Rh Haemolytic Disease of the Newborn

Rh haemolytic disease of the newborn is haemolysis of RhD-positive foetal red cells by maternal IgG anti-D antibodies produced after sensitisation to the RhD antigen. It ranges from mild anaemia and jaundice to hydrops foetalis and foetal death.

Since the widespread use of anti-D immunoglobulin, incidence has fallen greatly. Sensitisation still occurs after missed prophylaxis, large foetomaternal haemorrhage and unrecognised sensitising events, and other antibodies (anti-c, anti-E, anti-Kell) cause similar disease.

Disease usually worsens in each affected pregnancy. The first sensitised pregnancy is typically mildly affected.

Pathophysiology.

Foetal RhD-positive red cells enter the maternal circulation at delivery, miscarriage or procedures, causing sensitisation. In a later pregnancy, maternal IgG crosses the placenta and coats foetal red cells, which are destroyed in the spleen.

Foetal anaemia causes extramedullary haematopoiesis, hepatosplenomegaly, hypoalbuminaemia, heart failure and hydrops. After birth, bilirubin rises quickly because the maternal clearance is lost.

• Hydrops: generalised oedema, ascites, pleural and pericardial effusions, pallor and hepatosplenomegaly.
• Severe anaemia at birth with jaundice within 24 hours, rapid bilirubin rise and hypoglycaemia.
• Late anaemia at 3 to 12 weeks, after the early phase.

Red flags.

• Hydrops foetalis or foetal middle cerebral artery peak systolic velocity over 1.5 multiples of the median.
• Cord haemoglobin under 110 g/L with a strongly positive direct antiglobulin test.
• Bilirubin rising over 8.5 micromol/L/h or any neurological sign.

• Antenatal: maternal antibody screen and quantification (critical titre usually 1 in 16 to 1 in 32), paternal and foetal RhD genotyping, serial middle cerebral artery Doppler from 18 weeks, and ultrasound for hydrops.
• Newborn: blood group, direct antiglobulin test (strongly positive), full blood count, reticulocyte count, bilirubin and albumin.
• Neonatal glucose, platelets and liver function in severe disease.

Differential diagnosis. ABO disease and other antibody disease, non-immune hydrops, congenital infection (parvovirus, cytomegalovirus), alpha thalassaemia and G6PD deficiency.

Antenatal.

• Intrauterine red cell transfusion for severe foetal anaemia (middle cerebral artery velocity over 1.5 multiples of the median or hydrops) at a specialist foetal medicine centre.
• Delivery is timed by foetal condition, usually from 37 to 38 weeks.

Newborn.

• Resuscitate and drain effusions in hydrops. Give group O RhD-negative red cells for severe anaemia, and partial exchange transfusion for hydrops with high venous pressure.
• Intensive phototherapy from birth, using the gestation specific chart. Double volume exchange transfusion (160 to 180 mL/kg) when bilirubin reaches the exchange threshold or signs of bilirubin encephalopathy appear, with group O RhD-negative irradiated red cells cross-matched against the mother.
• IV immunoglobulin 500 mg/kg over 4 hours, repeated once at 12 hours, when bilirubin continues to rise despite intensive phototherapy.
• Monitor glucose, calcium and platelets, particularly after exchange transfusion.

Late anaemia. Weekly haemoglobin for 8 to 12 weeks. Transfuse when haemoglobin is under 80 g/L with symptoms. Folic acid 500 micrograms daily is used by many centres.

Prevention.

• Anti-D immunoglobulin 1500 IU (300 micrograms) IM to RhD-negative women at 28 weeks and within 72 hours of delivery of an RhD-positive infant, and after sensitising events. Some regimens use 500 IU at 28 and 34 weeks.
• Quantify foetomaternal haemorrhage and give an extra 100 IU of anti-D immunoglobulin for each mL of foetal red cells over the dose covered.

Monitoring. Bilirubin and haemoglobin until stable, then weekly. Hearing screen and neurodevelopmental review.

Referral and escalation. Refer to a foetal medicine unit for any sensitised pregnancy, and to a tertiary neonatal unit for hydrops or exchange transfusion.