Folate, distinct forms of which are known as folic acid, folacin, and
vitamin B9, is one of the B vitamins. The recommended daily
intake of folate in the US is 400 micrograms from foods or dietary
Folate in the form of folic acid is used to treat
anemia caused by folic acid deficiency.
Folic acid is also used as
a supplement by women during pregnancy to prevent neural tube defects
(NTD) in the baby. Low levels in early pregnancy are believed to
be the cause of more than half of babies born with neural tube
defects. More than 50 countries use fortification of certain foods
with folic acid as a measure to decrease the rate of NTDs in the
population. Long term supplementation is also associated with
small reductions in the risk of stroke and cardiovascular disease.
It may be taken by mouth or by injection.
There are no common side effects. It is not known whether high
doses over a long period of time are of concern. There are concerns
that large amounts of folic acid might hide vitamin B12 deficiency.
Folic acid is essential for the body to make DNA, RNA, and metabolise
amino acids which are required for cell division. As humans cannot
make folic acid, it is required from the diet, making it an essential
Not consuming enough folate can lead to folate deficiency. This may
result in a type of anemia in which low numbers of large red blood
cells occur. Symptoms may include feeling tired, heart
palpitations, shortness of breath, open sores on the tongue and
changes in the color of the skin or hair.
Folate deficiency in
children may develop within a month of poor dietary intake. In
adults, normal total body folate is between
10,000–30,000 micrograms (µg) with blood levels of greater
than 7 nmol/L (3 ng/mL).
Folic acid was discovered between 1931 and 1943. It is on the
World Health Organization's List of Essential Medicines, the most
effective and safe medicines needed in a health system. The
wholesale cost of supplements in the developing world is between 0.001
and 0.005 USD per dose as of 2014. The term "folic" is from the
Latin word folium, which means leaf. Folates occur naturally in
many foods, especially dark green leafy vegetables, liver, and
2 Health effects
2.3 Heart disease
2.7 Age related macular degeneration
2.8 Folic acid, B12 and iron
3 Dietary recommendations
5 Biological roles
DNA and cell division
DNA and amino acid production
5.3 Conversion to biologically active derivatives
5.3.1 Overview of drugs that interfere with folate reactions
6 Food fortification
6.2.1 Supplementation promotion
6.3 New Zealand
6.4 United Kingdom
6.5 United States
7 See also
"Folate" is the term used to name the many forms of the vitamin —
namely folic acid and its congeners, including tetrahydrofolic acid
(the activated form of the vitamin), methyltetrahydrofolate,
methenyltetrahydrofolate, folinic acid, and folacin.
People sometimes confuse this use of "folate" with the use of "folate"
in the standard way of naming acids in organic chemistry, in which the
complete compound is called "X-ic acid", but rather is called "X-ate"
when it loses a proton; acids shift back and forth between these forms
based on the acidity of the solution in which they are found. In this
usage, "folate" is just "folic acid" in a non-acidic solution.
Other names include vitamin B9, vitamin Bc, vitamin M, and
Folate intake during pregnancy has been linked to a lessened risk of
neural tube defects. Likewise a meta-analysis of folate
supplementation during pregnancy reported a 28% lower risk of newborn
congenital heart defects. The United States Preventive Services
Task Force recommends the folic acid supplementation for all women
able to become pregnant; forms of folate other than folic acid have
not been studied for this use and are not recommended.
Prenatal supplementation with folic acid did not appear to reduce the
risk of preterm births. One systematic review indicated no
effect of folic acid on mortality, growth, body composition,
respiratory, or cognitive outcomes of children from birth to 9 years
old. There was no correlation between maternal folic acid
supplementation and an increased risk for childhood asthma.
Folate is necessary for fertility in both men and women. It
contributes to spermatogenesis. Therefore, it is necessary to receive
sufficient amounts through the diet to avoid subfertility. Also,
polymorphisms in genes of enzymes involved in folate metabolism could
be one reason for fertility complications in some women with
Taking folic acid over years reduced the risk of cardiovascular
disease by 4%, where another study found it did not affect
cardiovascular disease, even while reducing homocysteine levels.
