Folate

Folate, also known as vitamin B9, is a water-soluble B vitamin that is essential for DNA synthesis, cell division and proper growth and development, particularly during pregnancy to prevent neural tube defects. It is a family of related compounds found naturally in foods such as leafy vegetables, legumes and liver, and it is distinct from folic acid, the oxidized synthetic form used in supplements and fortified foods. The two are handled differently by the body, and much of the public-health discussion about the vitamin depends on that difference. Folate works mainly as a carrier of one-carbon units in metabolism, supporting the synthesis of nucleotides and the methylation reactions that depend on amino acid chemistry.

This entry explains what folate is chemically and how its forms differ, traces how its biological role and its link to birth defects were discovered, and then describes absorption, dietary requirements and deficiency. It goes on to cover pregnancy and neural tube defects, the policy debate over mandatory food fortification, safety and drug interactions, and the clinical use of folate-related drugs. It ends with questions that remain under active research.

Chemical structure and forms

Folates are a family of chemically related compounds, and all of them are built on the same three-part framework. The first part is a pteridine ring, a bicyclic heterocycle that carries the reactive chemistry. The second is a para-aminobenzoic acid bridge, which connects to the pteridine through a methylene group. The third is a tail of glutamate residues, linked through their gamma-carboxyl groups. Natural folates typically carry several glutamates in this tail, and the number can run from one to around fourteen. Variation in three features produces the large number of known folate vitamers: the oxidation state of the pteridine ring, the one-carbon group attached at the N5 and N10 positions (methyl, formyl, methenyl and similar groups), and the length of the glutamate tail.

The tail matters for how folates behave inside cells. Once a folate enters a cell, it is often extended with additional glutamates, a step catalysed by folylpolyglutamate synthase. The longer, more charged molecule is poorly able to leave the cell, so polyglutamylation effectively traps folate inside it. Many of the enzymes that use folates also bind the polyglutamylated forms more tightly than the monoglutamates, which means the tail improves both retention and the efficiency with which folates are used as cofactors. The tail must be trimmed before the vitamin can be absorbed from food, a process described in the absorption section.

Natural folates and the synthetic compound folic acid differ mainly in their oxidation state. Folic acid, chemically pteroylglutamic acid, has a fully oxidized pteridine ring and a single glutamate. It is the most chemically stable form, which is why it is used in supplements and in fortified foods. Folates in food, by contrast, are reduced, and the predominant form is tetrahydrofolate (THF) or one of its one-carbon derivatives, such as 5-methyltetrahydrofolate, which is the main circulating form. Reduction of the pteridine ring occurs at positions 5, 6, 7 and 8. Folic acid has essentially no biological activity until the enzyme dihydrofolate reductase reduces it twice, first to dihydrofolate and then to THF. This conversion is limited in the intestinal cell. At intakes above roughly 200 µg in a single dose, the reaction can become saturated, and unconverted folic acid then appears in the circulation.

The terminology is not always used consistently. "Folate" is the general term for the whole family of compounds and for the vitamin in its natural and biologically active forms; it is sometimes written as vitamin B9. "Folic acid" refers specifically to the oxidized monoglutamate used in supplements and fortification. Because the two forms are absorbed and used differently, labelling and public-health documents keep them apart.

Intake is expressed in micrograms of dietary folate equivalents (DFE), a unit introduced by the US Institute of Medicine to put all sources of the vitamin on one scale. One microgram of food folate counts as one microgram DFE. One microgram of folic acid from fortified food or from a supplement taken with a meal counts as 1.7 micrograms DFE, reflecting its higher bioavailability. A supplement taken on an empty stomach is counted at two micrograms DFE per microgram. Total intake is therefore calculated as food folate plus 1.7 times the folic acid. The recommended dietary allowance for most adults is 400 micrograms DFE per day. DFE is a conversion convention rather than a measured chemical quantity, so a food containing 200 micrograms of natural folate and a supplement containing 200 micrograms of folic acid provide different amounts of usable vitamin.

Discovery and history of research

The story of folate starts with a clinical puzzle rather than a chemical one. Dietary folate deficiency was first reported in 1931 by English physician Lucy Wills, who described megaloblastic anemia among nutritionally deficient women at a hospital in India. Her patients were mostly poor women working in the textile industry in Bombay, and their anaemia looked like pernicious anaemia but was not caused by a lack of the factor that treats that disease. Wills found that a yeast extract provided to these nutritionally deficient individuals cured and prevented their anemia. Her unidentified factor was first called the "Wills factor," and in the 1930s other researchers gave the same material names such as vitamin M, based on its activity in monkeys, and vitamin Bc, based on its activity in chicks.

Chemical identification followed in the early 1940s. Folic acid was isolated in 1941 by Herschel Kenworthy Mitchell from spinach leaves. Mitchell then proposed the name folic acid, from the Latin word "folium," meaning the leaf from which the vitamin was extracted. The compound was defined by its effect on bacteria: it was required for the growth of <i>Streptococcus lactis</i> and of <i>Lactobacillus casei</i>, and this bacterial growth response later became the basis of the microbiological assays still used to measure folate. Parallel work at Lederle Laboratories and at Parke-Davis studied the same activity in bacterial cultures, yeast and liver, and the two groups' results were eventually shown to describe the same substance. Bob Stokstad at Lederle crystallized the compound in 1943 and identified it as pteroylglutamic acid, a molecule built from a pteridine ring, para-aminobenzoic acid and glutamic acid. In 1945, folic acid was chemically defined, and its industrial production began. That same year, Robert Angier and colleagues reported a laboratory synthesis of a compound identical to the <i>L. casei</i> factor that had been isolated from liver.

