Fetal Anaemia Due to Alloimmunisation

Fetal anaemia due to alloimmunisation is red cell destruction in the fetus by maternal IgG antibodies that cross the placenta, after sensitisation to a paternal red cell antigen the fetus has inherited, most often RhD, then Kell, c, E and others. It causes anaemia, extramedullary erythropoiesis, hydrops and death. It matters because anti-D prophylaxis prevents RhD disease, and treatment by intrauterine transfusion saves most affected fetuses.

• Risk factors: RhD negative women with a RhD positive partner, sensitising events without anti-D (delivery, miscarriage, ectopic pregnancy, abruption, abdominal trauma, amniocentesis), previous transfusion.
• Titres of 1 in 16 or more (1 in 8 for Kell is concerning) indicate risk.
• Hydrops develops when fetal anaemia is severe.

Women are well, and the problem is found by antibody screening or in a woman with a previous affected baby. Fetal hydrops causes a large uterus, polyhydramnios and reduced movements.

• Previous baby with jaundice, anaemia or hydrops.
• Rising antibody titres on serial tests.
• Differential diagnosis: parvovirus infection, alpha thalassaemia, fetomaternal haemorrhage, cytomegalovirus infection, other causes of hydrops, fetal heart failure.
• Complications: hydrops fetalis, stillbirth, preterm birth, neonatal anaemia, kernicterus, late anaemia in infancy.

The approach is antibody identification with serial Doppler assessment of the fetal middle cerebral artery.

• Maternal blood group and antibody screen at booking and at 28 weeks; indirect Coombs test with antibody identification and titre; partner genotype and fetal RHD genotyping on maternal plasma where available.
• Middle cerebral artery peak systolic velocity from 18 weeks, every 1 to 2 weeks; above 1.5 multiples of the median indicates moderate to severe anaemia.
• Ultrasound for ascites, hepatosplenomegaly, pericardial effusion, polyhydramnios, placental thickening.
• Fetal blood sampling for haemoglobin, direct Coombs test and blood group at transfusion where available; Kleihauer test after any sensitising event.

The principle is to prevent sensitisation, to monitor sensitised women with Doppler and to transfuse the fetus when anaemia is moderate to severe.

• Supportive: refer sensitised women to a fetal medicine unit; counselling; plan delivery in a unit with neonatal intensive care and exchange transfusion capability.
• Pharmacological: prevention in unsensitised RhD negative women with a RhD positive or unknown fetus: anti-D immunoglobulin 1500 IU IM at 28 weeks as a single dose (or 500 IU at 28 and 34 weeks), then 500 IU IM within 72 hours of birth of a RhD positive baby, plus 125 IU for each 1 mL of fetal red cells above 4 mL found on Kleihauer testing; sensitising events before 12 weeks 250 IU, after 12 weeks 500 IU within 72 hours; for severe early disease give immunoglobulin 1 g/kg IV weekly from 12 to 16 weeks until transfusion; betamethasone 12 mg IM twice, 24 hours apart, before transfusion at 24 to 34 weeks and 6 days; newborn immunoglobulin 0.5 g/kg IV over 2 hours for haemolysis.
• Procedures: intrauterine transfusion through the umbilical vein or intraperitoneally before 18 weeks, with O negative, Kell negative, cytomegalovirus negative, irradiated packed cells (haematocrit 75 to 80 percent), to a target fetal haematocrit of 40 to 50 percent and a rise of no more than 4 times in one session, repeated every 1 to 3 weeks (haematocrit falls about 1 percent per day); delivery at 37 to 38 weeks, earlier for hydrops or failing transfusion; newborn phototherapy and exchange transfusion at twice the blood volume (160 mL/kg) for bilirubin rising above 8.5 micromol/L per hour or above treatment thresholds.
• Special groups: Kell alloimmunisation suppresses erythropoiesis and causes severe anaemia at low antibody titres, so Doppler monitoring starts at 16 to 18 weeks regardless of titre and a lower threshold to transfuse is used; the fetal reticulocyte count is low and neonatal bilirubin is less raised.
• Red flags: hydrops, peak systolic velocity above 1.5 multiples of the median, reduced fetal movements, antibody titre of 1 in 16 or more, bradycardia during transfusion.
• Follow-up: Doppler every 1 to 2 weeks until transfusion, then 1 week after each transfusion; newborn haemoglobin, bilirubin and direct Coombs test; infant haemoglobin at 2, 4, 8 and 12 weeks; folic acid 250 micrograms oral daily to the infant.