Several studies provided preliminary evidence that folate-rich diets
were associated with reduced risk of cardiovascular diseases by
lowering blood levels of homocysteine.
Long-term supplementation with folic acid reduced the risk of stroke
by 10%, which may be due to the role folate plays in regulating
homocysteine concentration. The reviews indicate the risk of
stroke appears to be reduced only in some individuals, but a definite
recommendation regarding supplementation beyond the current RDA has
not been established for stroke prevention. Asian populations had
greater protection against stroke with folate supplementation than did
European or North American subjects.
Observed stroke reduction is consistent with the reduction in pulse
pressure produced by folate supplementation of 5 mg per day,
since hypertension is a key risk factor for stroke. Folic supplements
are inexpensive and relatively safe to use, which is why people who
have had strokes or who have hyperhomocysteinemia are encouraged to
B vitamins including folic acid.
Studies on folic acid intake from food and folate supplementation with
regards to cancer risk are based on the adequacy of chronic intake.
Chronically insufficient intake of folic acid (below the recommended
level of 400 micrograms per day) may increase the risk of
colorectal, breast, ovarian, pancreas, brain, lung, cervical, and
prostate cancers. Other studies showed that
excessive dietary supplementation with synthetic folate may increase
the risk of certain cancers, in particular prostate. A 2017
review found no relationship between taking folate supplements and
Folate is important for cells and tissues that divide rapidly.
Cancer cells divide rapidly, and drugs that interfere with folate
metabolism are used to treat cancer. The antifolate methotrexate is a
drug often used to treat cancer because it inhibits the production of
the active form of THF from the inactive dihydrofolate (DHF). However,
methotrexate can be toxic, producing side effects, such as
inflammation in the digestive tract that make it difficult to eat
normally. Also, bone marrow depression (inducing leukopenia and
thrombocytopenia), and acute kidney and liver failure have been
Folinic acid, under the drug name leucovorin, a form of folate
(formyl-THF), can help "rescue" or reverse the toxic effects of
Folinic acid is not the same as folic acid. Folic
acid supplements have little established role in cancer
chemotherapy. There have been cases of severe adverse effects
of accidental substitution of folic acid for folinic acid in people
receiving methotrexate cancer chemotherapy. It is important for anyone
receiving methotrexate to follow medical advice on the use of folic or
folinic acid supplements. The supplement of folinic acid in people
undergoing methotrexate treatment is to give cells dividing less
rapidly enough folate to maintain normal cell functions. The amount of
folate given is depleted by rapidly dividing cells (cancer) quickly,
and so does not negate the effects of methotrexate.
Some evidence links a shortage of folate with depression. Limited
evidence from randomised controlled trials showed using folic acid in
addition to SSRIs may have benefits. Research found a link between
depression and low levels of folate.
Folate may reduce
homocysteine levels which are associated with cognitive functions.
The exact mechanisms involved in the development of schizophrenia and
depression are not entirely clear, but the bioactive folate,
methyltetrahydrofolate (5-MTHF), a direct target of methyl donors like
S-adenosyl methionine (SAMe), recycles the inactive dihydrobiopterin
(BH2) into tetrahydrobiopterin (BH4), the necessary cofactor in
various steps of monoamine synthesis, including that of dopamine. BH4
serves a regulatory role in monoamine neurotransmission and is
required to mediate the actions of most antidepressants. 5-MTHF also
plays both direct & indirect roles in
DNA methylation, NO2
synthesis, and one-carbon metabolism.
Age related macular degeneration
A sub study of the Women's Antioxidant and Folic Acid Cardiovascular
Study published in 2009 reported use of a nutritional supplement
containing folic acid, pyridoxine, and cyanocobalamin decreased the
risk of developing age-related macular degeneration by 34.7%. The
amount of folic acid used in this clinical trial – 2500 μg – was
higher than the Tolerable Upper Intake Level of 1000 μg.
