Folate deficiency

13.9K views
Folate deficiency

Folic acid deficiency

Folate also known as “folacin” or “vitamin B9,” is a water-soluble B vitamin that is naturally present in some foods is called “folates” and the synthetic or man-made folate is called “folic acid” that is used in dietary supplements and added to certain foods (fortified foods) 1. Folate is critical in the metabolism of nucleic acid precursors and several amino acids, as well as in methylation reactions (Figures 1 and 2) 2. The potent form of folate is tetrahydrofolate (THF) 3. Folate deficiency usually coexists with other nutrient deficiencies because of its strong association with poor diet, alcoholism, and malabsorptive disorders 4. Megaloblastic anemia, which is characterized by large, abnormally nucleated red blood cells, is the primary clinical sign of folate or vitamin B12 deficiency 4, 5. Megaloblastic anemia symptoms include weakness, fatigue, difficulty concentrating, irritability, headache, heart palpitations, and shortness of breath 6. Folate deficiency can also produce soreness in and shallow ulcerations on your tongue and inside your mouth; changes in your skin, hair, or fingernail pigmentation; gastrointestinal symptoms; and elevated blood concentrations of homocysteine 5, 6, 4, 7, 8.

Women with inadequate folate intakes are at increased risk of giving birth to infants with birth defects of the brain and spine (neural tube birth defects) such as spina bifida and anencephaly 9, 6. Inadequate maternal folate status has also been associated with low infant birth weight, preterm delivery, and fetal growth retardation 5, 10. The Centers for Disease Control and Prevention (CDC) recommends ALL women of child bearing age should get 400 micrograms (mcg) of folic acid every day in addition to consuming food with folate from a varied diet 11, 9, 12. Whilst taking a higher dose of folic acid of more than 400 mcg each day is not necessarily better to prevent neural tube defects, unless a doctor recommends taking more due to other health conditions 9. The CDC further recommends that women who have already had a pregnancy affected by a neural tube defect consume 4,000 mcg of folic acid each day one month before becoming pregnant and through the first 3 months of pregnancy 9.

The latest research reveals the following about folic acid deficiency 3:

  • There may be a link between elevated homocysteine (a marker for an increased risk for arteriosclerosis) and folate deficiency.
  • A lowering of the risk of stroke but not adverse cardiac event when hyperhomocysteinemia is corrected with folic acid
  • Reduction in the incidence of neural tube defects with folic acid supplementation during pregnancy.
  • Lack of folic acid during pregnancy may increase the risk of diabetes-associated congenital disabilities and autism.
  • Maternal folic acid during pregnancy may lower the risk of childhood leukemia.
  • Folic acid supplementation may increase the risk of cancer.

Folic acid is available in multivitamins and prenatal vitamins, supplements containing other B-complex vitamins, and supplements containing only folic acid. Common doses range from 680 to 1,360 mcg dietary folate equivalent (DFE) (400 to 800 mcg folic acid) in supplements for adults and 340 to 680 mcg DFE (200 to 400 mcg folic acid) in children’s multivitamins 13. About 85% of supplemental folic acid, when taken with food, is bioavailable 6, 4. When consumed without food, nearly 100% of supplemental folic acid is bioavailable 1.

Dietary supplements containing 5-methylenetetrahydrofolate or 5-methyl-folate (5-MTHF) are also available 1. For some people with an methylenetetrahydrofolate reductase polymorphism (MTHFR polymorphism), supplementation with 5-methylenetetrahydrofolate (5-MTHF) might be more beneficial than with folic acid 14, 15. The bioavailability of 5-methylenetetrahydrofolate (5-MTHF) in supplements is the same as or greater than that of folic acid 16, 17, 18, 19. However, conversion factors between mcg and mcg dietary folate equivalent (DFE) for 5-MTHF (5-methyl-folate) have not been formally established. The U.S. Food and Drug Administration (FDA) allows manufacturers to use either a conversion factor of 1.7 to be comparable to folic acid, or their own established conversion factors not to exceed 1.7, where mcg DFE = mcg naturally occurring folate + (1.7 x mcg folic acid) 20. For example, a serving of food containing 60 microgram (mcg) of folate would provide 60 mcg of dietary folate equivalents (DFEs), while a serving of pasta fortified with 60 mcg of folic acid would provide 1.7 x 60 = 102 mcg of dietary folate equivalents (DFEs) due to the higher bioavailability of folic acid. A folic acid supplement of 400 mcg taken on an empty stomach would provide 800 mcg of dietary folate equivalents (DFEs). It should be noted that DFEs were determined in studies with adults and whether folic acid in infant formula is more bioavailable than folates in mother’s milk has not been studied. Use of dietary folate equivalents (DFEs) to determine a folate requirement for the infant would not be desirable.

Table 1. Biological roles of vitamin B

VitaminBiological Function
Vitamin B1 (thiamine)cofactor for enzymes in glucose metabolism, amino acid catabolism, nucleotide synthesis, and fatty acid synthesis 21
Vitamin B2 (riboflavin)precursor for flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) for cellular respiration 6
Vitamin B3 (nicotinamide)precursor for nicotinamide adenine dinucleotide (NAD) utilized in biosynthetic pathways, energy metabolism, and protection from reactive oxygen species 22
Vitamin B5 (pantothenic acid)precursor for coenzyme A (coA), an acyl-carrier required for the activity of many enzymes 23
Vitamin B6 (pyridoxine)cofactor for over 150 enzymes involved mainly in amino acid synthesis and degradation 24
Vitamin B7 (biotin)plays an essential role in carboxylation reactions 25 and also has many applications in laboratory research
Vitamin B9 (folate)substrate for nucleotide synthesis and methyl-donors in the one-carbon metabolism pathway 6
Vitamin B12 (cobalamin)cofactor for enzymes in one-carbon metabolism and the propionate catabolic pathway 6
[Source 26 ]

What is folate?

Folate also known as “folacin” or “vitamin B9,” is a water-soluble B vitamin that is naturally present in some foods is called “folates” and the synthetic or man-made folate is called “folic acid” that is used in dietary supplements and added to certain foods (fortified foods) 1. Folate is critical in the metabolism of nucleic acid precursors and several amino acids, as well as in methylation reactions (Figures 1 and 2) 2. Folate functions as a coenzyme or cosubstrate in single-carbon transfers in the synthesis of DNA and RNA (the building block of the human body, which carries genetic information) and metabolism of amino acids called the folate and methionine cycle (Figure 1) 5, 6, 27. Folate functions as a coenzyme or cosubstrate in single-carbon transfers in the synthesis of nucleic acids (DNA and RNA) and metabolism of amino acids 1. One of the most important folate-dependent reactions is the conversion of homocysteine to methionine in the synthesis of S-adenosyl-methionine (SAMe or SAM), an important methyl donor 1. Another folate-dependent reaction, the methylation of deoxyuridylate to thymidylate in the formation of DNA, is required for proper cell division 1. An impairment of this reaction initiates a process that can lead to megaloblastic anemia, one of the hallmarks of folate deficiency 4.

Naturally occurring folates or food folates are in the tetrahydrofolate (THF) form and usually have additional glutamate residues, making them polyglutamates 5. Folic acid (the man made folate) is the fully oxidized monoglutamate form of folate that is used in fortified foods and most dietary supplements 1. Some dietary supplements also contain folate in the monoglutamyl form, 5-MTHF, also known as L-5-MTHF, 5-methyl-folate, L-methylfolate, and methylfolate 1.

Heating during cooking destroys folic acid 3. Folate is absorbed in the jejunum (the 2nd part of your small intestine) by active and passive transport mechanisms across the intestinal wall 3. Folate or folic acid is a water-soluble type of vitamin B. This means it is not stored in the fat tissues of the body. Leftover amounts of the vitamin leave the body through the urine. The body has about 1,000-20,000 mcg of folate stores, and adults need about 400 mcg/day to replenish the daily losses. Folate deficiency may take 8-16 weeks to become evident 3.

Folate is poorly stored, and folate deficiency can develop in weeks to months in persons with folate-deficient diets. Most of the serum folate is present in the inactive 5-methyltetrahydrofolate (5-methyl THF) form 3. Upon entering cells, 5-methyltetrahydrofolate (5-methyl THF) demethylates to tetrahydrofolate (THF), the biologically active form of folate that is involved in folate-dependent enzymatic reactions. Cobalamin (vitamin B12) serves as a co-factor for this demethylation to occur, and in the absence of vitamin B12, folate is “trapped” inside cells as 5-methyltetrahydrofolate (5-methyl THF). Tetrahydrofolate (THF) is involved in the formation of many coenzymes in metabolic systems, particularly for purine and pyrimidine synthesis, nucleoprotein synthesis, and maintenance in red blood cells formation 28. The deficiency of folate, as a result, leads to impairment of cell division, accumulation of toxic metabolites, and impartment of methylation reactions required for regulation of gene expression, resulting in megaloblastic anemia, which is characterized by large, abnormally nucleated red blood cells 4, 5.

