Folate
All diets should be monitored for folate in females that are of reproductive age due to the critical nature folate plays in fetal development, particularly in the first trimester.
Other names: Vitamin B9 Folic acid - in supplements and fortified foods; the fully oxidized monoglutamate form of folate [1] Folate - naturally in food; folacin; [2] tetrahydrofolate (THF) with glutamates residues [1] or “pteropolyglutamates” [3]
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Folate is essential for fetal growth and development – lack of folate during pregnancy can lead to birth defects [1-4]
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Required for DNA production (and thus normal cell division) [1-3]
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Participates in reactions that create many amino acids [1-4]
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Involved in red blood cell formation [1,2]
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Involved in the generation and utilization of formate [3]
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As a major substrate in single carbon metabolism (i.e. methylating agent) [3]
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How much folate do you need each day? [1,3,4]
How it works
Recommended daily amount
†DFE, or dietary folate equivalents, is used to account for differences in absorption and bioavailability of the different forms of folate/folic acid. (See Absorption and Availability). *Higher folate may be needed for pregnancy with multiple infants or breastfeeding multiple children.[3]
Yeast extract spread
Whole and fortified grains and cereals
Legumes (beans, soy, lentils)
Sunflower seeds
Dark leafy greens (e.g., spinach)
Asparagus Brussels sprouts
Seaweed
Orange juice
Sources of nutrient
Daily upper limits
Folic acid supplements typically are: [1,4]
100% absorbed if taken without food
85% bioavailable if taken with food or as fortified foods
~50% bioavailable as naturally occurring folate in food
Thus, dietary folate equivalents (DFE) take into account the differences in absorption: [2]
1 mcg food folate = 1 mcg DFE
1 mcg folic acid supplement taken with food or as a fortified food = 1.7 mcg DFE
1 mcg folic acid supplement taken on an empty stomach = 2 mcg DFE
Some supplements provide folic acid as 5-methyl-THF and might be more bioavailable in persons with genetic polymorphisms (MTHFR variants); however, conversion factors (DFE) have not been established for this form (the FDA allows up to a 1.7 conversion factor to be used by manufacturers). [1] Furthermore, vitamin C may increase folate bioavailability when taken together. [2]
Bioavailability
Examples of nutrient-rich foods
Many countries, including the US, Canada, Chile, Costa Rica, and South Africa, have mandatory food fortification programs to enrich cereal grain products (such as wheat flour). [1,6] Fortification levels are between 140 to 220 mcg of folic acid per 100 grams of food. [6] The European Union does not mandate folic acid fortification for many reasons, including the potential for an increased risk of cancer due to excess folic acid intake. [6,7]
Heat, UV light, oxygen, and acidic pH have the potential to breakdown folate/folic acid during food storage and preparation:
Folic acid is relatively stable below 180C (~350F) but rapidly degrades at temperatures above 195C (380F).
Acidic pH of 4 or less tends to degrade folic acid rapidly; thus, folate/folic acid in acidic juices breaks down very quickly and limits the shelf life of these products.
Folate/folic acid is a water-soluble nutrient and can leach into water; thus, boiling, blanching, canning, and soaking tend to promote folate loss.
Storing food to limit light and air exposure (e.g., opaque containers, uncut produce), cooking methods, such as steaming and lowered heat/ cooking time, and consuming juices quickly can help to limit folate loss. Furthermore, proteins in food may help to stabilize, fermentation and germination may enhance availability, and antioxidants (e.g., vitamin C, polyphenols) often help preserve folate/folic acid in foods.
Stability
Measures of Adequate Status
People capable of pregnancy – red blood cell folate cut-off at 400 mcg/L (906 nmol/L) to reduce birth defect risks, but this value has not been fully established. [4]
Foodod folate is hydrolyzed to the monoglutamate form in the gut [1] before it is actively transported [1,2] across the proximal small intestine by a saturable, pH-dependent process. [3] However, pharmaceutical doses of folic acid are passively diffused. [1,2]
The main form of folate in plasma is 5-methyltetrahydrofolate (THF). [1] About two-thirds of plasma folate is bound to proteins, particularly albumin (50%). [3] Only a small amount of folate is stored in the liver and other tissues (estimated at ~15 to 30 mg in adults); [1] thus, regular folate intake is necessary to meet needs.
