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 ⁵⁾, ⁶⁾. Megaloblastic anemia symptoms include weakness, fatigue, difficulty concentrating, irritability, headache, heart palpitations, and shortness of breath ⁷⁾. 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 ⁸⁾, ⁹⁾, ¹⁰⁾, ¹¹⁾, ¹²⁾.

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 ¹³⁾, ¹⁴⁾. Inadequate maternal folate status has also been associated with low infant birth weight, preterm delivery, and fetal growth retardation ¹⁵⁾, ¹⁶⁾. 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 ¹⁷⁾, ¹⁸⁾, ¹⁹⁾. 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 ²⁰⁾. 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 ²¹⁾.

The latest research reveals the following about folic acid deficiency ²²⁾:

• 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 ²³⁾. About 85% of supplemental folic acid, when taken with food, is bioavailable ²⁴⁾, ²⁵⁾. When consumed without food, nearly 100% of supplemental folic acid is bioavailable ²⁶⁾.

Dietary supplements containing 5-methylenetetrahydrofolate or 5-methyl-folate (5-MTHF) are also available ²⁷⁾. For some people with an methylenetetrahydrofolate reductase polymorphism (MTHFR polymorphism), supplementation with 5-methylenetetrahydrofolate (5-MTHF) might be more beneficial than with folic acid ²⁸⁾, ²⁹⁾. The bioavailability of 5-methylenetetrahydrofolate (5-MTHF) in supplements is the same as or greater than that of folic acid ³⁰⁾, ³¹⁾, ³²⁾, ³³⁾. 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) ³⁴⁾. 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

Vitamin	Biological Function
Vitamin B1 (thiamine)	cofactor for enzymes in glucose metabolism, amino acid catabolism, nucleotide synthesis, and fatty acid synthesis 35)
Vitamin B2 (riboflavin)	precursor for flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) for cellular respiration 36)
Vitamin B3 (nicotinamide)	precursor for nicotinamide adenine dinucleotide (NAD) utilized in biosynthetic pathways, energy metabolism, and protection from reactive oxygen species 37)
Vitamin B5 (pantothenic acid)	precursor for coenzyme A (coA), an acyl-carrier required for the activity of many enzymes 38)
Vitamin B6 (pyridoxine)	cofactor for over 150 enzymes involved mainly in amino acid synthesis and degradation 39)
Vitamin B7 (biotin)	plays an essential role in carboxylation reactions 40) and also has many applications in laboratory research
Vitamin B9 (folate)	substrate for nucleotide synthesis and methyl-donors in the one-carbon metabolism pathway 41)
Vitamin B12 (cobalamin)	cofactor for enzymes in one-carbon metabolism and the propionate catabolic pathway 42)

[Source ⁴³⁾ ]

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) ⁴⁴⁾. Folate is critical in the metabolism of nucleic acid precursors and several amino acids, as well as in methylation reactions (Figures 1 and 2) ⁴⁵⁾. 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) ⁴⁶⁾, ⁴⁷⁾, ⁴⁸⁾. 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 ⁴⁹⁾. 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 ⁵⁰⁾. Another folate-dependent reaction, the methylation of deoxyuridylate to thymidylate in the formation of DNA, is required for proper cell division ⁵¹⁾. An impairment of this reaction initiates a process that can lead to megaloblastic anemia, one of the hallmarks of folate deficiency ⁵²⁾.

Naturally occurring folates or food folates are in the tetrahydrofolate (THF) form and usually have additional glutamate residues, making them polyglutamates ⁵³⁾. Folic acid (the man made folate) is the fully oxidized monoglutamate form of folate that is used in fortified foods and most dietary supplements ⁵⁴⁾. 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 ⁵⁵⁾.

Heating during cooking destroys folic acid ⁵⁶⁾. Folate is absorbed in the jejunum (the 2nd part of your small intestine) by active and passive transport mechanisms across the intestinal wall ⁵⁷⁾. 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 ⁵⁸⁾.

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 ⁵⁹⁾. 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 ⁶⁰⁾. 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 ⁶¹⁾, ⁶²⁾.