The clinical value of synthetic folic acid was tested almost immediately. In 1945, soon after the synthesis of folic acid, it was realized that it is effective in the treatment of megaloblastic anemia particularly related to pregnancy, lactation and malabsorption syndrome. Early work also revealed that the compound was not harmless in every setting. The haematologist Sidney Farber noted that folic acid appeared to stimulate the growth of leukemia cells. This observation contributed to the idea that folate metabolism could be a drug target, and by the late 1940s folate antagonists such as methotrexate were already in use in cancer treatment. Antifolate therapy and rescue with leucovorin are covered in later sections.

The biochemical explanation came more slowly. Folate derivatives were eventually shown to act as cofactors for enzymes that transfer one-carbon units in the synthesis of purines, pyrimidines and certain amino acids. The reduced coenzyme, tetrahydrofolate, carries these one-carbon units, and this explained why folate deficiency disturbs DNA synthesis in rapidly dividing cells. Stokstad's group extended this work to mammalian enzymes; in 1963, Bob Stokstad, along with his colleagues at Berkeley, were first to isolate, purify and characterize many of the mammalian enzymes involved in the metabolism of folate. The Nobel Prize in Physiology or Medicine in 1988 was awarded to George Hitchings, Gertrude Elion and James Black, mainly for principles of drug design. Hitchings and Elion's work on purine and pyrimidine metabolism, including antimetabolite drugs, is part of the wider history of how folate-dependent nucleic acid synthesis was understood, although the prize did not recognise folate chemistry as such.

Lucy Wills's contribution was recognised only gradually. Her discovery was not publicly honoured in her lifetime to the extent its importance later appeared to warrant, and her research is now regarded as the starting point of folate science.

Biochemical roles in one-carbon metabolism

Tetrahydrofolate as a carrier of one-carbon units

Folate's metabolic activity depends on its reduced form. Dihydrofolate reductase (DHFR) converts folic acid and dihydrofolate into tetrahydrofolate (THF), which is the functional coenzyme. THF carries single carbon units at different oxidation states, from the most reduced methyl group to the most oxidized formyl group. These units are attached mainly at the N5 and N10 positions of the pterin ring. Cells add further glutamate residues to THF, which keeps it inside the cell and improves its binding to enzymes. The main source of these units is serine. Serine hydroxymethyltransferase transfers its hydroxymethyl group to THF, forming 5,10-methylene-THF. Glycine cleavage supplies additional units. Mitochondria are a major source of formate, which the cytoplasm then uses. The reactions are split across the cytoplasm, mitochondria and nucleus, so the pathway functions as a connected network rather than a single reaction chain.

The main donor forms are 5,10-methylene-THF, 10-formyl-THF and 5-methyl-THF. Each one feeds a different branch of metabolism. 5,10-methylene-THF supplies the methyl group for thymidylate synthesis, and 10-formyl-THF supplies carbon for purine synthesis. 5-methyl-THF supplies the methyl group for methionine formation.

Nucleotide synthesis and DNA integrity

Thymidylate synthase converts deoxyuridine monophosphate (dUMP) into deoxythymidine monophosphate (dTMP), using 5,10-methylene-THF as the methyl donor. This is the only de novo source of thymidine for DNA, so the reaction is essential for nucleotide supply. Purine synthesis uses 10-formyl-THF at two steps, where the carbons that become C2 and C8 of the purine ring are added. Both pyrimidine and purine nucleotides are needed for DNA replication and repair, and for RNA synthesis.

When folate is short, the pool of THF-bound units falls, and dTMP and purine production slow. Cells that divide quickly are most affected. Uracil can then be misincorporated into DNA in place of thymine, and the resulting repair attempts can break strands. Because these processes depend on cell division, the effects are most visible in rapidly renewing tissues such as bone marrow and the intestinal lining. Antifolate drugs such as methotrexate exploit the same dependence by blocking DHFR or thymidylate synthesis.

Homocysteine remethylation and methylation

Methionine synthase is a vitamin B12-dependent enzyme. It transfers the methyl group from 5-methyl-THF to homocysteine, forming methionine and regenerating THF. The reaction needs both folate and vitamin B12 (as a cofactor). Without B12, 5-methyl-THF accumulates and cannot return to the active THF pool, a state sometimes called the "methyl trap". Homocysteine therefore rises when either vitamin is short, which is why it is a useful but non-specific marker. Under adequate dietary methionine, roughly 40% of homocysteine is remethylated through this route, and the remainder is handled by folate-independent routes such as betaine-homocysteine methyltransferase, mainly in the liver and kidney.

Methionine is then activated by ATP to form S-adenosylmethionine (SAM), the principal methyl donor in the cell. SAM transfers methyl groups to DNA, RNA, histones and many small molecules, and each transfer produces S-adenosylhomocysteine (SAH). SAH is hydrolysed to homocysteine and adenosine, which closes the cycle. Because DNA and histone methylation influence which genes are active, the folate-dependent supply of methyl groups is linked to gene expression. The strength of this link in humans, and how much it changes with folate status, remains an active research question. Methylation of DNA also depends on the availability of SAM, which can be reduced in folate deficiency, though the consequences for specific genes vary.

Methylenetetrahydrofolate reductase (MTHFR) produces 5-methyl-THF from 5,10-methylene-THF, so its activity directly controls how much methyl donor reaches methionine synthase. Its regulation and genetic variants are discussed in the sections on absorption and metabolism.

