Folic acid

Folic acid
Skeletal formula
Ball-and-stick model
Space-filling model
Folic acid as an orange powder
Names
IUPAC name
(2S)-2-[[4-[(2-Amino-4-oxo-1H-pteridin-6-yl)methylamino]benzoyl]amino]pentanedioic acid[1]
Other names
N-(4-{[(2-amino-4-oxo-1,4-dihydropteridin-6-yl)methyl]amino}benzoyl)-L-glutamic acid; pteroyl-L-glutamic acid; Vitamin B9; Vitamin Bc; Vitamin M; Folacin
Identifiers
59-30-3 YesY
ChEBI CHEBI:27470 YesY
ChEMBL ChEMBL1622 YesY
ChemSpider 5815 YesY
DrugBank DB00158 YesY
4563
Jmol interactive 3D Image
KEGG C00504 N
PubChem 6037
RTECS number LP5425000
UNII 935E97BOY8 YesY
Properties
C19H19N7O6
Molar mass 441.40 g·mol−1
Appearance yellow-orange crystalline powder
Melting point 250 °C (482 °F; 523 K) (decomposition) [2]
1.6 mg/L (25 °C)[2]
log P -2.5
Acidity (pKa) 1st: 4.65, 2nd: 6.75, 3rd: 9.00[3]
Pharmacology
ATC code B03BB01
Hazards
NFPA 704
Flammability code 0: Will not burn. E.g., water Health code 1: Exposure would cause irritation but only minor residual injury. E.g., turpentine Reactivity code 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g., liquid nitrogen Special hazards (white): no codeNFPA 704 four-colored diamond
0
1
0
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references

Folic acid or folate is a B vitamin. It is also referred to as vitamin M,[4] vitamin B9,[5] vitamin Bc[6] (or folacin), pteroyl-L-glutamic acid, and pteroyl-L-glutamate.[7]

Food supplement manufacturers often use the term folate for something different from "pure" folic acid: in chemistry, folate refers to the deprotonated ion, and folic acid to the neutral molecule—which both coexist in water. The International Union of Pure and Applied Chemistry and the International Union of Biochemistry and Molecular Biology state that folate and folic acid are the preferred synonyms for pteroylglutamate and pteroylglutamic acid, respectively.[8]

Folate indicates a collection of "folates" that is not chemically well-characterized, including other members of the family of pteroylglutamates, or mixtures of them, having various levels of reduction of the pteridine ring, one-carbon substitutions and different numbers of glutamate residues.

Folic acid is synthetically produced, and used in fortified foods and supplements on the theory that it is converted into folate.[9] However, folic acid is a synthetic oxidized form, not significantly found in fresh natural foods. To be used it must be converted to tetrahydrofolate (tetrahydrofolic acid) by dihydrofolate reductase (DHFR). Increasing evidence suggests that this process may be slow in humans.[10]

Vitamin B9 is essential for numerous bodily functions. Humans cannot synthesize folates de novo; therefore, folic acid has to be supplied through the diet to meet their daily requirements. The human body needs folate to synthesize DNA, repair DNA, and methylate DNA as well as to act as a cofactor in certain biological reactions.[11] It is especially important in aiding rapid cell division and growth, such as in infancy and pregnancy. Children and adults both require folate to produce healthy red blood cells and prevent anemia.[12]

Folate and folic acid derive their names from the Latin word folium, which means "leaf". Folates occur naturally in many foods and, among plants, are especially plentiful in dark green leafy vegetables.[13]

A lack of dietary folates can lead to folate deficiency. A complete lack of dietary folate takes months before deficiency develops as normal individuals have about 500–20,000 micrograms ( µg)[14] of folate in body stores.[15] This deficiency can result in many health problems, the most notable one being neural tube defects in developing embryos—a relatively rare birth defect affecting 300,000 (0.2%) births[16] globally each year and 3,000 pregnancies in the United States each year.[17] Common symptoms of folate deficiency include diarrhea, macrocytic anemia with weakness or shortness of breath, nerve damage with weakness and limb numbness (peripheral neuropathy),[18] pregnancy complications, mental confusion, forgetfulness or other cognitive deficits, mental depression, sore or swollen tongue, peptic or mouth ulcers, headaches, heart palpitations, irritability, and behavioral disorders. Low levels of folate can also lead to homocysteine accumulation.[11] Low levels of folate have been associated with specific cancers.[11] However, it is not clear whether consuming recommended (or higher) amounts of folic acid—from foods or in supplements—can lower cancer risk in some people.[19]

