Folic Acid Food Fortification Has Benefited the U.S.

and Should Be Implemented Worldwide

In 1998, the FDA implemented the fortification of folic acid in
the refined grain food supply in an effort to decrease the
occurrence of neural tub defects (NTD) in newborn children1.
Over 40 countries worldwide have adopted the fortification of
folic acid, and yet this remains a controversial topic. The
argument is that wide spread fortification exposes thousands
of people, without choice, to extra folic acid.
This fact sheet highlights the specific reasoning for the
promotion of folic acid fortification, as well as addresses the
issues of concern by opposing proponents.
FOLIC ACID BACKGROUND
Folic acid is the highly absorbable synthetic form of folate, a
water-soluble B vitamin essential for DNA replication and
enzymatic reactions involved in amino acid synthesis1. It is
required for the conversion of homocysteine to methionine in
the synthesis of S-adenosyl-methionine, an essential methyl
donor1.
Inadequate maternal folate status is associated with NTDs,
low infant birth weight, preterm delivery, and fetal growth
retardation1. Current recommendation to prevent NTDs is 400
mcg/day1. The tolerable upper limit for folic acid is 1000 mcg1.

A 2005 study applied a cost-benefit and costeffectiveness analysis of folic acid fortification and
estimated a 325-425$ million annual benefit in the US4.
Dementia and Cognitive Dysfunction
Folic acid supplementation over a 3-year period
significantly improved domains of cognitive function
related to information processing, reaction speed and
overall thinking5.
Cardiovascular Disease and Stroke
Supplementation reduced homocysteine levels and risk
of stroke6.
EVIDENCE AGAINST FORTIFICATION
Neurological Impacts
Doses >400 mcg/d may increase risk of cognitive
decline7.
Low doses (300-800 mcg/d) of folic acid can mask
hematologic signs of vitamin B-12 deficiency and may
aggravate neurological symptoms8,9.
Irreversible neurological impacts10.
Prevalent in elderly10.

Population groups at risk of folate deficiency1:

Women of child bearing years
Non-Hispanic black
women
Pregnant women
Alcoholics
People with
malabsorptive disorders

Tumor Progression
May promote progression of existing (pre)neoplastic
lesions11. However, evidence is inconclusive.

Population groups at risk of

folate toxicity1:
Aged >50 years (5% exceed UL)
Children

CONCLUSION

EVIDENCE SUPPORTING FORTIFICATION

Neural Tube Defects
Folic acid fortification was followed by a 25-30%
reduction in NTD frequency in the US2.
Periconceptual folic acid supplementation may reduce
NTDs by 50-60%2.
50% of pregnancies are unplanned, therefore FNB
advises intake of 400 mcg for women of childbearing
age3.

Impaired Immunity
Excess folic acid supplementation may suppress natural
killer (NK) cell function12.

The evidence supporting fortification concretely proves a

decline in the reduction of NTDs and instances of morbidity
and mortality in newborn infants. Furthermore, fortification
has resulted in a reduction of homocysteine levels and
reduced instances of cognitive dysfunction. Although
increased intake of folic acid may have negative
unintended consequences related to the masking
of B12 and increased rates of tumorigenesis,
these outcomes have yet to be confirmed and
require further investigation. Remember: An
ounce of prevention is worth a pound of cure!
B. Franklin

Resources
1. Brown J. Nutrition in the Lifecycle, 5th ed. Stamford, CT: Cengage Learning, 2011:113-17.
2. Pitkin RM. Folate and neural tube defects. Am J Clin Nutr. 2007;85(1):285S-288S.
3. Dietary Supplement Fact Sheet: FolateHealth Professional Fact Sheet. National Institute of Health Web site.
http://ods.od.nih.gov/factsheets/Folate-HealthProfessional/?print=1. Accessed February 12, 2014.
4. Grosse SD, Waitzman NJ, Romano PS, Mulinare J. Reevaluating the benefits of folic acid fortification in the United States:
economic analysis, regulation, and public health. American Journal of Public Health. 2005;95(11):1917-22.
5. Durga J, Van Boxtel MP, Schouten EG, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in
the FACIT trial: a randomized, double blind, controlled trial. The Lancet. 2007;369(9557):208-216.
6. Jacques PF, Selhub J, Bostom, A. G., Wilson, P. W., & Rosenberg, I. H. The effect of folic acid fortification on plasma folate
and total homocysteine concentrations. New England Journal of Medicine. 1999; 340(19):1449-1454.
7. Morris MC, Evans DA, Bienias JL, et al. Dietary folate and vitamin B12 intake and cognitive decline among communitydwelling older persons. Arch Neruol. 2005;62:641-645.
8. Chosy J, Clatanoff D, Schilling R. Responses to small doses of folic acid in pernicious anemia. Am J Clin Nutr. 1962;10:34950.
9. Savage DG, Lindenbaum J. Neurological complications of acquired cobalamin deficiency: clinical aspects. Baillieres Clin
Haematol. 1995;8:657-78.
10. Morris MS, Jacques PF, Rosenberg IH, Selhub J. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and
cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr. 2007;85:193-200.
11. Manshadi SK, Ishiguro L, Sohn K-J, Medline A, et al. Folic acid supplementation promotes mammary tumor progression in
rat model. PLOS ONE. 2014;9(1).
12. Troen AM, Mitchell B, Sorensen B, et al. Unmetabolized folic acid in plasma is associated with reduced natural killer cell
cytotoxicity among postmenopausal women. J Nutr. 2006;136:189-94.

