Paediatrics chapters
Megaloblastic anaemia
Macrocytic anaemia caused by vitamin B12 or folate deficiency: why DNA synthesis fails, which children are at risk (goat's milk, vegan mothers, ileal disease, anticonvulsants), how the two deficiencies differ, and why folate must never be given alone in B12 deficiency.
- Megaloblastic anaemia is a macrocytic anaemia caused by vitamin B12 or folate deficiency, which block DNA synthesis so the nucleus lags behind the cytoplasm (nuclear-cytoplasmic asynchrony) and the marrow makes large, abnormal cells that die early.
- Folate deficiency: goat's milk, poor diet, malabsorption (coeliac), chronic haemolysis, prematurity, phenytoin and methotrexate; develops within weeks. B12 deficiency: breastfed infants of vegan mothers, ileal resection or disease, congenital or juvenile pernicious anaemia, transcobalamin II deficiency; causes neurological damage.
- Blood: high MCV, macro-ovalocytes, hypersegmented neutrophils, sometimes low white cells and platelets; check serum B12 (with methylmalonic acid) and red cell folate; replace the missing vitamin, and never give folate alone in B12 deficiency.
On this page
Overview
Megaloblastic anaemia is a macrocytic anaemia in which the marrow makes large, abnormal red cell precursors (megaloblasts). In children it is almost always due to a deficiency of folic acid or vitamin B12 (cobalamin), or both. It is less common than iron deficiency, but it is examined often because of its dietary clues (goat's milk, vegan diet) and because B12 deficiency damages the nervous system.
Pathophysiology: impaired DNA synthesis
- Both vitamins are needed to make thymidine and hence DNA. Folate carries one-carbon units; B12 regenerates the active form of folate and is needed for normal lipid and myelin metabolism.
- When either is lacking, DNA synthesis slows but RNA and protein synthesis continue.
- The cell keeps growing while its nucleus lags behind: nuclear-cytoplasmic asynchrony. Nuclei look open and finely dispersed; cells are large.
- Many abnormal precursors die in the marrow (ineffective erythropoiesis), causing a mild rise in unconjugated bilirubin and LDH.
- All dividing cells are affected, so white cells and platelets may also fall, and the gut lining and tongue change.
The marrow is hypercellular but output is poor: this is ineffective erythropoiesis, as in thalassaemia.
Causes
Folate deficiency
| Mechanism | Examples |
|---|---|
| Poor intake | Goat's milk (very little folate), evaporated milk, heat-sterilised home feeds (folate is destroyed by heat), malnutrition |
| Malabsorption | Coeliac disease, chronic diarrhoea, short gut |
| Increased need | Rapid growth, prematurity (low stores), chronic haemolysis (sickle cell, thalassaemia, spherocytosis), pregnancy |
| Drugs | Phenytoin, phenobarbitone, methotrexate, trimethoprim |
- Infants need about ten times more folate per kilogram than adults and have small stores, so deficiency can appear within weeks (Nelson).
Vitamin B12 deficiency
B12 comes only from animal foods. It binds intrinsic factor from gastric parietal cells, is absorbed in the terminal ileum, and is carried by transcobalamin II. The liver holds large stores, so deficiency from poor intake takes months to years in older children.
| Mechanism | Examples |
|---|---|
| Diet | Breastfed infant of a strict vegetarian (vegan) mother or a mother with pernicious anaemia; vegan child |
| Lack of intrinsic factor | Congenital pernicious anaemia (no intrinsic factor), juvenile pernicious anaemia (autoimmune), gastric surgery |
| Ileal disease or loss | Terminal ileal resection, Crohn's disease |
| Competition in the gut | Bacterial overgrowth (blind loop), fish tapeworm (Diphyllobothrium latum) |
| Pancreatic | Chronic pancreatitis |
| Inborn errors | Transcobalamin II deficiency, defects of B12 metabolism (methylmalonic aciduria) |
- Most childhood B12 deficiency is not dietary but due to an absorption defect, so treatment is usually lifelong (Nelson).
Goat's milk = folate deficiency; vegan mother = B12 deficiency. Do not mix them up.
Clinical features
Common to both
- Pallor, tiredness, irritability, poor feeding and poor weight gain in infants.
- Mild jaundice from ineffective erythropoiesis.
- Smooth, beefy red tongue (glossitis).
- Tachycardia.
- Bruising or infection if white cells and platelets fall.
Only in B12 deficiency: the nervous system
- Paraesthesia, weakness, unsteady gait.
- Loss of vibration sense and proprioception (posterior columns), peripheral neuropathy.
- Irritability, depression, dementia and eventually coma.
- Vitiligo may accompany autoimmune disease.
- Nerve damage can become permanent, so early treatment matters.
Neurological signs occur in B12 deficiency, not in folate deficiency.
Investigations
Blood count and film
- Raised MCV and MCH; haemoglobin may be very low.
- Macro-ovalocytes with anisocytosis and poikilocytosis.
