Approach
Oral folic acid replacement is the preferred therapy for the management of folate deficiency (because several effective folate absorption pathways operate throughout the small intestine).[46] Folic acid is a synthetic, oxidised form of folate.[52] Oral preparations of folic acid are inexpensive and stable.[30]
Parenteral folic acid may be considered in severe malabsorption states. Folinic acid, a reduced form of folic acid, may be given parentally in some cases (e.g., patients taking drugs that affect the enzyme dihydrofolate reductase).
Acquired folate deficiency
Oral folic acid replacement therapy is usually sufficient to treat acquired folate deficiency. Haematological findings are corrected after about 8 weeks.[53] See Monitoring.
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.
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). Patients taking continued folic acid supplementation should have vitamin B12 levels monitored periodically to avert a missed diagnosis of vitamin B12 deficiency.
Folate deficiency-induced anaemia is generally well compensated. However, in severe cases where there is associated heart failure, packed red blood cell (RBC) transfusion should be considered as an additional treatment. 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.
Dietary modifications
An important consideration in certain populations. For example, 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.
Evaluation and treatment of underlying disorders
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). Malabsorptive states need correction of underlying disease and vitamin supplementation. Folate deficiency due to certain drugs may need modification of drug therapy.
Inborn errors of folate absorption, metabolism, and transport
All suspected inborn errors of folate absorption, metabolism, and transport in children should be promptly referred to major specialised paediatric hospitals.
Treatment requires large doses of folate that are started early in infancy and often given parenterally.[12][30] The goal of therapy is to maintain both blood and cerebrospinal fluid folate levels.
Hereditary folate malabsorption: caused by mutations in the proton-coupled folate transporter. Treated with parenteral folinic acid. High-dose oral folinic acid may be considered in select cases.
Polymorphisms of the enzyme methylenetetrahydrofolate reductase (MTHFR): common, can cause mildly reduced folate levels and mild hyperhomocysteinaemia. Treated with daily oral folic acid to ensure optimum protection against low folate status.
Cerebral folate transport deficiency: characterised by decreased folate transport across the blood-brain barrier; leading to neuropsychiatric or developmental disorders. Treated with high doses of folinic acid, which can bypass the transport defect.[55]
The management of MTHFR deficiency, glutamate formiminotransferase deficiency, and functional methionine synthase deficiency are beyond the scope of this topic.
Monitoring response to therapy
Reticulocyte response at 1 week, and the blood count normalisation at 8 weeks from the start of therapy, are useful parameters to monitor treatment response. Monitoring serum folate level has little value. Homocysteine levels usually fall within 7 days of therapy.
Reticulocyte count can be assessed at the end of the first week of therapy.[30] Increased haemoglobin level and reticulocytosis within 7-10 days of starting treatment suggests a positive response.[30]
Mean corpuscular volume (MCV) may increase during the first few days of treatment, presumably because of reticulocytosis.[56] As normocytic RBCs replace macrocytes, MCV decreases to normal range, usually within about 8 weeks of beginning treatment.[57]
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., coeliac disease) or loss (e.g., chronic haemolytic anaemias).
Pre-conception, pregnancy, and lactation
There is conclusive evidence that 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]
Guidelines recommend pre-conception 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.[34][35][36]
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
To achieve the greatest reduction of NTDs, World Health Organization (WHO) recommends a RBC folate level >906 nanomol/L (>400 nanograms/mL) in women of reproductive age.[38]
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
Supplementary folic acid during pregnancy is associated with a lower risk of small for gestational age infants, without increasing risk for large for gestational age infants.[40]
There is no conclusive evidence that supplementation prevents preterm birth, stillbirth, neonatal mortality, or miscarriage.[41][42][43]
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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 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.
Patients taking drugs that interfere with folate absorption and metabolism may require supplementation with oral or parenteral folinic acid to prevent folate deficiency.
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