FOLATE, forms of which are known as FOLIC ACID and VITAMIN B9, is one of the B vitamins . The recommended daily intake of folate is 400 micrograms from foods or dietary supplements . Folic acid is the form of folate 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 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 vitamin .
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 and liver .
* 1 Definition
* 2 Health effects
* 2.5 Cancer
* 2.5.1 Antifolate chemotherapy
* 3 Dietary reference intake
* 3.1 Sources
* 4 History
* 5 Biological roles
* 5.3 Conversion to biologically active derivatives
* 5.3.1 Overview of drugs that interfere with folate reactions
* 6.1 Australia
* 6.2 Canada
* 6.2.1 Supplementation promotion
* 7 See also * 8 References * 9 External links
"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, and folinic acid. 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 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, folacin, and pteroyl-L-glutamate.
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 unexplained infertility .
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.
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 consume daily 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 cancer risk.
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 reported.
Folinic acid , under the drug name leucovorin , a form of folate (formyl-THF), can help "rescue" or reverse the toxic effects of methotrexate. 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 at the University of York and Hull York Medical School has found a link between depression and low levels of folate. One study by the same team involved 15,315 subjects. 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. 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 white-space:nowrap;"> of potential negative impacts on health.
Main article: Folate deficiency
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 trimethoprim-sulfamethoxazole). 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 genetics.
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. People who are morbidly obese with BMIs of greater than 50 are more likely to develop folate deficiency. People with celiac disease have a higher chance of developing folate deficiency. 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.
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.
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 (µg DFE per day) AGE INFANTS (AI) INFANTS (UL ) ADULTS (RDA) ADULTS (UL) PREGNANT WOMEN (RDA) PREGNANT WOMEN (UL) LACTATING WOMEN (RDA) 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 Intakes (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 four reference values: Estimated Average Requirements (EARs), Recommended Dietary Allowances (RDAs; the daily intake level that is adequate for 97–98% of the population in the United States), Adequate Intakes, for when the existing science is inadequate to set EARs and RDAs, and tolerable upper intake levels (UL, the highest level of intake considered safe). The UL for folate refers to only synthetic folic acid, as no health risks have been associated with high intake of folate from food sources. The European Food Safety Authority reviewed the same safety question and also set the adult UL at 1000 μg.
For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For folic acid labeling purposes 100% of the Daily Value was 400 μg. As of the May 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 July 28, 2018 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 leafy vegetables ), fruits and fruit juices, nuts, beans, peas, dairy products, poultry and meat, eggs, seafood, grains, and some beers. Avocado , beetroot , spinach , liver , yeast , asparagus , and Brussels sprouts are among the foods with the highest levels of folate.
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. 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.
Folate naturally 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.
Some meal replacement products do not meet the folate requirements as specified by the RDAs .
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 proven by 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 , for 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 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 . 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 step. 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.
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 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 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 (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 adults)."
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. 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 fortification.
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 Food Fortification Initiative. 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.
As of November 2013, no EU country has mandated folic acid fortification.
There has been previous debate in Australia regarding the inclusion of folic acid in products such as bread and flour .
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. 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.
The requirement is 0.135 mg of folate per 100g of bread.
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. In 2009, further evidence from McGill University showed a 6.2% decrease per year in the birth prevalence of severe congenital heart defects.
Folic acid used in fortified foods is a synthetic form called pteroylmonoglutamate. It is in its oxidized state and contains only one conjugated glutamate residue. 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. Folic acid has a higher bioavailability than natural folates and are rapidly absorbed across the intestine; 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. 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 harm.
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 . The 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 . While the 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.
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.
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 (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, 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.
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 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 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. 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. 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 first projected.