Absorption, transport and metabolism

Intestinal absorption

Most folate in food is a polyglutamate, a chain of several glutamate residues attached to the pteridine-based core. Before it can be taken up, the chain must be trimmed to a single glutamate by brush-border enzymes known as γ-glutamyl hydrolases (conjugases). This hydrolysis happens mainly in the proximal small intestine. Its efficiency depends on luminal pH and on food components, which helps explain why folate from different foods is absorbed to very different degrees.

The monoglutamate is then carried across the apical membrane of the enterocyte. The main carrier is the proton-coupled folate transporter (PCFT), encoded by the SLC46A1 gene. PCFT works best at an acidic pH of about 5 to 6, which matches the conditions of the upper small intestine. Its role was only clearly established in 2006, after loss-of-function mutations in the gene were found in people with hereditary folate malabsorption, a rare recessive disorder. The reduced folate carrier (RFC) appears to matter more further down the gut, although the mechanism of colonic folate absorption is still not fully understood.

At pharmacological doses, above roughly 10 µM, a non-saturable, diffusion-like process also operates. Under these conditions much of the folic acid reaches the portal blood without being chemically changed.

Cellular uptake and distribution

Once in the circulation, folates reach tissues by several routes. RFC has a high affinity for reduced food folates but a low affinity for folic acid. PCFT, by contrast, binds folic acid and 5-methyltetrahydrofolate with high affinity, so it contributes to their uptake as well. Folate-binding proteins, which are folate receptors, take up both oxidized and reduced forms by receptor-mediated endocytosis. RFC also moves folate across the choroid plexus into the cerebrospinal fluid, and PCFT contributes to delivery to the central nervous system.

In plasma, 5-methyltetrahydrofolate is the dominant circulating form. It is the most biologically active derivative in blood, and its concentration is the one typically reflected in serum measurements. Folate is then distributed to tissues, where it is retained largely through the polyglutamate forms generated inside the cell.

Reduction of folic acid and the MTHFR step

Folic acid is not a coenzyme itself and must be reduced before use. In the cytosol, dihydrofolate reductase (DHFR) converts it first to dihydrofolate and then to tetrahydrofolate, the active carrier of one-carbon units. The capacity of this step is finite, and when intake exceeds it, unreduced folic acid can appear in the circulation.

Methylenetetrahydrofolate reductase (MTHFR) converts 5,10-methylenetetrahydrofolate into 5-methyltetrahydrofolate. The methyl group from this product is used by methionine synthase to remethylate homocysteine to methionine. Because 5-methyltetrahydrofolate is already the product of MTHFR, it does not depend on DHFR, a distinction that is relevant when comparing supplement forms.

Common variation in the MTHFR gene affects this step. The C677T mutation replaces alanine with valine at position 222, producing a thermolabile enzyme. Reported residual activity is about 65% in heterozygotes and about 30% in homozygotes, though other studies describe reductions of 50% to 75%, so the estimates vary. Homozygous carriers tend to have higher homocysteine and lower folate concentrations, and in some studies their folate levels remain lower even with folic acid supplementation. The A1298C variant reduces activity less strongly. Whether these differences translate into meaningful clinical effects remains debated.

Dietary sources, requirements and measurement of status

Food sources and losses during preparation

Natural folate is found in many plant and animal foods, but only a few are especially rich sources. Dark green leafy vegetables such as spinach, collards and kale, legumes such as lentils, chickpeas and black-eyed peas, peanuts, almonds and liver are the main examples. Cooked lentils supply roughly 350 µg per cup, while beef liver is the single richest common food, with about 215 µg DFE in a 3-ounce serving. Eggs contribute much less, at around 22 µg per large egg. Citrus fruit, avocado, asparagus and Brussels sprouts add further amounts. Because the folate in food is mostly reduced, methylated polyglutamates bound to proteins, its absorption is incomplete: bioavailability from a mixed diet is often estimated at about 50%, depending on intestinal pH, genetic variation in enzyme activity and the food matrix.

Food folate is unstable. It is water-soluble and breaks down under heat, light and oxygen, so losses during processing and cooking can be large. One dietary-assessment program assumed losses of about 5% for salads but 50–55% for boiled rice, soups and stewed vegetables. Boiling leaches folate into the cooking water, whereas steaming, quick cooking and eating some foods raw retain more. Prolonged storage of fresh produce also lowers content.

Recommended intakes

Folate requirements are expressed in micrograms of dietary folate equivalents (DFE), which allow for the greater absorption of folic acid. One µg DFE equals 1 µg of food folate, 0.6 µg of folic acid from fortified foods or supplements taken with food, or 0.5 µg of folic acid from supplements taken on an empty stomach. The US recommended dietary allowance for adult men and women is 400 µg DFE per day. Requirements for children rise with age, from 150 µg DFE at 1–3 years to 300 µg DFE at 9–13 years. For infants, adequate intake values are 65 µg DFE (0–6 months) and 80 µg DFE (7–12 months). The requirement increases to 600 µg DFE during pregnancy and to 500 µg DFE during breastfeeding, reflecting the demand for nucleic acid synthesis in a growing embryo and fetus.

Because about half of pregnancies in the United States are unplanned, US guidance advises that all women who could become pregnant take 400 µg of folic acid daily from supplements, fortified foods or both, in addition to food folate. Some clinical guidance gives a higher range of 400–800 µg. Recent US federal guidance also advises folic acid rather than 5-methyltetrahydrofolate for people who could become pregnant, even when they carry the MTHFR variant. Dietary surveys show that many people fall short. About a third of pregnant women in the United States have intakes below the estimated average requirement, and the US Dietary Reference Intakes panel has noted that the requirement can be hard to meet through diet alone.