Figure 1. Folate and methionine cycle

Folate and methionine cycle

Footnote: Folate and methionine cycle. The Folate cycle begins with the conversion of dietary folate (vitamin B9) into dihydrofolate (DHF) then tetrahydrofolate (THF) by dihydrofolate reductase (DHFR). Next, tetrahydrofolate (THF) is converted to 5, 10-methylene-THF by serine hydroxymethyltransferase (SHMT) before being reduced into 5-methyl-THF (5-mTHF) by methylenetetrahydrofolate reductase (MTHFR). As part of the methionine cycle, 5-methyl-THF (5-mTHF) donates its carbon group to convert homocysteine (Hcy) to methionine (Met), which is catalyzed by methionine synthase (MS) and requires vitamin B12 as a cofactor, hence initiating Methionine cycle. In turn, methionine (Met) is used by methionine adenosyltransferase (MAT) to generate S-Adenosyl-Methionine (SAM) – the principal donor of methyl groups for DNA and proteins methylation. Thus, SAM is used by different methyltransferases, resulting in S-adenosylhomocysteine after its demethylation. Finally, S-adenosylhomocysteine hydrolase (SAHH) mediates deadenylation of S-adenosylhomocysteine to hcysteine, enclosing the methionine cycle. Homocysteine can be used by cystathionine synthase (CBS), which converts it to cystathionine. In turn, cystathionine is a substrate for cystathionine gamma-lyase (CTH), which uses it for synthesis of cysteine. Cysteine is required for the synthesis of proteins as well as for generation of taurine and glutathione, the latter is one of the critical molecules for redox homeostasis.

Abbreviations: Ado = adenosine; ATP = adeno-sine triphosphate; vitamin B6, vitamin B9, vitamin B12; Cbs = cystathionine beta synthase; DHF = dihydrofolate; DHFR = dihydrofolate reductase; Cys = cysteine; GSH = glutathione; Hcy = homocysteine; MAT = methionine adenosyltransferase; Met = methionine; 5–methylTHF = 5, 10–methyleneTHF; MTHFR = methylenetetrahydrofolate reductase or 5,10-methylene-trahydrofolate reductase; MS = methionine synthase, SAM = S-adenosyl-methionine; SAH = S-adenosylhomocysteine; SHMT = hydroxymethyltransferase; THF = tetrahydrofolate.

[Source 29 ]

Figure 2. Homocysteine metabolism

Homocysteine metabolism

Footnote: Schematic representation of pathways of homocysteine metabolism. The metabolism of homocysteine, an intermediate in the metabolism of sulfur-containing amino acids, provides an example of the interrelationships among nutrients necessary for optimal physiological function and health. Healthy individuals utilize two different pathways to metabolize homocysteine. One pathway (methionine synthase) synthesizes methionine from homocysteine and is dependent on both folate and vitamin B12 as cofactors. The other pathway converts homocysteine to another amino acid, cysteine, and requires two vitamin B6-dependent enzymes. Thus, the concentration of homocysteine in the blood is regulated by three B-vitamins: folate (vitamin B9), vitamin B12 (cobalamin), and vitamin B6 (pyridoxine) 30. In some individuals, riboflavin (vitamin B2) is also involved in the regulation of homocysteine concentrations.

Abbreviations: DHFR = dihydrofolate reductase; THF = tetrahydrofolate; SHMT = serinehydroxymethyltransferase; MTHF = methylenetetrahydrofolate; MTHFR = 5,10-methylene-THF reductase; ATP = adenosine triphosphate; MAT = methionine adenosyltransferase; ADP = adenosine diphosphate; SAM = S-adenosylmethionine; SAH = S-adenosylhomocysteine; BHMT = betaine-Hcy S-methyltransferase; CBS = cystathionine beta-synthase; CSE = cystathionase; GSH = glutathione; H2S = hydrogen sulphide

[Source 7 ]

What does folate do?

Folate functions as a coenzyme or cosubstrate in single-carbon (1C-group) transfers in the synthesis of nucleic acids (DNA and RNA) and metabolism of amino acids (Figures 1 and 2) 5, 6, 27. One of the most important folate-dependent reactions is the conversion of homocysteine to methionine in the synthesis of S-adenosyl-methionine (SAM), an important methyl donor. Another folate-dependent reaction, the methylation of deoxyuridylate to thymidylate in the formation of DNA, is required for proper cell division. An impairment of this reaction initiates a process that can lead to megaloblastic anemia, one of the hallmarks of folate deficiency 4.

Once transported to the cell, folate undergoes covalent modification by polyglutamination 29. Folate is further substituted by the one-carbon moiety in the N5 and/or N10 position at different oxidation levels: formate (10-formyltetrahydrofolate), formaldehyde (5,10-methylenetetrahydrofolate), or methanol (5-methyltetrahydrofolate) 31. There are only two direct sources of one-carbon groups (1C-group) in one-carbon metabolism – serine and glycine 29. Therefore, the central reaction of the folate cycle is conversion of serine to glycine by serine hydroxymethyltransferase SHMT1 and SHMT2 enzymes. By transferring the one-carbon group (1C-group) from serine and tetrahydrofolate (THF), this reaction generates 5,10-methylenetetrahydrofolate – the first donor of one-carbon group (1C-group) in the folate cycle. Another source of 5,10-methylenetetrahydrofolate comes from the enzymatic cleavage of glycine by an enzyme called glycine decarboxylase (GLDC), which resides in mitochondria 29.

In turn, 5,10-methylenetetrahydrofolate can be used in three ways (Figures 1 and 2). First, it can serve as one-carbon-donor for the initial step of thymidylate biosynthesis, a reaction catalyzed by thymidylate synthase (TS). In this reaction 5,10-methylenetetrahydrofolate provides one-carbon group for the pyrimidine biosynthesis and is oxidized into dihydrofolate (DHF). In the next reaction dihydrofolate reductase (DHFR) reduces DHF to tetrahydrofolate (THF) enclosing this metabolic loop.

Second, 5,10-methylenetetrahydrofolate can be used by a cytosolic enzyme methylenetetrahydrofolate reductase 1 (MTHFD1), or mitochondrial tandem enzymes methylenetetrahydrofolate reductases MTHFD2L/MTHFD2, to generate 10-formyltetrahydrofolate 29. 10-formyltetrahydrofolate is a one-carbon-donor for the two reactions of purine biosynthesis catalyzed by Trifunctional enzyme Phosphoribosylglycinamide Formyltransferase/ Synthetase/ Phosphoribosylaminoimidazole Synthetase (GART) and Bifunctional 5-Aminoimidazole-4-Carboxamide Ribonucleotide Formyltransferase/IMP Cyclohydrolase (ATIC), both of which in turn generate tetrahydrofolate (THF).

Third, 5,10-methylenetetrahydrofolate is used by methylentetrahydrofolatereductase (MTHFR) to generate methyltetrahydrofolate. The latter donates a methyl group to homocycteine resulting in the formation of methionine and tetrahydrofolate (THF). By this way the Folate cycle is coupled with Methionine cycle (Shuvalov O, Petukhov A, Daks A, Fedorova O, Vasileva E, Barlev NA. One-carbon metabolism and nucleotide biosynthesis as attractive targets for anticancer therapy. Oncotarget. 2017 Apr 4;8(14):23955-23977. doi: 10.18632/oncotarget.15053)). Finally, tetrahydrofolate (THF) is converted into 5,10-methylenetetrahydrofolate by serine hydroxymethyltransferase SHMT1 and SHMT2 enzymes thus enclosing the Folate cycle 29.

Another arm of the one-carbon group (1C-group)-metabolic process is the methionine cycle (Figures 1 and 2). It starts with methionine synthesis from homocysteine and methyltetrahydrofolate catalyzed by methionine synthase (MS). Subsequently, methionine adenyltransferase (MAT) synthesizes S-adenosyl-methionine (SAM), the main donor of methyl groups in the cell. After demethylation, S-adenosyl-methionine (SAM) is converted to S-adenosylhomocysteine (SAH). Finally, S-adenosyl homocysteine hydrolase (SAHH) mediates de-adenylation of SAHH resulting in homocysteine and full turn of the cycle 29.

One-carbon metabolism

The only function of folate coenzymes in the body appears to be in mediating the transfer of one-carbon units 32. Folate coenzymes act as acceptors and donors of one-carbon units in a variety of reactions critical to the metabolism of nucleic acids and amino acids (Figures 1 and 2) 33.

Nucleic acid metabolism

Folate coenzymes play a vital role in DNA metabolism through two different pathways. (1) The synthesis of DNA from its precursors (thymidine and purines) is dependent on folate coenzymes. (2) A folate coenzyme is required for the synthesis of methionine from homocysteine, and methionine is required for the synthesis of S-adenosylmethionine (SAM). SAM is a methyl group (one-carbon unit) donor used in most biological methylation reactions, including the methylation of a number of sites within DNA, RNA, proteins, and phospholipids. The methylation of DNA plays a role in controlling gene expression and is critical during cell differentiation. Aberrations in DNA methylation have been linked to the development of cancer.

Amino acid metabolism

Folate coenzymes are required for the metabolism of several important amino acids, namely methionine, cysteine, serine, glycine, and histidine. The synthesis of methionine from homocysteine is catalyzed by methionine synthase, an enzyme that requires not only folate (as 5-methyltetrahydrofolate) but also vitamin B12. Thus, folate and/or vitamin B12 deficiency can result in decreased synthesis of methionine and an accumulation of homocysteine. Elevated blood concentrations of homocysteine have been considered for many years to be a risk factor for some chronic diseases, including cardiovascular disease and dementia.