Figure 1. 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 ⁶³⁾ ]

Figure 2. 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) ⁶⁴⁾. 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 ⁶⁵⁾ ]

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) ⁶⁶⁾, ⁶⁷⁾, ⁶⁸⁾. 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 ⁶⁹⁾.

Once transported to the cell, folate undergoes covalent modification by polyglutamination ⁷⁰⁾. 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) ⁷¹⁾. There are only two direct sources of one-carbon groups (1C-group) in one-carbon metabolism – serine and glycine ⁷²⁾. 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 ⁷³⁾.

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 ⁷⁴⁾. 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 ⁷⁵⁾.

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 ⁷⁶⁾.

One-carbon metabolism

The only function of folate coenzymes in the body appears to be in mediating the transfer of one-carbon units ⁷⁷⁾. 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) ⁷⁸⁾.

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 ⁷⁹⁾. 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 ⁸⁰⁾, ⁸¹⁾. 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 ⁸²⁾.

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) ⁸³⁾.

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 ⁸⁴⁾. Mean dietary intakes of folate from foods range from 417 to 547 mcg DFE per day for children aged 2–19 ⁸⁵⁾. Average daily intakes of folate from food are 602 mcg DFE for males aged 20 and older and 455 mcg DFE for females ⁸⁶⁾.

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 ⁸⁷⁾. 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) ⁸⁸⁾. 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 ⁸⁹⁾, ⁹⁰⁾. 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 ⁹¹⁾.

Measurements of reb blood cell folate levels also suggest that most people in the United States have adequate folate status ⁹²⁾. 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 ⁹³⁾. 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 ⁹⁴⁾.

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 ⁹⁵⁾. 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 ⁹⁶⁾. 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) ⁹⁷⁾. Little is known about the long-term effects of high folic acid doses in children ⁹⁸⁾.

Large amounts of folate can correct the megaloblastic anemia, but not the neurological damage, that can result from vitamin B12 deficiency ⁹⁹⁾. 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 ¹⁰⁰⁾, ¹⁰¹⁾. 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 ¹⁰²⁾, ¹⁰³⁾, ¹⁰⁴⁾, ¹⁰⁵⁾, ¹⁰⁶⁾.

Excess folate intake is also known to have a controversial and complex dual role in colorectal cancer ¹⁰⁷⁾. 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 ¹⁰⁸⁾, ¹⁰⁹⁾, ¹¹⁰⁾. 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 ¹¹¹⁾.

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 ¹¹²⁾, ¹¹³⁾. In addition, some scientists have hypothesized that unmetabolized folic acid might be related to cognitive impairment among older adults ¹¹⁴⁾. These potential negative health consequences are not well understood and warrant further research ¹¹⁵⁾, ¹¹⁶⁾, ¹¹⁷⁾.

Studies have found unmetabolized folic acid in blood from children, adolescents, and adults ¹¹⁸⁾, ¹¹⁹⁾; breastmilk ¹²⁰⁾; and cord blood from newborns ¹²¹⁾, ¹²²⁾. 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 ¹²³⁾, ¹²⁴⁾. 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 ¹²⁵⁾.

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) ¹²⁶⁾. 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 ¹²⁷⁾. 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 ¹²⁸⁾. 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 ¹²⁹⁾.

Table 2. Recommended Dietary Allowances (RDAs) for Folate

Life Stage	Recommended Amount
Birth to 6 months	65 mcg DFE
Infants 7–12 months	80 mcg DFE
Children 1–3 years	150 mcg DFE
Children 4–8 years	200 mcg DFE
Children 9–13 years	300 mcg DFE
Teens 14–18 years	400 mcg DFE
Adults 19+ years	400 mcg DFE
Pregnant teens and women	600 mcg DFE
Breastfeeding teens and women	500 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 ¹³⁰⁾ ]

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

Age	Male	Female	Pregnancy	Lactation
Birth to 6 months	Not possible to establish*	Not possible to establish*
7–12 months	Not possible to establish*	Not possible to establish*
1–3 years	300 mcg	300 mcg
4–8 years	400 mcg	400 mcg
9–13 years	600 mcg	600 mcg
14–18 years	800 mcg	800 mcg	800 mcg	800 mcg
19+ years	1,000 mcg	1,000 mcg	1,000 mcg	1,000 mcg

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

[Source ¹³¹⁾ ]

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) ¹³²⁾, ¹³³⁾. Spinach, liver, asparagus, and brussels sprouts are among the foods with the highest folate levels ¹³⁴⁾.

