Haemolytic disease of the fetus and newborn (HDFN)

Causes of HDFN

During the first pregnancy, if fetal red cells cross the placenta into the maternal circulation (fetomaternal haemorrhage; FMH), antibodies can develop against antigens on the fetus’ red cells that are inherited from the father but are absent on the mother’s red cells. This is because the mother’s immune system recognises the fetal red cell antigens as foreign and mounts an immune response (antibodies). 

In a subsequent pregnancy with an antigen-positive fetus, the immune system is restimulated and when the resulting IgG antibodies cross the placenta, they bind to the antigens on the fetus’ red cells, haemolysis (breakdown of the fetal red cells) occurs, and this leads to anaemia in the fetus. 

Antibody to the RhD antigen is a frequent cause of moderate to severe HDFN. IgG antibodies against other Rh antigens (particularly c and E) and other blood group antigens (including K, Fy^a, S and s) may also cause HDFN.

ABO incompatibility between the mother and fetus is common but usually only causes mild to moderate HDFN. ABO incompatibility ameliorates the effect of RhD incompatibility between mother and fetus. 

The rate of RhD 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 the birth of a RhD positive baby and for sensitising events.

RhD Antibody testing and RhD immunoglobulin use in pregnancy

Routine antenatal screening

All pregnant women

The ABO and RhD group of pregnant women should be determined, no later than 10 weeks of pregnancy when they first attend antenatal care.

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

RhD negative pregnant women

Testing of maternal blood to determine fetal RhD genotype to enable targeted antenatal RhD immunoprophylaxis, is recommended from 11 weeks of pregnancy.  However, non-invasive prenatal testing (NIPT) for fetal RhD status is not widely available in Australia. Universal RhD immunoprophylaxis should therefore be maintained until NIPT is widely accessible.

NIPT to determine the RhD status of the fetus, is provided by the Red Cell Reference Laboratory at Lifeblood and is currently publicly funded for high-risk pregnancies in the following categories: 

1. Rh D negative pregnant women who are RhD alloimmunised; 
2. Rh D negative pregnant women with obstetric indications such as severe fetomaternal haemorrhage during pregnancy, or intrauterine death; or
3. Other scenarios in non-sensitised RhD negative pregnant women with a relative contraindication to routine antenatal anti-D prophylaxis, such that the fetal RhD genotype result assists in the risk-benefit assessment to guide anti-D management decisions (for example, prior allergic reaction to the RhD immunoglobulin, or cultural/religious beliefs). 
    

In RhD negative pregnant women, RhD type and antibody screen should be retested at 28 weeks prior to administration of RhD immunoglobulin (unless NIPT for fetal Rh D has predicted that they are not carrying an RhD positive fetus).

Routine antenatal screening should be performed in accordance with the ANZSBT Guidelines for Transfusion and Immunohaematology Laboratory Practice, ANZSBT Guidance for RHD non-invasive prenatal testing (NIPT) for fetal RhD blood group prediction in pregnancy, and National Blood Authority Guideline for the prophylactic use of Rh D immunoglobulin in pregnancy care.

Routine antenatal RhD immunoglobulin prophylaxis

Routine RhD immunoglobulin prophylaxis is recommended for all RhD negative pregnant women with no preformed RhD antibodies, unless NIPT for fetal RhD has predicted they are not carrying a RhD positive fetus.

Week 28 and 34 gestation

625 IU RhD Immunoglobulin-VF Solution for intramuscular injection.

Recommendations for RhD immunoglobulin following a sensitising event

Administration of RhD immunoglobulin to RhD negative women is important after sensitising events. It should be given as soon as possible, preferably within 72 hours; a dose still may be given up to 10 days but may have lower efficacy.