Health effects

Pregnancy

Adequate folate intake during the preconception period (which is the time right before and just after a woman becomes pregnant) helps protect against a number of congenital malformations, including neural tube defects, which are the most notable birth defects that occur from folate insufficiency.[20] Neural tube defects are severe abnormalities of the central nervous system that develop in embryos during the first few weeks of pregnancy resulting in malformations of the spine, skull, and brain; the most common neural tube defects are spina bifida and anencephaly. The risk of neural tube defects is significantly reduced when supplemental folic acid is consumed in addition to a healthy diet before conception and during the first month after conception.[21][22] Supplementation with folic acid has also been shown to reduce the risk of congenital heart defects, cleft lips,[23] limb defects, and urinary tract anomalies.[24] Folate deficiency during pregnancy may also increase the risk of preterm delivery, infant low birth weight and fetal growth retardation, as well as increasing homocysteine level in the blood, which may lead to spontaneous abortion and pregnancy complications, such as placental abruption and pre-eclampsia.[25] Women who could become pregnant are advised to eat foods fortified with folic acid or take supplements in addition to eating folate-rich foods to reduce the risk of serious birth defects.[26] Some have suggested that all non-pregnant women take 400 micrograms of synthetic folic acid daily from fortified foods or supplements to ensure they have adequate folic acid intake, even in case of unplanned pregnancies.[27] The RDA for folate equivalents for pregnant women is set at 600 micrograms,[28] although a range of 400 µg up to 4 mg (4000 µg) reported in an old U.S. Public Health Service guideline is still followed by many health care providers.[27][29][30][31] The mechanisms and reasons why folic acid prevents birth defects is unknown.[32] It is hypothesized that the insulin-like growth factor 2 gene is differentially methylated and these changes result in improved intrauterine growth and development.[32] Failure of post-translational methylation of the cytoskeleton, required for differentiation has been implicated in neural tube defects.[33] Approximately 85% of women in an urban Irish study reported using folic acid supplements before they become pregnant, but only 18% used enough folic acid supplements to meet the current folic acid requirements due, it is reported, to socio-economic challenges.[34] Folic acid supplements may also protect the fetus against disease when the mother is battling a disease or taking medications or smoking during pregnancy.[35]

It also contributes to oocyte maturation, implantation, placentation, in addition to the general effects of folic acid and pregnancy. Therefore, it is necessary to receive sufficient amounts through the diet to avoid subfertility.[36]

There is growing concern worldwide that prenatal high folic acid in the presence of low vitamin B12 causes epigenetic changes in the unborn predisposing them to metabolic syndromes, central adiposity and adult diseases such as Type 2 diabetes.[37] Another active area of research and concern is that either too much or too little folic acid in utero causes epigenetic changes to the brain leading to autism spectrum disorders.[38][39][40] Epidemiologic studies have been demonstrating a correlation between maternal folic supplementation with folic acid and increased risk for asthma and respiratory diseases in children.[41][42] However, a systematic review and meta-analysis did not confirm such findings and recommends additional studies to verify the hypothesis.[43]

Fertility

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.[36] Also, polymorphisms in genes of enzymes involved in folate metabolism could be one reason for fertility complications in some women with unexplained infertility.[44]

Heart disease

Taking folic acid does not reduce cardiovascular disease even though it reduces homocysteine levels.[45]

Folic acid supplements consumed before and during pregnancy may reduce the risk of heart defects in infants.[46]

Stroke

Folic acid appears to reduce the risk of stroke, 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.[47] 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 stroke or hyperhomocysteinemia patients are encouraged to consume daily B vitamins including folic acid.[48]

Cancer

Folic acid supplementation does not appear to affect the rate of cancer.[49][50]

Diets high in folate are associated with decreased risk of colorectal cancer; some studies show the association is stronger for folate from foods alone than for folate from foods and supplements,[51] One broad cancer screening trial reported a potential harmful effect of too much folate intake on breast cancer risk, suggesting routine folate supplementation should not be recommended as a breast cancer preventive.[52] Most research studies indicate that dietary folate intake does not significantly increase or decrease the risk of prostate cancer.[53]

Antifolate chemotherapy

Folate is important for cells and tissues that rapidly divide.[54] 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,[55][56][57] 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 reported.