Most of the body’s folate is reabsorbed in the proximal renal tubule. [3] Folate is also excreted into bile, and the majority is reabsorbed in the small intestine (estimated as high as 100mcg/day). [3] Some folate can be made by some gut bacteria, [1,3] but the amount and the extent to which it supplies folate to the body is unclear. [1]
Metabolism
All women of childbearing age – folate is critical for proper fetal development, particularly in the first few weeks of pregnancy when the brain and spinal cord form. [1-4] A 400 mcg supplement in addition to food folate is recommended for all women capable of pregnancy to prevent birth defects. [1,2,4]
Frequent and/or high use of alcohol decreases folate absorption, disrupts folate uptake in the kidney, and accelerates folate breakdown and excretion into urine. [1-3]
Smoking is associated with low folate status, [2,3] although low intake may be more likely than increased requirements; [3] impaired folate transport to the fetus of pregnant smokers has been documented. [2]
Persons with malabsorption disorders and/or increased water losses (e.g., celiac disease, Crohn’s disease, diarrhea) [1,2,4]
Persons recovering from burns [1] or wounds [2]
Persons with low B12 intake/status since folate requires B12 to be recycled into its active form [3]
Persons with genetic variants of the enzyme MTHFR that requires folate (in the U.S., ~25% Hispanics, 10% Caucasian and Asians, and 1% African Americans are estimated to have these polymorphisms) [1]
Persons with gastric bypass surgery [4] Persons with conditions that increase cell division and metabolism (e.g., cancer, inflammation) [2]
Populations at risk for deficiency
Deficiency signs and symptoms
Inadequate folate intake leads to reduced serum folate concentrations, then lowered erythrocyte folate concentrations, elevated homocysteine, and megaloblastic changes in the bone marrow and other rapidly dividing tissues. [3,4]
Soreness and/or ulcers on the tongue and mouth [1]
Changes in skin, hair, or fingernail pigmentation [1] Gastrointestinal symptoms [1]
Weakness, fatigue [1,3]
Macrocytic Anemia [1-3]
Hypersegmented neutrophils [2,3]
Difficulty concentrating [2,3]
Irritability [1,3]
Headache [3]
Heart palpitations [1,3]
Shortness of breath [1,3]
During pregnancy – higher risk of low birth weight, premature delivery, maternal anemia, and birth defects (neural tube defects, e.g., spina bifida) [1-4]
Elevated homocysteine, which during pregnancy has been associated with increased risk of miscarriage, pre-eclampsia, and placental abruption [2]
The content provided is for informational purposes only and may not be an exhaustive list of potential interactions.
Chemotherapy agents (e.g., methotrexate) [1-4] - folate may interfere with the drug’s effectiveness. [1] Note: methotrexate used for other purposes (e.g., rheumatoid arthritis) may have fewer gastrointestinal side effects when used with folic acid supplements. [1,3]
Anti-epileptic drugs (e.g., phenytoin, [1-4] carbamazepine, [1,4] valproate, [1,2,4] primidone, [2] phenobarbital [3]) may reduce serum folate, [1,2] and with folic acid supplements may reduce serum levels of these medications.[1]
Sulfa drugs (e.g., sulfasalazine) [1,2,4] can inhibit folate absorption and cause a folate deficiency; [1] patients may need to increase dietary intake of folate and/or take folic acid supplements. [1]
Cholesterol-reducing drugs (cholestyramine) [2,4] may reduce folate absorption. [2]
NSAIDs taken in large therapeutic doses [2,3] (e.g., severe arthritis) may reduce folate absorption; however, this does not typically occur with routine use. [2]
Trimethoprim, pyrimethamine (antimalarial), and triamterene have anti-folate activities. [2,3]
Oral contraceptives have been suspected to impair folate metabolism and produce some degree of folate depletion,[8] but this has not been supported in large [3] and more recent studies [2] that controlled for folate intake and used low-dose oral contraceptives. [2,3]
Potential drug-nutrient interactions
Folic acid supplements >5000 mcg/day have the potential to mask a B12 deficiency. However, the Tolerable Upper Intake Limit has been set at 5x less than this amount (used as an uncertainty factor) at 1000 mcg/day. [4]
Many groups in the U.S. exceed the Tolerable Upper Intake Level due to supplement use – women older than 50 years, men older than 71 years, and many children 1 – 13 years. [1] Given the low incidence of insufficient folate intake in children and men in North America, it has been suggested that folic acid be removed from supplements intended for these subgroups. [4]
Toxicity signs and symptoms
Heading 3
Notes
Approximately 50% of pregnancies are unplanned, [6] and folate/folic acid is critical for proper brain and spinal cord development in the first few weeks of pregnancy. [1,3] A 400 microgram folic acid supplement (in addition to food folate) is recommended for all women who may become pregnant. [1,3,4,6]
Decreases in birth defects of 19-32% in the US and 19 – 55% in other countries have been reported since cereal/ grain folate fortification began. [6]
Although folate is often inversely associated with cancer risk, [1-4] high-dose folic acid supplements may increase cancer risk, particularly in those with neoplastic lesions. [1] Some but not all studies in humans suggest there may be a possible higher overall cancer risk [4] and higher risk of prostate, [1-4] colon, [1] bladder, [1] and gastrointestinal cancers [1] with high folic acid intake.
Notes
1. Folate. Fact Sheet for Health Professionals. Office of Dietary Supplements. National Institutes of Health. Updated Mar 2020. Accessed Nov 2020. https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/
2. Folate. Linus Pauling Institute Micronutrient Information Center, Oregon State University. Updated June 2014. Accessed Nov 2020. https://lpi.oregonstate.edu/mic/vitamins/folate.
3. Institute of Medicine 1998. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: The National Academies Press. https://doi.org/10.17226/6015
4. Chan Y, Bailey R, O’Connor D. Folate. Adv Nutr. 2013; 4: 123–125.
5. FoodData Central Database. United States Department of Agriculture. Accessed Oct 2021. https://fdc.nal.usda.gov.
6. Crider KS, Bailey LB, Berry RJ. Folic Acid Food Fortification – Its History, Effect, Concerns, and Future Direction. Nutr. 2011; 3(3):370-384.
7. Wusiglae LL. Folates: Stability and interaction with biological molecules. J Agr Food Res. 2020; (2):100039.
8. Palmery AS, Vaiarell A, Carolmagno G. Oral contraceptives and changes in nutritional requirements. Eur Rev Med Pharmacol Sci. 2013; 17:1804-1813.