* ^ _A_ _B_ _C_ _D_ _E_ _F_ _G_ _H_ "Folic Acid". _Drugs.com_. American Society of Health-System Pharmacists. 1 January 2010. Retrieved 1 September 2016. * ^ "Folic Acid". The PubChem Project. * ^ _A_ _B_ Fenech, Michael (May 2012). " Folate (vitamin B9) and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity". _Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis_. 733 (1–2): 21–33. PMID 22093367 . doi :10.1016/j.mrfmmm.2011.11.003 . * ^ _A_ _B_ "Definition of vitamin Bc". Medical-dictionary.thefreedictionary.com. Retrieved 9 September 2012. * ^ _A_ _B_ Darby, William J.; Jones, Edgar (1 November 1945). "Treatment of Sprue with Synthetic L. casei Factor (Folic Acid, Vitamin M).". _Experimental Biology and Medicine_. 60 (2): 259–262. doi :10.3181/00379727-60-15154P . Retrieved 13 December 2014. * ^ _A_ _B_ "Guidance for Industry: A Food Labeling Guide (14. Appendix F: Calculate the Percent Daily Value for the Appropriate Nutrients)". US Food and Drug Administration. January 2013. Retrieved 20 February 2017. * ^ Bibbins-Domingo, Kirsten; Grossman, David C.; Curry, Susan J.; Davidson, Karina W.; Epling, John W.; García, Francisco A.R.; Kemper, Alex R.; Krist, Alex H.; Kurth, Ann E.; Landefeld, C. Seth; Mangione, Carol M.; Phillips, William R.; Phipps, Maureen G.; Pignone, Michael P.; Silverstein, Michael; Tseng, Chien-Wen (10 January 2017). "Folic Acid Supplementation for the Prevention of Neural Tube Defects". _JAMA_. 317 (2): 183. doi :10.1001/jama.2016.19438 . * ^ _A_ _B_ _C_ _D_ _E_ _F_ _G_ " Dietary supplement fact sheet: Folate". _Health Information_. Office of Dietary Supplements, US National Institutes of Health . Retrieved 1 September 2016. * ^ Bailey, Lynn B. (2009). _ Folate in Health and Disease, Second Edition_. CRC Press. p. 198. ISBN 9781420071252 . * ^ Obeid, R; Herrmann, W (October 2012). "The emerging role of unmetabolized folic acid in human diseases: myth or reality?". _Current drug metabolism_. 13 (8): 1184–95. PMID 22746304 . * ^ _A_ _B_ _C_ _D_ Li Y, Huang T, Zheng Y, Muka T, Troup J, Hu FB (2016). "Folic Acid Supplementation and the Risk of Cardiovascular Diseases: A Meta-Analysis of Randomized Controlled Trials" . _J Am Heart Assoc_. 5 (8): e003768. PMC 5015297 _. PMID 27528407 . doi :10.1161/JAHA.116.003768 . CS1 maint: Uses authors parameter (link ) * ^ Pommerville, Glendale Community College Jeffrey C. (2009). Alcamo\'s Fundamentals of Microbiology: Body Systems_. Jones & Bartlett Publishers. p. 511. ISBN 9780763787127 . * ^ Marino, Bradley S.; Fine, Katie Snead (2009). _Blueprints Pediatrics_. Lippincott Williams & Wilkins. p. 131. ISBN 9780781782517 . * ^ Pond, Wilson G.; Nichols, Buford L.; Brown, Dan L. (2009). _Adequate Food for All: Culture, Science, and Technology of Food in the 21st Century_. CRC Press. p. 148. ISBN 9781420077544 . * ^ " WHO Model List of Essential Medicines (19th List)" (PDF). _World Health Organization_. April 2015. Retrieved 8 December 2016. * ^ "Folic Acid". _International Drug Price Indicator Guide_. Retrieved 1 September 2016. * ^ _Chambers Concise Dictionary_. Allied Publishers. 