How much folate do I need?

The amount of folate you need depends on your age. Average daily recommended amounts are listed below in micrograms (mcg) of dietary folate equivalents (DFEs).

Table 2 lists the current Recommended Dietary Allowances (RDAs) for folate as mcg of dietary folate equivalents (DFEs). The Recommended Dietary Allowance (RDA) is the average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals. The Food and Nutrition Board at the National Academies of Sciences, Engineering, and Medicine developed dietary folate equivalents (DFEs) to reflect the higher bioavailability of folic acid than that of food folate 6. At least 85% of folic acid is estimated to be bioavailable when taken with food, whereas only about 50% of folate naturally present in food is bioavailable 6, 5. Based on these values, the Food and Nutrition Board defined dietary folate equivalent (DFE) as follows:

  • 1 microgram (mcg) of food folate provides 1 mcg DFE (1 mcg DFE = 1 mcg food folate)
  • 1 mcg DFE = 0.6 mcg folic acid from fortified foods or dietary supplements consumed with foods (OR 1 mcg of folic acid taken with meals or as fortified food provides 1.7 mcg of DFEs)
  • 1 mcg DFE = 0.5 mcg folic acid from dietary supplements taken on an empty stomach (OR 1 mcg of folic acid (supplement) taken on an empty stomach provides 2 mcg of DFEs)

For example, a serving of food containing 60 microgram (mcg) of folate would provide 60 mcg of DFEs, while a serving of pasta fortified with 60 mcg of folic acid would provide 1.7 x 60 = 102 mcg of DFEs due to the higher bioavailability of folic acid. A folic acid supplement of 400 mcg taken on an empty stomach would provide 800 mcg of DFEs. It should be noted that DFEs were determined in studies with adults and whether folic acid in infant formula is more bioavailable than folates in mother’s milk has not been studied. Use of DFEs to determine a folate requirement for the infant would not be desirable.

Factors for converting mcg dietary folate equivalent (DFE) to mcg for supplemental folate in the form of 5-methylenetetrahydrofolate (5-MTHF) have not been formally established 1.

For infants from birth to 12 months, the Food and Nutrition Board established an Adequate Intake (AI) for folate that is equivalent to the mean intake of folate in healthy, breastfed infants in the United States (see Table 2). Adequate Intake (AI) is the intake level that is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an Recommended Dietary Allowance (RDA) 1.

According to data from the 2013–2014 National Health and Nutrition Examination Survey (NHANES), most people in the United States consume adequate amounts of folate 1. Mean dietary intakes of folate from foods range from 417 to 547 mcg DFE per day for children aged 2–19 34. Average daily intakes of folate from food are 602 mcg DFE for males aged 20 and older and 455 mcg DFE for females 1.

Although most people consume adequate amounts of folate, certain groups, including women of childbearing age and non-Hispanic black women, are at risk of insufficient folate intakes 1. Even when intakes of folic acid from dietary supplements are included, 19% of female adolescents aged 14 to 18 years and 17% of women aged 19 to 30 years do not meet the Estimated Average Requirement (the average daily level of intake estimated to meet the requirements of 50% of healthy individuals; usually used to assess the nutrient intakes of groups of people and to plan nutritionally adequate diets for them; can also be used to assess the nutrient intakes of individuals) 35. Similarly, 23% of non-Hispanic black women have inadequate total intakes, compared with 13% of non-Hispanic white women.

About 35% of adults and 28% of children aged 1 to 13 years in the United States use supplements containing folic acid 35, 36. Adults aged 51 to 70 years are more likely than members of other age groups to take supplements containing folic acid. Use is also higher among non-Hispanic whites than non-Hispanic blacks or Mexican Americans. People aged 2 years and older who take supplements containing folic acid get a mean of 712 mcg DFE from those supplements 34.

Measurements of reb blood cell folate levels also suggest that most people in the United States have adequate folate status 1. According to an analysis of National Health and Nutrition Examination Survey (NHANES) 2003–2006 data, less than 0.5% of children aged 1 to 18 years have deficient erythrocyte folate concentrations 13. Mean concentrations in this age group range from 211 to 294 ng/mL depending on age, dietary habits, and supplement use. In adults, mean red blood cell folate concentrations range from 216 to 398 ng/mL, also indicating adequate folate status 37.

Some population groups are at risk of obtaining excessive folic acid. About 5% of men and women aged 51-70 and men aged 71 and older have folic acid intakes exceeding the Tolerable Upper Intake Level (the maximum daily intake unlikely to cause adverse health effects) of 1,000 mcg per day, primarily because of the folic acid they obtain from dietary supplements 35. Furthermore, 30% to 66% of children aged 1 to 13 years who take folic acid-containing supplements have intakes of folic acid from both fortified food and dietary supplements exceeding the Tolerable Upper Intake Level (UL) of 300–600 mcg per day 36. Almost all children aged 1 to 8 years who consume at least 200 mcg/day folic acid from dietary supplements have total intakes that exceed the Tolerable Upper Intake Level (UL) 13. Little is known about the long-term effects of high folic acid doses in children 38.

Large amounts of folate can correct the megaloblastic anemia, but not the neurological damage, that can result from vitamin B12 deficiency 1. Excess intake of folate, especially in the elderly population high intakes of folate supplements might “mask” vitamin B12 deficiency until its neurological consequences become irreversible 1, 3. Questions about this possibility still remain, but the focus of concern has shifted to the potential for large amounts of folate to precipitate or exacerbate the anemia and cognitive symptoms associated with vitamin B12 deficiency 39, 40, 41, 42, 43.

Excess folate intake is also known to have a controversial and complex dual role in colorectal cancer 3. Concerns have also been raised that high folic acid intakes might accelerate the progression of preneoplastic lesions, increasing the risk of colorectal and possibly other cancers in certain individuals 44, 45, 46. In addition, folic acid from supplements intakes of 1,000 mcg per day or more during the periconception period have been associated with lower scores on several tests of cognitive development in children at ages 4–5 years than in children of mothers who took 400 mcg to 999 mcg 47.

Intakes of folic acid that exceed the body’s ability to reduce it to tetrahydrofolate (THF) lead to unmetabolized folic acid in the body, which has been linked to reduced numbers and activity of natural killer cells, suggesting that it could affect the immune system 48, 49. In addition, some scientists have hypothesized that unmetabolized folic acid might be related to cognitive impairment among older adults 50. These potential negative health consequences are not well understood and warrant further research 1, 5, 51.

Studies have found unmetabolized folic acid in blood from children, adolescents, and adults 52, 53; breastmilk 54; and cord blood from newborns 55, 56. Limited research suggests that single doses of 300 mcg or 400 mcg folic acid (a common amount in folic acid-containing supplements or servings of fortified foods, such as breakfast cereals) result in detectable serum levels of unmetabolized folic acid, whereas doses of 100 mcg or 200 mcg do not 57, 58. In addition, a dose-frequency interaction appears to occur in which smaller amounts of folic acid consumed more frequently produce higher unmetabolized folic acid concentrations than the same total dose consumed in larger, less frequent amounts 59.

Based on the metabolic interactions between folate and vitamin B12, the Food and Nutrition Board established a Tolerable Upper Intake Level (the maximum daily intake unlikely to cause adverse health effects) for the synthetic forms of folate available in dietary supplements and fortified foods (Table 3) 6. The Food and Nutrition Board did not establish a Tolerable Upper Intake Level (UL) for folate from food because high intakes of folate from food sources have not been reported to cause adverse effects 6. Thus, unlike the Recommended Dietary Allowances (RDAs), the Tolerable Upper Intake Level (the maximum daily intake unlikely to cause adverse health effects) are in mcg, not mcg DFE. For folic acid, 1,000 mcg is equivalent to 1,667 mcg DFE because 0.6 mcg folic acid = 1 mcg DFE 59. The Tolerable Upper Intake Level (the maximum daily intake unlikely to cause adverse health effects) do not apply to individuals taking high doses of supplemental folate under medical supervision 6.

Table 2. Recommended Dietary Allowances (RDAs) for Folate

Life StageRecommended Amount
Birth to 6 months65 mcg DFE
Infants 7–12 months80 mcg DFE
Children 1–3 years150 mcg DFE
Children 4–8 years200 mcg DFE
Children 9–13 years300 mcg DFE
Teens 14–18 years400 mcg DFE
Adults 19+ years400 mcg DFE
Pregnant teens and women600 mcg DFE
Breastfeeding teens and women500 mcg DFE

Footnote: All women and teen girls who could become pregnant should consume 400 mcg of folic acid daily from supplements, fortified foods, or both in addition to the folate they get from following a healthy eating pattern.

[Source 60 ]

Table 3. Tolerable Upper Intake Levels (ULs) for Folate from Supplements or Fortified Foods

AgeMaleFemalePregnancyLactation
Birth to 6 monthsNot possible to establish*Not possible to establish*
7–12 monthsNot possible to establish*Not possible to establish*
1–3 years300 mcg300 mcg
4–8 years400 mcg400 mcg
9–13 years600 mcg600 mcg
14–18 years800 mcg800 mcg800 mcg800 mcg
19+ years1,000 mcg1,000 mcg1,000 mcg1,000 mcg

Footnote: * Breast milk, formula, and food should be the only sources of folate for infants.

