Primary prevention
Folic acid supplementation can prevent folate deficiency in states of increased demand (e.g., pregnancy and lactation) and in conditions with folate malabsorption (e.g., celiac disease) or loss (e.g., chronic hemolytic disorder).
There is conclusive evidence that folic acid supplementation preconceptually and during pregnancy reduces the incidence of fetal neural tube defects (NTDs).[15][30][40]
Pregnancy and lactation
Guidelines recommend preconception folic acid supplementation at a dose of 400-800 micrograms/day for the prevention of NTDs in women who are planning to conceive or who are capable of becoming pregnant.[31][32][33] Higher doses (up to 4 mg/day) are recommended for certain risk groups. Canadian guidelines use the following risk stratification for women at risk for a fetal NTD or other folic acid-sensitive congenital anomaly:[31]
Low risk: no personal or family history of fetal NTD or folate-related congenital abnormalities.
Medium risk: family history of fetal NTD; personal history in the patient or male partner of folate-related congenital abnormality; or diabetes, teratogenic medication, or malabsorption in the patient.
High risk: personal history of fetal NTD in the patient or her male partner; or previous fetal NTD birth by the patient.
In the US, the recommended dietary allowance for folate during pregnancy and lactation varies from 400-800 micrograms/day depending upon factors such as diet, inclusion of food fortified with folic acid, socioeconomic status, and individual medical history. US Department of Agriculture and US Department of Health and Human Services: dietary guidelines for Americans, 2020-2025 Opens in new window NIH: dietary supplement fact sheet - folate Opens in new window
The World Health Organization recommends a red blood cell (RBC) folate level >400 nanograms/mL in women of reproductive age.[41]
Randomized clinical trial data suggest that a plasma folate level of 11.22 nanograms/mL corresponds to the recommended RBC folate level (≥400 nanograms/mL) in most situations.[42] Higher plasma folate levels (15 nanograms/mL) are required in women with vitamin B12 (cobalamin) deficiency.
For maximal protection against fetal NTDs, the optimal calculated RBC folate level is 442-574 nanograms/mL at the end of the first 4 weeks of pregnancy, when neural tube closure is achieved.[43]
The US Preventive Services Task Force advises that the critical period for beginning supplementation is at least 1 month before conception.[32]
Reproductive-age women (without folate fortification) randomized to 800 micrograms/day folate supplementation were more likely to achieve desirable RBC-folate concentrations (≥400 nanograms/mL) at 4 weeks than women receiving 400 micrograms/day.[44] Similar results were reported at an 8-week timepoint.
Evidence suggests that folic acid supplementation during pregnancy reduces megaloblastic anemia in mothers. While there is no conclusive evidence that supplementation prevents preterm birth, stillbirth, neonatal mortality, or miscarriage, data from the Screening for Pregnancy Endpoints (SCOPE) study indicate that folic acid supplementation during pregnancy is associated with a lower risk of small for gestational age infants, without increasing the risk for large for gestational age infants.[45][46][47]
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In low- and middle-income countries, maternal multiple micronutrient supplementation with iron and folic acid reduces the number of infants born with low birth weight.[48]
Folate malabsorption and loss
Correction of the underlying cause and/or folic acid supplementation can prevent folate deficiency in patients with malabsorptive disorders, such as tropical sprue and celiac disease (nontropical sprue).
Increased folate loss occurs in patients with chronic hemolytic disorder (due to increased cell turnover), and in those undergoing chronic peritoneal dialysis (due to loss of folate in dialysis fluid). Daily folic acid supplementation may be required in these patients to prevent folate deficiency.
Patients taking drugs that interfere with folate absorption and metabolism may require supplementation with oral or parenteral leucovorin to prevent folate deficiency. Leucovorin, a reduced form of folic acid, can be converted into biologically active tetrahydrofolate without the action of dihydrofolate reductase, which is inhibited by drugs such as methotrexate, pyrimethamine, and trimethoprim.[49] Leucovorin supplementation can reduce the risk of hepatotoxicity and gastrointestinal side effects in patients with rheumatoid arthritis.[50] In some cases, where a drug has reduced efficacy when administered with leucovorin, a change to another drug may be required.
Secondary prevention
Continued folic acid supplementation is necessary in certain conditions with poor folate absorption or ongoing losses (e.g., celiac disease, chronic hemolytic disease) and states of increased demand (e.g., pregnancy, lactation, prematurity).
National food fortification can prevent folate deficiency on a large scale.[99] This can positively affect the folate status of the population at large, and specifically of certain vulnerable populations, such as pregnant and lactating women and older people.
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