B16. The mechanism and the prevention of Rh-isoimmunisation, erythroblastosis fetalis

From greek.doctor

Haemolytic disease of the newborn (previously called erythroblastosis foetalis) is a condition where haemolysis occurs due to incompatibility between the mother’s and foetus’ RBC antigens. In most cases, we talk about rhesus (Rh) incompatibility. ABO incompatibility can also occur but causes only mild disease. Kell incompatibility may also occur.

Haemolysis may cause neonatal anaemia or jaundice. In the most severe case (and only in case of Rh incompatibility, not ABO), hydrops foetalis can develop.

Nowadays, Rh incompatibility is routinely prevented with anti-D prophylaxis.

Etiology

  • Rhesus (Rh) incompatibility – due to Rh negative mother with Rh positive foetus
    • Nowadays rare due to routine anti-D prophylaxis
  • Kell blood group system incompatibility
    • Second most common cause of severe haemolysis after Rhesus (but still rare)
  • ABO incompatibility – due to e.g., blood type O mother with blood type A or B foetus
    • Occurs in 20% of pregnancies but is rarely symptomatic

Alloimmunisation may occur due to:

  • Labour
  • Miscarriage
  • Abortion
  • Abdominal trauma
  • External cephalic version
  • Invasive procedures like amniocentesis, chorionic villus biopsy

Pathomechanism

Maternal alloimmunisation must occur for haemolytic disease of the newborn to develop. Alloimmunisation (or sensitisation) is a process where the mother produces antibodies against antigens on foetal RBCs after having come into contact with foetal blood (as little as 10 µL is enough). These antibodies are called alloantibodies. In most cases, these antigens are D antigens, the antigens present on Rh positive RBCs, in which case RhD alloimmunisation occurs. Alloimmunisation may occur during events described above. Most cases of alloimmunisation occur during the third trimester.

The term “isoimmunisation” is sometimes used instead of “alloimmunisation”, but the latter is more correct. The prefix “iso-” means “same” or “equal”, while the prefix “allo-“ means “different” or “other”, which more closely explains the pathomechanism, as the mother is immunised against a different individual.

If the mother has become alloimmunised, anti-foetal-RBC antibodies can later cross the placenta and bind to foetal RBCs, causing haemolysis. If alloimmunisation occurred during birth, then the newborn is obviously outside of harm from placenta-crossed antibodies. However, a future Rh-positive pregnancy may be affected. As you may recall from immunology, the initial antibody formed is IgM, which doesn’t cross the placenta. Seroconversion to IgG, which can cross the placenta, occurs later.

However, if alloimmunisation occurs during pregnancy, such as due to amniocentesis or chorionic biopsy, haemolysis may rarely occur in the same pregnancy.

Maternal alloimmunisation does not occur if the maternal RBCs express the same antigens as the foetal RBCs. A foeto-maternal blood group incompatibility must be present.

Clinical features

The worst-case scenario is the development of hydrops foetalis in the foetus. This is a condition characterised by generalised oedema and accumulation of fluid in serious cavities, including pleural effusion, pericardial effusion, and ascites.

Haemolytic disease of the newborn can cause problems postnatally as well. There’s also a risk for neonatal anaemia and jaundice.

Diagnosis and evaluation

Foetal anaemia can be diagnosed based on doppler analysis of the middle cerebral artery. An increased blood flow compared to normal indicates anaemia. Ultrasound can diagnose foetal hydrops.

Postnatally, a Coombs test can be used to diagnose Rh and ABO incompatibility. A positive Coombs indicates Rh incompatibility, while a weakly positive or negative Coombs indicates ABO incompatibility.

Prevention

Blood typing and screening of all pregnant mothers is routinely performed during prenatal care visits. This screening can determine whether the mother is already sensitised (whether alloantibodies are present in the mother’s blood). In some countries (like Norway, unsure about Hungary), a simple blood test of the mother in week 24 can determine the Rh status of the foetus (based on analysis of cell-free foetal DNA). In countries where this is not performed, the Rh status of the foetus cannot be known ahead of birth.

RhD-negative mothers with foetuses who are known to be RhD-positive (due to cffDNA test) or who may be RhD-positive (cffDNA test not performed but father is RhD-positive) should routinely receive anti-D prophylaxis in the third trimester, preferably in week 28.

Anti-D prophylaxis should also be administered ASAP in case of an event which is associated with alloimmunisation, such as abortion, amniocentesis, etc.

Anti-D prophylaxis should also be administered ASAP after delivery of an RhD-positive infant to an RhD-negative mother (even if they’ve received prophylaxis earlier).

The mechanism whereby anti-D immunoglobulins prevent RhD alloimmunisation is not well known. It’s often taught that anti-D binds to the D antigen and “masks” it from the maternal immune system, but this is likely not the reason (as most D antigen sites on foetal RBCs in the maternal circulation are not bound by passive anti-D immune globulin). Possibilities include rapid macrophage-mediated clearance of anti-D-coated RBCs and/or down-regulation of antigen-specific B cells before an immune response occurs.

The routine dose of anti-D immunoglobulin (300 µg) is adequate to protect against maternal alloimmunisation from as much as 30 mL RhD-positive foetal blood. In cases where foetomaternal bleeding is excessive, additional doses may be necessary.

If blood typing and screening reveals that the mother is already sensitised, anti-D prophylaxis serves no benefit and is not given. The foetus should be monitored regularly for evidence of haemolysis.

ABO and Kell alloimmunisation are not routinely prevented.

Treatment

If foetal anaemia is already established and severe, intrauterine transfusions can be administered to the foetus. Transfusion or phototherapy may be necessary postnatally to treat anaemia or severe jaundice, respectively.