Folinic acid, under the drug name leucovorin, a form of folate (formyl-THF), can help "rescue" or reverse the toxic effects of methotrexate.[58] Folinic acid is not the same as folic acid. Folic acid supplements have little established role in cancer chemotherapy.[59][60] There have been cases of severe adverse effects of accidental substitution of folic acid for folinic acid in patients 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 patients 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.

Psychological

Some evidence links a shortage of folate with depression.[61] Limited evidence from randomised controlled trials showed using folic acid in addition to SSRIs may have benefits.[62] Research at the University of York and Hull York Medical School has found a link between depression and low levels of folate.[63] One study by the same team involved 15,315 subjects.[64] However, the evidence is probably too limited at present for this to be a routine treatment recommendation. Folic acid supplementation affects noradrenaline and serotonin receptors within the brain, which could be the cause of folic acid's possible ability to act as an antidepressant.[65][66] 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.[67]

Macular degeneration

A substudy 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%.[68]

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.[69][70][71]

Toxicity

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.[72] 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),[31] and a variety of concerns of potential negative impacts on health.[73]

Folate deficiency

Main article: Folate deficiency

Folate deficiency can be caused by unhealthy diets that do not include enough fruits and vegetables, diseases in which folic acid is 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 trimethoprim-sulfamethoxazole).[74] Folate deficiency is accelerated by alcohol consumption.[75]

Folate deficiency may lead to glossitis, diarrhea, depression, confusion, anemia, and fetal neural tube defects and brain defects (during pregnancy).[76] Other symptoms include fatigue, gray hair, mouth sores, poor growth, and swollen tongue.[74] Folate deficiency is diagnosed by analyzing CBC and plasma vitamin B12 and folate levels.[76] CBC may indicate megaloblastic anemia but this could also be a sign of vitamin B12 deficiency.[76] A serum folate of 3 μg/L or lower indicates deficiency.[76] Serum folate level reflects folate status but erythrocyte folate level better reflects tissue stores after intake.[76] Serum folate reacts more rapidly to folate intake than erythrocyte folate.[77] An erythrocyte folate level of 140 μg/L or lower indicates inadequate folate status.[76] Increased homocysteine level suggests tissue folate deficiency but homocysteine is also affected by vitamin B12 and vitamin B6, renal function, and genetics.[76]

One way to differentiate between folate deficiency from vitamin B12 deficiency is by testing for methylmalonic acid levels.[76] Normal MMA levels indicate folate deficiency and elevated MMA levels indicate vitamin B12 deficiency.[76] Folate deficiency is treated with supplemental oral folate of 400 to 1000 μg per day. This treatment is very successful in replenishing tissues, even if deficiency was caused by malabsorption.[76] Patients with megaloblastic anemia need to be tested for vitamin B12 deficiency before folate treatment, because if the patient has vitamin B12 deficiency, folate supplementation can remove the anemia, but can also worsen neurologic problems.[76] Morbidly obese patients with BMIs of greater than 50 are more likely to develop folate deficiency.[78] Patients with celiac disease have a higher chance of developing folate deficiency.[78] Cobalamin deficiency may lead to folate deficiency, which, in turn, increases homocysteine levels and may result in the development of cardiovascular disease or birth defects.[79]

Malaria

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 India.[80]

Dietary reference intake

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, or 0.6 μg of folic acid supplement.