[Source 60 ]

What foods provide folate?

Folate is naturally present in a wide variety of foods including vegetables (especially dark green leafy vegetables), fruits and fruit juices, nuts, beans, peas, seafood, eggs, dairy products, meat, poultry, and grains (Table 4) 4, 61. Spinach, liver, asparagus, and brussels sprouts are among the foods with the highest folate levels 1.

Folate is naturally present in 60:

  • Beef liver
  • Vegetables (especially asparagus, brussels sprouts, and dark green leafy vegetables such as spinach and mustard greens)
  • Fruits and fruit juices (especially oranges and orange juice)
  • Nuts, beans, and peas (such as peanuts, black-eyed peas, and kidney beans)

Folic acid (man-made folate) is added to the following foods 60:

  • Enriched bread, flour, cornmeal, pasta, and rice
  • Fortified breakfast cereals
  • Fortified corn masa flour (used to make corn tortillas and tamales, for example)

In January 1998, the U.S. Food and Drug Administration (FDA) began requiring manufacturers to add 140 mcg folic acid/100 g to enriched breads, cereals, flours, cornmeals, pastas, rice, and other grain products to reduce the risk of neural tube defects 62. Because cereals and grains are widely consumed in the United States, these products have become important contributors of folic acid to the American diet 1. The fortification program increased mean folic acid intakes in the United States by about 190 mcg/day 63. In April 2016, FDA approved the voluntary addition of up to 154 mcg folic acid/100 g to corn masa flour 64.

Since November 1, 1998, the Canadian government has also required the addition of 150 mcg folic acid/100 g to many grains, including enriched pasta, cornmeal, and white flour 65, 66. Many other countries, including Costa Rica, Chile, and South Africa, have also established mandatory folic acid fortification programs 66, 64.

To find out whether a food has added folic acid, look for “folic acid” on its Nutrition Facts label.

Table 4. Folate and Folic Acid content of selected foods

FoodMicrograms
(mcg) DFE per
serving		Percent
DV*
Beef liver, braised, 3 ounces21554
Spinach, boiled, ½ cup13133
Black-eyed peas (cowpeas), boiled, ½ cup10526
Breakfast cereals, fortified with 25% of the DV†10025
Rice, white, medium-grain, cooked, ½ cup†9022
Asparagus, boiled, 4 spears8922
Brussels sprouts, frozen, boiled, ½ cup7820
Spaghetti, cooked, enriched, ½ cup†7419
Lettuce, romaine, shredded, 1 cup6416
Avocado, raw, sliced, ½ cup5915
Spinach, raw, 1 cup5815
Broccoli, chopped, frozen, cooked, ½ cup5213
Mustard greens, chopped, frozen, boiled, ½ cup5213
Bread, white, 1 slice†5013
Green peas, frozen, boiled, ½ cup4712
Kidney beans, canned, ½ cup4612
Wheat germ, 2 tablespoons4010
Tomato juice, canned, ¾ cup369
Crab, Dungeness, 3 ounces369
Orange juice, ¾ cup359
Turnip greens, frozen, boiled, ½ cup328
Peanuts, dry roasted, 1 ounce277
Orange, fresh, 1 small297
Papaya, raw, cubed, ½ cup277
Banana, 1 medium246
Yeast, baker’s, ¼ teaspoon236
Egg, whole, hard-boiled, 1 large226
Cantaloupe, raw, cubed, ½ cup174
Vegetarian baked beans, canned, ½ cup154
Fish, halibut, cooked, 3 ounces123
Milk, 1% fat, 1 cup123
Ground beef, 85% lean, cooked, 3 ounces72
Chicken breast, roasted, 3 ounces31

Footnotes: * DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed Daily Value (DVs) to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV (Daily Value) for folate is 400 mcg DFE for adults and children aged 4 years and older, where mcg DFE = mcg naturally occurring folate + (1.7 x mcg folic acid) 20. The labels must list folate content in mcg DFE per serving and if folic acid is added to the product, they must also list the amount of folic acid in mcg in parentheses. The FDA does not require food labels to list folate content unless folic acid has been added to the food. Foods providing 20% or more of the DV are considered to be high sources of a nutrient, but foods providing lower percentages of the DV also contribute to a healthful diet.

† Fortified with folic acid as part of the folate fortification program.

The U.S. Department of Agriculture’s FoodData Central lists the nutrient content of many foods and provides a comprehensive list of foods containing folate arranged by nutrient content and by food name.

[Source 1 ]

Folic acid deficiency causes

Isolated folate deficiency is rare in the United States and folic acid deficiency can arise from multiple causes, including inadequate dietary intake. The body has about 1,000-20,000 mcg of folate stores, and adults need about 400 mcg/day to replenish the daily losses. Folate deficiency may take 8-16 weeks to become evident 3.

The following groups are among those most likely to be at risk of folate deficiency 1:

  • People with alcohol use disorder
  • Women of childbearing age
  • Pregnant women
  • People with malabsorption disorders such as celiac disease, tropical sprue or inflammatory bowel disease
  • People who eat overcooked fruits and vegetables. Folate can be easily destroyed by heat. Heating during cooking destroys folic acid 3.
  • Certain medicines (such as phenytoin, sulfasalazine, or trimethoprim-sulfamethoxazole)
  • Eating an unhealthy diet that does not include enough fruits and vegetables
  • Kidney dialysis

Folate is absorbed in the jejunum (the 2nd part of your small intestine) by active and passive transport mechanisms across the intestinal wall 3. Hence, diseases such as celiac disease, tropical sprue, inflammatory bowel disease, short bowel syndrome, amyloidosis, gastric bypass surgery, or mesenteric vascular insufficiency can inhibit folate absorption resulting in a deficiency. Elevated pH, as occurs in achlorhydria, can also lead to poor folate absorption.

Drugs such as methotrexate, phenytoin, sulfasalazine, and trimethoprim can antagonize folate utilization, inhibit its absorption or conversation to its active form resulting in folate deficiency 3. Congenital deficiencies of enzymes required in folate metabolism can lead to folate deficiency. Folic acid deficiency can occur subsequent to vitamin B12 deficiency due to an impairment of methionine synthase resulting in the trapping of folate as methyltetrahydrofolate whereby methylene tetrahydrofolate accumulates in serum leading to folate trap phenomenon and increased urinary excretion of folate.

Alcoholism is a significant cause of folate deficiency. Pregnancy, hemolytic anemia, and dialysis can also result in folate deficiency.

The following groups are among those most likely to be at risk of folate deficiency 1.

People with alcohol use disorder

People with alcohol use disorder frequently have poor-quality diets that contain insufficient amounts of folate 1. Moreover, alcohol interferes with folate absorption and hepatic uptake, accelerates folate breakdown, and increases its renal excretion 5, 51. An evaluation in Portugal, where the food supply is not fortified with folic acid, found low folate status in more than 60% of people with chronic alcoholism 67. Even moderate alcohol consumption of 240 ml (8 fluid ounces) red wine per day or 80 ml (2.7 fluid ounces) vodka per day for 2 weeks can significantly decrease serum folate concentrations in healthy men, although not to levels below the cutoff for folate adequacy of 3 ng/ml 68.

Women of childbearing age

All women capable of becoming pregnant should obtain adequate amounts of folate to reduce the risk of neural tube birth defects such as spina bifida and anencephaly and other birth defects 9, 69. However, some women of childbearing age get insufficient amounts of folate even if they take dietary supplements 35. Women of childbearing age should obtain 400 mcg/day folic acid from dietary supplements and/or fortified foods in addition to the folate provided by a varied diet 12.

Pregnant women

During pregnancy, demands for folate increase because of its role in nucleic acid synthesis 10. To meet this need, the Food and Nutrition Board increased the folate Recommended Dietary Allowance (the average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals) from 400 mcg DFE/day for nonpregnant women to 600 mcg DFE/day during pregnancy 6. This level of intake might be difficult for some women to achieve through diet alone. The American College of Obstetricians and Gynecologists recommends a prenatal folic acid of at least 400 micrograms starting at least 1 month before pregnancy and during the first 12 weeks of pregnancy for most pregnant women to ensure that they obtain adequate amounts of folic acid and other nutrients 70. Women who have had a child with an neural tube birth defect should take 4 milligrams (4000 micrograms) of folic acid each day as a separate supplement at least 3 months before pregnancy and for the first 3 months of pregnancy 70. You and your ob-gyn or other obstetric care provider can discuss whether you need to supplement with more than 400 micrograms daily 70.

People with malabsorptive disorders

Several medical conditions increase the risk of folate deficiency. People with malabsorptive disorders—including tropical sprue, celiac disease, and inflammatory bowel disease—might absorb less folate than people without these disorders 4; for example, about 20–60% of patients with inflammatory bowel disease have folate deficiency 71. Diminished gastric acid secretion associated with atrophic gastritis, gastric surgery, and other conditions can also reduce folate absorption 4.