Folic Acid SupplementationPRO

Annotated Bibliography

Pro Folic acid fortification of the US food supply has been beneficial and should be
implemented globally
I. Background information
Folate is a B vitamin that is essential for DNA replication and as a component of
enzymatic reactions involved in amino acid synthesis and vitamin metabolism. Inadequate
folate status early in pregnancy is related to the development of neural tube defects
(NTDs), specifically spina bifida and anencephaly. Folic acid is the oxidized and most active
form of this B vitamin. Folic acid is rarely found in food. This form is used in supplements
and food fortification. Folic acid is also twice as bioavailable as folate. In 1998, the FDA
mandated that refined grains be fortified with folic acid, since a reduction in NTDs did not
follow the promotion of recommended folic acid intake by health care programs.
Currently, over 40 countries fortify grain products with folic acid.
The first two papers are reviews of the studies that have lead to food fortification
policies. The authors highlight the evidence to support the benefit of folic acid
supplementation in prevention of neural tube-defects. The study by De Wals et al.
examines the amount of reduction of NTDs in Canada after food fortification became
mandatory by analyzing medical records between 1993-2002. The last two articles are
clinical studies that aimed to determine the effect of varying folic acid doses to ascertain
how beneficial food fortification is on prevention of NTDs.

Folic Acid SupplementationPRO

Annotated Bibliography

Czeizel AE, Duds I, Vereczkey A, Bnhidy F. Folate Deficiency and Folic Acid Supplementation: The
Prevention of Neural-Tube Defects and Congenital Heart Defects. Nutrients. 2013;5(11):4760-4775.
The aim of this review paper was to show the characteristics of neural tube defects (NTD) and
congenital heart defects (CHD) along with how certain vitamin deficiencies contribute to their origin.
NTDs and CHDs typically have very early onset, thus there is no or a very limited chance to recovery
from these conditions. Prevention is the only medical solution and periconceptual folic acid
supplementation was a breakthrough measure in prevention of NTDs. The authors gave a brief history
on the research that led to the recommendation of periconceptual folic acid supplementation, which
included the Hungarian randomized controlled trial (RCT). In 1984, the Hungarian Periconception
Service (HPS) launched a RCT, in which half of the participants were given a multivitamin containing 0.8
mg of folic acid and the other half were given a placebo. The women used these supplements during at
least one month before conception and at least during two months after conception (periconception
period). They found that NTD did not occur in 2391 offspring of the group that received the
multivitamin, while six NTDs were found in 2471 offspring of the placebo group. The Hungarian RCT
first showed that a multivitamin containing 0.8 mg of folic acid prevented approximately 90% of the
first occurrences of NTDs. An unexpected finding of the Hungarian trials was that they found a
significant reduction in congenital heart defects after multivitamin supplementation. The combined
results from the RCT and a cohort-controlled trial indicated a 43% reduction in CHD risk.
The authors examined three applications of folic acid intake (diet, supplementation and food
fortification) and found that food fortification seemed to be the most practical, since about 50% of
pregnancies are unplanned in industrialized countries such as the US. The periconceptual use of folic
acid or multivitamin supplementation for women expecting to become pregnant would be a useful
approach, however this opportunity is frequently missed. If women have an unplanned pregnancy and
are not already using a supplement, they cannot prevent an NTD during the periconception period. In
January 1998 all cereal grain products in the US were fortified with 0.14 mg/100 g folic acid and there
was a 26% reduction in the total prevalence of NTDs. Canada also began mandatory flour fortification
in September 1998 and had a 42% reduction in the total prevalence of NTDs along with a 6% decrease
in CHD. The authors also believe that flour fortification is especially important for lower SES women
who have limited resources and have difficulty buying foods rich in folate, as well as have more
unplanned pregnancies. Folic acid food fortification also has significant economic benefit, the
estimated cost savings is in the range of 145-588 million US dollars each year.
However, the main concern the authors had with food fortification is the low dose of folic acid and the
lack of vitamin B12. They feel that 0.14 mg is too low of a dose, since a high dose of 4mg is was
recommended for the prevention of recurrent NTDs. In patients with pernicious anemia, high levels of
folic acid can mask the neurological symptoms. There also may be a carcinogenic effect of high doses of
folic acid, and thus a U-shaped risk of cancer associated with folic acid intake. In spite of these risks,
folic acid food fortification has been shown to be beneficial in regards to prevention of NTDs, CHDs and
be significantly cost-effective.