Measuring folate status

Folate status is assessed mainly from blood. Serum folate reflects recent intake, whereas red blood cell (erythrocyte) folate reflects longer-term stores and is the main indicator used to set the adult requirement, together with plasma homocysteine. The reference method for total folate has long been the microbiological assay, which measures the growth of the bacterium Lactobacillus rhamnosus in response to the sample. It is considerably cheaper than chromatographic methods and is still treated as a reference point. Newer methods use isotope-dilution liquid chromatography–tandem mass spectrometry (LC-MS/MS), which can separate individual forms such as 5-methyltetrahydrofolate and folic acid. For serum, the two approaches agree within about 10%. For whole blood, the microbiological assay often reads 10–25% higher, and polyglutamates must be converted to monoglutamates before LC-MS/MS analysis.

Population surveys track these measures over time. The US National Health and Nutrition Examination Survey (NHANES) began measuring folate in 1974–75 using the microbiological assay, and in 2011–2012 it combined that assay for whole blood with LC-MS/MS for serum forms. Expert review concluded that LC-MS/MS was suitable for serum but premature for red cells, because the microbiological assay gave red cell values about 25% higher. Red cell folate measured this way was broadly similar across the 2007–2012 survey cycles. Before fortification, the median US food folate intake in 1988–1994 was about 250 µg per day, and the 95th percentile of intake from food and supplements later reached roughly 900 µg per day overall and about 1,700 µg per day among pregnant women.

Deficiency and its health consequences

Causes of deficiency

Folate deficiency usually reflects a mismatch between supply and demand. The Merck Manual notes that it most commonly results from reduced intake, increased demand, or impaired absorption. In practice, the body keeps little reserve. The liver stores only a few months' supply, so deficiency can appear within weeks of an inadequate diet. Diets low in raw green vegetables and enriched grains are a major risk, and prolonged cooking destroys a further share of the folate in food.

Alcohol is one of the most important contributors. It can reduce intake through poor nutrition, and it also interferes directly with absorption, hepatic storage and the enterohepatic recycling of folate, while increasing urinary loss. Malabsorption is the second major route. Coeliac disease, other disorders of the small intestine, short-bowel syndrome and bacterial overgrowth can all impair uptake, and rare inherited defects in the proton-coupled folate transporter block it at the gut and at the blood-brain barrier.

Demand rises sharply in pregnancy and lactation, in infancy and in periods of rapid growth. Chronic haemolytic anaemia and malignancy, with their high cell turnover, also increase requirements, and dialysis can remove folate from the body. Several drugs cause deficiency by blocking folate uptake or its enzymatic use, including some antiseizure medicines and antifolates such as methotrexate and trimethoprim. Finally, a shortage of vitamin B12 can cause folate to become trapped in the methylated form, which is discussed in the vitamin B12 section and leads to a functional folate deficiency.

Megaloblastic anaemia and impaired cell division

The best-characterised consequence of deficiency is megaloblastic anaemia. Folate supplies one-carbon units for converting deoxyuridine monophosphate into thymidylate, and for building purine rings. When these supplies run short, DNA synthesis slows while RNA and protein synthesis are much less affected. The nucleus therefore falls behind the cytoplasm in maturation. The resulting precursor cells, called megaloblasts, are abnormally large and contain more DNA than normal yet cannot complete cell division. Many die within the marrow, which makes the marrow look crowded while the number of mature cells entering the blood falls.

The tissues most affected are those that renew rapidly. The process affects haematopoiesis as well as rapidly renewing tissues such as gastrointestinal cells. In the bone marrow, this ineffective blood cell production can progress to pancytopenia in severe cases. In the gut lining, impaired epithelial renewal contributes to diarrhoea and inflamed mucosa, and inflammation of the tongue is a classic sign.

Peripheral blood and marrow findings are characteristic. Red cells become macrocytic, with oval macrocytes common, and neutrophils show hypersegmented nuclei. Serum and red-cell folate concentrations are reduced. Symptoms usually develop gradually, and early deficiency may be silent. As the haematocrit falls, people experience fatigue, breathlessness, palpitations, pallor and light-headedness. Because folate and vitamin B12 deficiency produce indistinguishable blood changes, clinicians often use methylmalonic acid to identify B12 deficiency specifically. Haematological responses to folate replacement begin within days, with reticulocyte counts rising shortly after treatment starts.

Homocysteine and cardiovascular risk

Folate's role in cardiovascular risk is mainly indirect, through homocysteine. The active 5-methyltetrahydrofolate form supplies the methyl group that converts homocysteine back to methionine. By inhibiting this remethylation pathway, folate deficiency induces homocysteine efflux into the circulation. In healthy populations, serum folate is inversely related to serum homocysteine concentrations. Hyperhomocysteinaemia, commonly defined as a fasting level above 15 µmol/L, is considered an accepted risk factor for atherosclerosis, and it is thought to injure the vascular endothelium.