Folic acid, B12 and iron
There is a complex interaction between folic acid, vitamin B12 and
iron. A deficiency of one may be "masked" by excess of another so the
three must always be in balance.
The risk of toxicity from folic acid is low, because folate is a
water-soluble vitamin and is regularly removed from the body through
urine. One potential issue associated with high dosages of folic
acid is that it has a masking effect on the diagnosis of pernicious
anaemia (vitamin B12 deficiency), and a variety of
concerns[clarification needed] of potential negative impacts on
Folate deficiency can be caused by unhealthy diets that do not include
enough fruits and vegetables, diseases in which folates are not well
absorbed in the digestive system (such as
Crohn's disease or celiac
disease), some genetic disorders that affect levels of folate, and
certain medicines (such as phenytoin, sulfasalazine, or
Folate deficiency is accelerated
by alcohol consumption.
Folate deficiency may lead to glossitis, diarrhea, depression,
confusion, anemia, and fetal neural tube defects and brain defects
(during pregnancy). Other symptoms include fatigue, gray hair,
mouth sores, poor growth, and swollen tongue.
Folate deficiency is
diagnosed by analyzing CBC and plasma vitamin B12 and folate
levels. CBC may indicate megaloblastic anemia but this could also
be a sign of vitamin B12 deficiency. A serum folate of 3 μg/L or
lower indicates deficiency. Serum folate level reflects folate
status but erythrocyte folate level better reflects tissue stores
after intake. Serum folate reacts more rapidly to folate intake
than erythrocyte folate. An erythrocyte folate level of 140 μg/L
or lower indicates inadequate folate status. Increased
homocysteine level suggests tissue folate deficiency but homocysteine
is also affected by vitamin B12 and vitamin B6, renal function, and
One way to differentiate between folate (vitamin B9) deficiency from
vitamin B12 deficiency is by testing for methylmalonic acid
levels. Normal MMA levels indicate folate deficiency and elevated
MMA levels indicate vitamin B12 deficiency.
Folate deficiency is
treated with supplemental oral folic acid of 400 to 1000 μg per day.
This treatment is very successful in replenishing tissues, even if
deficiency was caused by malabsorption. People with megaloblastic
anemia need to be tested for vitamin B12 deficiency before treatment
with folic acid, because if the person has vitamin B12 deficiency,
folic acid supplementation can remove the anemia, but can also worsen
neurologic problems. Cobalamin deficiency may lead to folate
deficiency, which, in turn, increases homocysteine levels and may
result in the development of cardiovascular disease or birth
Some studies show iron–folic acid supplementation in children under
5 may result in increased mortality due to malaria; this has prompted
the World Health Organization to alter their iron–folic acid
supplementation policies for children in malaria-prone areas, such as
Because of the difference in bioavailability between supplemented
folic acid and the different forms of folate found in food, the
dietary folate equivalent (DFE) system was established. One DFE is
defined as 1 μg of dietary folate. One μg of folic acid
supplement counts as 1.7 μg DFE. The reason for the difference is
that at least 85% of folic acid is estimated to be bioavailable when
taken with food, whereas only about 50% of folate naturally present in
food is bioavailable.
National Institutes of Health
National Institutes of Health (US) nutritional recommendations
(µg DFE per day for RDA, µg folic acid for UL )
Pregnant women (RDA)
Pregnant women (UL)
Lactating women (RDA)
Lactating women (UL)
Institute of Medicine
Institute of Medicine (IOM) updated Recommended Dietary
Allowances (RDAs) for folate in 2001. As for safety, the IOM sets
Tolerable upper intake levels (ULs) for vitamins and minerals when
evidence is sufficient. The UL for folate refers to only micrograms of
synthetic folic acid, as no health risks have been associated with
high intake of folate from food sources. Collectively the EARs, RDAs,
AIs and ULs are referred to as Dietary Reference Intakes
European Food Safety Authority
European Food Safety Authority (EFSA) refers to the collective set
of information as Dietary Reference Values, with Population Reference
Intake (PRI) instead of RDA, and Average Requirement instead of EAR.