Folic Acid SupplementationPRO

Annotated Bibliography

Pitkin RM. Folate and neural tube defects. The American Journal of Clinical Nutrition.
2007;85(1):285S-288S.
This article is a summary of the more important studies that have led to the current recommendation
that all women capable of becoming pregnant should intake folic acid regularly. The author also
describes background information about the types of NTDS that are affected by folate status. Spina
bifida is failure of the caudal end of the neural tube to close during embryogenesis, whereas
anencephaly occurs when the cranial end is affected. Four out of the five retrospective studies he
examined found statistically significant reductions in risk, in the range of 35-75%. The definitive
controlled trial he described was the multi-institutional study sponsored by the Medical Research
Council (MRC; United Kingdom). This was a masked, randomized trial that compared 4mg/d of folic
acid with a placebo in a group of women who had previously had a NTD pregnancy. The trial began at
least one month before conception and continued through the first trimester. There were 6 NTD cases
among 593 supplemented women, compared with 21 cases among 692 placebo control women, which
was a risk reduction of 72%. Soon after the publication of the MRC study in 1991, the CDC advised
women that had a previous NTD pregnancy to ingest 4 mg of folic acid daily to prevent another NTD
birth. In 1992, the CDC came out with a report that all women of reproductive age should consume 0.4
mg of folic acid in addition to a folate-rich diet. The proportion of NTDs that can be prevented with
periconceptual folic acid supplementation of 0.4 mg/d is assumed to be approximately 50-60%.
Pitkin recognized that there were several areas where further research was needed, the most
important being the understanding of the mechanism of NTD development. This research could
improve results with folic acid supplementation. The next is to determine the relative effectiveness
between dietary folate, folic acid food fortification and folic acid supplementation alone. The most
effective dose of folic acid supplementation also needs to be reexamined. Since 4mg is four times
higher than the UL it is important to know if recurrent NTDs can be prevented with a smaller dose.

Folic Acid SupplementationPRO

Annotated Bibliography

De Wals P, Tairou F, Van Allen MI, et al. Reduction in neural tube defects after folic acid fortification in
Canada. New England Journal of Medicine. 2007;357(2):135-42.
In November 1998, the fortification of all types of white flour, enriched pasta and cornmeal became
mandatory in Canada, with a goal of increasing average folic acid intake among women of childbearing
age by 30-70%. The aim of this study was to assess the changes in prevalence of NTDs after food
fortification in Canada. The population of the study was all live births, stillbirths and pregnancy
terminations in Canadian provinces (7 out of 10) from 1993 to 2001. In each province, the authors
identified the amount of subjects with NTDs using analysis of medical databases and medical records.
They found that the overall prevalence of NTDs at birth decreased by 46% after fortification. Their
results showed an occurrence pattern that was stable from 1993 to 1997, then a decrease from 1998 to
2000, and stabilization after that. Even though Health Canada began recommending daily folic acid
supplementation for pregnant women in 1993-1997, there were no observed changes in prevalence of
NTDs during this time period. The greatest risk reduction appeared to be in areas where the rates of
NTDs were the highest before the fortification program began. The authors concluded that significant
reductions in NTDs occurred in Canada after food fortification was implemented. The level of food
fortification needs to consider both the safety of it, particularly for those who may have unrecognized
B12 deficiency, and the goal of maximizing NTD reduction.
The results of this study help to support the position that fortification of the food supply with folic acid
has been beneficial in regards to lowering NTDs in other countries as well as the United States.