The strength of the evidence is more limited at the clinical level. Observational studies consistently link high homocysteine with cardiovascular disease, but the association between folate itself and cardiovascular or all-cause mortality has been described as inconclusive. One cohort found that both the highest and the lowest serum folate quartiles were associated with adverse outcomes, which suggests a complex relationship and possible confounding. Randomised trials of homocysteine-lowering B-vitamin supplementation have produced mixed results. A Cochrane review showed no difference compared with placebo in cardiovascular or overall mortality. A later meta-analysis of randomised trials reported a modest reduction in stroke risk and in overall cardiovascular events with folic acid, but no clear effect on coronary heart disease. Associations with liver disease and other conditions have also been reported in observational work, but these findings remain preliminary.

Pregnancy, neural tube defects and supplementation

Neural tube defects and their timing

Neural tube defects (NTDs) are malformations of the brain and spinal cord. The three most common forms are anencephaly, encephalocele, and spina bifida. In the United States, an estimated 3,000 pregnancies a year involve an NTD , and NTDs can cause death or lasting disability.

The defects originate very early in embryonic life. The embryonic structure that becomes the brain and spinal cord begins as a flat plate that folds into a tube, and the seal that closes this tube is completed roughly between days 21 and 28 after conception . Because this happens before many women know they are pregnant, timing is central. A large share of pregnancies in the US are unplanned, meaning that many persons may not know they are pregnant during the crucial time.

Evidence from trials and cohort studies

Observational work preceded the trials. Most case-control studies from the early 1980s linked low folate levels with NTD occurrence, with odds ratios of about 0.4 to 0.65 . The first randomized test was small. A 1981 Cardiff trial enrolled only 111 women, so its results, though consistent with a protective effect, could not settle the question . A larger Irish trial randomized 354 women to folic acid, multivitamins without folic acid, or both, but it ended before reaching its target size and without a clear treatment effect being observed.

The decisive study was the Medical Research Council (MRC) Vitamin Study, which began in 1983 and was halted in 1991. Among its participants, women with a previous NTD-affected pregnancy were randomized to four groups, and the trial reported a 72% protective effect against recurrence with 4 mg of folic acid daily . Two other controlled trials showed reductions as well, with a pooled reduction of about 87% among women who took their supplements as directed . A Hungarian trial comparing 0.8 mg of folic acid with trace-element supplements also reported lower NTD rates . Across published studies from 1981 to 1992, eight of nine studies demonstrated a 50–70% reduction in NTDs with preconceptional folic acid intake.

These findings have limits. The MRC population consisted of women with a prior affected pregnancy, who are probably influenced by genetic and other factors beyond folate alone . The doses also varied between trials, which makes it hard to define a single optimal dose . Moreover, after countries issued recommendations, the frequency of NTDs recorded in birth defect registries of 13 (mainly Western) European countries showed no discernible improvement for about a decade, a gap that contributed to the move toward food fortification.

Dosage, timing and recipients

For the general population, the US Preventive Services Task Force recommends a daily supplement containing 0.4 to 0.8 mg (400 to 800 μg) of folic acid for all persons who are planning or could become pregnant. Women at higher risk receive higher doses. Those with diabetes, those taking antiseizure medication, or those with a previous NTD-affected pregnancy have been advised to take more folic acid (0.8–5 mg daily) during the periconception phase. In the 1991 CDC guidance, women with a prior affected pregnancy were advised to take 4 mg daily, starting before conception and continuing through the first trimester . The American College of Obstetricians and Gynecologists recommends beginning a higher dose at least three months before pregnancy , and individuals with other indications need individualized advice .

The critical period starts before conception and extends into early pregnancy. The critical period for folic acid supplementation starts at least 1 month before conception and continues through the first 2 to 3 months of pregnancy. If a pregnancy is discovered unexpectedly, supplementation should begin immediately rather than being regarded as too late . Continuing beyond the first trimester does not have conclusive benefit: a review of 31 trials involving 17,771 women found no conclusive evidence of overall benefit from supplementation after 12 weeks of gestation. Observational data add nuance. In a Norwegian cohort of 66,014 women, starting folic acid more than eight weeks before conception was associated with a higher risk of spontaneous preterm delivery, while dietary folate showed no significant association . Such cohort findings are not causal evidence and do not overturn the neural tube recommendations.

Who is advised to take supplements, and why many pregnancies are unplanned

Because many pregnancies are unplanned and the neural tube closes early, the USPSTF advises supplementation for everyone who could become pregnant rather than only for women trying to conceive . Uptake remains uneven. In a North Carolina cohort, 51% of women reported folic acid supplementation before pregnancy and 66% reported it during pregnancy. In France, pharmacy dispensing of periconceptional folic acid after prescription was very low and does not follow international recommendations. These gaps help explain why governments have turned to food fortification as a complementary measure, a topic covered in the following section.

Food fortification and public health policy

Adoption and design choices

Mandatory fortification of staple foods has spread widely since the late 1990s, while some countries rely on voluntary schemes. Many countries worldwide have implemented either mandatory or voluntary folic acid fortification for prevention of neural tube defects. The United States and Canada began in 1998, requiring folic acid in cereal grains at 140 and 150 µg per 100 g respectively. Mandatory folic acid fortification was first implemented in the United States (USA) (140 μg of folic acid per 100 g of cereal grains) and Canada (150 μg of folic acid per 100 g of cereal grains) in 1998. Chile followed in 2000, and 2 years later, there was a 40% reduction in the prevalence of NTDs. By mid-2023, 69 countries implemented mandatory folic acid fortification, 47 had voluntary fortification, but 77 had no fortification.

