FOLIC ACID FORTIFICATION

Too Much of a Good Thing?

BY: EWELINA BORKOWSKA, PAULA MACOVEI, MARGARET POLKOWSKI

BACKGROUND

Folate:
water soluble vitamin (B9) naturally
occurring in food
ex: beans, lentils, DGLV, whole grains, breakfast
cereals
Folic acid: synthetic form of Folate (synthetized
in 1943)
found in fortified foods and supplements.
Bioavailability: Folate 60% vs Folic acid 100%
Function: DNA synthesis, repair and methylation,
cell
division and growth, maintenance of RBCs and

SOURCES

** fortified foods

SAMPLE MEAL
B: 1c fortified cereal 500 g
1c milk
1oz nuts 40 g
1 med banana 20 g
1 c orange Juice 70 g
L.: 1c egg noodles 100 g
3 oz. Chicken
c cooked spinach 100 g
c tomato sauce 20 g
1 sl. white garlic bread 25 g
D: 1 c white rice 130 g
3 oz. shredded pork
cooked beans 90 g
sliced avocado 45 g
c shredded romaine lettuce 20 g
1 c orange juice 70 g
TOTAL: 1230 g

Can too much of a good thing be

bad?

Pregnant
women

Infants

FOLIC ACID
FORTIFICATION

?
US
Population

Elderly

Author

Study
Purpose

Subjects/
Methods

Results

Conclusion

Morris et
al.,
2010

To determine association
btw (H) folate status,
anemia & cognitive
performance & circulating
UMFA or 5MeTHF.

n=1858, American
seniors, mean age ~70
y/o from NHANES
(1999-2002). Cognitive
& dietary assessment.
Complete blood count,
serum B12 & FA

UMFA detected in (33%)

25% showed low
Vit.B12+ (H) FA-> (L)
cognitive performance
& (L) cell volume, (H)
odds anemia,
macrocytosis

L Vit.B12 increased
odds of hematologic &
cognitive problems, due
to H concentration of
detectable circulating
UMFA from diet,
fortification &
supplements

Wyckoff
et al.,
2007

To determine if the
proportion of subjects with
low serum Vitamin B12 w/o
macrocytosis has
increased in pre, peri &
post-fortification period.

n=633 American
subjects, mean age~
65y y/o, Medical Center
(1995-2005)
3 groups: pre, peri,
post fortification,
Serum B12+ MCV, OR
Low serum w/o
macrocytosis

87% w/ L concertation
serum B12 w/o
macrocytosis in
postfortification group,
compared to
prefortification 70%, in
>65 y/o & <65 y/o
Significantly lower MCV
in postfortification
period

H # of participants w/ L
serum B12 in postfort.
period suggests FA
fortification is r/t
correction (masking)
of macrocytosis r/t
vitamin B12 deficiency,
in young & older adults.

Moore et
al.,
2014

To investigate the
association between serum
vitamin B12, red cell folate
(RCF) and cognitive
impairment

1354 Australian
participants, 70y/o,
recruited (2001-2011)
from 2 prev. studies on
late life cognition. B12,
RCF& scores of
cognitive performance

~Half of participants w/
L B12 & H RCF, had
impaired cognitive
performance.
Participants w/H folate
& normal B12, also
increased risk for

H RCF levels & L B12

x3 more impaired
cognitive performance.
H folate suggested as
detrimental to cognition
in older adults w/ L
serum vitamin B12.

Elder
ly

Elderly

Bailey et al., 2010

Study
Purpose

Subjects/
Methods

High folic acid intake

may promote the
growth of preexisting
cancers

NHANES data (2001UMFA was detected in

2002) of cross-sectionally 38% of older adults
representative population nationwide
(N=1121; >60 y)
Buildup of UMFA impair
24-h dietary recall and
the reduction
FFQ FA exposure from
mechanism of synthetic
both supplemental and
folate in the body
fortified foods
UMFA contributing
Blood samples were
factor in the increased
collected in the fasting
risk of cancer
state

Elderly population
prone to life span
exposure of folic acid
fortification

Results

Conclusion

Excessive FA exposure
may cause cancer
events for individuals
with MTHFR gene
23% of US population is
60 y or older

Pregnant
women

Plumptre et al., 2015

Study
Purpose

Subjects/
Methods

Results

Conclusion

Increased demand for

folate during
pregnancy
Rapid rate of
maternal & fetal
cellular growth
Development

368 Canadian pregnant

women
110-item FFQ for FAF
foods & supplements

UMFA was 20% higher

in maternal blood

Prolonged exposure
from fortification may
increase UMFA and not
necessarily the
supplementation
needed during
pregnancy

FAF implemented to
prevent NTDs

Early (0-16 wk.) and late

(23-37 wk.) blood
samples

Blood concentrations of
folate and UMFA were
Explore effects of
measured in maternal
increased exposure to samples and
high amount of folate mononuclear cells (MNCs)
in the form of folic
in blood cord
acid fortification
and/or

Maternal plasma
[UMFA] not different
between subjects who
took folic acidcontaining supplements
and those who did not
intake of folic acid
(p<0.001)
causes a buildup of
UMFA in the maternal
blood

Fetus has a set amount

of folate take-up by the
liver, the mom has
unlimited capacity for

Infants

Zhou et al., 2013

Study
Purpose

Subjects/
Methods

Results

Conclusion

Autism =
neurodevelopmental
disorder
Altered metabolism
of NTR serotonin
and dopamine
Boys

1987-1992 birth cohorts

High FA intake
increases the levels of
monoamine
neurotransmitters
high neurotoxicity
autism