People with an methylenetetrahydrofolate reductase (MTHFR) polymorphism

People with a genetic polymorphism, MTHFR C677T (MTHFR 677 C>T or MTHFR 677 C→T), in the methylenetetrahydrofolate reductase (MTHFR) gene have a reduced ability to convert folate to one of its active forms, 5-MTHF, because the methylenetetrahydrofolate reductase (MTHFR) enzyme needed for this conversion is less active 15. About 25% of Hispanics, 10% of Caucasians and Asians, and 1% of African Americans are homozygous for the 677C>T MTHFR polymorphism 19. A gene variant is a change in a DNA sequence that is different from the expected DNA sequence. This means in MTHFR C677T at the 677 position in the MTHFR gene, “C” is the expected DNA base and “T” is the gene variant 72.

The methylenetetrahydrofolate reductase (MTHFR) polymorphism results in less biologically available 5-MTHF and, thus, reduced methylation potential, leading to elevated homocysteine levels and an increased risk of neural tube defects 14, 73. Although the research on the benefits of folate supplementation for people with this genetic polymorphism is inconclusive, some of these people might benefit from supplementation with 5-MTHF 14, 15. However, the Centers for Disease Control and Prevention (CDC) recommends 400 mcg/day of folic acid, not 5-MTHF, for people who could become pregnant, even if they have a 677C>T MTHFR polymorphism 74.

Folate deficiency prevention

The best way to get folate your body needs is to eat a balanced diet. Most people in the United States eat enough folic acid because it is plentiful in the food supply.

Folate occurs naturally in the following foods:

  • Beans and legumes
  • Citrus fruits and juices
  • Dark green leafy vegetables such as spinach, asparagus, and broccoli
  • Liver
  • Mushrooms
  • Poultry, pork, and shellfish
  • Wheat bran and other whole grains

The recommended daily amount of folic acid for adults is 400 mcg of folate daily. Specific recommendations depend on a person’s age, sex, and other factors (such as pregnancy and lactation) (see Table 2). Many foods, such as fortified breakfast cereals, now have extra folic acid added to help prevent birth defects.

The Centers for Disease Control and Prevention (CDC) recommends ALL women of child bearing age should get 400 micrograms (mcg) of folic acid every day in addition to consuming food with folate from a varied diet 11, 9, 12. Whilst taking a higher dose of folic acid of more than 400 mcg each day is not necessarily better to prevent neural tube defects, unless a doctor recommends taking more due to other health conditions 9. The CDC further recommends that women who have already had a pregnancy affected by a neural tube defect consume 4,000 mcg (4 mg) of folic acid each day one month before becoming pregnant and through the first 3 months of pregnancy 9.

Folate deficiency symptoms

Folate deficiency signs and symptoms include the following 75:

  • Glossitis (inflammation of the tongue). Glossitis is a problem in which your tongue is swollen and inflamed making makes the surface of the tongue appear smooth. The tongue may appear swollen, beefy, red, or shiny, usually around the edges and tips initially. Some patients complain of a sore tongue or pain upon swallowing.
  • Angular stomatitis also may be observed. These oral lesions typically occur at the time when folate depletion is severe enough to cause megaloblastic anemia, although, occasionally, lesions may occur before the anemia.
  • Gastrointestinal signs and symptoms such as anorexia, nausea, vomiting, abdominal pain, diarrhea, especially after meals. Anorexia also is common and, in combination with nausea, vomiting, abdominal pain, diarrhea, may lead to marked weight loss. However, an underlying malabsorption disorder could be causing these symptoms, as well as folate deficiency. The lack of folate itself may not be the culprit.
  • Manifestations of anemia. Folate deficiency causes a shortage of healthy red blood cells or anemia. In folate-deficiency anemia, the red blood cells are abnormally large (megaloblastic anemia). If you have anemia, your blood does not carry enough oxygen to the rest of your body. Anemia can produce other symptoms, such as:
    • Paleness
    • Shortness of breath
    • Cold hands and feet
    • Headaches
    • Dizziness
    • Fast, slow, or uneven heartbeat
    • Brittle nails or hair loss
    • Strange food cravings (known as pica)
  • Neuropsychiatric symptoms include cognitive impairment, dementia, and depression. These manifestations overlap with those of vitamin B12 deficiency.{ref50)
  • Patchy skin hyperpigmentation, especially particularly at the dorsal surfaces of the fingers, toes, and creases of palms and soles.
  • Low-grade fever
  • In severe folate deficiency you can have low levels of white blood cells and platelets
  • Lack of folate causes a number of pregnancy-related complications, including placenta abruptio, spontaneous abortion, neural tube defects, and severe language deficits in children.

Folate deficiency in pregnant women can result in birth defects known as neural tube defects (anencephaly and spina bifida), which underlies the strong recommendation for folic acid supplementation in women of reproductive age 76, 9. Folate is important to the growth of the fetus’s spinal cord and brain. The Recommended Dietary Allowance (RDA) for folate during pregnancy is 600 micrograms (mcg)/day.

People with folate deficiency may also have darkening of the skin and mucous membranes, particularly at the upper side surfaces of the fingers, toes, and creases of palms and soles 77. Distribution typically is patchy. Fortunately, the skin hyperpigmentation gradually should resolve after weeks or months of folate treatment 77.

A modest temperature elevation (< 102°F) is common in patients who are folate deficient, despite the absence of any infection 77. Although the underlying mechanism is obscure, the temperature typically falls within 24-48 hours of vitamin treatment and returns to normal within a few days 77.

Folate deficiency complications

Failure to provide folic acid supplementation to pregnant females may lead to spontaneous abortion and fetal abnormalities, including neural tube defects and increased risk of severe language delay in the child 78.

Providing only folic acid supplementation to a patient who has cobalamin (vitamin B12) deficiency may lead to development of irreversible neuropathies 78.

Folate deficiency diagnosis

Folate deficiency can be diagnosed with a blood test. Pregnant women commonly have this blood test at prenatal checkups.

Medical history

In folate deficiency, the patient’s history is important because it may reveal the underlying reason for the folate deficiency. Very often, a patient presents with a history of excessive alcohol intake with concurrent poor diet intake. Other patients may be pregnant or lactating; may take certain drugs, such as phenytoin, sulfonamides, or methotrexate; may have chronic hemolytic anemia; or may have underlying malabsorption.

Blood test

Initial laboratory tests should include a complete blood count (CBC) and a peripheral blood smear. Laboratory tests in folic acid deficiency would reveal anemia, manifesting as a decrease in hemoglobin and hematocrit levels. The mean corpuscular volume (MCV) would be increased to a level greater than 100 consistent with a diagnosis of macrocytic anemia. In addition, a peripheral blood smear would show macrocytic red blood cells (RBCs)and/or megaloblasts and hypersegmented neutrophils. Ordering serum vitamin B12 (cobalamin) and folate levels can help differentiate between the two.

Serum folate and serum cobalamin testing

Ruling out vitamin B12 (cobalamin) deficiency is very important because deficiency of folic acid and vitamin B12 produce overlapping neurologic manifestations, and both cause megaloblastic anemia, but folate treatment will not improve neurologic abnormalities due to cobalamin deficiency 79. The reference range for serum vitamin B12 (cobalamin) is 200-900 pg/mL 80.

The usual reference range of serum folate is 2.5-20 ng/mL 80. By statistical definition, 2-5% of healthy individuals will have a serum folate level of less than 2.5 ng/mL; hence, the serum folate level cannot be used alone to establish the diagnosis of folate deficiency 80. Therefore, the serum folate test is definitive only when the level is greater than 5.0 ng/mL, which rules out folate deficiency. Otherwise, additional follow-up tests include serum homocysteine (reference range 5-16 mmol/L), which is elevated in vitamin B12 and folate deficiency, and serum methylmalonic acid (MMA) (reference range 70-270 mmol/L), which is elevated in vitamin B12 (cobalamin) deficiency only.

In most cases, serum folate testing alone is sufficient for assessment of folate status, but if there is strong clinical suspicion of folate deficiency and the serum folate level is normal and vitamin B12 (cobalamin) deficiency has been ruled out, the red blood cell (RBC) folate level may be measured 81. Red blood cell folate levels tend to reflect long-term folate status rather than acute changes in folate that are reflected in serum folate levels. However, many confounding factors, such as transfused red cells, can make this unreliable as a test for folate deficiency states 80.

Folate deficiency can be confirmed with a normal vitamin B12 and methylmalonic acid (MMA) level and elevated homocysteine levels, while vitamin B12 deficiency can be confirmed with elevated methylmalonic acid (MMA) and homocysteine levels and low vitamin B12 levels 28. Red blood cell folate levels are a very useful index of body stores and can help access the duration of folate deficiency 82, 79.

Other than folate or vitamin B12 (cobalamin) deficiency, the only other confounding causes for elevation of these compounds include kidney failure, intravascular volume depletion, and some rare inborn errors of metabolism involving folate or cobalamin-dependent enzymes.

Bone marrow biopsy

Bone marrow biopsy and aspirate is not required for evaluation of vitamin B12 or folate deficiency, but if done for other reasons in patients with folate deficiency may show hypercellular bone marrow with a megaloblastic maturation of cells 83. This cannot be differentiated from changes observed with vitamin B12 deficiency.

