Folic Acid

Folic acid is the synthetic form of vitamin B9, used to treat and prevent folate deficiency and to lower neural tube defect risk. It is inactive until reduced to tetrahydrofolate.

Classification. Haematinic; water-soluble vitamin.

Mechanism. Reduced by dihydrofolate reductase to tetrahydrofolate, a cofactor in purine and thymidylate synthesis and in methylation, and therefore needed for DNA synthesis in rapidly dividing cells.

Pharmacokinetics. Rapidly absorbed from the proximal small intestine, with a half-life of about 1 hour for the parent drug, and stored in the liver. Excess is excreted in urine.

Megaloblastic anaemia due to folate deficiency (adults).

• Dose: 5 mg orally once daily for 4 months; or until the cause is corrected. Where cobalamin deficiency has not been excluded, give cobalamin first or with it.
• Malabsorption: up to 15 mg daily. Maximum: 15 mg daily.

Periconception and pregnancy.

• Prophylaxis: 400 µg orally daily from at least 1 month before conception to 12 weeks of pregnancy; often continued through pregnancy where anaemia is a concern.
• High neural tube defect risk (prior affected pregnancy, antiepileptic drug treatment, diabetes, obesity, sickle cell disease, thalassaemia, coeliac disease): 5 mg daily to 12 weeks.

Haemolytic anaemia and sickle cell disease. 5 mg daily (1 mg daily is also used) while haemolysis continues.

Methotrexate toxicity prevention. 5 mg once weekly, taken on a day other than the methotrexate day (usually 24 to 72 hours after).

Children. Under 1 year: 500 µg/kg daily (maximum 5 mg); 1 to 17 years: 5 mg daily for deficiency and haemolytic states; lower doses are used for prophylaxis.

Adjustments. Kidney: no reduction; dialysis removes folate, so 1 mg daily is often used. Liver: none. Loading dose and titration: not applicable.

Contraindications. Untreated cobalamin deficiency without cobalamin cover; hypersensitivity; use alone in megaloblastic anaemia of undetermined cause.

Warnings. Folic acid can correct the anaemia of cobalamin deficiency while allowing subacute combined degeneration of the cord to progress. Folate at 5 mg or more may mask this.

Adverse effects. Rare: nausea, bloating, rash, hypersensitivity.

Interactions. Lowers phenytoin, phenobarbital and primidone levels, with loss of seizure control possible. Methotrexate, trimethoprim, pyrimethamine and sulfasalazine antagonise or are antagonised by folate. In East Africa, folic acid at 5 mg daily or more reduces the efficacy of sulfadoxine-pyrimethamine for malaria prevention in pregnancy; use 400 µg daily when sulfadoxine-pyrimethamine is used.

Pregnancy and breastfeeding. Safe and advised in both.

Common errors. Giving folic acid alone to a patient with cobalamin deficiency; the wrong dose with sulfadoxine-pyrimethamine; taking it on the same day as methotrexate.

Administration. Oral, with or without food; intramuscular or intravenous 5 mg daily is possible if absorption is impaired.

Baseline. Full blood count, blood film, serum or red cell folate and cobalamin.

Monitoring. Reticulocytes rise in 2 to 5 days; haemoglobin rises within 2 weeks and normalises within 4 to 8 weeks. Stop when the cause is corrected, except in chronic haemolysis and methotrexate or antiepileptic therapy.

Referral and escalation. No response by 4 weeks suggests a wrong diagnosis, mixed deficiency or malabsorption; refer to haematology.