- Hypersegmented neutrophils (large neutrophils with many lobes), often an early sign.
- Reticulocytes low for the degree of anaemia.
- White cells and platelets normal in mild cases, reduced in severe cases (pancytopenia).
Hypersegmented neutrophils are an early clue and are seen in both B12 and folate deficiency.
Bone marrow
- Hypercellular with erythroid hyperplasia.
- Megaloblasts: large erythroid and myeloid precursors with immature-looking nuclei.
- Rarely needed if the blood picture and vitamin levels are clear.
Biochemistry
| Test | B12 deficiency | Folate deficiency |
|---|---|---|
| Serum B12 | Low | Normal |
| Red cell folate | Normal or low | Low (better than serum folate) |
| Methylmalonic acid (serum or urine) | Raised | Normal |
| Homocysteine | Raised | Raised |
| Unconjugated bilirubin, LDH | Mildly raised | Mildly raised |
- Look for the cause: diet history, coeliac screening, tests for pernicious anaemia, stool for fish tapeworm, ileal imaging.
Differential diagnosis of macrocytosis
| Megaloblastic | Non-megaloblastic |
|---|---|
| B12 deficiency, folate deficiency, drugs (methotrexate), inborn errors | Diamond-Blackfan anaemia, Fanconi anaemia, aplastic anaemia, liver disease, hypothyroidism |
Diamond-Blackfan anaemia is macrocytic but not megaloblastic: no hypersegmented neutrophils, and B12 and folate are normal.
Management
Treat the deficiency
- Folate deficiency: oral folic acid daily for a few weeks (both books include about 1 mg daily in their ranges), then treat or remove the cause (stop goat's milk, treat coeliac disease, review drugs).
- B12 deficiency: intramuscular vitamin B12 (cyanocobalamin). Oral treatment is unreliable when absorption is the problem. A course of loading injections is followed by regular (often monthly) injections, lifelong if the absorption defect is permanent.
- Treat the cause: deworm, treat bacterial overgrowth, give B12 to the vegan mother as well.
Do not give folate alone until B12 deficiency is excluded
Folic acid can correct the blood picture in B12 deficiency while the nerve damage continues or worsens. Confirm which vitamin is lacking first, or give both if the child is very ill and the tests are pending.
"Folate fixes the blood, not the brain" in B12 deficiency.
Supportive
- Blood transfusion only for severe anaemia with cardiac strain, given cautiously.
- Response: reticulocytes rise within days and the child feels better quickly; neurological recovery is slower and may be incomplete.
Prevention
- Folic acid supplements for preterm infants and children with chronic haemolytic anaemia (sickle cell, thalassaemia, spherocytosis) and on long-term anticonvulsants.
- B12 supplements for vegetarian and vegan mothers who breastfeed, and for vegan children.
- Avoid goat's milk as the main milk in infancy.
Expect: a 6-month-old fed goat's milk with pallor and macrocytosis (folate deficiency); a breastfed infant of a vegan mother with anaemia, irritability and poor feeding (B12 deficiency); the basic defect of impaired DNA synthesis with nuclear-cytoplasmic asynchrony; hypersegmented neutrophils and macro-ovalocytes; terminal ileum and intrinsic factor in B12 absorption; methylmalonic acid raised only in B12 deficiency; neurological signs only in B12 deficiency; drugs such as phenytoin and methotrexate; and the danger of giving folic acid alone.
Quick revision
- Megaloblastic = macrocytic anaemia from B12 or folate deficiency.
- Defect: impaired DNA synthesis; nucleus lags behind cytoplasm.
- Film: high MCV, macro-ovalocytes, hypersegmented neutrophils; may be pancytopenic.
- Folate: goat's milk, heat-treated feeds, coeliac, haemolysis, prematurity, phenytoin, methotrexate.
- B12: vegan mother, ileal resection, Crohn's, pernicious anaemia, fish tapeworm, transcobalamin II deficiency.
- Only B12 causes neurological signs and raised methylmalonic acid.
- Red cell folate is the better test for folate stores.
- Folic acid by mouth; B12 by injection, often lifelong.
- Never give folate alone in B12 deficiency.
Written by The House Job from standard references (Basis of Paediatrics by Pervez Akbar; Nelson Essentials of Paediatrics).
FAQ
Why does goat's milk cause anaemia in infants?
Goat's milk contains very little folate, and infants have small folate stores and high needs, so an infant fed mainly goat's milk soon develops megaloblastic anaemia.
Can a breastfed baby get vitamin B12 deficiency?
Yes, if the mother is a strict vegetarian without supplements or has pernicious anaemia, because her milk then contains too little B12.
Which test helps separate B12 from folate deficiency when levels are borderline?
Methylmalonic acid, which rises in B12 deficiency but not in folate deficiency; homocysteine rises in both.
Why should B12 usually be given by injection?
Most childhood B12 deficiency is due to poor absorption from the gut, so oral treatment is unreliable and injections are needed, often for life.