2004. p. 451. ISBN 979-8186-06236-3 . * ^ "Folic Acid". NIH LiverTox. 2 June 2017. * ^ _A_ _B_ "FAQ\'s Folic Acid". CDC. 16 December 2016. * ^ "Nomenclature and symbols for folic acid and related compounds". _IUPAC-IUB Joint Commission on Biochemical Nomenclature_. * ^ "Folic Acid vs. Folate". Health Tips From The Professor. October 11, 2016. Archived from the original on March 2, 2017. * ^ Wilson RD, Wilson RD, Audibert F, Brock JA, Carroll J, Cartier L, Gagnon A, Johnson JA, Langlois S, Murphy-Kaulbeck L, Okun N, Pastuck M, Deb-Rinker P, Dodds L, Leon JA, Lowel HL, Luo W, MacFarlane A, McMillan R, Moore A, Mundle W, O'Connor D, Ray J, Van den Hof M (2015). "Pre-conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies". _J Obstet Gynaecol Can_. 37 (6): 534–52. PMID 26334606 . doi :10.1016/s1701-2163(15)30230-9 . * ^ Feng Y, Wang S, Chen R, Tong X, Wu Z, Mo X (2015). "Maternal folic acid supplementation and the risk of congenital heart defects in offspring: a meta-analysis of epidemiological observational studies" . _Sci Rep_. 5: 8506. PMC 4330542 _. PMID 25687545 . doi :10.1038/srep08506 . * ^ Fekete K, Berti C, Trovato M, Lohner S, Dullemeijer C, Souverein OW, Cetin I, Decsi T (2012). "Effect of folate intake on health outcomes in pregnancy: a systematic review and meta-analysis on birth weight, placental weight and length of gestation" . Nutr J_. 11: 75. PMC 3499376 _. PMID 22992251 . doi :10.1186/1475-2891-11-75 . * ^ Saccone G, Berghella V (2016). " Folic acid supplementation in pregnancy to prevent preterm birth: a systematic review and meta-analysis of randomized controlled trials". Eur. J. Obstet. Gynecol. Reprod. Biol_. 199: 76–81. PMID 26901401 . doi :10.1016/j.ejogrb.2016.01.042 . * ^ Devakumar D, Fall CH, Sachdev HS, Margetts BM, Osmond C, Wells JC, Costello A, Osrin D (2016). "Maternal antenatal multiple micronutrient supplementation for long-term health benefits in children: a systematic review and meta-analysis" . _BMC Med_. 14: 90. PMC 4910255 _. PMID 27306908 . doi :10.1186/s12916-016-0633-3 . * ^ Crider KS, Cordero AM, Qi YP, Mulinare J, Dowling NF, Berry RJ (2013). "Prenatal folic acid and risk of asthma in children: a systematic review and meta-analysis" (PDF). Am. J. Clin. Nutr_. 98 (5): 1272–81. PMID 24004895 . doi :10.3945/ajcn.113.065623 . * ^ Ebisch IM, Thomas CM, Peters WH, Braat DD, Steegers-Theunissen RP (2007). "The importance of folate, zinc and antioxidants in the pathogenesis and prevention of subfertility". _Hum. Reprod. Update_. 13 (2): 163–74. PMID 17099205 . doi :10.1093/humupd/dml054 . * ^ Altmäe S, Stavreus-Evers A, Ruiz JR, et al. (June 2010). "Variations in folate pathway genes are associated with unexplained female infertility". _Fertil. Steril_. 94 (1): 130–7. PMID 19324355 . doi :10.1016/j.fertnstert.2009.02.025 . * ^ Bazzano LA (August 2011). "No effect of folic acid supplementation on cardiovascular events, cancer or mortality after 5 years in people at increased cardiovascular risk, although homocysteine levels are reduced". _Evid Based Med_. 16 (4): 117–8. PMID 21402567 . doi :10.1136/ebm1204 . * ^ " Folic acid \'reduces stroke risks\'". _BBC News_. London. 