Haemolytic disease of the newborn (HDN), or haemolytic disease of the fetus and newborn (HDFN) used to be a major cause of fetal loss and neonatal death. It is an alloimmune condition, meaning that an individual develops immunity against antigens of another individual.
In HDN, the mother produces IgG-type antibodies against red cell antigens on fetal red blood cells (RBC); these antibodies pass through the placenta into the fetal circulation. Once in the fetal circulation, the offending antibodies attach to corresponding antigens on fetal RBC, marking them to be destroyed by haemolysis. The rate of haemolysis determines whether the clinical picture of HDN is mild, moderate or severe.
Mild cases may have only mild anaemia and jaundice at birth. In severe cases, the bilirubin level may rise dramatically within 24 hours of birth, and enter the brain to cause kernicterus, a potentially fatal condition.
The most important cause of HDN is antibody to the rhesus D antigen (RhD), which will be the focus of this article.
Sensitisation to an antigen occurs when the immune system encounters that antigen for the first time and mounts an immune response. As maternal and fetal circulations are separate, for HDN to occur, fetal RhD-positive cells must enter the RhD-negative maternal circulation, allowing her immune system to see the foreign red cell antigen and form an antibody against it.
Only a small amount of fetal blood need enter the mother's circulation for sensitisation to occur. HDN does not usually affect the first pregnancy unless there is a sensitising event or the mother already has RhD antibodies.
Potential sensitising events are listed in the box below. In subsequent pregnancies, pre-sensitised RhD-negative mothers, carrying RhD-positive babies, boost antibody production progressively, putting later pregnancies at increasing risk.
In all expectant mothers, blood type (ABO and Rh groups) should be determined and serum screened for atypical antibodies (that will recognise antigens on fetal RBC), in the first trimester and again at 28 weeks' gestation to identify at-risk pregnancies.
In RhD-negative women with a negative antibody screen, the risk of sensitisation is reduced by administering anti-RhD immunoglobulin when sensitising events occur and routinely in the third trimester (routine antenatal anti-D prophylaxis); this should be offered to all RhD-negative women, as per NICE recommendations.
Anti-D immunoglobulin destroys the RhD-positive RBC and prevents active immunisation, thus preventing production of RhD antibodies.
Following delivery, a repeat maternal group and antibody screen is performed and the baby's blood group determined. If the baby is grouped RhD-positive then the mother should receive further anti-D immunoglobulin within 72 hours and a Kleihauer test should be performed on maternal blood to look for evidence of fetomaternal haemorrhage (FMH) occurring at birth.
Further anti-D immunoglobulin may be required depending on the amount of FMH detected in the Kleihauer, as set out in guidelines for the estimation of fetomaternal haemorrhage (see resources). The baby should also be monitored and treated for anaemia and jaundice.
In addition, in the UK, RhD-negative girls and women of childbearing age should never receive RhD-positive cellular blood products if they require transfusion, to prevent sensitisation occurring.
This use of anti-D immunoglobulin has led to a dramatic decrease in the incidence of HDN, particularly severe cases, and the mortality rate has decreased from 1.2 to 0.02 per 1,000 births.
Management of sensitised mothers
Where the presence of maternal anti-D is confirmed in a pregnancy, the next step is to determine whether fetal RBCs are a target. Determining the paternal rhesus genotype will answer this question, if the father is homozygous for the D allele.
If the father is heterozygous (D/d) then fetal genotyping is required. There are two methods of obtaining fetal cells. The non-invasive method for RhD analyses fetal DNA that is present in the plasma of pregnant women. The second method, for RhD and also other antigens, analyses fetal DNA in amniotic fluid or chorionic villus biopsy.
If the fetus is RhD-positive, the pregnancy is monitored for signs of HDN by regular fetal ultrasound scans and measurement of anti-D titres in the mother's serum. Rising anti-D levels indicates active haemolysis.
If a fetal blood test confirms anaemia, an in utero blood transfusion may be required. In the neonatal period anaemia and hyperbilirubinaemia may require blood transfusions and phototherapy or exchange transfusion.
The RhD antibody remains the most frequent cause of severe HDN but other alloimmune antibodies of the Kell, Duffy, Kidd and MNS systems can cause HDN.
Routine antibody screening of all mothers will identify other antibodies of clinical significance to the fetus. The antibody should be quantified and follow-up tests performed as recommended in British Committee for Standards in Haematology (BCSH) guidelines for antibody testing in pregnancy.
- Dr Bonney is a consultant paediatric heamatologist, Royal Manchester Children's Hospital