New insights on the lowest dose for mandatory folic acid fortification?

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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 improving folate status in women

of childbearing age, thereby reducing the incidence of neural tube defects

(NTDs) in newborns (1 <http://www.ajcn.org/content/93/1/1.full#ref-1>,

2<http://www.ajcn.org/content/93/1/1.full#ref-2>).

This strategy appears to have been effective, because the incidence of NTDs

in North America and several other developed countries has declined in the

years after the introduction of fortification

(1<http://www.ajcn.org/content/93/1/1.full#ref-1>,

3 <http://www.ajcn.org/content/93/1/1.full#ref-3>). The estimated average

increase in intake of folic acid after the introduction of mandatory

fortification in 1998 was ≈0.15–0.25 mg/d

(1<http://www.ajcn.org/content/93/1/1.full#ref-1>,

4 <http://www.ajcn.org/content/93/1/1.full#ref-4>). In parallel, folate

status in all population segments in, for example, the United States—young,

old, women, men—went 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<http://www.ajcn.org/content/93/1/1.full#ref-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 doctor's delay

may be a nonissue if appropriate markers of vitamin B-12 are measured, the

“patient's delay†may occur

(6<http://www.ajcn.org/content/93/1/1.full#ref-6>).

Furthermore, there have been reports on increased colorectal cancer risk as

a consequence of folic acid supplementation

(7<http://www.ajcn.org/content/93/1/1.full#ref-7>),

but a meta-analysis of randomized controlled trials of folic acid

supplementation has not confirmed these concerns

(8<http://www.ajcn.org/content/93/1/1.full#ref-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 incidence of NTDs?

For difficult questions such as these, the fact that folic acid lowers

fasting concentrations of total homocysteine—which, in the late 1990s, was a

frequently studied risk factor for cardiovascular disease

(9<http://www.ajcn.org/content/93/1/1.full#ref-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<http://www.ajcn.org/content/93/1/1.full#ref-8>),

homocysteine is still considered a useful marker of the intracellular status

of the B-vitamins involved in the homocysteine-methionine metabolism, in

particular folate (10 <http://www.ajcn.org/content/93/1/1.full#ref-10>).

Even though folate concentrations increase linearly with increasing doses of

folic acid, the homocysteine concentration reaches a plateau—ie, it cannot

be lowered further—when 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<http://www.ajcn.org/content/93/1/1.full#ref-11>).

In this issue of the Journal, Tighe et al

(12<http://www.ajcn.org/content/93/1/1.full#ref-12>)

conducted a randomized, placebo-controlled, dose-finding trial with folic

acid in 101 patients with ischemic heart disease and 71 healthy volunteers,

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<http://www.ajcn.org/content/93/1/1.full#ref-12>)

proposed that previous dose-finding studies probably overestimated 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<http://www.ajcn.org/content/93/1/1.full#ref-13>),

and it has also been shown that the combination of folic acid and vitamin

B-12 is (slightly) more effective in homocysteine lowering than is folic

acid alone (14 <http://www.ajcn.org/content/93/1/1.full#ref-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 intake induced by mandatory

fortification (4 <http://www.ajcn.org/content/93/1/1.full#ref-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 <http://www.ajcn.org/content/93/1/1.full#ref-15>).

However, considering the 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<http://www.ajcn.org/content/93/1/1.full#ref-16>)

or 12 wk (11 <http://www.ajcn.org/content/93/1/1.full#ref-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 biomarker to study in

folic acid dose-finding studies. Although some epidemiologic studies have

found positive associations between homocysteine and risk of NTDs

(17<http://www.ajcn.org/content/93/1/1.full#ref-17>),

homocysteine concentrations have not been clearly established as being in

the causal pathway. Furthermore, although some studies still leave some

space for a cardiovascular disease–preventive effect of homocysteine

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<http://www.ajcn.org/content/93/1/1.full#ref-18>).

et al (18 <http://www.ajcn.org/content/93/1/1.full#ref-18>)

speculated that in those with low homocysteine concentrations, folic acid

has a positive effect on endothelial function, whereas in those with high

homocysteine concentrations, folic acid may have a proliferative effect in

the atherosclerotic process.

In conclusion, an ongoing, uncontrolled population-based experiment 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 childbearing age in many developing and emerging countries,

where it contributes 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 countries

where mandatory folic acid fortification is not yet in place, targeted

supplementation of women of childbearing age has become ever so important.

Full article and references here <http://www.ajcn.org/content/93/1/1.full>

--

Ortiz, MS, RD

*The FRUGAL Dietitian* <http://www.thefrugaldietitian.com>

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