Folates
Folates are water-soluble B vitamins that are critical for ensuring normal growth, development and maintenance of optimal health. A folate deficiency in women of reproductive age can increase the risk of neural tube defects in any offspring. Public health preventive measures to ensure population-level adequate intakes include the widespread use of folic acid as a supplement and food fortificant. Date of preparation: April 2019
Contribution:
- Jessica Farebrother from the OpeN-Global team
- Sarah Meadows, OpeN-Global Expert Partner, Lead Analyst and Laboratory Manager, NIHR BRC Nutritional Biomarker Laboratory, University of Cambridge, UK
Importance of folate for health
Folate is a generic term for water-soluble B vitamins that are found widely in the diet, in leafy vegetables, legumes, egg yolks, liver and some citrus fruits (1, 2). Folate is key in ensuring normal growth, development and maintenance of optimal health. Folate deficiency can have several important consequences, the most well-known being an increase in risk of neural tube defects e.g. spina bifida, due to inadequate maternal folate intakes during gestation (3-5). Public health preventive measures to ensure population-level adequate intakes include the widespread use of folic acid as a supplement and food fortificant, and 400 μg folic acid supplementation is recommended by WHO from when trying to conceive until week 12 of gestation (5). Folic acid – pteroylglutamic acid – is a synthetic vitamin seldom found in nature, however used for supplementation and fortification purposes due to its stability and low cost (4).
The function of folate is to accept, redox process and transfer one-carbon units, in the complex series of biochemical and metabolic reactions known as one-carbon metabolism (3, 4, 6). In human and mammalian cells, one-carbon metabolism occurs in the cell cytosol, mitochondria and nucleus. Folate has a major role in the body in the biosynthesis of purine and thymidine nucleotides, and the re-methylation of homocysteine to methionine. Methionine can then go on to be used in protein synthesis, or converted to S-adenosylmethionine, which is the primary methyl donor in the body (4). In this way, folate makes a critical contribution to synthesis and repair of DNA, RNA and proteins (3, 4). Body stores of folate are generally adequate for 2-3 months (3).
As folate status drops, the remethlyation of homocysteine to methionine is reduced leading to raised plasma homocysteine levels. Elevated homocysteine has been linked to several non-communicable diseases including cardiovascular disease.
However, though the conversion of homocysteine to methionine is dependent upon folate, it is catalysed by the MTR enzyme, which is vitamin B12- dependent. Therefore, though homocysteine is a sensitive functional biomarker of folate status, it will also be elevated with a concomitant deficiency in vitamin B12.
Risk and consequences of deficiency
Risk of folate deficiency is highest with inadequate dietary intakes; however certain physiological conditions increase requirement. These include neoplastic diseases, malabsorptive conditions (e.g. Crohn’s disease and tropical sprue), the use of antifolate drugs or metabolic inhibitors (e.g. some anticonvulsants such as phenytoin, sulfasalazine and metformin) and alcoholism, which affects both folate intake and absorption.
Pregnancy is a period of increased folate requirements and risk of deficiency due to it being a period of rapid cell replication and growth, necessitating the de novo synthesis of DNA and proteins. Increased requirements continue throughout lactation (3). A deficiency during this period has been associated with several adverse gestational outcomes, including neural tube and other congenital defects (e.g. of the heart), foetal growth retardation, preterm delivery, pre-eclampsia, placental abruption, spontaneous abortion and stillbirth, low birth weight, and neonatal folate deficiency (1).
In addition to congenital deformations linked to folate deficiency during gestation, epidemiological data show an increased risk of cardiovascular disease with folate deficiency (3). This is possibly due to the high levels of circulating homocysteine, caused by an inadequate intake or metabolism of folate with vitamin B12 deficiency (3).
WHO recommendation: Periconceptional folic acid supplementation to prevent neural tube defects
All women, from the moment they begin trying to conceive until 12 weeks of gestation, should take a folic acid supplement (400 μg folic acid daily).
Women who have had a foetus diagnosed as affected by a neural tube defect or have given birth to a baby with a neural tube defect should:
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receive information on the risk of recurrence;
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be advised on the protective effect of periconceptional folic acid supplementation;
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be offered high-dose supplementation (4000 – 5000 μg folic acid daily); and
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be advised to increase their food intake of folate.
See the following WHO resources for more information:
Consequences of excess
There are no reported adverse effects associated with folate intake from foods, whether from intrinsic dietary sources, or fortified foods. However, there are upper limits set on the intake of folic acid, since total folate intakes above 5000 μg/day, e.g. from additional supplement intakes, can mask vitamin B12 deficiency. If untreated, this can lead to permanent nerve damage that can be precipitated by folic acid during treatment for megaloblastic anaemia (4).