Haemolytic Disease of the Newborn (HDN)
IgG red cell antibodies produced by the mother can cross the placenta and destroy the baby’s red cells, causing haemolytic disease of the newborn.
In the most severe cases of HDN the foetus may die in utero or be born with severe anaemia that requires replacement of red cells by exchange transfusion. There may also be severe neurological damage after birth as a result of a high bilirubin level (kernicterus). Effective care during the affected pregnancy and of the newborn requires the skills of a specialist team.
The antibodies that cause HDN are directed against antigens on the baby's red cells that are inherited from the father and are absent in the mother. The mother may develop these antibodies if fetal red blood cells cross the placenta (feto-maternal haemorrhage) during pregnancy or delivery. They may also result from a previous red cell transfusion.
Antibody to the Rh(D) antigen is the most frequent cause of HDN. IgG antibodies against other Rh antigens including c, e, C, E and blood group antigens including Fya and K occur in about 0.5% of pregnancies.
It is interesting to note that anti-Kell (anti-K) antibody produces anaemia in the neonate by suppressing marrow erythroid activity, rather than by increased haemolysis of fetal red cells(23). Although ABO incompatibility between mother and foetus is common, severe HDN due to IgG anti-A and anti-B antibodies is very rare.
Routine antenatal screening
The ABO and Rh(D) group of all pregnant women should be determined when they first attend for antenatal care. The mother's blood should also be tested for atypical IgG red cell antibodies, as these may also cause HDN. Routine antenatal screening should be performed in accordance with the ANZSBT guidelines(24) and the Royal Australian and New Zealand College of Obstetrics and Gynaecology (RANZCOG) guidelines(25).
Management of HDN
Specialist teams should care for pregnancies that are potentially affected by HDN with facilities for early diagnosis, intrauterine transfusion and support of high dependency neonates.
The referral should be made before 20 weeks in those women who have had a previously severely affected baby, unless there is a new partner who is negative for the relevant antigen.
If antibodies are detected, the levels should be monitored frequently throughout the pregnancy in case they increase in titre. Rising levels are likely to be indicative of HDN developing in the foetus. Amniocentesis and the level of bilirubin in the amniotic fluid will give a clearer guide to the severity of the disease. Management of an affected foetus may include intrauterine transfusion, early delivery, phototherapy and exchange transfusion.
Rh(D) HDN Prophylaxis
One of the most successful medical advances has been the prevention of HDN by the discovery, introduction and utilisation of Rh(D) immunoglobulin.
In 1968, Australia became the first country in the world to be self sufficient in production of Rh(D) immunoglobulin. As a result, we have seen a dramatic decline in mortality rates among unborn and newborn Rh(D) positive children of Rh(D) negative mothers.
However, at the same time, the anti-D antibody levels among naturally immunised donors have declined, and in recent years there has been an insufficient Rh(D) immunoglobulin supply to satisfy Australian requirements.
Recruitment of new donors for immunisation, and a booster program, have been initiated by the ARCBS to increase the production of Rh(D) immunoglobulin. However, there will be a delay before Australian anti-D production meets national self-sufficiency.
To deal with the limited supply, the National Health and Medical Research Council (NHMRC) in 1999 issued Guidelines on the Prophylactic Use of Rh(D) Immunoglobulin (Anti D) in Obstetrics(26). These guidelines stated that: 'Universal prophylaxis with Rh(D) immunoglobulin to Rh(D) negative women with no preformed anti-D antibodies at 28 and 34 weeks gestation is generally regarded as best practice. However, due to supply constraints, routine antenatal prophylaxis should not be administered until further notice'.
In November 2002, the Commonwealth Department of Health announced changes in the availability of Rh(D) immunoglobulin and its appropriate use. This followed the introduction of the 250 IU dose of Rh(D) immunoglobulin for first trimester use, in addition to the 625 IU dose. The importation of WinRho SDF™, a 600 IU Rh(D) immunoglobulin dose from Canada was also arranged.