AI and UL defined the same as in United States. For women and men over
age 18 the PRI is set at 330 μg/day. PRI for pregnancy is 600
μg/day, for lactation 500 μg/day. For children ages 1–17 years the
PRIs increase with age from 120 to 270 μg/day. These values differ
somewhat from the U.S. RDAs. The EFSA also reviewed the safety
question and agreed with United States that the UL be set at 1000
For U.S. food and dietary supplement labeling purposes, the amount in
a serving is expressed as a percent of Daily Value (%DV). For folate
labeling purposes, 100% of the Daily Value was 400 μg. As of the May
27, 2016 update, it was kept unchanged at 400 μg. A table of the
old and new adult Daily Values is provided at Reference Daily Intake.
Food and supplement companies have until January 1, 2020 to comply
with the change.
Vitamins C and M as featured on a monument in front of University of
Warsaw's Centre of New Technologies
Folate naturally occurs in a wide variety of foods, including
vegetables (particularly dark green leaf vegetables), fruits and fruit
juices, nuts, soybeans, chickpeas, dairy products, poultry and meat,
eggs, seafood, grains, and some beers. Avocado, beetroot,
spinach, liver, yeast, asparagus, kale, and Brussels sprouts are among
the foods with the highest levels of folate.
found in food is susceptible to high heat and ultraviolet light, and
is soluble in water. It is heat-labile in acidic environments and
may also be subject to oxidation.
Folic acid is added to grain products in many countries, and these
fortified products make up a significant source of the population's
Enriched flour – used for processed foods like
pasta, bread, and breakfast cereals – and fortified rice typically
In the 1920s, scientists believed folate deficiency and anemia were
the same condition. In 1931, researcher
Lucy Wills made a key
observation that led to the identification of folate as the nutrient
required to prevent anemia during pregnancy. Wills demonstrated that
anemia could be reversed with brewer's yeast. In the late 1930s,
folate was identified as the corrective substance in brewer's yeast.
It was first isolated via extraction from spinach leaves by Herschel
K. Mitchell, Esmond E. Snell, and
Roger J. Williams in 1941. Bob
Stokstad isolated the pure crystalline form in 1943, and was able to
determine its chemical structure while working at the Lederle
Laboratories of the American Cyanamid Company. This historical
research project, of obtaining folic acid in a pure crystalline form
in 1945, was done by the team called the "folic acid boys," under the
supervision and guidance of Director of Research Dr. Yellapragada
Subbarow, at the Lederle Lab, Pearl River, NY.
This research subsequently led to the synthesis of the antifolate
aminopterin, the first-ever anticancer drug, the clinical efficacy was
Sidney Farber in 1948. In the 1950s and 1960s, scientists
began to discover the biochemical mechanisms of action for folate.
In 1960, experts first linked folate deficiency to neural tube
defects. In the late 1990s, US scientists realized, despite the
availability of folate in foods and in supplements, there was still a
challenge for people to meet their daily folate requirements, which is
when the US implemented the folate fortification program.
DNA and cell division
A diagram of the chemical structure of folate
Folate is necessary for the production and maintenance of new cells,
DNA synthesis and
RNA synthesis through methylation, and for
preventing changes to DNA, and, thus, for preventing cancer. It is
especially important during periods of frequent cell division and
growth, such as infancy and pregnancy.
Folate is needed to carry
one-carbon groups for methylation reactions and nucleic acid synthesis
(the most notable one being thymine, but also purine bases). Thus,
folate deficiency hinders
DNA synthesis and cell division, affecting
hematopoietic cells and neoplasms the most because of their greater
frequency of cell division.