31 May 2007. * ^ Terwecoren A, Steen E, Benoit D, Boon P, Hemelsoet D (September 2009). "Ischemic stroke and hyperhomocysteinemia: truth or myth?". _Acta Neurol Belg_. 109 (3): 181–8. PMID 19902811 . * ^ Glynn, SA; Albanes, D (1994). " Folate and cancer: a review of the literature.". _ Nutrition and cancer_. 22 (2): 101–19. PMID 14502840 . doi :10.1080/01635589409514336 . * ^ Jägerstad, M (2012). " Folic acid fortification prevents neural tube defects and may also reduce cancer risks". _Acta Paediatrica_. 101 (10): 1007–12. PMID 22783992 . doi :10.1111/j.1651-2227.2012.02781.x . * ^ "Common questions about diet and cancer: Folate and folic acid". American Cancer Society. 2017. * ^ Weinstein, S. J.; Hartman, T. J.; Stolzenberg-Solomon, R; Pietinen, P; Barrett, M. J.; Taylor, P. R.; Virtamo, J; Albanes, D (2003). "Null association between prostate cancer and serum folate, vitamin B(6), vitamin B(12), and homocysteine". _ Cancer Epidemiology, Biomarkers & Prevention_. 12 (11 Pt 1): 1271–2. PMID 14652294 . * ^ Wien TN, Pike E, Wisløff T, Staff A, Smeland S, Klemp M (2012). " Cancer risk with folic acid supplements: a systematic review and meta-analysis" . _BMJ Open_. 2 (1): e000653. PMC 3278486 _. PMID 22240654 . doi :10.1136/bmjopen-2011-000653 . * ^ Wang, R; Zheng, Y; Huang, JY; Zhang, AQ; Zhou, YH; Wang, JN (29 December 2014). " Folate intake, serum folate levels, and prostate cancer risk: a meta-analysis of prospective studies." . BMC Public Health_. 14 (1): 1326. PMC 4320532 _. PMID 25543518 . doi :10.1186/1471-2458-14-1326 . * ^ Schwingshackl, L; Boeing, H; Stelmach-Mardas, M; Gottschald, M; Dietrich, S; Hoffmann, G; Chaimani, A (January 2017). "Dietary Supplements and Risk of Cause-Specific Death, Cardiovascular Disease, and Cancer: A Systematic Review and Meta-Analysis of Primary Prevention Trials.". Advances in Nutrition_. 8 (1): 27–39. PMC 5227980 _. PMID 28096125 . doi :10.3945/an.116.013516 . * ^ A_ _B_ Kamen B (October 1997). " Folate and antifolate pharmacology". _Semin. Oncol_. 24 (5 Suppl 18): S18–30–S18–39. PMID 9420019 . * ^ Rubio IT, Cao Y, Hutchins LF, Westbrook KC, Klimberg VS (May 1998). "Effect of glutamine on methotrexate efficacy and toxicity" . _Ann. Surg_. 227 (5): 772–8; discussion 778–80. PMC 1191365 _. PMID 9605669 . doi :10.1097/00000658-199805000-00018 . * ^ Wolff JE, Hauch H, Kuhl J, Egeler RM, Jurgens H (1998). "Dexamethasone increases hepatotoxicity of MTX in children with brain tumors". Anticancer Research_. 18 (4B): 2895–9. PMID 9713483 . * ^ Kepka L, De Lassence A, Ribrag V, et al. (March 1998). "Successful rescue in a patient with high dose methotrexate-induced nephrotoxicity and acute renal failure". _Leuk. Lymphoma_. 29 (1–2): 205–9. PMID 9638991 . doi :10.3109/10428199809058397 . * ^ Branda RF, Nigels E, Lafayette AR, Hacker M (1998). "Nutritional folate status influences the efficacy and toxicity of chemotherapy in rats". _Blood_. 92 (7): 2471–6. PMID 9746787 . * ^ Shiroky JB; Frcp(c) (November 1997). "The use of folates concomitantly with low-dose pulse methotrexate". _Rheum. Dis. Clin. North Am_. 