Folic Acid SupplementationPRO

Annotated Bibliography

Tighe P, Ward M, Mcnulty H, et al. A dose-finding trial of the effect of long-term folic acid intervention:
implications for food fortification policy. The American Journal of Clinical Nutrition. 2011;93(1):11-8.
Since there have been concerns about the potential adverse effects of overexposure to folic acid, such
as cancer and masking a B12 deficiency, it is important for food fortification policy to determine what is
the lowest dose required to be effective in lowering homocysteine levels.
The aim of this study was to determine the minimum dose of folic acid (within the range of 0.2-0.8
mg/d) required to effectively lower homocysteine levels over a longer period of time than had
previously been examined. Participants were recruited from the Cardiac Rehabilitation program in
Northern Ireland. As a comparison, healthy subjects were also recruited that had no history of
cardiovascular disease. The study was a double-blinded, randomized placebo controlled trial. There
were four stratum with 35 participants in each that were randomly assigned to receive either a
placebo, 0.2, 0.4, or 0.8 mg folic acid/d for a total period of 26 weeks. Blood samples were collected at
the beginning of the study and at 26 weeks to assess for homocysteine levels. The results of the study
showed that a dose of folic acid as low as 0.2 mg/d, taken for 6 months, resulted in an effective
lowering of homocysteine concentrations and that there was not a significant difference in the
homocysteine response in the groups receiving 0.4-0.8 mg/d. The authors concluded that folic acid as
low as 0.2 mg/d can be effective and higher doses of folic acid may not be necessary. However, the
authors suggest that folic acid alone may not lower homocysteine to desirable levels and future
research is needed to determine if inclusion of vitamin B-12 would be beneficial. This research could
likely have an effect on future emerging fortification policies.
The results of this trial support the efficacy of the low dose of folic acid from food fortification over a
sufficient amount of time. These finding indicate that food fortification with folic acid can be effective
in lowering homocysteine levels, and therefore reduce risk of cardiovascular disease.

Folic Acid SupplementationPRO

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Houghton LA, Gray AR, Rose MC, Miller JC, Hurthouse NA, Gregory JF. Long-term effect of low-dose
folic acid intake: potential effect of mandatory fortification on the prevention of neural tube defects.
The American Journal of Clinical Nutrition. 2011;94(1):136-41.
The role of periconceptual folic acid supplementation in preventing NTDs has been well established and
has lead to food fortification policies as well as public health efforts to promote folate intake for all
reproductive-aged women. Data from the US National Birth Defects Prevention Study (1998-2003)
showed that folic acid supplements, after fortification become mandatory, no longer appeared to
reduce NTD risk. A possible explanation of this finding could be that fortification may provide enough
folic acid to prevent most NTDs that are sensitive to folate levels. The aim of this study was to assess
the effect of daily supplementation of 140 microgram (dose designed to mimic fortification) and 400
microgram (dose that is recommended to prevent NTDs) on RBC folate over a 40-week period in a
group of healthy women that were of reproductive age. The women in this study were recruited from
the University of Otago, Dunedin, New Zealand. Exclusion criteria included being pregnant or lactating,
planning a pregnancy in the next 12 months, regularly using folic acid-containing supplements, or selfreported history of cardiovascular, gastrointestinal, hepatic, renal or hematologic disease. One hundred
and forty-nine women were recruited total, 49 received the 140 microgram folic acid/d pill, 48 received
the 400 microgram/d pill and the rest received the placebo. Overall, the mean pill compliance of the
group was 88%. To date, this was the longest trial conducted measuring the folate level and rate of
saturation in RBCs. However, their results indicated that folate concentration in RBCs did not reach a
steady state in either of the treatment groups. They found that RBC folate increased in both folic acid
dosage groups during the 40-week period, but there was no indication that the folate concentrations in
RBCs plateaued in either group. From their results, the authors calculated that it would take about 74
weeks at 140 microgram/d and 86 weeks at 400 microgram/d to reach approximately 90% of the
average steady state. From analysis of their model, they showed that hypothetically with sufficient time
to reach a steady state, an extra 140 microgram/d (the typical amount delivered by food fortification),
could be as protective against NTDs as 400 microgram/d (the current periconceptual recommended
dose).
The authors did have limitations when analyzing their results. Since they included data from
participants that had <95% compliance, it could have introduced a potential source of error in the
analysis of the dose of folate that had an effect on RBCs. Also, whole-body folate turnover is highly
variable, therefore they were not able to determine an exact plateau or amount of time required to
reach a steady state. However, the objective of the study was to reach an approximation of the rate of
RBC folate steady state after initiation of dietary treatment and that was achieved. The authors
recognized that additional long-term folic acid supplementation studies are required to confirm the
effect of varying doses on RBC folate concentration.
The findings of this article give further evidence to support the efficacy of folic acid fortification of the
food supply in reduction of NTDs as well as prevention of other health risks associated with inadequate
folate status.