RNA transcription, and subsequent protein
synthesis, are less affected by folate deficiency, as the m
RNA can be
recycled and used again (as opposed to
DNA synthesis, where a new
genomic copy must be created). Since folate deficiency limits cell
division, erythropoiesis, production of red blood cells, is hindered
and leads to megaloblastic anemia, which is characterized by large
immature red blood cells. This pathology results from persistently
thwarted attempts at normal
DNA repair, and cell
division, and produces abnormally large red cells called megaloblasts
(and hypersegmented neutrophils) with abundant cytoplasm capable of
RNA and protein synthesis, but with clumping and fragmentation of
nuclear chromatin. Some of these large cells, although immature
(reticulocytes), are released early from the marrow in an attempt to
compensate for the anemia. Both adults and children need folate to
make normal red and white blood cells and prevent anemia.
Deficiency of folate in pregnant women has been implicated in neural
tube defects (NTD); therefore, many developed countries have
implemented mandatory folic acid fortification in cereals, etc. NTDs
occur early in pregnancy (first month), therefore women must have
abundant folate upon conception.
Folate is required to make red blood
cells and white blood cells and folate deficiency may lead to anemia,
which causes fatigue, weakness and inability to concentrate.
DNA and amino acid production
Metabolism of folic acid to recycle homocysteine into methionine
In the form of a series of tetrahydrofolate (THF) compounds, folate
derivatives are substrates in a number of single-carbon-transfer
reactions, and also are involved in the synthesis of dTMP
(2′-deoxythymidine-5′-phosphate) from dUMP
(2′-deoxyuridine-5′-phosphate). It is a substrate for an important
reaction that involves vitamin B12 and it is necessary for the
synthesis of DNA, and so required for all dividing cells.
The pathway leading to the formation of tetrahydrofolate (FH4) begins
when folic acid (F) is reduced to dihydrofolate (DHF) (FH2), which is
then reduced to THF.
Dihydrofolate reductase catalyses the last
Vitamin B3 in the form of
NADPH is a necessary cofactor for
both steps of the synthesis. Thus, hydride molecules are transferred
NADPH to the C6 position of the pteridine ring to reduce folic
acid to THF.
Methylene-THF (CH2FH4) is formed from THF by the addition of a
methylene bridge from one of three carbon donors: formate, serine, or
Methyl tetrahydrofolate (CH3-THF, or methyl-THF) can be made
from methylene-THF by reduction of the methylene group with NADPH.
Another form of THF, 10-formyl-THF, results from oxidation of
methylene-THF or is formed from formate donating formyl group to THF.
Also, histidine can donate a single carbon to THF to form
Vitamin B12 is the only acceptor of methyl-THF, and this reaction
produces methyl-B12 (methylcobalamin). There is also only one acceptor
for methyl-B12, homocysteine, in a reaction catalyzed by homocysteine
methyltransferase. These reactions are important because a defect in
homocysteine methyltransferase or a deficiency of B12 may lead to a
so-called "methyl-trap" of THF, in which THF converts to a reservoir
of methyl-THF. Thereafter, this THF has no way of being metabolized,
and serves as a sink of THF that causes a subsequent deficiency in
folate. Thus, a deficiency in B12 can generate a large pool of
methyl-THF that is unable to undergo reactions and mimics folate
The reactions that lead to the methyl-THF reservoir can be shown in
folate → dihydrofolate → tetrahydrofolate ↔ methylene-THF →
Conversion to biologically active derivatives
All the biological functions of folic acid are performed by
tetrahydrofolate and other derivatives. Their biological availability
to the body depends upon dihydrofolate reductase action in the liver.