Folate deficiency treatment

All patients with folate deficiency should be offered supplemental folic acid for the correction of the deficiency. The dosage of folic acid needed to prevent or reverse folate deficiency varies with the clinical circumstances, as follows 81:

  • Folate-deficient megaloblastic anemia due to dietary insufficiency or antiepileptic drugs: 5 mg/day folic acid for 4 months
  • Malabsorption: Up to 15 mg/day folic acid for 4 months
  • Chronic hemolytic states and kidney dialysis: for prophylaxis, 5 mg folic acid daily to weekly, depending on the patient’s diet and rate of hemolysis

Typically, oral folic acid (1 to 5 mg daily) suffices to treat folate deficiency 28. Intravenous, subcutaneous, or intramuscular formulations of folic acid can be used for patients unable to tolerate oral medications 3. Folinic acid also called leucovorin, a reduced form of folate, is primarily used to prevent the toxicities of methotrexate 3. The duration of therapy depends on whether the cause of the initial folate deficiency persists. Patients with malabsorption or short gut syndromes may typically require long-term treatment 3.

In patients who have a concomitant vitamin B12 deficiency, it is imperative to replenish vitamin B12 as well 3. Folate treatment alone does not improve neurological symptoms and signs due to B12 deficiency, which, if untreated, may likely progress and cause permanent neurological damage 82.

All patients should be encouraged to a diet rich in fruits and vegetables. Referral to a dietician may be indicated to ensure that the patient has appropriate dietary intake of folic acid. Fruits, vegetables, and fortified foods constitute the primary dietary source of folic acid 84.

Table 2 lists the current Recommended Dietary Allowances (RDAs) for folate as mcg of dietary folate equivalents (DFEs). The Recommended Dietary Allowance (RDA) is the average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals. The Food and Nutrition Board at the National Academies of Sciences, Engineering, and Medicine developed dietary folate equivalents (DFEs) to reflect the higher bioavailability of folic acid than that of food folate 6. At least 85% of folic acid is estimated to be bioavailable when taken with food, whereas only about 50% of folate naturally present in food is bioavailable 6, 5. Based on these values, the Food and Nutrition Board defined dietary folate equivalent (DFE) as follows:

  • 1 mcg DFE = 1 mcg food folate
  • 1 mcg DFE = 0.6 mcg folic acid from fortified foods or dietary supplements consumed with foods
  • 1 mcg DFE = 0.5 mcg folic acid from dietary supplements taken on an empty stomach

Because of variable absorption rates, an approximation of total folate intake in a day can be calculated as follows:

Grams of DFEs provided = grams of food folate + 1.7 × (grams of folic acid supplementation)

Factors for converting mcg dietary folate equivalent (DFE) to mcg for supplemental folate in the form of 5-methylenetetrahydrofolate (5-MTHF) have not been formally established 1.

For infants from birth to 12 months, the Food and Nutrition Board established an Adequate Intake (AI) for folate that is equivalent to the mean intake of folate in healthy, breastfed infants in the United States (see Table 2). Adequate Intake (AI) is the intake level that is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an Recommended Dietary Allowance (RDA) 1.

Table 2. Recommended Dietary Allowances (RDAs) for Folate

Life StageRecommended Amount
Birth to 6 months65 mcg DFE
Infants 7–12 months80 mcg DFE
Children 1–3 years150 mcg DFE
Children 4–8 years200 mcg DFE
Children 9–13 years300 mcg DFE
Teens 14–18 years400 mcg DFE
Adults 19+ years400 mcg DFE
Pregnant teens and women600 mcg DFE
Breastfeeding teens and women500 mcg DFE

Footnote: All women and teen girls who could become pregnant should consume 400 mcg of folic acid daily from supplements, fortified foods, or both in addition to the folate they get from following a healthy eating pattern.

[Source 60 ]

Folate deficiency prognosis

The prognosis is excellent for most patients with folic acid deficiency if it is corrected and generally reverses most clinical and biochemical abnormalities seen with folic acid deficiency 3. However, a lack of folate can lead to macrocytic anemia. In addition, lack of folate raises levels of homocysteine, which is associated with atherosclerotic disease 5, 6. Lack of folate causes a number of pregnancy-related complications, including placenta abruptio, spontaneous abortion, neural tube defects, and severe language deficits in children.