23 (4): 969–80. PMID 9361164 . doi :10.1016/S0889-857X(05)70369-0 . * ^ Keshava C, Keshava N, Whong WZ, Nath J, Ong TM (February 1998). "Inhibition of methotrexate-induced chromosomal damage by folinic acid in V79 cells". _Mutat. Res_. 397 (2): 221–8. PMID 9541646 . doi :10.1016/S0027-5107(97)00216-9 . * ^ Coppen A, Bolander-Gouaille C (January 2005). "Treatment of depression: time to consider folic acid and vitamin B12". _J. Psychopharmacol. (Oxford)_. 19 (1): 59–65. PMID 15671130 . doi :10.1177/0269881105048899 . * ^ Taylor MJ, Carney SM, Goodwin GM, Geddes JR (June 2004). " Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials". _J. Psychopharmacol. (Oxford)_. 18 (2): 251–6. PMID 15260915 . doi :10.1177/0269881104042630 . * ^ Gilbody S, Lewis S, Lightfoot T (January 2007). "Methylenetetrahydrofolate reductase (MTHFR) genetic polymorphisms and psychiatric disorders: a HuGE review". _Am. J. Epidemiol_. 165 (1): 1–13. PMID 17074966 . doi :10.1093/aje/kwj347 . * ^ Gilbody S, Lightfoot T, Sheldon T (July 2007). "Is low folate a risk factor for depression? A meta-analysis and exploration of heterogeneity" . _J Epidemiol Community Health_. 61 (7): 631–7. PMC 2465760 _. PMID 17568057 . doi :10.1136/jech.2006.050385 . * ^ Gaweesh S, Ewies AA (February 2010). "Folic acid supplementation cures hot flushes in postmenopausal women". Med. Hypotheses_. 74 (2): 286–8. PMID 19796883 . doi :10.1016/j.mehy.2009.09.010 . * ^ García-Miss Mdel R, Pérez-Mutul J, López-Canul B, et al. (May 2010). "Folate, homocysteine, interleukin-6, and tumor necrosis factor alfa levels, but not the methylenetetrahydrofolate reductase C677T polymorphism, are risk factors for schizophrenia". _J Psychiatr Res_. 44 (7): 441–6. PMID 19939410 . doi :10.1016/j.jpsychires.2009.10.011 . * ^ Krebs MO, Bellon A, Mainguy G, Jay TM, Frieling H (December 2009). "One-carbon metabolism and schizophrenia: current challenges and future directions". _Trends Mol Med_. 15 (12): 562–70. PMID 19896901 . doi :10.1016/j.molmed.2009.10.001 . * ^ Christen WG, Glynn RJ, Chew EY, Albert CM, Manson JE (February 2009). "Folic acid, pyridoxine, and cyanocobalamin combination treatment and age-related macular degeneration in women: the Women\'s Antioxidant and Folic Acid Cardiovascular Study" . _Arch. Intern. Med_. 169 (4): 335–41. PMC 2648137 _. PMID 19237716 . doi :10.1001/archinternmed.2008.574 . * ^ Vreugdenhil G, Wognum AW, van Eijk HG, Swaak AJ (February 1990). "Anaemia in rheumatoid arthritis: the role of iron, vitamin B12, and folic acid deficiency, and erythropoietin responsiveness" . Ann. Rheum. Dis_. 49 (2): 93–8. PMC 1003985 _. PMID 2317122 . doi :10.1136/ard.49.2.93 . * ^ Reynolds E (November 2006). " Vitamin B12, folic acid, and the nervous system". Lancet Neurol_. 5 (11): 949–60. PMID 17052662 . doi :10.1016/S1474-4422(06)70598-1 . * ^ Allen RH, Stabler SP, Savage DG, Lindenbaum J (June 1990). "Diagnosis of cobalamin deficiency I: usefulness of serum methylmalonic acid and total homocysteine concentrations". _Am. J. Hematol_. 34 (2): 90–8. PMID 2339683 . doi :10.1002/ajh.2830340204 .