This action is unusually slow in humans, being less than 2% of that in
rats (and with an almost-5-fold variation in enzymatic activity),
leading to the accumulation of unmetabolized folic acid. It has
been suggested this low activity limits the conversion of folic acid
into its biologically active forms "when folic acid is consumed at
levels higher than the Tolerable Upper Intake Level (1 mg/d for
Overview of drugs that interfere with folate reactions
A number of drugs interfere with the biosynthesis of folic acid and
THF. Among them are the dihydrofolate reductase inhibitors such as
trimethoprim, pyrimethamine, and methotrexate; the sulfonamides
(competitive inhibitors of
4-aminobenzoic acid in the reactions of
Valproic acid, one of the most commonly prescribed anticonvulsants
that is also used to treat certain psychological conditions, is a
known inhibitor of folic acid, and as such, has been shown to cause
neural tube defects and cases of spina bifida and cognitive impairment
in the newborn. Because of this considerable risk, those mothers who
must continue to use valproic acid or its derivatives during pregnancy
to control their condition (as opposed to stopping the drug or
switching to another drug or to a lesser dose) should take folic acid
supplements under the direction and guidance of their health care
The National Health and
Nutrition Examination Survey (NHANES III
1988–91) and the Continuing Survey of Food Intakes by Individuals
(1994–96 CSFII) indicated most adults did not consume adequate
folate. However, the folic acid fortification program in the
United States has increased folic acid content of commonly eaten foods
such as cereals and grains, and as a result, diets of most adults now
provide recommended amounts of folate equivalents.
In the USA many grain products are fortified with folic acid.
See also: Food fortification
Folic acid fortification is a process where folic acid is added to
flour with the intention of promoting public health through increasing
blood folate levels in the populace. In the USA, food is fortified
with folic acid, only one of the many naturally occurring forms of
folate, and a substance contributing only a minor amount to the
folates in natural foods.
Since the discovery of the link between insufficient folic acid and
neural tube defects, governments and health organizations worldwide
have made recommendations concerning folic acid supplementation for
women intending to become pregnant.
Fortification is controversial, with issues having been raised
concerning individual liberty, as well as the health concerns
described in the Toxicity section above. In the USA, there is concern
that the federal government mandates fortification, but does not
provide monitoring of potential undesirable effects of
There has been previous debate in
Australia regarding the inclusion of
folic acid in products such as bread and flour.
New Zealand have jointly agreed to fortification though
the Food Standards
Australia New Zealand.
Australia will fortify all
flour from 18 September 2009. Although the food standard covers
Australia and New Zealand, an Australian government official has
stated it is up to
New Zealand to decide whether to implement it
there, and they will watch with interest.
The requirement is 0.135 mg of folate per 100g of bread.
Folic acid food fortification became mandatory in
Canada in 1998, with
the fortification of 150 µg of folic acid per 100 grams of
enriched flour and uncooked cereal grains. The purpose of
fortification was to decrease the risk of neural tube defects in
newborns. It is important to fortify grains because it is a widely
eaten food and the neural tube closes in the first four weeks of
gestation, often before many women even know they are pregnant.
Canada's fortification program has been successful with a decrease of
neural tube defects by 19% since its introduction. A
seven-province study from 1993 to 2002 showed a reduction of 46% in
the overall rate of neural tube defects after folic acid fortification
was introduced in Canada. The fortification program was estimated
to raise a person’s folic acid intake level by
70–130 µg/day; however, an increase of almost double that
amount was actually observed. This could be from the fact that
many foods are over fortified by 160–175% the predicted value.
In addition, much of the elder population take supplements that adds
400 µg to their daily folic acid intake. This is a concern
because 70–80% of the population have detectable levels of
unmetabolized folic acid in their blood and high intakes can
accelerate the growth of preneoplastic lesions. It is still
unknown the amount of folic acid supplementation that might cause
According to a Canadian survey, 58% of women said they took a folic
acid containing multivitamin or a folic acid supplement as early as
three months before becoming pregnant. Women in higher income
households and with more years of school education are using more
folic acid supplements before pregnancy. Women with planned
pregnancies and who are over the age of 25 are more likely to use
folic acid supplement. Canadian public health efforts are focused on
promoting awareness of the importance of folic acid supplementation
for all women of childbearing age and decreasing socio-economic
inequalities by providing practical folic acid support to vulnerable
groups of women.
New Zealand was planning to fortify bread (excluding organic and
unleavened varieties) from 18 September 2009, but has opted to wait
until more research is done.