  1. Folate. https://ods.od.nih.gov/factsheets/Folate-HealthProfessional[↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩]
  2. Folate. https://lpi.oregonstate.edu/mic/vitamins/folate[↩][↩]
  3. Khan KM, Jialal I. Folic Acid Deficiency. [Updated 2022 Jun 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK535377[↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩]
  4. Carmel R. Folic acid. In: Shils M, Shike M, Ross A, Caballero B, Cousins RJ, eds. Modern Nutrition in Health and Disease. 11th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2005:470-81.[↩][↩][↩][↩][↩][↩][↩][↩][↩][↩]
  5. Bailey LB, Caudill MA. Folate. In: Erdman JW, Macdonald IA, Zeisel SH, eds. Present Knowledge in Nutrition. 10th ed. Washington, DC: Wiley-Blackwell; 2012:321-42.[↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩]
  6. Institute of Medicine. Food and Nutrition Board. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 1998.[↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩][↩]
  7. Azzini E, Ruggeri S, Polito A. Homocysteine: Its Possible Emerging Role in At-Risk Population Groups. Int J Mol Sci. 2020 Feb 20;21(4):1421. doi: 10.3390/ijms21041421[↩][↩]
  8. Ho RC, Cheung MW, Fu E, Win HH, Zaw MH, Ng A, Mak A. Is high homocysteine level a risk factor for cognitive decline in elderly? A systematic review, meta-analysis, and meta-regression. Am J Geriatr Psychiatry. 2011 Jul;19(7):607-17. doi: 10.1097/JGP.0b013e3181f17eed[↩]
  9. Folic Acid. https://www.cdc.gov/ncbddd/folicacid/about.html[↩][↩][↩][↩][↩][↩][↩][↩][↩]
  10. Scholl TO, Johnson WG. Folic acid: influence on the outcome of pregnancy. Am J Clin Nutr. 2000 May;71(5 Suppl):1295S-303S. doi: 10.1093/ajcn/71.5.1295s[↩][↩]
  11. Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep. 1992 Sep 11;41(RR-14):1-7. https://www.cdc.gov/mmwr/preview/mmwrhtml/00019479.htm[↩][↩]
  12. Folic Acid Recommendations. https://www.cdc.gov/ncbddd/folicacid/recommendations.html[↩][↩][↩]
  13. Yeung LF, Cogswell ME, Carriquiry AL, Bailey LB, Pfeiffer CM, Berry RJ. Contributions of enriched cereal-grain products, ready-to-eat cereals, and supplements to folic acid and vitamin B-12 usual intake and folate and vitamin B-12 status in US children: National Health and Nutrition Examination Survey (NHANES), 2003-2006. Am J Clin Nutr. 2011 Jan;93(1):172-85. doi: 10.3945/ajcn.2010.30127[↩][↩][↩]
  14. Scaglione F, Panzavolta G. Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. Xenobiotica. 2014 May;44(5):480-8. doi: 10.3109/00498254.2013.845705[↩][↩][↩]
  15. Greenberg JA, Bell SJ, Guan Y, Yu YH. Folic Acid supplementation and pregnancy: more than just neural tube defect prevention. Rev Obstet Gynecol. 2011 Summer;4(2):52-9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218540[↩][↩][↩]
  16. Henderson AM, Aleliunas RE, Loh SP, Khor GL, Harvey-Leeson S, Glier MB, Kitts DD, Green TJ, Devlin AM. l-5-Methyltetrahydrofolate Supplementation Increases Blood Folate Concentrations to a Greater Extent than Folic Acid Supplementation in Malaysian Women. J Nutr. 2018 Jun 1;148(6):885-890. doi: 10.1093/jn/nxy057[↩]
  17. Green TJ, Liu Y, Dadgar S, Li W, Böhni R, Kitts DD. Wheat rolls fortified with microencapsulated L-5-methyltetrahydrofolic acid or equimolar folic acid increase blood folate concentrations to a similar extent in healthy men and women. J Nutr. 2013 Jun;143(6):867-71. doi: 10.3945/jn.113.174268[↩]
  18. Lamers Y, Prinz-Langenohl R, Brämswig S, Pietrzik K. Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age. Am J Clin Nutr. 2006 Jul;84(1):156-61. doi: 10.1093/ajcn/84.1.156[↩]
  19. Pietrzik K, Bailey L, Shane B. Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2010 Aug;49(8):535-48. doi: 10.2165/11532990-000000000-00000[↩][↩]
  20. Food Labeling: Revision of the Nutrition and Supplement Facts Labels. https://www.federalregister.gov/documents/2016/05/27/2016-11867/food-labeling-revision-of-the-nutrition-and-supplement-facts-labels[↩][↩]
  21. Kerns JC, Gutierrez JL. Thiamin. Adv Nutr. 2017 Mar 15;8(2):395-397. doi: 10.3945/an.116.013979[↩]
  22. Sauve A.A. NAD+ and vitamin B3: From metabolism to therapies. J. Pharmacol. Exp. Ther. 2008;324:883–893. doi: 10.1124/jpet.107.120758[↩]
  23. Plesofsky-Vig N., Brambl R. Pantothenic acid and coenzyme A in cellular modification of proteins. Annu. Rev. Nutr. 1988;8:461–482. doi: 10.1146/annurev.nu.08.070188.002333[↩]
  24. Ueland P.M., Ulvik A., Rios-Avila L., Midttun Ø., Gregory J.F. Direct and Functional Biomarkers of Vitamin B6 Status. Annu. Rev. Nutr. 2015;35:33–70. doi: 10.1146/annurev-nutr-071714-034330[↩]
  25. McMahon R.J. Biotin in metabolism and molecular biology. Annu. Rev. Nutr. 2002;22:221–239. doi: 10.1146/annurev.nutr.22.121101.112819[↩]
  26. Lyon P, Strippoli V, Fang B, Cimmino L. B Vitamins and One-Carbon Metabolism: Implications in Human Health and Disease. Nutrients. 2020 Sep 19;12(9):2867. doi: 10.3390/nu12092867[↩]
  27. Stover PJ. Folic acid. In: Ross AC, Caballero B, Cousins RJ, Tucker KL, Ziegler TR, eds. Modern Nutrition in Health and Disease. 11th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2012:358-68.[↩][↩]
  28. Green R, Datta Mitra A. Megaloblastic Anemias: Nutritional and Other Causes. Med Clin North Am. 2017 Mar;101(2):297-317. doi: 10.1016/j.mcna.2016.09.013[↩][↩][↩]
  29. Shuvalov O, Petukhov A, Daks A, Fedorova O, Vasileva E, Barlev NA. One-carbon metabolism and nucleotide biosynthesis as attractive targets for anticancer therapy. Oncotarget. 2017 Apr 4;8(14):23955-23977. doi: 10.18632/oncotarget.15053[↩][↩][↩][↩][↩][↩][↩]
  30. Gerhard GT, Duell PB. Homocysteine and atherosclerosis. Curr Opin Lipidol. 1999 Oct;10(5):417-28. doi: 10.1097/00041433-199910000-00006[↩]
  31. Stover PJ, Field MS. Trafficking of intracellular folates. Adv Nutr. 2011 Jul;2(4):325-31. doi: 10.3945/an.111.000596[↩]
  32. Choi SW, Mason JB. Folate and carcinogenesis: an integrated scheme. J Nutr. 2000 Feb;130(2):129-32. doi: 10.1093/jn/130.2.129[↩]
  33. Bailey LB, Gregory JF 3rd. Folate metabolism and requirements. J Nutr. 1999 Apr;129(4):779-82. doi: 10.1093/jn/129.4.779[↩]
  34. U.S. Department of Agriculture, Agricultural Research Service. What We Eat in America, 2013-2014. https://www.ars.usda.gov/northeast-area/beltsville-md-bhnrc/beltsville-human-nutrition-research-center/food-surveys-research-group/docs/wweia-data-tables[↩][↩]
  35. Bailey RL, Dodd KW, Gahche JJ, Dwyer JT, McDowell MA, Yetley EA, Sempos CA, Burt VL, Radimer KL, Picciano MF. Total folate and folic acid intake from foods and dietary supplements in the United States: 2003-2006. Am J Clin Nutr. 2010 Jan;91(1):231-7. doi: 10.3945/ajcn.2009.28427[↩][↩][↩][↩]
  36. Bailey RL, McDowell MA, Dodd KW, Gahche JJ, Dwyer JT, Picciano MF. Total folate and folic acid intakes from foods and dietary supplements of US children aged 1-13 y. Am J Clin Nutr. 2010 Aug;92(2):353-8. doi: 10.3945/ajcn.2010.29652[↩][↩]
  37. Yang Q, Cogswell ME, Hamner HC, Carriquiry A, Bailey LB, Pfeiffer CM, Berry RJ. Folic acid source, usual intake, and folate and vitamin B-12 status in US adults: National Health and Nutrition Examination Survey (NHANES) 2003-2006. Am J Clin Nutr. 2010 Jan;91(1):64-72. doi: 10.3945/ajcn.2009.28401. Epub 2009 Oct 14. Erratum in: Am J Clin Nutr. 2010 Oct;92(4):1001. Dosage error in article text.[↩]
  38. Yetley EA, Pfeiffer CM, Phinney KW, Fazili Z, Lacher DA, Bailey RL, Blackmore S, Bock JL, Brody LC, Carmel R, Curtin LR, Durazo-Arvizu RA, Eckfeldt JH, Green R, Gregory JF 3rd, Hoofnagle AN, Jacobsen DW, Jacques PF, Molloy AM, Massaro J, Mills JL, Nexo E, Rader JI, Selhub J, Sempos C, Shane B, Stabler S, Stover P, Tamura T, Tedstone A, Thorpe SJ, Coates PM, Johnson CL, Picciano MF. Biomarkers of folate status in NHANES: a roundtable summary. Am J Clin Nutr. 2011 Jul;94(1):303S-312S. doi: 10.3945/ajcn.111.013011[↩]
  39. Berry RJ, Carter HK, Yang Q. Cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr. 2007 Jul;86(1):265-7; author reply 267-9. doi: 10.1093/ajcn/86.1.265[↩]
  40. Carmel R. Does high folic acid intake affect unrecognized cobalamin deficiency, and how will we know it if we see it? Am J Clin Nutr. 2009 Dec;90(6):1449-50. doi: 10.3945/ajcn.2009.28835[↩]
  41. Mary Ann Johnson, PhD, If High Folic Acid Aggravates Vitamin B12 Deficiency What Should Be Done about It?, Nutrition Reviews, Volume 65, Issue 10, October 2007, Pages 451–458, https://doi.org/10.1111/j.1753-4887.2007.tb00270.x[↩]
  42. Selhub J, Morris MS, Jacques PF, Rosenberg IH. Folate-vitamin B-12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B-12 deficiency. Am J Clin Nutr. 2009 Feb;89(2):702S-6S. doi: 10.3945/ajcn.2008.26947C. Epub 2009 Jan 13. Erratum in: Am J Clin Nutr. 2009 Jun;89(6):1951[↩]
  43. Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE, Bønaa KH, Spence JD, Nygård O, Jamison R, Gaziano JM, Guarino P, Bennett D, Mir F, Peto R, Collins R; B-Vitamin Treatment Trialists’ Collaboration. Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: Meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med. 2010 Oct 11;170(18):1622-31. doi: 10.1001/archinternmed.2010.348[↩]
  44. Ulrich CM, Potter JD. Folate supplementation: too much of a good thing? Cancer Epidemiol Biomarkers Prev. 2006 Feb;15(2):189-93. doi: 10.1158/1055-9965.EPI-152CO[↩]