The Guideline for the use of RhD immunoglobulin in pregnancy care recommends that all RhD negative women who have not developed RhD antibodies should be offered RhD Immunoglobulin in the following clinical situations:

Week 1 to week 12 (first trimester)

• Singleton or multiple pregnancy: miscarriage 
• Termination of pregnancy (after 10 weeks gestation)
• Ectopic pregnancy
• Molar pregnancy
• Chorionic villus sampling

Note: There is insufficient evidence to suggest that women with an ongoing pregnancy who have uterine bleeding before 12 weeks gestation requires routine use of RhD immunoglobulin. However, where the bleeding is repeated, heavy, or associated with abdominal pain or significant pelvic trauma, immunoprophylaxis may be considered in women with no preformed RhD antibodies.
For sensitising events in the first 12 weeks of pregnancy, where there is any uncertainty of gestational age, consider offering RhD immunoglobulin. Consider ultrasound to confirm gestational age.

Dose of RhD immunoglobulin 
250 IU RhD Immunoglobulin-VF Solution for intramuscular injection

• For new sensitising events a repeat dose of RhD immunoglobulin may be indicated. 
• For ongoing uterine bleeding alone, a repeat dose of RhD immunoglobulin may be appropriate after an interval of 6 weeks.
• For repeated sensitising events, there is no evidence to guide practice. Specialist obstetric consultation is advised regarding further administration of RhD immunoprophylaxis.

Beyond week 12 (second & third trimester)

• Genetic studies (chorionic villus sampling, amniocentesis and cordocentesis) 
• Abdominal trauma considered sufficient to cause FMH, even if FMH testing is negative 
• Each occasion of revealed or concealed antepartum haemorrhage. Where the woman suffers unexplained uterine pain the possibility of concealed antepartum haemorrhage (and the need for immunoprophylaxis) should be considered
• External cephalic version (successful or attempted) 
• Miscarriage or termination of pregnancy

Dose of RhD immunoglobulin 
625 IU RhD Immunoglobulin-VF Solution for deep intramuscular injection

• For ongoing uterine bleeding alone, a repeat dose of RhD immunoglobulin may be appropriate after an interval of 6 weeks.
• For sensitising events after 20 weeks, the magnitude of fetomaternal haemorrhage should be assessed and further doses of RhD immunoglobulin given if required. Refer to section 6.5 Dosing of RhD immunoglobulin after fetomaternal haemorrhage quantification in the Guideline for the prophylactic use of RhD immunoglobulin in pregnancy care.

Recommendations for RhD immunoglobulin following the birth of a RhD positive baby

Routine RhD immunoglobulin prophylaxis is recommended for all RhD negative women with no preformed RhD antibodies who have a baby who is predicted to be RhD positive based on NIPT for fetal RHD, or cord blood or neonatal RhD typing.

The cord blood or neonatal testing should be performed regardless of the results of NIPT for fetal RHD but need not delay administration of RhD immunoprophylaxis when the fetus has been shown to be RHD positive by NIPT testing. If the baby is RhD positive on cord or neonatal testing, administer RhD immunoglobulin even if the NIPT predicted an RhD negative baby.

RhD immunoglobulin should be administered as soon as possible following birth, ideally within 72 hours for most effective prophylaxis. 

If RhD immunoglobulin has not been administered within 72 hours, a dose should be given up to 10 days from the sensitising event but may have lower efficacy. 

If the baby is preterm, give the postnatal dose even if the birth is within 72 hours of a dose given for routine antenatal immunoprophylaxis or for a sensitising event.

Dose of RhD immunoglobulin

625 IU RhD Immunoglobulin-VF Solution for deep intramuscular injection. 

• The magnitude of fetomaternal haemorrhage should be determined after delivery and further doses of RhD immunoglobulin given if required.  A method capable of quantifying a haemorrhage of ≥ 6 mL of fetal red cells (equivalent to 12 mL of whole blood) should be used. Flow cytometry is accepted as the most accurate quantitative test for FMH and is the method of choice for quantitation if readily available.
• Refer to Section 6.5 Dosing of RhD immunoglobulin after fetomaternal haemorrhage quantification in the Guideline for the prophylactic use of RhD immunoglobulin in pregnancy care. 

In some circumstances for very large FMH intravenous RhD immunoglobulin (Rhophylac®) is recommended.  Rhophylac® (1500 IU; 2mL) is administered undiluted intravenously over 15 to 60 seconds.