Anaemia in pregnancy

Physiological anaemia of pregnancy

• Plasma volume rises 40–50%, red cell mass only 20–30% (driven by erythropoietin), so haemoglobin falls by haemodilution, lowest at 28–34 weeks. Lower viscosity helps placental flow.
• MCV rises slightly (younger, larger cells). Serum B12 falls physiologically; TIBC rises because oestrogen raises transferrin output.

• Anaemic hypoxia: anaemia lowers oxygen content, while PaO2 and saturation stay normal, so pulse oximetry is reassuring in a breathless anaemic woman.

Classifying any anaemia by mechanism

Iron metabolism in pregnancy

• Extra need is about 1 g; requirement is highest in the third trimester (about 6–7 mg absorbed daily).
• Absorption: duodenal cytochrome b reduces Fe3+ to Fe2+, DMT1 takes it in, ferroportin exports it. Hepcidin falls in pregnancy, so less ferroportin is degraded and absorption rises several-fold.
• Inhibitors: phytates (chapati, pulses), tannins (tea), calcium and antacids. Vitamin C helps.
• Placental transfer is active via transferrin receptors on syncytiotrophoblast, so the fetus keeps a normal Hb but a mother with deficiency or a preterm baby has low iron stores at birth. Delayed cord clamping adds 30–50 mg iron.

Iron deficiency anaemia

• Commonest anaemia in pregnancy. Sequence: ferritin falls first, then transferrin saturation, then microcytic hypochromic anaemia with pencil cells.
• Best single test: serum ferritin (below about 30 µg/L). Ferritin is an acute phase protein, so a woman with fever or infection can have a "normal" ferritin despite deficiency; check CRP.
• Zinc protoporphyrin: when iron is scarce, ferrochelatase inserts zinc instead of iron into protoporphyrin. ZPP also rises in lead poisoning.
• RDW (red cell distribution width) measures variation in cell size: high in iron deficiency (mixed old and new cells), normal in thalassaemia trait (uniformly small cells). It can be normal early, so it only supports.
• Restless legs and pica (pagophagia): iron is a cofactor of tyrosine hydroxylase, the rate-limiting step of dopamine synthesis in the brain. Check ferritin in any pregnant woman with restless legs.
• Other features: glossitis, angular cheilosis, koilonychia, reactive thrombocytosis.
• Treatment: reticulocytes rise in 7–10 days; Hb rises about 2 g/dL in 3–4 weeks. Ferrous sulphate 200 mg contains 65 mg elemental iron. Intravenous iron is avoided in the first trimester.

Lead: a hidden cause in South Asian women

• Surma and kohl may contain lead. Lead inhibits ferrochelatase and ALA dehydratase, giving microcytic anaemia with basophilic stippling (retained RNA from inhibited pyrimidine 5'-nucleotidase).
• About 90% of body lead is stored in bone. Pregnancy increases bone turnover to supply fetal calcium, so lead released from her own bones raises blood lead even when exposure is unchanged; it crosses the placenta freely. Adequate calcium intake reduces this release.

Folate and B12 deficiency (megaloblastic anaemia)

• Folate is needed by thymidylate synthase (dUMP to dTMP). DNA synthesis lags while cytoplasm matures: large erythroblasts, oval macrocytes (MCV over 100 fL), hypersegmented neutrophils, ineffective erythropoiesis (raised LDH and bilirubin).
• The DNA defect affects all dividing marrow precursors, so severe deficiency causes pancytopenia. Pancytopenia in a poorly nourished woman with twins is usually nutritional, not leukaemia.
• Folate deficiency is the commonest cause of megaloblastic anaemia in pregnancy: twins nearly double fetal need; stores last only 3–4 months; long boiling destroys food folate. Red cell folate reflects stores.
• B12 deficiency (strict vegetarians, pernicious anaemia, gastrectomy, ileal resection) adds neuropathy and subacute combined degeneration; give B12 before folate. Total gastrectomy removes intrinsic factor and causes megaloblastic anaemia within years; partial gastrectomy more often causes iron deficiency (less acid). Pernicious anaemia is confirmed by intrinsic factor antibodies (specific; parietal cell antibodies are sensitive but not specific).
• Dimorphic film with a falsely normal MCV means combined iron and folate deficiency.

Haemoglobinopathies

• Ferritin shows whether iron is lacking; HbA2 confirms trait. Iron deficiency lowers HbA2 and can hide trait, so do not delay partner testing.
• Beta-thalassaemia major: unpaired alpha chains precipitate in precursors (ineffective erythropoiesis), marrow expansion (frontal bossing, hair-on-end skull), hepatosplenomegaly and transfusion iron overload. Diagnosis is confirmed by haemoglobin electrophoresis or HPLC (HbF dominant, HbA absent or low); a high ferritin is a consequence, not the diagnosis.
• Alpha-thalassaemia: two genes deleted is trait (normal HbA2, needs DNA testing); three is HbH disease, where excess beta chains form β4 tetramers seen as golf-ball inclusions with brilliant cresyl blue; it worsens in pregnancy and with oxidant drugs. Four is Hb Barts (gamma4) and hydrops.
• Sickle cell: missense glutamate to valine; deoxygenated HbS polymerises. Repeated splenic infarction causes autosplenectomy, so Howell–Jolly bodies (nuclear remnants normally removed by the spleen) appear, with risk from encapsulated bacteria. Osteomyelitis is caused by *S. aureus* overall, but Salmonella is characteristic in sickle cell. Leg ulcers and painful crises occur. HbSS pregnancy: placental infarcts, growth restriction, pre-eclampsia. Trait has no crises but more urinary infection.

Malaria and anaemia

• *P. falciparum*-infected red cells express VAR2CSA, which binds chondroitin sulphate A on syncytiotrophoblast, so parasites pack the placenta. Primigravidae lack antibodies to this variant and suffer most anaemia and low birth weight; peripheral films can be negative while the placenta is heavily infected.

Remember Small cells with a high red cell count and normal ferritin: think thalassaemia trait, not iron deficiency.

Exam trap Ferritin can be normal in an infected iron-deficient woman because it is an acute phase protein.

Exam trap Do not give iron blindly to a microcytic woman: thalassaemia carriers do not need it.

How FCPS asks about this

• Best test for iron deficiency: serum ferritin; ferritin and HbA2 separate it from thalassaemia trait.
• Child with frontal bossing, hepatosplenomegaly, hair-on-end skull: beta-thalassaemia major; confirm by Hb electrophoresis.
• Anaemia in chronic renal failure: normocytic, from reduced erythropoietin.
• Raised MCV and neuropathy after gastrectomy: B12 deficiency (loss of intrinsic factor).
• Howell–Jolly bodies in sickle cell: autosplenectomy.
• High reticulocytes and unconjugated bilirubin: haemolysis.
• Golf-ball inclusions: HbH (β4 tetramers).