  45. Edward Giovannucci, Meir J. Stampfer, Graham A. Colditz, Eric B. Rimm, Dimitrios Trichopoulos, Bernard A. Rosner, Frank E. Speizer, Walter C. Willett, Folate, Methionine, and Alcohol Intake and Risk of Colorectal Adenoma, JNCI: Journal of the National Cancer Institute, Volume 85, Issue 11, 2 June 1993, Pages 875–883, https://doi.org/10.1093/jnci/85.11.875[↩]
  46. Kim YI. Folate: a magic bullet or a double edged sword for colorectal cancer prevention? Gut. 2006 Oct;55(10):1387-9. doi: 10.1136/gut.2006.095463[↩]
  47. Valera-Gran D, Navarrete-Muñoz EM, Garcia de la Hera M, Fernández-Somoano A, Tardón A, Ibarluzea J, Balluerka N, Murcia M, González-Safont L, Romaguera D, Julvez J, Vioque J; INMA Project. Effect of maternal high dosages of folic acid supplements on neurocognitive development in children at 4-5 y of age: the prospective birth cohort Infancia y Medio Ambiente (INMA) study. Am J Clin Nutr. 2017 Sep;106(3):878-887. doi: 10.3945/ajcn.117.152769[↩]
  48. Paniz C, Bertinato JF, Lucena MR, De Carli E, Amorim PMDS, Gomes GW, Palchetti CZ, Figueiredo MS, Pfeiffer CM, Fazili Z, Green R, Guerra-Shinohara EM. A Daily Dose of 5 mg Folic Acid for 90 Days Is Associated with Increased Serum Unmetabolized Folic Acid and Reduced Natural Killer Cell Cytotoxicity in Healthy Brazilian Adults. J Nutr. 2017 Sep;147(9):1677-1685. doi: 10.3945/jn.117.247445[↩]
  49. Troen AM, Mitchell B, Sorensen B, Wener MH, Johnston A, Wood B, Selhub J, McTiernan A, Yasui Y, Oral E, Potter JD, Ulrich CM. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr. 2006 Jan;136(1):189-94. doi: 10.1093/jn/136.1.189[↩]
  50. Morris MS, Jacques PF, Rosenberg IH, Selhub J. Circulating unmetabolized folic acid and 5-methyltetrahydrofolate in relation to anemia, macrocytosis, and cognitive test performance in American seniors. Am J Clin Nutr. 2010 Jun;91(6):1733-44. doi: 10.3945/ajcn.2009.28671. Epub 2010 Mar 31. Erratum in: Am J Clin Nutr. 2010 Oct;92(4):1002.[↩]
  51. Bailey LB, Stover PJ, McNulty H, Fenech MF, Gregory JF 3rd, Mills JL, Pfeiffer CM, Fazili Z, Zhang M, Ueland PM, Molloy AM, Caudill MA, Shane B, Berry RJ, Bailey RL, Hausman DB, Raghavan R, Raiten DJ. Biomarkers of Nutrition for Development-Folate Review. J Nutr. 2015 Jul;145(7):1636S-1680S. doi: 10.3945/jn.114.206599[↩][↩]
  52. Stamm RA, March KM, Karakochuk CD, Gray AR, Brown RC, Green TJ, Houghton LA. Lactating Canadian Women Consuming 1000 µg Folic Acid Daily Have High Circulating Serum Folic Acid Above a Threshold Concentration of Serum Total Folate. J Nutr. 2018 Jul 1;148(7):1103-1108. doi: 10.1093/jn/nxy070. Erratum in: J Nutr. 2019 Apr 1;149(4):698.[↩]
  53. Pfeiffer CM, Sternberg MR, Fazili Z, Yetley EA, Lacher DA, Bailey RL, Johnson CL. Unmetabolized folic acid is detected in nearly all serum samples from US children, adolescents, and adults. J Nutr. 2015 Mar;145(3):520-31. doi: 10.3945/jn.114.201210[↩]
  54. Page R, Robichaud A, Arbuckle TE, Fraser WD, MacFarlane AJ. Total folate and unmetabolized folic acid in the breast milk of a cross-section of Canadian women. Am J Clin Nutr. 2017 May;105(5):1101-1109. doi: 10.3945/ajcn.116.137968[↩]
  55. Obeid R, Kasoha M, Kirsch SH, Munz W, Herrmann W. Concentrations of unmetabolized folic acid and primary folate forms in pregnant women at delivery and in umbilical cord blood. Am J Clin Nutr. 2010 Dec;92(6):1416-22. doi: 10.3945/ajcn.2010.29361[↩]
  56. Plumptre L, Masih SP, Ly A, Aufreiter S, Sohn KJ, Croxford R, Lausman AY, Berger H, O’Connor DL, Kim YI. High concentrations of folate and unmetabolized folic acid in a cohort of pregnant Canadian women and umbilical cord blood. Am J Clin Nutr. 2015 Oct;102(4):848-57. doi: 10.3945/ajcn.115.110783[↩]
  57. Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM. Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr. 1997 Jun;65(6):1790-5. doi: 10.1093/ajcn/65.6.1790[↩]
  58. Sweeney MR, McPartlin J, Scott J. Folic acid fortification and public health: report on threshold doses above which unmetabolised folic acid appear in serum. BMC Public Health. 2007 Mar 22;7:41. doi: 10.1186/1471-2458-7-41[↩]
  59. Sweeney MR, McPartlin J, Weir DG, Daly L, Scott JM. Postprandial serum folic acid response to multiple doses of folic acid in fortified bread. Br J Nutr. 2006 Jan;95(1):145-51. doi: 10.1079/bjn20051618[↩][↩]
  60. Folate. https://ods.od.nih.gov/factsheets/Folate-Consumer[↩][↩][↩][↩][↩]
  61. U.S. Department of Agriculture, Agricultural Research Service. FoodData Central. https://fdc.nal.usda.gov[↩]
  62. U.S. Food and Drug Administration. Food Standards: Amendment of Standards of Identity For Enriched Grain Products to Require Addition of Folic Acid. Federal Register 1996;61:8781-97. https://www.govinfo.gov/content/pkg/FR-1996-03-05/pdf/96-5014.pdf[↩]
  63. Choumenkovitch SF, Selhub J, Wilson PW, Rader JI, Rosenberg IH, Jacques PF. Folic acid intake from fortification in United States exceeds predictions. J Nutr. 2002 Sep;132(9):2792-8. doi: 10.1093/jn/132.9.2792[↩]
  64. Centers for Disease Control and Prevention (CDC). CDC Grand Rounds: additional opportunities to prevent neural tube defects with folic acid fortification. MMWR Morb Mortal Wkly Rep. 2010 Aug 13;59(31):980-4. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5931a2.htm[↩][↩]
  65. Government of Canada. Regulations amending the food and drug regulations (1066). Canada Gazette 1998;132.[↩]
  66. Crider KS, Bailey LB, Berry RJ. Folic acid food fortification-its history, effect, concerns, and future directions. Nutrients. 2011 Mar;3(3):370-84. doi: 10.3390/nu3030370[↩][↩]
  67. Glória L, Cravo M, Camilo ME, Resende M, Cardoso JN, Oliveira AG, Leitão CN, Mira FC. Nutritional deficiencies in chronic alcoholics: relation to dietary intake and alcohol consumption. Am J Gastroenterol. 1997 Mar;92(3):485-9.[↩]
  68. Gibson A, Woodside JV, Young IS, Sharpe PC, Mercer C, Patterson CC, McKinley MC, Kluijtmans LA, Whitehead AS, Evans A. Alcohol increases homocysteine and reduces B vitamin concentration in healthy male volunteers–a randomized, crossover intervention study. QJM. 2008 Nov;101(11):881-7. doi: 10.1093/qjmed/hcn112[↩]
  69. US Preventive Services Task Force; Bibbins-Domingo K, Grossman DC, Curry SJ, Davidson KW, Epling JW Jr, García FA, Kemper AR, Krist AH, Kurth AE, Landefeld CS, Mangione CM, Phillips WR, Phipps MG, Pignone MP, Silverstein M, Tseng CW. Folic Acid Supplementation for the Prevention of Neural Tube Defects: US Preventive Services Task Force Recommendation Statement. JAMA. 2017 Jan 10;317(2):183-189. doi: 10.1001/jama.2016.19438[↩]
  70. Nutrition During Pregnancy. https://www.acog.org/womens-health/faqs/nutrition-during-pregnancy[↩][↩][↩]
  71. Rossi RE, Whyand T, Murray CD, Hamilton MI, Conte D, Caplin ME. The role of dietary supplements in inflammatory bowel disease: a systematic review. Eur J Gastroenterol Hepatol. 2016 Dec;28(12):1357-1364. doi: 10.1097/MEG.0000000000000728[↩]
  72. Wilcken B, Bamforth F, Li Z, Zhu H, Ritvanen A, Renlund M, Stoll C, Alembik Y, Dott B, Czeizel AE, Gelman-Kohan Z, Scarano G, Bianca S, Ettore G, Tenconi R, Bellato S, Scala I, Mutchinick OM, López MA, de Walle H, Hofstra R, Joutchenko L, Kavteladze L, Bermejo E, Martínez-Frías ML, Gallagher M, Erickson JD, Vollset SE, Mastroiacovo P, Andria G, Botto LD. Geographical and ethnic variation of the 677C>T allele of 5,10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas world wide. J Med Genet. 2003 Aug;40(8):619-25. doi: 10.1136/jmg.40.8.619. Erratum in: J Med Genet. 2004 May;41(5):400. Redlund, M [corrected to Renlund, M].[↩]
  73. Molloy AM, Pangilinan F, Brody LC. Genetic Risk Factors for Folate-Responsive Neural Tube Defects. Annu Rev Nutr. 2017 Aug 21;37:269-291. doi: 10.1146/annurev-nutr-071714-034235[↩]
  74. MTHFR Gene, Folic Acid, and Preventing Neural Tube Defects. https://www.cdc.gov/ncbddd/folicacid/mthfr-gene-and-folic-acid.html[↩]
  75. Folate Deficiency Clinical Presentation. https://emedicine.medscape.com/article/200184-clinical[↩]
  76. Li J, Xie Q, Gao J, Wang F, Bao Y, Wu L, Yang L, Liu Z, Guo R, Khan A, Dan Liu, Li C, Wu J, Xie J. Aberrant Gcm1 expression mediates Wnt/β-catenin pathway activation in folate deficiency involved in neural tube defects. Cell Death Dis. 2021 Mar 4;12(3):234. doi: 10.1038/s41419-020-03313-z[↩]
  77. Folate Deficiency Clinical Presentation. https://emedicine.medscape.com/article/200184-clinical#b2[↩][↩][↩][↩]
  78. Folate Deficiency Clinical Presentation. https://emedicine.medscape.com/article/200184-clinical#b3[↩][↩]
  79. Reynolds EH. The neurology of folic acid deficiency. Handb Clin Neurol. 2014;120:927-43. doi: 10.1016/B978-0-7020-4087-0.00061-9[↩][↩]
  80. Folate Deficiency Workup. https://emedicine.medscape.com/article/200184-workup[↩][↩][↩][↩]
  81. Devalia, V., Hamilton, M.S., Molloy, A.M. and (2014), Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol, 166: 496-513. https://doi.org/10.1111/bjh.12959[↩][↩]
  82. Okada A, Koike H, Nakamura T, Watanabe H, Sobue G. Slowly progressive folate-deficiency myelopathy: report of a case. J Neurol Sci. 2014 Jan 15;336(1-2):273-5. doi: 10.1016/j.jns.2013.10.032[↩][↩]
  83. Folate Deficiency Workup. https://emedicine.medscape.com/article/200184-workup#c7[↩]
  84. Folate Deficiency Treatment & Management. https://emedicine.medscape.com/article/200184-treatment[↩]

you might also like

Health Jade