Design choices, namely which staple is fortified and at what level, shape the benefit. Higher dosage of FA is associated with higher reduction of NTD cases, according to a systematic review. An Oxford-led ecological study reported that the risk of babies developing a neural tube defect during pregnancy was halved in countries with mandatory folic acid fortification of cereal grains compared with countries without any folic acid fortification. Voluntary schemes performed worse, with the number of neural tube defects in countries with voluntary fortification were only 20% lower than in unfortified countries. Australia and New Zealand illustrate the political side of these choices: they approved joint flour fortification in 2007, but at the last minute, industry lobbying led to the New Zealand government not proceeding with fortification. New Zealand approved it in 2021.

The UK decision

The UK has moved from voluntary to mandatory fortification. Its rules followed legislation introduced in 2024. From 13 December 2026, folic acid will become an additional mandatory fortificant for non-wholemeal common wheat flour, at 0.25mg per 100g of flour.

The government's stated rationale centres on neural tube defects. Folate deficiency is a known cause of neural tube defects (NTDs) in pregnancy. Officials estimate that NTD rates will be reduced by around 20%, roughly 200 cases a year. Because the measure does not depend on planning, it reaches women not taking supplements or who become pregnant unexpectedly. Officials also expect the wider benefit of increasing the intake of folic acid and improving folate status across the whole population. Government data cited by one industry-facing source show that 12% of children aged 11 to 18, 4% of adults aged 19 to 64, and 2% of adults aged 65 years and over were considered to have low folate intake.

The scope is narrow. The rule covers only non-wholemeal wheat flour, excluding wholemeal flour, some imported products and many non-wheat flours that are important staples for some cultural and ethnic communities. Commentators have noted that the estimated reduction falls short of the reduction of between 25 and 50% seen in countries fully effective fortification levels. Supplements therefore remain advised for women planning pregnancy.

Ongoing debate

A central scientific dispute concerns unmetabolized folic acid (UMFA). Synthetic folic acid can circulate in blood without being processed. Irish researchers, before any mandatory rule, warned that the potential of folic acid to mask pernicious anaemia and possibly accelerate the growth of existing cancers made circulating UMFA worth investigating. Evidence on its health effects remains contested. One cord-blood study found UMFA slightly higher but "nonsignificantly higher" in cord blood from supplemented women than in cord blood from nonsupplemented women. A New Zealand expert review found no evidence that unmetabolised folic acid that remains within the body's circulation is harmful. Other reviewers describe the UMFA evidence as not very conclusive yet. Two specific concerns are that high folic acid intake can mask the symptoms of vitamin B-12 deficiency, and that cancer data remain mixed; one review notes that most data suggest no effect.

Socioeconomic factors complicate the attribution of falling birth-defect rates. Declines were decreasing in the United States, Canada and Australia prior to fortification. A population-level study found a strong linear response of reduced NTDs with better SES. A reassessment that compared countries with and without national fortification concluded that socioeconomic factors are confounding the comparison, and it reports that there was no association between national folic acid fortification and decreased prevalence of NTDs in its cross-country analysis.

Monitoring is a recurring theme. A review of Americas programs noted that most of these countries do not have an adequate monitoring system for NTD and other malformations, which may limit the validity of the final evaluation. Reviewers recommend that it is important to monitor the impact of folic acid fortification periodically. Some groups accept a possible benefit for vulnerable people while opposing the mandate; the Soil Association, for example, recognise[s] however, that in the absence of a cohesive food strategy, and in the context of folate deficiencies, fortification of non-wholemeal wheat flour might provide benefit for vulnerable groups.

Safety, excess intake and drug interactions

Upper intake level for synthetic folic acid

The Tolerable Upper Intake Level (UL) for folic acid is set at 1000 µg per day for adults. The 1998 DRIs for folate set this UL for adults, including pregnant women aged 19 and over, covering folic acid from fortified foods and/or dietary supplements. The limit does not extend to food folate, since high intakes of naturally occurring folate had not been reported to cause adverse effects. The figure was derived indirectly. The IOM identified a lowest observed adverse effect level of 5000 µg/day, linked to progression of neuropathy in vitamin B12-deficient people, and divided it by an uncertainty factor of five. The European Food Safety Authority's 2023 review kept 1000 µg per day for adults and pregnant and breastfeeding women, with lower values for children. It applies to folate from fortified foods and food supplements.

Research on real-world intake has mostly looked at how often people exceed this level. In NHANES 2003–2010 data, 2.7% of U.S. adults had usual daily folic acid intake above the UL, and 98.5% of them took supplements containing folic acid. A systematic review of high-income countries with mandatory fortification reached a stronger conclusion for women of childbearing age: women did not get enough folate from food alone even with fortified products, yet almost all women taking a folic acid supplement exceeded the upper limit. The authors argued that the limit and supplement guidance deserved review. Intervention data point in a similar direction. In one trial, a daily 1,000 µg dose offered no protection against new colorectal polyps and increased the risk of multiple or more serious polyps.

Masking of vitamin B12 deficiency

The main safety concern is that folic acid can hide a vitamin B12 deficiency. Both vitamin B12 and folate are required for the DNA synthesis needed to produce red blood cells. Because the two deficiencies produce similar megaloblastic anemia, folic acid supplements may mask the anemia and leave an underlying vitamin B12 deficiency undetected. Folic acid corrects the blood changes but not the nerve damage, so a B12 problem can progress silently, sometimes toward lasting nerve damage, before anyone notices. Older adults and people on vegan or vegetarian diets are most at risk, since B12 deficiency is more common in these groups.