National Institutes of Health (US) Nutritional Requirements[81] (µg per day)
Age Infants (RDI) Infants (UL) Adults (RDI) Adults (UL) Pregnant women (RDI) Pregnant women (UL) Lactating women (RDI) Lactating women (UL)
0–6 months 65 None set – – – – – –
7–12 months 80 None set – – – – – –
1–3 years – – 150 300 – – – –
4–8 years – – 200 400 – – –  –
9–13 years – – 300 600 – – – –
14–18 – – 400 800 600 800 500 800
19+ – – 400 1000 600 1000 500 1000

The Dietary Reference Intake (DRIs) were developed by the United States National Academy of Sciences to set reference values for planning and assessing nutrient intake for healthy people. DRIs incorporate two reference values, the Reference Daily Intake (RDI, the daily intake level that is adequate for 97–98% of the population in the United States where the standards were set) and tolerable upper intake levels (UL, the highest level of intake that is known to avoid toxicity). The UL for folate refers to only synthetic folate, as no health risks have been associated with high intake of folate from food sources.[81]

Sources

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 leafy vegetables), fruits and fruit juices, nuts, beans, peas, dairy products, poultry and meat, eggs, seafood, grains, and some beers.[13][82] Avocado,[83] spinach, liver, yeast, asparagus, and Brussels sprouts are among the foods with the highest levels of folate.[13]

Folic acid is added to grain products in many countries, and in these countries, fortified products make up a significant source of the population's folic acid intake.[84] 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. 1 DFE is defined as 1 μg of dietary folate, or 0.6 μg of folic acid supplement. This is reduced to 0.5 μg of folic acid if the supplement is taken on an empty stomach.[85]

Folate naturally found in food is susceptible to high heat and ultraviolet light, and is soluble in water.[86] It is heat-labile in acidic environments and may also be subject to oxidation.[86]

Some meal replacement products do not meet the folate requirements as specified by the RDAs.[87]

Folate (B9) can also be processed from the provitamin Pteroylmonoglutamic acid (Vitamin B10).

History

In the 1920s, scientists believed folate deficiency and anemia were the same condition.[88] 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. Dr. 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 in and extracted from spinach leaves by Mitchell and others in 1941.[89] 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.[90] 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.[91]

This research subsequently led to the synthesis of the antifolate aminopterin, the first-ever anticancer drug, the clinical efficacy was proven by Sidney Farber in 1948. In the 1950s and 1960s, scientists began to discover the biochemical mechanisms of action for folate.[88] In 1960, experts first linked folate deficiency to neural tube defects.[88] 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.[88]

Biological roles

A diagram of the chemical structure of folate

DNA and cell division

Folate is necessary for the production and maintenance of new cells, for DNA synthesis and RNA synthesis, and for preventing changes to DNA, and, thus, for preventing cancer.[54] 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).[92] 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 mRNA 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 replication, 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.[93] Both adults and children need folate to make normal red and white blood cells and prevent anemia.[94] 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.[95]

Biochemistry of DNA base 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.[24]

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 step.[96] Vitamin B3 in the form of NADPH is a necessary cofactor for both steps of the synthesis. Thus, hydride molecules are transferred from NADPH to the C6 position of the pteridine ring to reduce folic acid to THF.[97]

Methylene-THF (CH2FH4) is formed from THF by the addition of a methylene bridge from one of three carbon donors: formate, serine, or glycine. 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 methenyl-THF.

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 THE has no way of being metabolized, and serves as a sink of THF that causes a subsequent deficiency in folate.[90] Thus, a deficiency in B12 can generate a large pool of methyl-THF that is unable to undergo reactions and mimics folate deficiency.

The reactions that lead to the methyl-THF reservoir can be shown in chain form:

folate → dihydrofolate → tetrahydrofolate ↔ methylene-THF → methyl-THF
Folate metabolism

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. Moreover, in contrast to rats, an almost-5-fold variation in the activity of this enzyme exists between humans.[10] Due to this low activity, it has been suggested this 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 adults)."[10]

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 dihydropteroate synthetase).

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 providers.

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.[98][99] 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.[100]

Dietary fortification

In the USA many grain products are fortified with folic acid.

