Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

INITIAL

at risk of folate deficiency due to pregnancy or lactation

1st line – oral folic acid + multivitamin supplementation

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INITIAL
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at risk of folate deficiency due to pregnancy or lactation
1st line – 

oral folic acid + multivitamin supplementation

There is conclusive evidence that use of folic acid supplementation pre-conceptually and during pregnancy reduces the incidence of fetal neural tube defects (NTDs).[19][20][21]

The US Preventive Services Task Force advises that the critical period for beginning supplementation is at least 1 month before conception.[35] Persons planning pregnancy, or who could become pregnant, should begin daily folic acid supplementation at least 1 month prior to anticipated conception and continue through the first 2-3 months of pregnancy.[35]

US recommendations vary from 400 to 800 micrograms/day depending upon factors such as diet, inclusion of food fortified with folic acid, socio-economic status, and individual medical history.​ NIH: dietary supplement fact sheet - folate Opens in new window

Higher folic acid doses (up to 5 mg/day) may be recommended for certain at-risk groups pre-conceptually and during the first 12 weeks of pregnancy.[34][39]

Features associated with increased risk for folate deficiency and/or having a fetus with an NTD include: personal or family history of fetal NTD or congenital malformation in the patient or her male partner; previous fetal NTD or congenital malformation birth by the patient; personal history of type 1 or type 2 diabetes or a haematological condition requiring folic acid supplementation; personal use of drugs affecting folic acid absorption or metabolism, or any teratogenic drug.

The National Institutes of Health recommends a dietary folate equivalent of 500 micrograms/day for breastfeeding women. NIH: dietary supplement fact sheet - folate Opens in new window​​

Primary options

folic acid: low risk: 0.4 mg orally once daily starting at least 1 month prior to pregnancy and continue through 12 weeks’ gestation; high risk: 4 mg orally once daily starting at least 1-3 months before pregnancy and continue through 12 weeks’ gestation

More

at risk of folate deficiency due to malabsorption disorders, chronic haemolytic disorder, or chronic dialysis

1st line – oral folic acid supplementation + treatment of underlying disorder

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INITIAL
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at risk of folate deficiency due to malabsorption disorders, chronic haemolytic disorder, or chronic dialysis
1st line – 

oral folic acid supplementation + treatment of underlying disorder

Correction of underlying cause and/or folic acid supplementation can prevent folate deficiency in patients with malabsorption disorders, such as tropical sprue and coeliac disease.

Increased folate loss occurs in patients with exfoliative dermatitis, chronic haemolytic anaemias, and in those undergoing chronic peritoneal dialysis (due to loss of folate in dialysis fluid).[14][15] Daily folic acid supplementation may be required in these patients to prevent folate deficiency.

Primary options

folic acid: 3-5 mg orally once daily, maximum 15 mg/day

at risk of folate deficiency due to certain drugs

1st line – folinic acid

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INITIAL
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at risk of folate deficiency due to certain drugs
1st line – 

folinic acid

Certain drugs (e.g., sulfasalazine, trimethoprim, methotrexate, pyrimethamine, and anticonvulsants [phenytoin, phenobarbital]) interfere with folate function or absorption by inhibiting enzymes involved in folate metabolism, and by other unknown mechanisms.[32]

Folinic acid can be used to prevent folate deficiency in patients taking drugs that affect dihydrofolate reductase activity, such as methotrexate, pyrimethamine, and trimethoprim.[52]

Folinic acid supplementation can reduce the risk of hepatotoxicity and gastrointestinal adverse effects in patients with rheumatoid arthritis.[58]

In some cases, where a drug has reduced efficacy when administered with folinic acid, a change to another drug may be required.

Primary options

folinic acid: consult specialist for guidance on dose

ACUTE

acquired: macrocytosis without anaemia

1st line – oral folic acid replacement

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ACUTE
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acquired: macrocytosis without anaemia
1st line – 

oral folic acid replacement

Ruling out vitamin B12 (cobalamin) deficiency is important. Initiation of folic acid therapy may resolve the haematological manifestations of vitamin B12 deficiency, but allow the neurological manifestations of underlying vitamin B12 deficiency to progress.

Oral folic acid therapy should be given to asymptomatic patients with documented folate deficiency, with or without macrocytosis.

Folic acid is better absorbed than natural folate (in food) in malabsorption states; hence, oral therapy is usually adequate.