The historical evidence is disputed. Early reports described neurological problems in patients with pernicious anemia treated with very high oral folic acid. In 1951, Conley and Krevans reported neurological manifestations in new pernicious anemia patients linked to high oral doses of folic acid of 20 to 28 mg per day. A 2022 historical review, however, argued that the historical record does not provide compelling evidence that folic acid can cause neurologic complications in people with low vitamin B12 status, and it supports reconsidering the basis for the UL. A 2024 hypothesis proposes a mechanism: folic acid may reduce the transport of B12 in people with low B12 status, which could produce a more pronounced biochemical deficiency and reduced B12 availability for the nervous system. Surveillance data from the United States have not shown a clear rise in masked deficiency. After cereal fortification in the U.S., the proportion of people with low vitamin B12 but without anemia did not increase significantly. A Dutch review concluded that there was no conclusive evidence that folic acid supplementation alone, without vitamin B12, causes or worsens B12-deficiency neuropathy.

Antifolate drugs, anticonvulsants and other interactions

Several medicines interact with folate metabolism. Methotrexate is the best-characterised case: it inhibits dihydrofolate reductase, blocking DNA synthesis and cell division. Folate supplementation can blunt its effect. Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate. The reverse problem also occurs: folate deficiency may increase methotrexate toxicity.

Trimethoprim, a bacterial enzyme inhibitor, adds to this effect. Trimethoprim has a higher affinity for bacterial dihydrofolate reductase but also affects the human enzyme. Co-trimoxazole combines it with sulfamethoxazole, which blocks an earlier step in folate synthesis by inhibiting dihydropteroate synthase. Combined with methotrexate, the result can be serious. One case report describes severe pancytopenia and hemorrhagic oral mucositis despite a serum methotrexate concentration well below the commonly accepted toxic threshold.

Interactions with anticonvulsant drugs are better documented in older pharmacology texts than in recent trials. Long-term use of some older agents, such as phenytoin and phenobarbital, is generally associated with lower folate status, and some drug information sources report that high folate doses may lower serum levels of certain first-generation anticonvulsants. Clinicians therefore check folate status in patients on these drugs, in those on antifolates, and in anyone with malabsorption or suspected B12 deficiency. In such cases, testing folate and B12 together is generally recommended, especially before supplementing with folic acid.

New keywords: tolerable-upper-intake-level | Tolerable Upper Intake Level | 可耐受最高摄入量 | nutrition anticonvulsant | Anticonvulsant | 抗惊厥药 | pharmacology

Clinical uses and antifolate drugs

Antifolates are drugs that interfere with folate-dependent reactions. Because folate coenzymes supply the one-carbon units needed to build nucleotides, these drugs deprive rapidly proliferating cells of the precursors they need for DNA synthesis. That property underlies their use in cancer treatment and in some immune-mediated diseases.

Methotrexate and pemetrexed

Methotrexate is a close structural analogue of folic acid that binds dihydrofolate reductase with very high affinity, which stops the regeneration of tetrahydrofolate. The resulting shortage of reduced folates impairs thymidylate and purine synthesis, so cells with high turnover, such as leukemic cells, bone marrow precursors and the lining of the gut, are the most affected. High-dose regimens are used in acute lymphoblastic leukemia, osteosarcoma and some lymphomas, and the drug is also a standard chemotherapy agent in gestational trophoblastic disease. At much lower weekly doses, methotrexate is a mainstay of treatment for rheumatoid arthritis and psoriasis. Its anti-inflammatory mechanism in these conditions is not fully settled, and it is not simply a scaled-down version of the anticancer effect.

Pemetrexed is a multitargeted antifolate. It inhibits thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyltransferase, the last of which acts in de novo purine synthesis. It is usually combined with a platinum drug for non-squamous non-small-cell lung cancer and for pleural mesothelioma. Because its toxicity can be severe, patients are normally pretreated with folic acid and given vitamin B12 injections, a regimen intended to reduce hematologic and gastrointestinal side effects. Pralatrexate, approved for peripheral T-cell lymphoma, and raltitrexed, a thymidylate synthase inhibitor used for colorectal cancer in some countries, belong to the same broad class.

Methotrexate toxicity includes mucositis, myelosuppression and kidney injury. Renal damage at high doses is linked partly to drug precipitation in acidic urine, so clinicians use hydration and urinary alkalinization. When levels are dangerously high and kidney function is impaired, the enzyme glucarpidase can be given to hydrolyze the drug.

Leucovorin rescue

Leucovorin, also called folinic acid, is a reduced folate derivative that can be used without first passing through the step that methotrexate blocks. Giving it after high-dose methotrexate therefore supplies downstream one-carbon carriers, allowing normal tissues to keep making nucleotides while the drug is cleared. Leucovorin also protects tumor cells, so its timing is critical. Rescue is generally started about a day after the methotrexate infusion and continued until plasma drug concentrations fall below a set threshold. Giving it too early can weaken the anticancer effect. Leucovorin is also used to potentiate fluorouracil, a thymidylate synthase inhibitor, in colorectal cancer. In toxoplasmosis, it is sometimes added to pyrimethamine to limit bone marrow toxicity, although concerns have been raised that it may reduce the antiparasitic effect.

Antimicrobial and antiparasitic agents

Bacteria, many protozoa and plants synthesize folate de novo, whereas humans cannot make the pteridine ring and rely on dietary folate. This difference is the basis of selective toxicity. Sulfonamides such as sulfamethoxazole are analogues of para-aminobenzoic acid that competitively inhibit dihydropteroate synthase, the enzyme that joins PABA to the pterin moiety. Trimethoprim inhibits bacterial dihydrofolate reductase far more strongly than the human enzyme. Combined as co-trimoxazole, the two drugs act in sequence on the same pathway and are used against urinary tract infections and Pneumocystis jirovecii pneumonia. Dapsone, a sulfone with a related mechanism, is used in leprosy.