Folic Acid SupplementationPRO

Annotated Bibliography

I. Evidence for our position

Since the implementation of folic acid fortification in 1998, there has been a significant decrease in
NTDs in the US. Over 40 countries have also chosen to fortify with folic acid and are seeing substantial
declines as well. In addition to these benefits, folic acid has also been linked to reduced homocysteine
levels and a reduction in cognitive decline. This is of great importance when considering our aging
population. High homocysteine levels have been linked to increased risk of heart disease, a known
contributor of death in the US. Furthermore, the benefits of folic acid in relation to cognitive function
are important for the elderly as well since they often exhibit cognitive impairments. These factors, in
combination with the positive economic outcomes, promote the belief that folic acid fortification is
beneficial and should be implemented globally.

Honein MA, Paulozzi LJ, Mathews TJ, Erickson J, Wong LC. Impact of Folic Acid Fortification of the US
Food Supply on the Occurrence of Neural Tube Defects. JAMA. 2001;285(23):2981-2986.
In order to assess the prevalence of NTDs and the impact of folic acid fortification, birth certificate
data for live births of women in 45 different states and Washington, DC were assessed between
January 1990 and December 1999.
To determine if birth certificate data was sensitive to birth defects during this period, the percentage
of certificates with at least one NTD was calculated. Birth certificates that did not indicate an NTD, but
did identify 1 of 19 other congenital anomalies were included in this. However, birth certificates that
only had other checked for the congenital anomaly list were not included.
For this analysis, congenital anomalies were compared alongside NTDs because a decline in these
anomalies accompanied by a decline in NTD would mean the causation for NTDs should be scrutinized
more carefully. Furthermore, since fortification became mandatory in January 1998, this study looked
at birth certificate reports of spina bifida and anencephaly from October 1995 through December 1996
and compared them to birth certificate reports from October 1998 through December 1999.
Birth certificates with at least 1 congenital anomaly remained relatively stable from 1991 through
1999. Following fortification, data from birth certificates revealed a 19% decline in the birth prevalence
of NTDs and a 23% decline in the birth prevalence of spina bifida. More specifically, a statistically
significant decline in spina bifida was noted during the fourth quarter of 1998, as well as the second
and third quarters of 1999.

Folic Acid SupplementationPRO

Annotated Bibliography

Gibson TM, Weinstein SJ, Pfeiffer RM, Hollenback AR, et al. Pre- and postfortification intake of folate
and risk of colorectal cancer in a large prospective cohort study in the United States. The American
Journal of Clinical Nutrition. 2011;ajcn.002659.
In order to assess the association between folate fortification and colorectal cancer, a US cohort
study examined 525,488 individuals ranging between 50-71 years of age. These individuals were
selected because they responded to a questionnaire utilized in the NIH-AARP Diet and Health Study.
A food frequency questionnaire was used to calculate dietary, supplemental and total folate intake
for both pre and post fortification periods. After approximately 9.1 years, participants were
reevaluated and 7212 incident colorectal cancer cases were identified using state and metropolitan
area cancer registries. These cases were defined as those with a first time, primary, invasive colorectal
cancer diagnosis.
Data from the same participants was compared prior to and post folic acid fortification in order to
assess colorectal cancer incidence.
In the postfortification analysis, higher total folate intake was associated with a decreased colorectal
cancer risk. The highest intakes specifically from supplements or from diet appeared to in fact be
protective against colorectal cancer. However, considering that adenoma carcinoma may take over 10
years to develop, more follow up is needed.

Folic Acid SupplementationPRO

Annotated Bibliography

Durga, J., Van Boxtel, M. P., Schouten, E. G., Kok, F. J., Jolles, J., Katan, M. B., & Verhoef, P. Effect of 3year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomized,
double blind, controlled trial. The Lancet. 2007;369(9557):208-216.
To determine the role of folic acid supplementation on cognitive performance, men and postmenopausal women aged 50-70 years from the Netherlands who were originally part of the Folic Acid
and Carotid Intima-media Thickness (FACIT) trial were recruited. From there, patients with high
homocysteine levels were chosen. Those that appeared to have high homocysteine levels due to other
factors besides a suboptimal folate concentration were eliminated.
Patients were given either a placebo or 800 per day of folic acid. Cognitive function was assessed
using 5 separate tests designed to measure memory, sensorimotor speed, complex speed, information
processing speed, and word fluency. Participants underwent testing after an overnight fast, where after
measurements for serum folate, serum vitamin B12, plasma total homocysteine and other markers
were measured. Two research assistants gave patients the test in the same room, with the same props.
The placebo group and the supplement group were compared at the start of this study, as well as after
a 3-year placebo or folic acid supplementation period. Initially, both groups demonstrated similar
baseline scores on the cognitive tests.
After the 3-year period, participants taking the folic acid supplement showed a 576% increase in serum
folate concentration and a 26% decrease in plasma total homocysteine concentrations. Overall, in
comparison with the placebo group, those taking the folic acid supplement showed greater
improvement in the domains of memory, information processing speed and sensorimotor speed.