The Association of Bakers  and the Green Party  have opposed
mandatory fortification, describing it as "mass medication". Food
Safety Minister Kate Wilkinson reviewed the decision to fortify in
July 2009, citing links between overconsumption of folate with cancer
New Zealand Government is reviewing whether it will
continue with the mandatory introduction of folic acid to bread.
There has been previous debate in the
United Kingdom regarding the
inclusion of folic acid in products such as bread and flour.
Food Standards Agency
Food Standards Agency has recommended folic acid
fortification, and wheat flour is fortified with
iron, folic acid fortification of wheat flour is allowed
voluntarily rather than required.
United States Public Health Service
United States Public Health Service recommends an extra
0.4 mg/day for newly pregnant women, which they can take as a
pill. However, many researchers believe this supplementation can never
work effectively enough, since about half of all pregnancies in the
U.S. are unplanned, and not all women comply with the recommendation.
Approximately 53% of the US population uses dietary supplements and
35% uses dietary supplements that contain folic acid.
Men consume more folate (in dietary folate equivalents) than women,
and non-Hispanic whites have higher folate intakes than Mexican
Americans and non-Hispanic blacks. Twenty-nine percent of black
women have inadequate intakes of folate. The age group consuming
the most folate and folic acid is the >50 group. 5% of the
population exceeds the Tolerable Upper Intake Level.
In 1996, the United States
Food and Drug Administration
Food and Drug Administration (FDA)
published regulations requiring the addition of folic acid to enriched
breads, cereals, flours, corn meals, pastas, rice, and other grain
products. This ruling took effect on 1 January 1998, and was
specifically targeted to reduce the risk of neural tube birth defects
in newborns. There are concerns that the amount of folate added
is insufficient . In October 2006, the Australian press claimed
that U.S. regulations requiring fortification of grain products were
being interpreted as disallowing fortification in non-grain products,
Vegemite (an Australian yeast extract containing folate).
The FDA later said the report was inaccurate, and no ban or other
action was being taken against Vegemite.
As a result of the folic acid fortification program, fortified foods
have become a major source of folic acid in the American diet. The
Centers for Disease Control and Prevention
Centers for Disease Control and Prevention in
Atlanta, Georgia used
data from 23 birth defect registries covering about half of United
States births, and extrapolated their findings to the rest of the
country. These data indicate that, since the addition of folic acid in
grain-based foods as mandated by the FDA, the rate of neural tube
defects dropped by 25% in the United States. Before folic acid
fortification, about 4,100 pregnancies were affected by a neural tube
defect each year in the United States. After fortification, this
number declined to around 3,000. The results of folic acid
fortification on the rate of neural tube defects in
Canada have also
been positive, showing a 46% reduction in prevalence of NTDs; the
magnitude of reduction was proportional to the prefortification rate
of NTDs, essentially removing geographical variations in rates of NTDs
Canada before fortification.
When the U.S.
Food and Drug Administration
Food and Drug Administration set the folic acid
fortification regulation in 1996, the projected increase in folic acid
intake was 100 µg/d. Data from a study with 1480 subjects
showed that folic acid intake increased by 190 µg/d and total
folate intake increased by 323 µg dietary folate equivalents
Folic acid intake above the upper tolerable intake level
(1000 µg folic acid/d) increased only among those individuals
consuming folic acid supplements as well as folic acid found in
fortified grain products. Taken together, folic acid
fortification has led to a bigger increase in folic acid intake than
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Folate biosynthesis (early stages)
Folate biosynthesis (later stages)
C1 metabolism with folate
Formylation, hydroxymethylation and methylation using folate
chemical elements ("minerals")
Pantothenic acid (B5)
Folic acid (B9)
Ascorbic acid (
Other common ingredients
Cod liver oil
Grape seed extract
Red yeast rice
St John's wort
Pyridoxine#, Pyridoxal phosphate
‡Withdrawn from market
§Never to phase III
Pharmacy and pharmacology port