Key Facts

Folate (vitamin B9) deficiency is a common cause of megaloblastic anaemia. Unlike B12 deficiency, it does not cause neurological damage. Folate supplementation in pregnancy is critical for preventing neural tube defects.

Epidemiology

• Common: estimated ~5% of UK population may have suboptimal folate
• Elderly, alcoholics, and lower socioeconomic groups at highest risk
• Pregnancy: increased demand → deficiency common without supplementation

Aetiology

• Dietary insufficiency (most common): poor intake of green vegetables, liver, fortified foods; alcoholism
• Increased demand: pregnancy, lactation, haemolytic anaemia (sickle cell, thalassaemia), malignancy, psoriasis, exfoliative dermatitis
• Malabsorption: coeliac disease, Crohn disease (proximal jejunum), tropical sprue
• Drugs: methotrexate (DHFR inhibitor), trimethoprim, phenytoin, carbamazepine, sodium valproate

Pathophysiology

• Folate is essential for one-carbon metabolism and DNA synthesis (thymidylate synthesis)
• Deficiency → impaired DNA synthesis → megaloblastic erythropoiesis
• Nuclear-cytoplasmic dissociation: delayed nuclear maturation with normal cytoplasmic maturation → large cells
• Body stores last only 3–4 months (cf. B12 stores last 3–5 years)
• Folate absorbed in proximal jejunum

Haematological

• Anaemia symptoms: fatigue, dyspnoea, pallor
• Glossitis (smooth, red tongue)
• Mild jaundice (ineffective erythropoiesis)

No Neurological Features

• Key distinction from B12 deficiency
• If neurological signs present: suspect B12 deficiency (or combined)

Red Flags

• Neurological symptoms (suggests B12 deficiency — check both)
• Pancytopenia (severe deficiency; exclude other causes)
• Pregnancy with no folate supplementation (NTD risk)
• Suspected coeliac disease (weight loss, diarrhoea, iron deficiency)

Bloods

• FBC: low Hb, raised MCV (>100 fL), ± pancytopenia
• Blood film: oval macrocytes, hypersegmented neutrophils (identical to B12 deficiency)
• Serum folate: low (<3 µg/L) — affected by recent dietary intake
• Red cell folate: more reliable for tissue stores (low <150 µg/L) — but less commonly available
• Serum B12: MUST check before starting folate (exclude B12 deficiency)
• Homocysteine: elevated (non-specific)
• MMA: NORMAL (distinguishes from B12 deficiency where MMA is elevated)
• LDH, bilirubin: elevated (ineffective erythropoiesis)

Special Tests

• Coeliac screen: anti-tTG (if unexplained folate deficiency)
• Reticulocyte count: low

Pharmacological

• Folic acid 5mg daily for 4 months (standard treatment dose)
• Identify and treat underlying cause (diet, coeliac, drugs)
• CRITICAL: check and correct B12 deficiency BEFORE or alongside folate replacement

Pregnancy/Pre-conception

• All women: folic acid 400mcg daily from pre-conception through first 12 weeks
• High-risk (previous NTD, diabetes, BMI >30, epilepsy on valproate/carbamazepine, sickle cell/thalassaemia, coeliac): folic acid 5mg daily from pre-conception through first 12 weeks

Ongoing Supplementation

• If cause is ongoing (haemolytic anaemia, chronic malabsorption): long-term folic acid 5mg daily
• Methotrexate patients: folic acid 5mg once weekly (not on methotrexate day)

Dietary Advice

• Green leafy vegetables (spinach, broccoli, Brussels sprouts)
• Fortified cereals and bread
• Liver, legumes, oranges

Referral Criteria

• Haematology: pancytopenia, diagnostic uncertainty
• Gastroenterology: suspected coeliac or malabsorption
• Obstetrics: high-risk pregnancy

• Excellent with appropriate replacement
• Reticulocyte count rises within 5–7 days of starting treatment
• Hb normalises within 6–8 weeks
• Stores replenished within 4 months
• Folate supplementation: reduces NTD risk by ~70% (400mcg); high dose (5mg) for high-risk
• If underlying cause treated: folate deficiency unlikely to recur
• Long-term folate needed if ongoing cause (haemolysis, malabsorption)

Drugs Causing Folate Deficiency