Folic Acid SupplementationPRO

Annotated Bibliography

PF, Selhub J, Bostom AG, Wilson PW, & Rosenberg IH. The effect of folic acid fortification on plasma
folate and total homocysteine concentrations. New England Journal of Medicine. 1999;340(19):14491454.

To measure the impact of folic acid fortification on total homocysteine levels, offspring
and the spouses offspring from the Framingham Heart Study were invited to participate
in Selhub et al.s study. The original Framingham Heart Study included married couples
that had developed cardiovascular disease. In the first examination of the Framingham
Offspring Study, 5235 of the 6838 eligible persons participated.
A fifth examination of the Framingham Offspring Study cohort was done prior to folic acid
fortification to measure plasma folate and total homocysteine levels, along with other
markers. Following fortification, a sixth examination was conducted to measure these
levels as well. Participants were also asked to take a food-frequency questionnaire to
determine dietary intake of folate from both fortified and unfortified foods, as well as
supplements.
The cohort was then divided into two groups based on their follow up exam. The first
group consisted of 360 individuals that were seen post-fortification. The second group
was a control group, consisting of 756 individuals that were seen prior to fortification.
These groups were then compared to assess time-related changes for folic acid
fortification and homocysteine levels over a 3-year period. These groups were further
divided into those who were using a folic acid containing supplement and those who were
not.
For the control group, no statistically significant changes were seen for folate or
homocysteine levels. For the first group though, those that did not use supplements
demonstrated an increase of 5.4 ng per milliliter in mean folate concentration following
with the prevalence of high homocysteine concentration dropping from 18.7 to 9.8
percent.

10

Folic Acid SupplementationPRO

Annotated Bibliography

Grosse SD, Waitzman NJ, Romano PS, Mulinare J. Reevaluating the benefits of folic acid
fortification in the United States: economic analysis, regulation, and public health. American
Journal of Public Health. 2005;95(11):1917-22.
To determine the economic benefits following fortification, this study evaluated the rate
of NTDs the costs associated with it. To inform public health decisions, a CBA (cost-benefit
analysis) and a CEA (cost-effectiveness analysis) are utilized. A CBA assesses outcomes in
monetary terms, taking into account deaths and diseases averted. A CEA uses the ratio of
net costs, meaning it is determined as intervention costs minus medical costs and other
direct, prevention averted costs. For this study, researchers assessed post fortification
using both a CBA and a CBE, excluding NTD-affected pregnancies not ending in live birth.
Economic evaluations were prepared both before and after fortification. Prior to
fortification, a CBA was published in 1993 and 1995 and a CEA was published in 1996.
Post fortification, this study conducted its own CEA and CBA. These evaluations were used
to assess the cost-effectiveness of folic acid fortification.

According to the CBA approach, the net benefit of folic acid fortification in reducing NTDs
is $422 million. This includes the $3 million reduction per year for fortification costs. In
comparison to the pre-fortification analysis, the economic benefits are 4.5 greater than
those originally projected. Additionally, the NTD prevention rate is 2 times greater than
what was predicted.

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Folic Acid SupplementationPRO

Annotated Bibliography

III. Evidence against our position.

The primary arguments against our position include folates role in cognitive
impairment, tumor progression, and impaired immunity. These cases provide data and cause
for concern against folic acid fortification of the U.S. food supply, and offer results that
contradict those presented by the PRO side. The results demonstrate significant detriments to
the health of a specific population--individuals over the age of 50, who have an increased risk
of vitamin B12 deficiency and colorectal cancer, associated with aging and lifestyle factors.
Evidence presented in studies such as these have formed the basis for the controversy
regarding folic acid fortification and have led some professionals to question the validity of the
folic acid recommendation and fortification dosage. These studies also contribute evidence to
the fact that much of the research regarding folate status and its implication on health
outcomes is varied and conflicting.

