Haemolytic disease of the newborn

Pregnant mothers produce IgG red cell antibodies, which can cross the placenta and destroy the baby’s red cells, causing haemolytic disease of the newborn (HDN).

HDN has devastating effects to the fetus and newborn, such as severe anaemia or neurological damage; thus, requires effective care and specialist skills.

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 (fetomaternal haemorrhage) during pregnancy or delivery. They may also result from a previous red cell transfusion.

Antibody to the RhD 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.

In the most severe cases of HDN, the fetus may die in utero or be born with severe anaemia that requires replacement of red cells by exchange transfusion.

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.(1)

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 require the skills of a specialist team.

Although ABO incompatibility between mother and fetus is common, severe HDN due to IgG anti-A and anti-B antibodies is very rare.

Routine antenatal screening

The ABO and RhD group of all pregnant women should be determined when they first attend for antenatal care.

The mother's blood should also be tested for the presence of IgG red cell antibodies, as these may also cause HDN.

Routine antenatal screening should be performed in accordance with the ANZSBT Guidelines for Transfusion and Immunohaematology Laboratory Practice.(2)  

Routine RhD Prophylaxis Guidelines

Routine Prophylaxis for All RhD negative Pregnant Women (Primigravida/Multigravida)*

625 IU  RhD Immunoglobulin-VF Solution for intramuscular injection

625 IU  RhD Immunoglobulin-VF Solution for intramuscular injection

Note: *Routine prophylaxis is recommended best practice; the doses given at 28 and 34 weeks are in ADDITION to any doses given following sensitising events.(3)


Recommendations for RhD immunoglobulin following a sensitising event:

Administration of RhD immunoglobulin to RhD negative women is important after sensitising events and following delivery of an RhD positive baby. This reduces the incidence of devastating effects for the fetus and the newborn.

The Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) recommends that all RhD negative women who have not actively formed their own anti-D should be offered RhD Immunoglobulin in the following clinical situations (3):

  • Chorionic Villus Sampling;
  • Miscarriage;
  • Termination of pregnancy (either medical or surgical); and
  • Ectopic pregnancy.

Note: There is insufficient evidence to suggest that a threatened miscarriage before 12 weeks gestation necessitates anti-D.

  • Obstetric haemorrhage;
  • Amniocentesis, cordocentesis;
  • External cephalic version of breech presentation, whether successful or not; and
  • Abdominal trauma, or any other suspected intra-uterine bleeding or sensitising event.
  • Delivery of an RhD positive baby.


  • RhD immunoglobulin should be administered as soon as possible after the sensitising event or following delivery, but always within 72 hours for successful prophylaxis.

  • If RhD immunoglobulin has not been administered within 72 hours, a dose offered within 10 days may provide protection.

  • There is some evidence that the intramuscular administration of Rh(D) Immunoglobulin-VF in patients with a high body mass index (BMI) > 30 is associated with an increased risk of lack of effectiveness. Therefore in these patients, it is recommended that the clearance of fetal cells and the presence of circulating anti-D is confirmed following administration of RhD immunoglobulin.

Dosage of RhD Immunoglobulin for Each Sensitising Event or At Delivery*

(Single pregnancy)
250 IU RhD Immunoglobulin-VF Solution for intramuscular injection
(Multiple pregnancy)
625 IU RhD Immunoglobulin-VF Solution for intramuscular injection

625 IU RhD Immunoglobulin-VF Solution for intramuscular injection

625 IU RhD Immunoglobulin-VF Solution for intramuscular injection; more than one dose may be required depending on magnitude of feto-maternal haemorrhage (FMH)

Notes: *The batch number of every vial of RhD immunoglobulin administered must be recorded in the patient's medical history and in accordance with other legal statutory requirements; **In some circumstances, administration of an intravenous preparation may be warranted. A quantity of intravenous RhD immunoglobulin will be available for this purpose. Contact Lifeblood for more information.
  • To avoid unnecessary use, RhD immunoglobulin should not be given to women with pre-existing anti-D antibodies, except where the pre-existing anti-D is due to the antenatal administration of RhD immunoglobulin (and not alloimmunisation to RhD).
  • Studies have shown that RhD immunoglobulin 100 IU is sufficient to protect against a feto-maternal haemorrhage (FMH) of 1.0 mL of fetal red cells (2.0 mL whole blood).
    • For example, RhD immunoglobulin 625 IU is sufficient to protect against a FMH of 6 mL of fetal red cells (12 mL of whole blood).
  • Quantify the magnitude of the FMH following a sensitising event (including delivery) to ensure an adequate dose of RhD immunoglobulin is offered, as more than one dose may be required.
  • Tests to assess the volume of FMH include, but are not limited to, the Kleihauer-Betke test and flow cytometry.
  • The majority of fetal bleeds are less than 5 mL of red blood cells.
    • FMH is less than 0.05 mL in about 50% of cases
    • FMH is greater than 0.5 mL in about 5% of cases
    • FMH is greater than 1 mL in about 3% of cases
    • FMH is 30 mL or greater in up to 0.6% of cases
  • A quantity of intravenous RhD immunoglobulin (Rhophylac) will be available in some circumstances where use of an intravenous RhD immunoglobulin preparation is warranted. Contact Lifeblood for more information.
  • Approximately 15% of pregnant Caucasian women will be RhD negative, and their babies [if RhD positive] may be at risk of developing Haemolytic Disease of the Newborn (HDN) due to RhD incompatibility.
  • Antibody formation occurs during pregnancy in about 1%–1.5% of RhD negative women carrying a RhD positive infant, despite use of postnatal prophylaxis.
    • The rate of antibody formation can be reduced to 0.2% or less by the administration of RhD immunoglobulin during pregnancy, at 28 weeks and 34 weeks (antenatal prophylaxis), as well as after delivery.

Management of HDN (4)

Specialist fetal medicine 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 fetus.

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 fetus may include intrauterine transfusion, early delivery, phototherapy and exchange transfusion.

  1. Vaughan JI, et al. Inhibition of erythroid progenitor cells by anti-Kell antibodies in fetal alloimmune anemia. N Engl J Medicine 1998;338:798–803.
  2. Australian & New Zealand Society of Blood Transfusion. Guidelines for Transfusion and Immunohaematology Laboratory Practice. Australia, 2016.
  3. Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG). Guidelines for the use of Rh(D) Immunoglobulin (Anti-D) in obstetrics in Australia. 2015.
  4. Royal College of Obstetricians and Gynaecologists (RCOG).  The management of women with red cell antibodies during pregnancy.  Green-top guideline No. 65 RCOG May 2014 (referred to by RANZCOG at https://www.ranzcog.edu.au/Statements-Guidelines)