Haematological findings are corrected after about 8 weeks.[53]

Primary options

folic acid: children: 1 mg orally once daily; adults: 1-5 mg orally once daily

Plus – treatment of underlying disorder

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ACUTE
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acquired: macrocytosis without anaemia
Plus – 

treatment of underlying disorder

Treatment recommended for ALL patients in selected patient group

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 haemolytic anaemia and exfoliative dermatitis need daily folic acid supplementation).

Patients taking continued folic acid supplementation should have vitamin B12 levels monitored periodically to prevent a missed diagnosis of vitamin B12 deficiency.

Malabsorptive states need correction of underlying disease and vitamin supplementation.

Folate deficiency due to certain drugs may need modification of drug therapy.

Older people and those with poor nutrition (and, therefore, with inadequate intake of folate) should be advised to increase the proportion of folate-rich foods in their diet (i.e., legumes, leafy vegetables, and some fruits).[54] In addition, folic acid may be supplemented by taking multivitamin preparations.

acquired: macrocytic anaemia

1st line – oral folic acid replacement

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ACUTE
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acquired: macrocytic anaemia
1st line – 

oral folic acid replacement

Ruling out vitamin B12 (cobalamin) deficiency is important. Initiation of folic acid therapy may resolve the haematological manifestations of vitamin B12 deficiency, but allow the neurological manifestations of underlying vitamin B12 deficiency to progress.

In severe megaloblastic anaemia where it is essential to initiate therapy immediately, concomitant folic acid and vitamin B12 should be given (until vitamin B12 testing is undertaken). Vitamin B12 and folate status determine subsequent therapy.

Primary options

folic acid: children: 1 mg orally once daily; adults: 1-5 mg orally once daily

OR

folic acid: children: 1 mg orally once daily; adults: 1-5 mg orally once daily

and

cyanocobalamin: consult specialist for guidance on dose

Plus – treatment of underlying disorder

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ACUTE
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acquired: macrocytic anaemia
Plus – 

treatment of underlying disorder

Treatment recommended for ALL patients in selected patient group

Assessment 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 haemolytic anaemia and exfoliative dermatitis need continued daily folic acid supplementation).

Patients taking continued folic acid supplementation should have vitamin B12 levels monitored periodically to prevent a missed diagnosis of vitamin B12 deficiency.

Malabsorptive states need correction of underlying disease and vitamin supplementation.

Folate deficiency due to certain drugs may need modification of drug therapy.

Plus – packed red blood cell transfusion

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ACUTE
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acquired: macrocytic anaemia
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with heart failure
Plus – 

packed red blood cell transfusion

Treatment recommended for ALL patients in selected patient group

Folic acid replacement therapy and packed red blood cell transfusion should be started simultaneously in cases where there is anaemia and associated heart failure.

Blood should be transfused slowly, with the use of diuretics to avoid volume overload.

Patients should be monitored for hypokalaemia following the commencement of folic acid therapy for severe megaloblastic anaemia.[50] Serum potassium should be replaced as needed.

Primary options

furosemide: children: 1-2 mg/kg intravenously/intramuscularly every 6-12 hours initially, increase according to response, maximum 6 mg/kg/dose, or 0.5 to 2 mg/kg orally every 6-12 hours initially, increase according to response, maximum 6 mg/kg/dose; adults: 20-80 mg orally every 6-8 hours initially, increase according to response, maximum 600 mg/day, or 20-40 mg intravenously/intramuscularly every 6-12 hours initially, increase according to response, maximum 80 mg/dose

congenital: hereditary folate malabsorption

1st line – folinic acid

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ACUTE
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congenital: hereditary folate malabsorption
1st line – 

folinic acid

Hereditary folate malabsorption is treated with parenteral folinic acid.

High-dose oral folinic acid may be considered in select cases.

Primary options

folinic acid: consult specialist for guidance on dose

congenital: methylenetetrahydrofolate reductase (MTHFR) polymorphisms

1st line – folic acid

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ACUTE
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congenital: methylenetetrahydrofolate reductase (MTHFR) polymorphisms
1st line – 

folic acid

MTHFR polymorphisms should be treated with daily oral folic acid to ensure optimum protection against low folate status.

Primary options

folic acid: children and adults: 0.4 mg orally once daily

congenital: cerebral folate transport deficiency

1st line – folinic acid

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ACUTE
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congenital: cerebral folate transport deficiency
1st line – 

folinic acid

Cerebral folate transport deficiency is treated with high doses of folinic acid, which can bypass the transport defect across the blood-brain barrier.[55]

Primary options

folinic acid: consult specialist for guidance on dose

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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