vlaardingen, Netherlands. E-mail: petra.
verhoef@unilever.com.
First published online December 1, 2010; doi: 10.3945/ajcn.110.006387.
1
2 EDITORIAL
worries on adverse effects of too high an intake of folic acid, it
is unfortunate that Tighe et al did not include lower doses.
Previous studies had already tested doses as low as 0.05 and
0.1 mg/d, but these did not go beyond 6 wk (16) or 12 wk
(11) of treatment. In the latter study, 0.4 mg/d was defined as
the minimum dose for adequate homocysteine lowering.
One could question whether homocysteine is a relevant bio-
marker to study in folic acid dose-finding studies. Although some
epidemiologic studies have found positive associations between
homocysteine and risk of NTDs (17), homocysteine concentra-
tions have not been clearly established as being in the causal
pathway. Furthermore, although some studies still leave some
space for a cardiovascular diseasepreventive effect of homo-
cysteine lowering by folic acid and vitamins B-12 and B-6, the
overall evidence indicates no beneficial effect or even an adverse
effect of B-vitamin treatment on risk of cardiovascular disease,
especially in those patients with initially high homocysteine
concentrations (18). Miller et al (18) speculated that in those
with low homocysteine concentrations, folic acid has a positive
effect on endothelial function, whereas in those with high ho-
mocysteine concentrations, folic acid may have a proliferative
effect in the atherosclerotic process.
In conclusion, an ongoing, uncontrolled population-based ex-
periment has already indicated that folic acid supplementation
at a level of 0.2 mg/d is likely to lower NTD incidence. Whether
lower fortification levels are as effective or safer is currently still
unknown. Folate status is low among young women of childbear-
ing age in many developing and emerging countries, where it con-
tributes to maternal and childhood mortality. In those countries,
folic acid fortification of flour or other staple foods may be the
best approach to reach the groups at risk. In the developed coun-
tries where mandatory folic acid fortification is not yet in place,
targeted supplementation of women of childbearing age has
become ever so important.
The author is employed by Unilever R&D in Vlaardingen, Netherlands.
The research at this food company entails examining the health benefits of
a variety of food ingredients, including folic acid. Unilever markets food prod-
ucts, some of which are enriched with folic acid.
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