* ^ Hathcock JN (August 1997). "Vitamins and minerals: efficacy and safety". _Am. J. Clin. Nutr_. 66 (2): 427–37. PMID 9250127 . * ^ FAO ; WHO (2002), "ch. 4, Folate and Folic Acid", _Human Vitamin and Mineral Requirements_ * ^ _A_ _B_ _C_ _D_ Smith AD (January 2007). "Folic acid fortification: the good, the bad, and the puzzle of vitamin B-12". _Am. J. Clin. Nutr_. 85 (1): 3–5. PMID 17209170 . * ^ _A_ _B_ " Folate deficiency: MedlinePlus Medical Encyclopedia". _www.nlm.nih.gov_. Retrieved 16 November 2015. * ^ Diaz, V. H. US Patent 20080020071, 24 January 2008. * ^ _A_ _B_ _C_ _D_ _E_ _F_ _G_ _H_ _I_ _J_ _K_ http://www.merck.com * ^ Lohner, Szimonetta; Fekete, Katalin; Berti, Cristiana; Hermoso, Maria; Cetin, Irene; Koletzko, Berthold; Decsi, Tamás (2012). "Effect of folate supplementation on folate status and health outcomes in infants, children and adolescents: A systematic review". _International Journal of Food Sciences and Nutrition_. 63 (8): 1014–20. PMID 22574624 . doi :10.3109/09637486.2012.683779 . * ^ _A_ _B_ Malterre T (September 2009). "Digestive and nutritional considerations in celiac disease: could supplementation help?" (PDF). _Altern Med Rev_. 14 (3): 247–57. PMID 19803549 . * ^ Varela-Moreiras G, Murphy MM, Scott JM (May 2009). "Cobalamin, folic acid, and homocysteine". _Nutr. Rev_. 67 Suppl 1: S69–72. PMID 19453682 . doi :10.1111/j.1753-4887.2009.00163.x . * ^ Pasricha S, Shet A, Sachdev HP, Shet AS (October 2009). "Risks of routine iron and folic acid supplementation for young children" (PDF). _Indian Pediatr_. 46 (10): 857–66. PMID 19887691 . * ^ _A_ _B_ "Dietary Supplement Fact Sheet: Folate". National Institutes of Health . * ^ Folate. IN: Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. National Academy Press. 2001, PP.196–305. * ^ _Tolerable Upper Intake Levels For Vitamins And Minerals_ (PDF), European Food Safety Authority, 2006 * ^ Owens, Janel E.; Clifford, Andrew J.; Bamforth, Charles W. (2007). " Folate in Beer". _Journal of the Institute of Brewing_. 113 (3): 243–248. ISSN 0046-9750 . doi :10.1002/j.2050-0416.2007.tb00283.x . * ^ "USDA Nutrient Database (Table)". United States Department of Agriculture. Retrieved 14 August 2014. * ^ Dietrich, M; Brown, CJ; Block, G (2005). "The effect of folate fortification of cereal-grain products on blood folate status, dietary folate intake, and dietary folate sources among adult non-supplement users in the United States". _J Am Coll Nutr_. 24 (4): 266–274. PMID 16093404 . doi :10.1080/07315724.2005.10719474 . * ^ Suitor, CW; Bailey, LB (2000). "Dietary folate equivalents: interpretation and application". _J Am Diet Assoc_. 100 (1): 88–94. PMID 10646010 . doi :10.1016/S0002-8223(00)00027-4 . * ^ _A_ _B_ "Effects of Cooking on Vitamins (Table)". Beyondveg.com. Retrieved 9 September 2012. * ^ Cabanillas, M; Moya Chimenti, E; González Candela, C; Loria Kohen, V; Dassen, C; Lajo, T. (2009). "Usefulness of meal replacement: analysis of the principal meal replacement products commercialised in Spain". _Nutr Hosp_. 