Rh Alloimmunisation

Rh alloimmunisation occurs when an RhD-negative woman is exposed to RhD-positive fetal red cells (transplacental haemorrhage, abdominal trauma, invasive procedures, miscarriage, ectopic pregnancy, delivery) and forms IgG anti-D antibodies. These cross the placenta, bind fetal RhD-positive red cells and cause haemolysis (haemolytic disease of the fetus and newborn), with anaemia, hydrops fetalis and death.

About 15% of Caucasians are RhD negative (3 to 5% of Africans and Asians). Without prophylaxis, the sensitisation risk after a first RhD-positive, ABO-compatible pregnancy is about 16%; with prophylaxis it is under 0.1 to 0.3%. Other clinically significant antibodies (anti-Kell, anti-c, anti-E, anti-Fya) cause similar disease, and Kell antibodies also suppress erythropoiesis.

• Mother is asymptomatic; a positive antibody screen is found at booking or later
• Fetus: anaemia (raised middle cerebral artery Doppler velocity), hydrops (ascites, pleural and pericardial effusions, skin oedema, polyhydramnios, thick placenta), cardiomegaly, hepatosplenomegaly
• Neonate: jaundice within 24 hours, anaemia, hepatosplenomegaly, kernicterus, late anaemia
• Sensitising events: bleeding in pregnancy, miscarriage, termination, ectopic pregnancy, amniocentesis, chorionic villus sampling, external cephalic version, abdominal trauma, intrauterine death

• Blood group and antibody screen at booking and at 28 weeks in RhD-negative women. Anti-D titre of 1:16 or 1:32 or more (laboratory dependent) triggers intensified fetal assessment; quantified anti-D below 4 IU/mL is low risk, 4 to 15 IU/mL moderate and above 15 IU/mL high risk. For Kell and some other antibodies there is no safe titre
• Fetal genotyping: cell free fetal DNA in maternal plasma (non-invasive RHD genotyping from 11 weeks), paternal zygosity testing, or amniocentesis
• Middle cerebral artery peak systolic velocity (MCA-PSV) above 1.5 multiples of the median predicts moderate to severe anaemia (sensitivity 88%); measure weekly to fortnightly from 16 to 18 weeks
• Kleihauer-Betke test or flow cytometry to quantify fetomaternal haemorrhage
• Cordocentesis for fetal haemoglobin, haematocrit and direct antiglobulin test when MCA-PSV is raised
• Postnatal: cord blood group, direct Coombs test, bilirubin, haemoglobin

Prevention with anti-D immunoglobulin.

• Routine antenatal prophylaxis for RhD-negative, non-sensitised women: 1,500 IU (300 micrograms) IM at 28 weeks, or 500 IU at 28 and 34 weeks in a two dose schedule
• After a sensitising event, within 72 hours: 250 IU before 20 weeks and 500 IU from 20 weeks; the dose is increased according to the Kleihauer-Betke estimate of fetomaternal haemorrhage (every 125 IU covers 1 mL of fetal red cells, so 500 IU covers 4 mL)
• Postpartum: 500 IU within 72 hours if the baby is RhD positive (administration up to 10 days later may still be partly effective)

Sensitised pregnancy.

• Maternal antibody titre every 2 to 4 weeks; MCA-PSV Doppler weekly or fortnightly from 16 to 18 weeks
• Intrauterine transfusion (intravascular, through the umbilical vein or intrahepatic vein) for fetal haemoglobin more than 5 SD below normal or haematocrit below 30%, using group O RhD-negative, irradiated, CMV-safe, washed red cells, aiming for a haematocrit of 40 to 45%. Volume is estimated as fetal weight x 3 mL x (target Hct minus current Hct). Repeat at intervals set by MCA-PSV and haemoglobin fall (about 1% per day)
• Early severe disease: plasmapheresis and IVIG 0.5 to 1 g/kg weekly are used to delay transfusions; nipocalimab (FcRn blocker) is under investigation
• Corticosteroids for lung maturity if delivery is likely
• Delivery at 37 to 38 weeks, or at 32 to 35 weeks for severe disease, in a tertiary centre

Neonatal care. Intensive phototherapy guided by bilirubin thresholds, IVIG 0.5 to 1 g/kg for infants at risk of exchange transfusion, exchange transfusion for severe or rapidly rising hyperbilirubinaemia, top up transfusions for late anaemia, folate and iron monitoring, and neurodevelopmental and hearing follow up.