Antiparasitic agents exploit the same principle. Pyrimethamine targets the dihydrofolate reductase of Plasmodium and Toxoplasma. Proguanil, which is converted to the active metabolite cycloguanil, is used for malaria prophylaxis. Resistance arising from mutations in the parasite's dihydrofolate reductase and dihydropteroate synthase has reduced the usefulness of sulfadoxine-pyrimethamine in many regions. The selectivity is not absolute, since human dihydrofolate reductase is still inhibited at high doses, which explains why bone marrow suppression can occur with these drugs.

Open questions and current research

Genetic variation and testing

Common variants in the gene for methylenetetrahydrofolate reductase, the enzyme that generates the main circulating folate form, are the best-studied example of how individual differences could change folate requirements. The c.665C>T variant, when present in two copies, is the genotype most consistently linked to a moderate fall in enzyme activity and higher plasma homocysteine, whereas heterozygotes and carriers of the c.1286A>C variant generally show changes that are considered clinically minor (Homozygosity for c.665C>T is associated with moderate reduction in enzyme activity and increased plasma homocysteine levels). Whether these mutations meaningfully raise disease risk remains unresolved, because their association with health conditions varies among different populations.

The practical value of testing is contested. Direct-to-consumer kits are widely sold, which raises concerns about the accuracy of the results and the lack of proper genetic interpretation and counseling. Professional reviews have reached a more restrictive position: meta-analyses suggest testing for the MTHFR polymorphisms has minimal clinical utility for thrombophilia and recurrent pregnancy loss, and routine testing for these indications is no longer recommended. A narrower question concerns drug response. Some laboratories advise patients to share their genotype with prescribers before folate-dependent chemotherapy such as methotrexate, but testing to predict treatment toxicity is not widely adopted and literature is conflicting, and a variant does not guarantee toxicity.

Folate and cancer

The concern that folate might promote cancer rests on biochemistry: folate coenzymes supply the carbon units needed for purine and thymine nucleotide synthesis, which rapidly dividing cells, including tumour cells, depend on (Folate has a unique role because its coenzymes are needed for de novo purine and thymine nucleotide biosynthesis.). Trial evidence has been inconsistent. A 2011 analysis that weighted six supplementation trials by duration estimated higher cancer incidence in supplemented groups (relative risk=1.21 [95% confidence interval: 1.05-1.39]), and its authors called for close monitoring of cancer incidence. Larger later syntheses have not confirmed this. A 2013 meta-analysis of 13 trials found no significant effect on total cancer incidence, while the prostate estimate, based on five trials, was higher but not statistically significant. A pooled analysis by the B-Vitamin Treatment Trialists' Collaboration likewise found that those who took daily folic acid for 5 years or less were not significantly more likely to develop cancer than those who took placebo. Because cancers develop over long periods and most trials were short, questions about long-term effects remain open.

Cognition and mood

Research on cognitive decline and depression is less settled. Trials of folic acid combined with other B vitamins in older adults have produced mixed results, and benefit has been suggested mainly in people with high homocysteine or poor baseline folate status, a subgroup that has not been defined consistently. For mood, testing for common MTHFR polymorphisms is sometimes used to identify patients with depression who may improve with folate supplementation, but this use has not been validated in trials. Clinicians and researchers therefore treat folate supplementation as an adjunct question rather than an established treatment, and the links to brain function remain under study in observational and trial data alike.

Unmetabolized folic acid and fortification

The most pressing open question for public health is what happens when synthetic folic acid circulates unchanged. Before mandatory fortification in Ireland, researchers found that circulatory unmetabolised folic acid was present in 18 out of 20 mothers (fasted), and they raised concerns that it could mask vitamin B12-related anaemia and possibly accelerate existing tumours. In the United States, the picture is similar: We detected UMFA in 96% and 98% of the SUP− and SUP+ groups, respectively. Fortified cereal contributed to the higher levels, and detection rose with intake: the prevalence increased from ≈20% of subjects who consumed <84 μg folic acid/d to ≈50% of those with daily folic acid intakes ≥584 μg/d. Dose-finding work suggests a threshold, with unmetabolized folic acid absent after 100 or 200 μg doses but present at the highest level (400 μg) tested. Unmetabolized folic acid has also been detected in breastmilk and umbilical cord blood, so fetuses and breastfed infants are exposed as well.

Two questions follow. First, what the long-term biological effects of these exposures are; a recent review notes that additional research is required to fully understand the biological effects of higher than recommended folic acid intakes. Second, how to monitor. One commentary argues that the risk of folate intake >1 mg/day does not outweigh the benefits of folic acid fortification, provided un-metabolized folic acid, RBC folate and vitamin B_12 are monitored periodically. Measuring unmetabolized folic acid requires specialised methods, such as the affinity HPLC approach developed for epidemiological work, which is why it is not routine in clinical or survey settings.

Optimal status for different populations

No single target folate status has been agreed for all populations, and baseline differences complicate comparison. One study reported that the share of people with serum total folate above 30 nmol/L was only 9% (56) as compared with 65% in the general US population, reflecting the different fortification regimes. Balancing the protection that fortification provides against neural tube defects with exposure to unmetabolized folic acid therefore depends on monitoring that reports both population distributions and individual vitamer concentrations, a combination that few countries currently measure consistently.

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