Folate is naturally present in ¹³⁵⁾:

• 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 ¹³⁶⁾:

• 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 ¹³⁷⁾. Because cereals and grains are widely consumed in the United States, these products have become important contributors of folic acid to the American diet ¹³⁸⁾. The fortification program increased mean folic acid intakes in the United States by about 190 mcg/day ¹³⁹⁾. In April 2016, FDA approved the voluntary addition of up to 154 mcg folic acid/100 g to corn masa flour ¹⁴⁰⁾.

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 ¹⁴¹⁾, ¹⁴²⁾. Many other countries, including Costa Rica, Chile, and South Africa, have also established mandatory folic acid fortification programs ¹⁴³⁾, ¹⁴⁴⁾.

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

Food	Micrograms (mcg) DFE per serving	Percent DV*
Beef liver, braised, 3 ounces	215	54
Spinach, boiled, ½ cup	131	33
Black-eyed peas (cowpeas), boiled, ½ cup	105	26
Breakfast cereals, fortified with 25% of the DV†	100	25
Rice, white, medium-grain, cooked, ½ cup†	90	22
Asparagus, boiled, 4 spears	89	22
Brussels sprouts, frozen, boiled, ½ cup	78	20
Spaghetti, cooked, enriched, ½ cup†	74	19
Lettuce, romaine, shredded, 1 cup	64	16
Avocado, raw, sliced, ½ cup	59	15
Spinach, raw, 1 cup	58	15
Broccoli, chopped, frozen, cooked, ½ cup	52	13
Mustard greens, chopped, frozen, boiled, ½ cup	52	13
Bread, white, 1 slice†	50	13
Green peas, frozen, boiled, ½ cup	47	12
Kidney beans, canned, ½ cup	46	12
Wheat germ, 2 tablespoons	40	10
Tomato juice, canned, ¾ cup	36	9
Crab, Dungeness, 3 ounces	36	9
Orange juice, ¾ cup	35	9
Turnip greens, frozen, boiled, ½ cup	32	8
Peanuts, dry roasted, 1 ounce	27	7
Orange, fresh, 1 small	29	7
Papaya, raw, cubed, ½ cup	27	7
Banana, 1 medium	24	6
Yeast, baker’s, ¼ teaspoon	23	6
Egg, whole, hard-boiled, 1 large	22	6
Cantaloupe, raw, cubed, ½ cup	17	4
Vegetarian baked beans, canned, ½ cup	15	4
Fish, halibut, cooked, 3 ounces	12	3
Milk, 1% fat, 1 cup	12	3
Ground beef, 85% lean, cooked, 3 ounces	7	2
Chicken breast, roasted, 3 ounces	3	1

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) ¹⁴⁵⁾. 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 ¹⁴⁶⁾ ]

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 ¹⁴⁷⁾.

The following groups are among those most likely to be at risk of folate deficiency ¹⁴⁸⁾:

• 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 ¹⁴⁹⁾.
• 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 ¹⁵⁰⁾. 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 ¹⁵¹⁾. 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 ¹⁵²⁾.

People with alcohol use disorder

People with alcohol use disorder frequently have poor-quality diets that contain insufficient amounts of folate ¹⁵³⁾. Moreover, alcohol interferes with folate absorption and hepatic uptake, accelerates folate breakdown, and increases its renal excretion ¹⁵⁴⁾, ¹⁵⁵⁾. 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 ¹⁵⁶⁾. 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 ¹⁵⁷⁾.

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 ¹⁵⁸⁾, ¹⁵⁹⁾. However, some women of childbearing age get insufficient amounts of folate even if they take dietary supplements ¹⁶⁰⁾. 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 ¹⁶¹⁾.