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Folic Acid SupplementationPRO

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Manshadi SD, Ishiguro L, Sohn KJ, Medline A, Renlund R, et al. (2014) Folic acid
supplementation promotes mammary tumor progression in a rat model. PLoS ONE 9(1):
e84635. Doi:10.1371/journal.pone.0084635
In an effort to establish the effect of folic acid supplementation on the progression of sentinel
mammary tumors, Manshadi, et al. conducted a chemical carcinogen rodent model clinical
trial, using 120 pathogen-free, 3-week-old female Sprague Dawley rats.
All of the rats were fed a control diet and were administered a single dose of 5 mg of 7,12dimethylbenza[a]anthracene (DMBA) to induce mammary tumor production at 7 weeks old.
Once the tumor reached its predetermined size, the rats were randomly divided to receive
diets containing 2mg (control), 5 mg, 8 mg, and 10 mg folic acid/kg for up to 12 weeks. The
control group received a dose of folic acid that mimics the RDA requirement for humans, and is
the standard basal dietary requirement for rats. The 5 mg group represents the average intake
of North American populations after the
fortification mandate, and approximately
matches the recommended amount for
females of childbearing years. The 8 and 10
mg/kg supplement groups reflect average
intake of patients receiving supplementation
for under medical supervision.
Tumor growth was monitored weekly and
upon necropsy, the tumors were weighed and analyzed to assess folic acids role in protein
expression and tissue growth.
Results indicate that folic acid supplementation significantly advanced the progression of
cancer, as measured by sentinel tumor weight, volume, and surface area. The most
accelerated growth occurred in the group supplemented with 5 mg of folic acid, the dosage
representing the average intake from fortified foods and multi-vitamin supplements. Folic acid
supplementation in the rats was also significantly associated with the expression of PARP (poly
[ADP-ribose] polymerase) and HER2 (human epidermal growth factor receptor 2), indicating a
role in cell apoptosis and tumorigenesis.

Figure 2. Effect of folic acid supplementation on the progression of sentinel mammary tumors. Folic acid supplementation at 5
mg/kg diet significantly accelerated the progression of sentinel mammary tumor over time compared with the control diet and two
higher supplemental levels of folic acid after correcting for age at randomization and days on diet (p=0.001).

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Annotated Bibliography

Morris MC, Evans DA, Bienias JL, et al. Dietary folate and vitamin B12 intake and cognitive
decline among community-dwelling older persons. Arch Neurol. 2005;62:641-645.
This study investigated the effect of vitamin B12 and folate intake on the rate of cognitive
decline in an elderly population. 3,718 residents of a specific biracial community, aged 65
years and older and participants of the Chicago Health and Aging Project took part in this
cohort study between the years 1993 and 2002.
The subjects completed a cognitive assessment at baseline, followed by a food frequency
questionnaire (FFQ) a median of 1.2 years later. 86% of the FFQs were completed before the
1998 United States folate fortification. The subjects participated in one to two cognitive
assessments at 3- and 6-year follow up dates, with 91% having at least one follow-up
assessment occurring post-fortification.
The participants were divided into five quintiles, based on level of total folate intake reported
in the FFQ:
Q1: 186 mcg/d
Q4: 419 mcg/d
Q2: 251 mcg/d
Q5: 742 mcg/d
Q3: 311 mcg/d
Results from the FFQs indicated that one-third of the participants consumed a multivitamin on
a regular basis, supplying 99% and 97% of the supplemented folic acid and vitamin B12. Only 10
subjects reported use of an individual folic acid vitamin. 42 members reported consuming an
individual B12 vitamin supplement. Participants with a greater total folate intake, from both
food and supplements, tended to be more educated, have higher baseline cognition scores,
greater consumption of antioxidants, and less disease history. However, these subjects also
demonstrated a faster rate of cognitive decline, compared to their lower folate-consuming
counterparts. The rate difference in cognitive decline was significantly different between Q1
and Q5. Furthermore, subjects who consumed more than 400 mcg/d from folate supplements
experienced a significantly faster rate of decline than non-supplement users. Vitamin B12 intake
only produced significant delays in cognitive function among the oldest members of the
population.

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Folic Acid SupplementationPRO

Annotated Bibliography

Guelpen BV, Hultdin J, Johansson L, et al. Low folate levels may protect against colorectal
cancer. An Int J of Gastroeneterology and Hepatology. 2006:55(10): 1461-1466.
The aim of this study was to address folic acid supplementations role in the development of
colorectal cancer (CRC). Reports have indicated that dietary folate may be both protective of
and pathogenic towards tumorigenesis in certain individuals. The researchers sought to
evaluate the relationship between pre-diagnostic plasma folate, homocysteine, and
methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C polymorphism
concentrations to the risk of developing CRC in this prospective population-based study.
Participants from the Northern Swedish Health and Disease Cohort were enlisted and included
subjects from the Northern Sweden WHO Monitoring of Trends and Cardiovascular Disease
(MONICA) Study, the Vasterbotten Intervention Project (VIP), and the local Mammography
Screening Project (MSP). Of these subjects, 226 cases and 437 matched referents (controls)
were enrolled. All CRC cases were diagnosed between 1985 and 2002 and confirmed at the
start of the study. Referents were cancer-free upon pairing to their matched case and all
subjects were free from previous colorectal cancer diagnoses.
Participants completed extensive food frequency and lifestyle questionnaires and donated
fasting blood samples at the start of the experiment. Follow-up samples were collected
between 2.4 and 6.7 (median of 4.2) years later.
Results indicated that plasma folate concentrations were significantly related to the risk of CRC
in a bell-shaped, rather than linear, manner. The odds ratio (OR) for the middle versus lowest
quintile of plasma folate concentration was 2.26 (95% CI). The OR for the highest versus lowest
quintile (>15.0 vs <5 nmol/L) was only 1.10 (95% CI). A subgroup analysis of subjects with
follow-up dates longer than the median 4.2 years interestingly indicated that plasma folate was
strongly positively related to CRC risk in a linear pattern. The OR for highest versus lowest
quintile in this subgroup was 3.87 (95% CI).
Plasma homocysteine concentrations, on the
other hand, were not associated with CRC risk
in any group. The results also suggest a
reduced risk associated with the MTHFR
677C>T polymorphism, independent of folate
status.