24 (5): 535–42. PMID 19893863 . * ^ _A_ _B_ _C_ _D_ Lanska, DJ. (2009). "Chapter 30 Historical aspects of the major neurological vitamin deficiency disorders: the water-soluble B vitamins". _Handb Clin Neurol_. Handbook of Clinical Neurology. 95: 445–76. ISBN 978-0-444-52009-8 . PMID 19892133 . doi :10.1016/S0072-9752(08)02130-1 . * ^ Mitchell HK, Snell EE, Williams RJ (1941). "The concentration of "folic acid"". _J Am Chem Soc_. 63 (8): 2284. doi :10.1021/ja01853a512 . * ^ _A_ _B_ Hoffbrand AV, Weir DG (June 2001). "The history of folic acid". _Br. J. Haematol_. 113 (3): 579–89. PMID 11380441 . doi :10.1046/j.1365-2141.2001.02822.x . * ^ Angier RB, Boothe JH, Hutchings BL, et al. (August 1945). "Synthesis of a Compound Identical with the L. Casei Factor Isolated from Liver". _Science_. 102 (2644): 227–8. Bibcode :1945Sci...102..227A. PMID 17778509 . doi :10.1126/science.102.2644.227 . * ^ Figueiredo JC, Grau MV, Haile RW, et al. (March 2009). "Folic acid and risk of prostate cancer: results from a randomized clinical trial" . _J. Natl. Cancer Inst_. 101 (6): 432–5. PMC 2657096 _. PMID 19276452 . doi :10.1093/jnci/djp019 . * ^ Smith C, Lieberman M, Marks DB, Marks AD (2007). Marks' essential medical biochemistry_. Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-9340-8 . * ^ Zittoun J (1993). "Anemias due to disorder of folate, vitamin B12 and transcobalamin metabolism". _La Revue du praticien_ (in French). 43 (11): 1358–63. PMID 8235383 . * ^ " Folate and Your Health – HealthLinkBC File #68g". Healthlinkbc.ca. Retrieved 9 September 2012. * ^ Goh YI, Koren G (January 2008). " Folic acid in pregnancy and fetal outcomes". _J Obstet Gynaecol_. 28 (1): 3–13. PMID 18259891 . doi :10.1080/01443610701814195 . * ^ "EC 126.96.36.199". Us.expasy.org. Retrieved 9 September 2012. * ^ Benkovic SJ, Hammes-Schiffer S (August 2003). "A perspective on enzyme catalysis". _Science_. 301 (5637): 1196–202. Bibcode :2003Sci...301.1196B. PMID 12947189 . doi :10.1126/science.1085515 . * ^ _A_ _B_ Bailey SW, Ayling JE (September 2009). "The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake" . _Proceedings of the National Academy of Sciences of the United States of America_. 106 (36): 15424–9. Bibcode :2009PNAS..10615424B. PMC 2730961 _. PMID 19706381 . doi :10.1073/pnas.0902072106 . * ^ Alaimo K, McDowell MA, Briefel RR, Bischof AM, Caughman CR, Loria CM, Johnson CL (1994). "Dietary intake of vitamins, minerals, and fiber of persons ages 2 months and over in the United States: Third National Health and Nutrition Examination Survey, Phase 1, 1988–91". Advance Data from Vital and Health Statistics_ (258): 1–28. PMID 10138938 . * ^ Raiten DJ, Fisher KD (1995). "Assessment of folate methodology used in the Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994)". _The Journal of Nutrition_. 125 (5): 1371S–1398S. PMID 7738698 . * ^ Lewis CJ, Crane NT, Wilson DB, Yetley EA (August 1999). "Estimated folate intakes: data updated to reflect food fortification, increased bioavailability, and dietary supplement use". _Am. J. Clin. Nutr_. 70 (2): 198–207. PMID 10426695 . * ^ _A_ _B_ _C_ _D_ "Why fortify?". Food Fortification Initiative. 