Approach
Oral folic acid replacement is the preferred therapy (because several effective pathways of specific and nonspecific folate absorption operate throughout the small intestine).[51] Folic acid is a synthetic, oxidized form of folate.[49] Oral preparations of folic acid are inexpensive and stable.[37]
Parenteral folic acid may be considered in severe malabsorptive states. Patients with hereditary folate malabsorption require large doses of folic acid that are often given parenterally in specialized regimens.
Ruling out vitamin B12 (cobalamin) deficiency is important because initiation of folic acid therapy may resolve the hematologic manifestations of vitamin B12 deficiency but allow the neurologic manifestations of underlying vitamin B12 deficiency to progress.
In states of severe megaloblastic anemia, where it is essential to initiate therapy immediately, concomitant folic acid and vitamin B12 should be given. Tests for vitamin B12 deficiency should be ordered, in addition to those for folate deficiency. Test results determine subsequent therapy.
Leucovorin, a reduced form of folic acid, can be converted to biologically active tetrahydrofolate without the action of dihydrofolate reductase. Consequently, it can be used to prevent folate deficiency in patients taking drugs that affect the enzyme dihydrofolate reductase, such as methotrexate, pyrimethamine, and trimethoprim.[49]
Acquired folate deficiency
Severe anemia symptoms
Folate deficiency-induced anemia is generally well compensated. When the anemia is severe and is associated with symptoms of heart failure, packed red blood cell (RBC) transfusion should be considered. Blood should be transfused slowly, with the use of diuretic drugs to avoid volume overload. Folic acid replacement therapy should be instituted simultaneously. Patients should be monitored for hypokalemia following the commencement of folic acid therapy for severe megaloblastic anemia.[60]
Nonsevere anemia symptoms
Patients with megaloblastic anemia due to acquired causes of folate deficiency respond well to folic acid replacement therapy. Oral folic acid should be instituted once a diagnosis of deficiency is confirmed. Folic acid is better absorbed than natural folate (in food) in malabsorptive states; hence, oral therapy is usually adequate to treat deficiency. Hematologic findings are corrected after about 8 weeks.
Additional management strategies are essential in certain conditions.
Pregnant and lactating women need daily doses of folic acid.[24] The recommended dietary allowance (RDA) 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
Chronic malabsorptive states need continued folic acid supplementation if the underlying disorder is not fully corrected.
Hematologic disorders with increased RBC turnover may need continued replacement of folic acid to meet the chronic demand; patients taking continued folic acid supplementation should have vitamin B12 levels monitored periodically to prevent a missed diagnosis of vitamin B12 deficiency. Randomized clinical trials of folic acid supplementation in the common hemolytic state sickle cell disease are lacking.[61]
Dietary modifications are important in certain populations: older people and lower socioeconomic groups need dietary modifications to include legumes, leafy vegetables, and fruits.[62] In addition, folic acid may be supplemented by taking multivitamin preparations, or by national food fortification programs that enrich certain foods, such as cereals, with folic acid.
Asymptomatic patients
Oral folic acid therapy should be given to asymptomatic patients with documented folate deficiency, with or without macrocytosis.
Inborn errors of folate metabolism
Treatment of children with inborn errors of folate metabolism requires extremely large doses of folic acid that are started early in infancy and often given parenterally.[10][37] The goal of therapy is to maintain both blood and cerebrospinal fluid folate levels.
Inborn errors of folate metabolism require different treatment approaches:
Hereditary folate malabsorption, caused by mutations in the proton-coupled folate transporter, is treated with daily leucovorin injections.
Severe methylenetetrahydrofolate reductase deficiency, the most common disorder of folate metabolism, is treated with betaine (a substrate for betaine homocysteine methyltransferase that catalyzes conversion of homocysteine to methionine without requiring folate or vitamin B12). In addition, folic acid, cyanocobalamin, riboflavin, methionine, pyridoxine, and levocarnitine have been tried.[10]
Glutamate formiminotransferase deficiency is treated with folic acid plus methionine.[63][64]
Anecdotal evidence suggests that dihydrofolate reductase deficiency may respond to leucovorin.[65]
Cerebral folate transport deficiency is characterized by decreased folate transport across the blood-brain barrier. It is frequently caused by antibodies to folate receptor proteins that transport folate into the central nervous system (CNS). Multiple neuropsychiatric disorders result from decreased folate transport to the brain, but may respond to treatment with leucovorin (which delivers folate to the CNS via the reduced folate carrier protein).[66][67]
Management of underlying disorders
Evaluation and treatment of underlying disorders is essential to prevent and treat ongoing deficiency states. Ongoing losses of folate may need continued replacement (e.g., chronic hemolytic anemia and exfoliative dermatitis need continued daily folic acid supplementation). Malabsorptive states need correction of underlying disease and vitamin supplementation. Folate deficiency due to certain drugs may need modification of drug therapy.
Monitoring response to therapy
Reticulocyte response at 1 week, and the blood count normalization at 8 weeks from the start of therapy, are useful parameters to monitor treatment response. Monitoring serum folate level has little value. Homocysteine levels fall within a few days of therapy and may be used to assess treatment response.
Reticulocyte count can be assessed at the end of the first week of therapy.[37] Increased hemoglobin level and reticulocytosis within 7 to 10 days of starting treatment suggests a positive response.[37]
Mean corpuscular volume (MCV) may increase during the first few days of treatment, presumably because of reticulocytosis.[68] As normocytic RBCs replace macrocytes, MCV decreases to normal range, usually within about 8 weeks of beginning treatment.[69][70]
Neutrophil hypersegmentation may persist during the first 2 weeks of therapy, but platelet and white blood cell count rise in the first week of therapy.
In patients with ongoing losses, periodic monitoring of serum folate may be considered.
At risk of folate deficiency
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 use of folic acid supplementation preconceptually and during pregnancy reduces the incidence of fetal neural tube defects (NTDs).[15][30][40] Population-based studies suggest that female fetuses/infants may derive greater benefit (rate of decrease in NTDs) from maternal folic acid supplementation than males.[71][72]
Continued folic acid supplementation beyond the first trimester until the end of pregnancy may confer neurodevelopmental benefits.[73] Further randomized trials are needed.
Pregnancy and lactation
Guidelines recommend preconception folic acid supplementation at a dose of 400-800 micrograms/day for the prevention of fetal 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 RDA 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 an 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] [
]
In low- and middle-income countries, maternal multiple micronutrient supplementation with iron and folic acid reduces the number of infants born at 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 to 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.
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