Exposure to superfortified formula may

have a direct toxic
effect on the infant

Explore assessment
between exposure to
excess multivitamins and
the
etiology of autism

UMFA, a sign of folic

acid overload was
detected in the serum
of 4-day-old infants fed
with formula

Upper limit safety

US
Populatio
n

Zhou et al., 2015

Study
Purpose

Subjects/
Methods

Results

Conclusion

Fortification of grainderived products w/

FA followed by
increase in obesity

Review studies

Excess of vitamins
contributes to obesity

Current folic acid intake

has exceeded excretory
capacity

Obese individuals
lower fasting serum
folate concentrations
paradoxically their RBC
folate concentration and
MeFox are significantly
higher when compared
with nonobese individuals
FA fortification

FA overload during a
persons lifespan from
conception to old age
builds up as UMFA
*nearly all serum
samples measured
were higher than 1
nmol/L in older, nonfasting population

Revision of fortification
dosage

US
Populatio
n

Bae et al., 2014

(postmenopau
sal women)

Study
Purpose

Subjects/
Methods

Results

Conclusion

Investigate the effect

of FA fortification on
DNA methylation and
other one-carbon
biomarkers

408 postmenopausal
women aged 677 from
WHI-OS in the highest
and lowest tertiles of RBC
folate distribution

Plasma and RBC folate

higher in post than prefortification period
(p<0.001)

During FA fortification,
higher RBC folate
leukocyte DNA
methylation but
opposite during preperiod

Blood samples taken

during pre-, peri-, and
post-fortification period

Compared to women
with lower RBC folate,
women with higher RBC
folate had:
DNA methylation
in pre-period
(5.12% v 4.99%,
p=0.05)
DNA methylation
in post-period
(4.95% v 5.16%,
p=0.03)

Possible:
Metabolized folate in
pre-period DNA
methylation
UMFA in post-period
DNA methylation

US
Populatio
n

Patanwalla et al., 2014

Study
Purpose

Subjects/
Methods

Results

Conclusion

Identify the site of

biotransformation of
FA to 5-MTHF in
humans

Crossover design
6 subjects aged 557
years with TIPSS* and
stable liver
cirrhosis/abstention from
alcohol

Portal vein
[UMFA] >> [5-FTHF] at
each interval
(p<0.0001)

Liver DHFR, not gut

DHFR, reduces FA

Prior thinking based

on rodent studies:
intestinal mucosa
DHFR reduces FA

Subjects orally ingested

220g of isotope-labeled
FA (n=6) or 5-FormylTHF
(n=4)
Blood samples were
collected from the portal
vein from 15-85 minutes
post-dose

Post-dose FA:
15min: 8012% UMFA
85min: [UMFA]=[5MTHF]
Post-dose 5-FTHF:
15min: 418% 5-FTHF
85min: [5-FTHF]
insignificant

Liver DHFR = low and

highly variable activity
Consistent exposure to
FA DHFR saturation
systemic circulation
of UMFA
Consider alternatives to
FA in DS and fortified
foods

TIPSS-transjugular intrahepatic

Bailey et al.,
2010

Reproductive
-aged
women

Children

FOLIC ACID
INTAKES
Whos getting how
much?

US
Population

Adults 51+

Bailey et al.,
2010

Intakes above
UL may be even
higher

Children
>95% consume
EAR
Age 1-3:
exceed
Age 4-8:
exceed

20%
UL
27%
UL

28% use DS w/FA*

*In national chemical analysis sample of DS:

FA was 12-14% GREATER than the label
level
*We as humans also tend to underreport
*DS w/FA dietary supplement containing

Bailey et al.,
2010

Total folate
intakes are
highest for this
group

Mean Totals:
Men: ~930g
Women: ~800900g
5% exceed UL
~50% use DS w/FA

Adults 51+

Bailey et al.,
2010

Mean Totals:
Men: 81314g
Women: 72416g
34.5% use DS w/FA

US
Population
(14 y)

Bailey et al.,
2010

Reproductive
-aged
women
Age 14-18: 19%
below EAR
Age 19-30: 17%
below EAR

FA fortification was aimed at this group, and while it

succeeded in decreasing NTDs women still have
significantly higher prevalence of inadequate intakes of
total folate than other subgroups in the US

Non-Hispanic black
women are at highest
risk of inadequate
intake:
23% below EAR

CONCLUSION
While the US mandated FA fortification program
proved to decrease NTD rates, increasing evidence
suggests that ingestion of high amounts of FA may
have deleterious effects in children and the elderly.
Fortification laws should be reevaluated in terms of
dosage and alternatives to folic acid.
Is it justifiable to expose entire population to FA with
uncertain risk associated with excess intake?

REFERENCES
1.

Morris MS, Jacques PF, Rosenberg IH, Selhub J. Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in relation to anemia, macrocytosis,
and cognitive test performance in American seniors. Am J Clin Nutr 2010;91:1733-44.

2.

Wyckoff KF, Ganji V. Proportion of individuals with low serum vitamin B-12 concentrations without macrocytosis is higher in the post folic acid
fortification period than in the pre folic acid fortification period. Am J Clin Nutr 2007; 86:1187-92.

3.

Moore E, Amesa D, Manderb A, Carneb R, Brodatye H, Woodwardg M, Boundyh K, Ellisa K, Bushi A, Fauxi N. Among vitamin B12 deficient older people,
high folate levels are associated with worse cognitive function: combined data from three cohorts. prevalence 2014;8:86.

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