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.[73]

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,[73] 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 fortification.[73]

76 countries worldwide require mandatory folic acid fortification of at least one major cereal grain, with nearly all fortifying at least wheat flour, according to November 2013 data from the Flour Fortification Initiative.[101] These countries are:

Antigua and Barbuda, Argentina, Australia, Bahamas, Bahrain, Barbados, Belize, Benin, Bolivia (Plurinational State of), Brazil, Burkina Faso, Cameroon, Canada, Chile, Colombia, Costa Rica, Cote d'Ivoire, Cuba, Dominica, Dominican Republic, Ecuador, Egypt, El Salvador, Fiji, Ghana, Grenada, Guatemala, Guinea, Guyana, Haiti, Honduras, Indonesia, Iran (Islamic Republic of), Iraq, Jamaica, Jordan, Kazakhstan, Kenya, Kosovo, Kuwait, Kyrgyzstan, Liberia, Mali, Mauritania, Mexico, Morocco, Nepal, Nicaragua, Niger, Nigeria, Oman, Palestine (Occupied Territory), Panama, Papua New Guinea, Paraguay, Peru, Republic of Moldova, Rwanda, Saint Kitts and Nevis, Saint Lucia, Saint Vincent and the Grenadines, Saudi Arabia, Senegal, Sierra Leone, Solomon Islands, South Africa, Suriname, Tanzania (United Republic of), Togo, Trinidad and Tobago, Turkmenistan, Uganda, United States of America, Uruguay, Uzbekistan, and Yemen.[101]

As of November 2013, no EU country has mandated folic acid fortification.[101]

Australia

There has been previous debate in Australia regarding the inclusion of folic acid in products such as bread and flour.[102]

Australia and New Zealand have jointly agreed to fortification though the Food Standards Australia New Zealand. Australia will fortify all flour from 18 September 2009.[103] Although the food standard covers both 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.[104]

The requirement is 0.135 mg of folate per 100g of bread.

Canada

In 2003, a Hospital for Sick Children, University of Toronto research group published findings showing the fortification of flour with folic acid in Canada has resulted in a dramatic decrease in neuroblastoma, an early and very dangerous cancer in young children.[105] In 2009, further evidence from McGill University showed a 6.2% decrease per year in the birth prevalence of severe congenital heart defects.[106]

Folic acid used in fortified foods is a synthetic form called pteroylmonoglutamate.[107] It is in its oxidized state and contains only one conjugated glutamate residue.[107] Folic acid therefore enters via a different carrier system from naturally occurring folate, and this may have different effects on folate binding proteins and its transporters.[108] Folic acid has a higher bioavailability than natural folates and are rapidly absorbed across the intestine,[107] therefore it is important to consider the Dietary Folate Equivalent (DFE) when calculating one's intake. Natural occurring folate is equal to 1 DFE, however 0.6 µg of folic acid is equal to 1 DFE.

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.[109] The purpose of fortification was to decrease the risk of neural tube defects in newborns.[109] 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.[110] 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.[111] 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.[110] This could be from the fact that many foods are over fortified by 160–175% the predicted value.[110] 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 preneoplasmic lesions.[112] It is still unknown the amount of folic acid supplementation that might cause harm.[109]

Supplementation promotion

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.[111]

New Zealand

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.[103]

The Association of Bakers [113] and the Green Party [114] 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 .[115] The New Zealand Government is reviewing whether it will continue with the mandatory introduction of folic acid to bread.[116]

United Kingdom

There has been previous debate in the United Kingdom regarding the inclusion of folic acid in products such as bread and flour.[117] While the Food Standards Agency has recommended folic acid fortification,[118][119][120] and wheat flour is fortified with iron,[101] folic acid fortification of wheat flour is allowed voluntarily rather than required.

United States

The 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.[121]

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.[121] Twenty-nine percent of black women have inadequate intakes of folate.[121] The age group consuming the most folate and folic acid is the >50 group.[121] 5% of the population exceeds the Tolerable Upper Intake Level.[121]

In 1996, the United States 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.[122][123] This ruling took effect on January 1, 1998, and was specifically targeted to reduce the risk of neural tube birth defects in newborns.[124] There are concerns that the amount of folate added is insufficient .[125] 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, specifically 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.[126]

As a result of the folic acid fortification program, fortified foods have become a major source of folic acid in the American diet.[13] The 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.[127] 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.[17] 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;[128] the magnitude of reduction was proportional to the prefortification rate of NTDs, essentially removing geographical variations in rates of NTDs seen in Canada before fortification.

When the U.S. Food and Drug Administration set the folic acid fortification regulation in 1996, the projected increase in folic acid intake was 100 µg/d.[129] 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 (DFE)/d.[129] 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.[129] Taken together, folic acid fortification has led to a bigger increase in folic acid intake than first projected.[129]

See also

References

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