The additional supply of product allowed for the introduction of antenatal prophylaxis for women who are Rh(D) negative having their first baby reaching at least 28 weeks gestation. This was the first stage of a three stage process towards universal antenatal prophylaxis using solely domestic Rh(D) immunoglobulin. To ensure the most efficient use of these resources, the integrity of supply and taking into account the national focus for increased domestic production, it was essential that the three products be used as indicated below unless alternative supply arrangements are made:
First trimester indications (<12 weeks – ARCBS/CSL Ltd Rh(D) immunoglobulin 250IU
Second and third trimester indications – ARCBS/CSL Ltd Rh(D) immunoglobulin 625IU
Antenatal prophylaxis at 28 and 34 weeks in women who are Rh(D) negative having their first baby reaching at least 28 weeks gestation – ARCBS/CSL Ltd Rh(D) immunoglobulin 625 IU
Postnatal prophylaxis - ARCBS/CSL Ltd Rh(D) immunoglobulin 625 IU.
Limited amounts of WinRho SDF™ 600 IU intravenously administered product may be indicated.are held by ARCBS and can be provided in case of large volume FMH where an intravenously administered product may be indicated. It should be noted that WinRho SDF™ 600 IU is a freeze-dried product and must be reconstituted with the accompanying vial of 0.9% Sodium Chloride injection according to the manufacturer’s instructions prior to use.
Feto-maternal or Neonatal Alloimmune Thrombocytopenia (FMAIT or NAIT)
Feto-maternal or neonatal (FMAIT or NAIT) is the platelet equivalent of haemolytic disease of the newborn and occurs with a frequency of 1 in 2000 to 3000 live births in Caucasians. This is a rare, potentially serious condition and specialist advice is required. NAIT is caused by maternal IgG alloantibodies against a fetal platelet specific alloantigen in the Human Platelet Antigen (HPA) system.
Approximately 75% of cases in a Caucasian population are caused by anti-HPA-1a and 20% by anti-HPA-5a. In oriental populations, anti-HPA-4b is more common than anti-HPA-1a. There may or may not be a history of thrombocytopenia in a previous infant. NAIT often (>60%) occurs during the first pregnancy. Affected infants may be severely thrombocytopenic and at high risk, especially for intracranial bleeding.
Management of the neonate
The condition is self-limiting, usually resolving within two weeks, but occasionally persisting for up to six weeks.
Rapid treatment is required when there is bleeding or a platelet count <30 x 10^9 /L. Several transfusions of compatible platelets may be needed. The treatment of choice is to give platelets lacking the relevant HPA antigen. In the absence of suitable donor platelets, the mother's platelets may be used. They must be plasma-reduced (to remove maternal antibody) and irradiated. Surprisingly, however, provision of untyped (presumably HPA-1a-positive) platelets may be clinically effective in many cases of haemorrhage due to NAIT associated with anti-HPA-1a alloantibodies, and are preferable to delaying any transfusion during attempts to identify HPA-1a-negative donors. Suggest give the reference here: Kiefel V et al: Blood. 2006 May 1;107(9):3761-3.
High dose intravenous immunoglobulin (IVIG, 1-2 g/kg body weight) given to the neonate is effective in about 75% of cases. Additional doses may be required 2-4 weeks after the initial response due to recurrence of thrombocytopenia.
Management of subsequent pregnancies
Subsequent pregnancies should be carefully monitored. Intracranial bleeding in utero can occur, and most obstetricians will monitor the fetal platelet count and administer intravenous immunoglobulin IVIG to the mother, and intrauterine platelet transfusions should the platelet count be very low.
When possible, compatible platelets should be maintained on hand at the expected delivery time.
Maternal serum is the test sample usually required for the reference laboratory investigation of possible NAIT. Usually the mother’s serum is tested against both panel cells from known HPA-typed donors and against platelets from the father. Reactivity with only the father’s platelets may indicate the presence of antibody directed to a low-incidence antigen.
Antibodies to HLA antigens have also been reported to cause NAIT although the extent of their involvement is controversial.