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Folic Acid SupplementationPRO

Annotated Bibliography

Morris, MS, Jacques PF, Rosenberg IH, Selhub J. Folate and vitamin B-12 status in relation to
anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid
fortification. Am J Clin Nutr. 2007;85:193-200.
Seniors aged 60 and older (mean age 70 +/- 0.32 y) who participated in the 1999-2002 U.S.
National Health and Nutrition Examination Survey (NHANES) were included in this study to
assess anemia, macrocytosis, and cognitive impairment related to folate and vitamin B-12
status.
Trained interviewers conducted assessments both in the participants homes and again at
mobile examination centers, where lab tests and physical exams were also performed. Blood
tests were analyzed for prevalence of anemia (women Hgb <12g/dL; men <13 g/dL) and
macrocytosis (MCV >99 fL). Cognitive function was assessed using the Digit Symbol-Coding
subtest of the Wechsler Adult Intelligence Scale III.
Serum levels of folate and vitamin B-12 were measured and classified as low (<148 pmol/L) or
elevated (>60-210 nmol/L). For the purpose of this experiment, folate was classified as a
continuous variable.
Anemia was identified in 4.5% of the seniors, with 25% of anemic subjects also expressing low
vitamin B-12 status (<148 pmol/L or serum MMA >210 nmol/L). Seniors with combined low
vitamin B-12 status and high serum folate concentrations accounted for about 4% of the total
study population. The researchers observed a significant association between serum vitamin B12 and serum folate, regardless of supplementation. Overall results indicate that low B-12
status may be indicative of cognitive impairment (OR: 2.5), macrocytosis (OR: 1.8), and anemia
(OR: 2.7). Low B-12 status and high serum folate (>59 nmol/L) status was associated with
anemia and cognitive impairment. In subjects with normal B-12 status, high folate status was
protective against cognitive impairment, compared to normal folate levels.

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Annotated Bibliography

Troen AM, Mitchell B, Sorensen B, Wener MH, Johnston A, et al. Unmetabolized folic acid in
plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal
women. J Nutr. 2006;136:189-194.
105 healthy postmenopausal women from the greater Seattle area were recruited from the
years 1998-2000 to participate in this study relating folic acid to natural kill (NK) cell
cytotoxicity. The women were between the ages 50-75 years, had a BMI between 25 and 40
kg/m2, and had no significant medical history.
Folate intake from food sources was assessed at the start of the study, using a 120-item FFQ.
Supplemental intake was recorded through interviews in which subjects brought their
supplement and vitamin containers to the meeting where labels were photocopied and
frequency of intake was recorded. Fasted blood draws were collected and analyzed at the
University of Washington to assess NK cell cytotoxicity. Follow-up blood samples were collected
and plasma concentrations of 5-methyl-tetrahydrofolate (THF), unmetabolized folic acid, and
total plasma folate concentrations were measured .
Subjects were classified 4 groups:
Low folate status (<233 mcg/d), with supplementation >400 mcg/d
Low folate status (<233 mcg/d), without supplementation
High folate status (>233 mcg/d), with supplementation >400 mcg/d
High folate status (>233 mcg/d), without supplementation
Association between FA supplementation and NK cell toxicity was observed in an inverse Ushape, indicating that moderate supplementation may increase NK cytotoxicity in the setting of
low dietary folate intake. Extreme high and low folate status may suppress NK cytotoxicity.
Additionally, NK cytotoxicity was significantly lower in women with unmetabolized circulating
FA. The findings suggest that immune function may be more easily modified among older
populations and that more research is needed to gain a better understanding of the
relationship between folate status and NK cell cytotoxicity.

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