What three stages are required for haemolytic disease of the newborn (HDN) to occur?

1. The fetus inherits a paternally-derived red-cell antigen that is foreign to the mother (e.g. RhD-positive fetus of an RhD-negative mother)
2. A sufficient volume of fetal red cells enters the maternal circulation to stimulate a maternal immune response (sensitisation)
3. Maternal IgG antibodies cross the placenta and cause immune destruction of the fetal red cells -> fetal anaemia

Clinical relevance. Understanding the three stages explains why the first sensitising pregnancy is usually spared and prevention targets sensitisation.

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Pathophysiology of HDN

Haemolytic disease of the newborn requires three sequential events.

The three stages

1. Antigen inheritance - the fetus inherits a paternal red-cell antigen foreign to the mother (classically RhD - an RhD-positive fetus of an RhD-negative mother).
2. Sensitisation - a sufficient volume of fetal red cells reaches the maternal circulation (feto-maternal haemorrhage) to stimulate a maternal immune response.
3. Transplacental antibody and haemolysis - maternal antibodies (IgG) cross the placenta, bind fetal red cells, and the fetal reticuloendothelial system destroys them, causing fetal anaemia.

The immune response

• The primary response is weak and IgM (does not cross the placenta) - so the first sensitising pregnancy is usually unaffected.
• The secondary response is IgG, which crosses the placenta and affects subsequent pregnancies.
• Once sensitised, the woman remains sensitised for life.