Pregnant women

During pregnancy, demands for folate increase because of its role in nucleic acid synthesis ¹⁶²⁾. 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 ¹⁶³⁾. 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 ¹⁶⁴⁾. 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 ¹⁶⁵⁾. You and your ob-gyn or other obstetric care provider can discuss whether you need to supplement with more than 400 micrograms daily ¹⁶⁶⁾.

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 ¹⁶⁷⁾; for example, about 20–60% of patients with inflammatory bowel disease have folate deficiency ¹⁶⁸⁾. Diminished gastric acid secretion associated with atrophic gastritis, gastric surgery, and other conditions can also reduce folate absorption ¹⁶⁹⁾.

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 ¹⁷⁰⁾. About 25% of Hispanics, 10% of Caucasians and Asians, and 1% of African Americans are homozygous for the 677C>T MTHFR polymorphism ¹⁷¹⁾. 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 ¹⁷²⁾.

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 ¹⁷³⁾, ¹⁷⁴⁾. 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 ¹⁷⁵⁾, ¹⁷⁶⁾. 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 ¹⁷⁷⁾.

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 ¹⁷⁸⁾, ¹⁷⁹⁾, ¹⁸⁰⁾. 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 ¹⁸¹⁾. 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 ¹⁸²⁾.

Folate deficiency symptoms

Folate deficiency signs and symptoms include the following ¹⁸³⁾:

• 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 ¹⁸⁴⁾, ¹⁸⁵⁾. 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 ¹⁸⁶⁾. Distribution typically is patchy. Fortunately, the skin hyperpigmentation gradually should resolve after weeks or months of folate treatment ¹⁸⁷⁾.

A modest temperature elevation (< 102°F) is common in patients who are folate deficient, despite the absence of any infection ¹⁸⁸⁾. 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 ¹⁸⁹⁾.

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 ¹⁹⁰⁾.

Providing only folic acid supplementation to a patient who has cobalamin (vitamin B12) deficiency may lead to development of irreversible neuropathies ¹⁹¹⁾.

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 ¹⁹²⁾. The reference range for serum vitamin B12 (cobalamin) is 200-900 pg/mL ¹⁹³⁾.

The usual reference range of serum folate is 2.5-20 ng/mL ¹⁹⁴⁾. 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 ¹⁹⁵⁾. 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 ¹⁹⁶⁾. 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 ¹⁹⁷⁾.

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 ¹⁹⁸⁾. Red blood cell folate levels are a very useful index of body stores and can help access the duration of folate deficiency ¹⁹⁹⁾, ²⁰⁰⁾.

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 ²⁰¹⁾. 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 ²⁰²⁾:

• 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 ²⁰³⁾. Intravenous, subcutaneous, or intramuscular formulations of folic acid can be used for patients unable to tolerate oral medications ²⁰⁴⁾. Folinic acid also called leucovorin, a reduced form of folate, is primarily used to prevent the toxicities of methotrexate ²⁰⁵⁾. 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 ²⁰⁶⁾.

In patients who have a concomitant vitamin B12 deficiency, it is imperative to replenish vitamin B12 as well ²⁰⁷⁾. 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 ²⁰⁸⁾.

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 ²⁰⁹⁾.

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 ²¹⁰⁾. 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 ²¹¹⁾, ²¹²⁾. 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 ²¹³⁾.

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) ²¹⁴⁾.

Table 2. Recommended Dietary Allowances (RDAs) for Folate

Life Stage	Recommended Amount
Birth to 6 months	65 mcg DFE
Infants 7–12 months	80 mcg DFE
Children 1–3 years	150 mcg DFE
Children 4–8 years	200 mcg DFE
Children 9–13 years	300 mcg DFE
Teens 14–18 years	400 mcg DFE
Adults 19+ years	400 mcg DFE
Pregnant teens and women	600 mcg DFE
Breastfeeding teens and women	500 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 ²¹⁵⁾ ]

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 ²¹⁶⁾. 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 ²¹⁷⁾, ²¹⁸⁾. Lack of folate causes a number of pregnancy-related complications, including placenta abruptio, spontaneous abortion, neural tube defects, and severe language deficits in children.