2017. Retrieved 4 April 2017. * ^ " Bread fortification \'not justified\'". The Sydney Morning Herald. 29 July 2006. * ^ _A_ _B_ NZPA (22 June 2007). " Bread to be fortified with folic acid". NZ Herald. Retrieved 13 July 2009. * ^ " Bread additive call \'up to NZ\'". Retrieved 15 July 2009. * ^ French AE, Grant R, Weitzman S, et al. (September 2003). "Folic acid food fortification is associated with a decline in neuroblastoma". _Clin. Pharmacol. Ther_. 74 (3): 288–94. PMID 12966372 . doi :10.1016/S0009-9236(03)00200-5 . * ^ Ionescu-Ittu R, Marelli AJ, Mackie AS, Pilote L (2009). "Prevalence of severe congenital heart disease after folic acid fortification of grain products: time trend analysis in Quebec, Canada" . _BMJ_. 338: b1673. PMC 2682153 _. PMID 19436079 . doi :10.1136/bmj.b1673 . * ^ A_ _B_ _C_ Smith AD, Kim YI, Refsum H (March 2008). "Is folic acid good for everyone?". _Am. J. Clin. Nutr_. 87 (3): 517–33. PMID 18326588 . * ^ Ulrich CM, Potter JD (February 2006). " Folate supplementation: too much of a good thing?". _ Cancer Epidemiol. Biomarkers Prev_. 15 (2): 189–93. PMID 16492904 . doi :10.1158/1055-9965.EPI-152CO . * ^ _A_ _B_ _C_ Mason JB, Dickstein A, Jacques PF, et al. (July 2007). "A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis". _ Cancer Epidemiol. Biomarkers Prev_. 16 (7): 1325–9. PMID 17626997 . doi :10.1158/1055-9965.EPI-07-0329 . * ^ _A_ _B_ _C_ Quinlivan EP, Gregory JF (January 2003). "Effect of food fortification on folic acid intake in the United States". _Am. J. Clin. Nutr_. 77 (1): 221–5. PMID 12499345 . * ^ _A_ _B_ "Welcome to the Health Canada Web site". Hc-sc.gc.ca. Retrieved 9 September 2012. * ^ Chustecka, Z. (2009). "Folic-acid fortification of flour and increased rates of colon cancer". Retrieved 9 November 2009. * ^ "Work Starts on Wilkinson’s Mass Medication Plan" (Press release). Association Of Bakers. 8 July 2009. Retrieved 13 July 2009. * ^ "NZ should push pause on folic fortification" (Press release). Green Party. 9 July 2009. Retrieved 13 July 2009. * ^ NZPA (8 July 2009). "Bakers, Govt battle over folic acid". NZ Herald. Retrieved 13 July 2009. * ^ "Govt reviewing folic acid policy". Stuff. Retrieved 15 July 2009. * ^ BBC \'Put folic acid in bread\' 13 January 2000 * ^ FSA (17 May 2007). "Board recommends mandatory fortification". Retrieved 18 May 2007. * ^ "Backing for folic acid in bread". _BBC News_. 17 May 2007. Retrieved 18 May 2007. * ^ BBC Experts back folic acid in flour 11 May 2007 * ^ _A_ _B_ _C_ _D_ _E_ Bailey RL, Dodd KW, Gahche JJ, et al. (January 2010). "Total folate and folic acid intake from foods and dietary supplements in the United States: 2003–2006" . _Am. J. Clin. Nutr_. 91 (1): 231–7. PMC 2793110 _. PMID 19923379 . doi :10.3945/ajcn.2009.28427 . * ^ Malinow MR, Duell PB, Hess DL, et al. (April 1998). "Reduction of plasma homocyst(e)ine levels by breakfast cereal fortified with folic acid in patients with coronary heart disease". N. Engl. J. Med_. 338 (15): 1009–15. PMID 9535664 . doi :10.1056/NEJM199804093381501 .
* ^ Daly S, Mills JL, Moll