Overview
Haemolytic disease of the foetus and newborn (HDFN) describes an alloimmune disorder where maternal antibodies cross the placenta and attack foetal or newborn red blood cells. This can lead to haemolytic anaemia, hydrops fetalis in the foetus, and hyperbilirubinaemia and kernicterus in the newborn.
HDFN occurs due to:
- Rhesus incompatibility – see pathophysiology below
- ABO incompatibility
HDFN is not to be confused with haemorrhagic disease of the newborn (vitamin K deficiency bleeding).
Rhesus and ABO Incompatibility
The rhesus blood group system
Alongside the ABO blood group, there are also rhesus antigens on the surface of red blood cells, resulting in the rhesus blood group system. There are many different types of rhesus antigens, however, the most relevant one is the rhesus-D antigen (Rh(D)). Both ABO and rhesus antigens are most likely to be involved in transfusion reactions.
Pathophysiology of HDFN
When the body is exposed to a foreign antigen, antibodies are made. Foetal-maternal haemorrhage (FMH) describes the entry of foetal blood cells into the maternal circulation, which can occur due to childbirth, placental injuries, abortion, ectopic pregnancies, or medical procedures that breach the uterus (e.g. caesarean section).
If the foetal red blood cells have ABO or Rh(D) antigens and the maternal red blood cells do not, sensitisation occurs (IgG antibodies are made). The sensitisation event does not cause problems during the first pregnancy, but in subsequent pregnancies, these IgG antibodies cross the placenta and attach to the red blood cells of the foetus resulting in haemolysis. The only antibody that can cross the placenta is IgG antibodies.
A very small amount (<0.1 mL) of FMH needs to occur for sensitisation to happen and is often unnoticed. Once sensitisation has occurred, it is irreversible, therefore, screening and prevention measures using anti-D prophylaxis have been put in place to reduce the risk of sensitisation and HDFN.
Types
As a result, HDN can be classified based on the antigens involved:
- ABO haemolytic disease of the newborn – due to anti-A and/or anti-B antibodies
- Rhesus D haemolytic disease of the newborn (Rh disease) – due to anti-D antibodies
Epidemiology
- Around 15% of people are Rh(D) negative
- Screening and anti-D prophylaxis have reduced the frequency of HDFN to around 1 in 21,000 births
Risk Factors
- Any cause of FMH:
- Childbirth
- Placental injuries
- Abortion
- Ectopic pregnancies
- Medical procedures that breach the uterus (e.g. caesarean section)
- Failed prophylaxis
- Alloimmunisation
Presentation
Overview
All pregnant people are offered antenatal screening for rhesus status and prophylaxis is given to rhesus-negative people. Features of HDFN include:
- Jaundice within the first 24 hours – jaundice within the first 24 hours of life is always pathological
- Pallor – due to haemolytic anaemia
- Kernicterus
- Hepatosplenomegaly
- Petechiae
If haemolysis occurs antenatally, an ultrasound scan may show features of hydrops fetalis (such as polyhydramnios and oedema in at least 2 fluid compartments).
Investigations
Maternal investigations
- Indirect Coombs’ test:
- Performed in all Rh(D)-negative mothers
- If positive, antibodies against Rh(D)-positive blood are present
- Kleihauer test:
- Measures the amount of foetal blood in the maternal circulation
- Involves adding acid to a maternal blood sample. Foetal blood is more resistant to acid, therefore foetal haemoglobin persists while maternal haemoglobin is destroyed.
Neonatal/foetal investigations
- Full blood count (FBC):
- Shows low haemoglobin due to the destruction of red blood cells
- Shows increased reticulocyte count as the bone marrow tries to compensate by making new, immature red blood cells
- Foetal biochemistry tests including bilirubin:
- Bilirubin is elevated
- Indirect Coomb’s test:
- If positive, antibodies against Rh(D)-positive blood are present
- Blood group:
- Identifies the neonate’s blood group
- Foetal blood sampling:
- May be performed if Doppler scans show features suggesting HDFN (e.g. hydrops fetalis)
Management
Prevention and prophylaxis
Preventing sensitisation is essential and this involves giving anti-D immunoglobulin injections to Rh(D)-negative women. Sensitisation cannot be reversed, therefore, this step is essential.
The anti-D immunoglobulin binds to Rh(D) on foetal blood cells that are in the maternal circulation, leading to their destruction. This prevents the maternal immune system from becoming sensitised to them.
The key points in the NICE guidelines are:
- Test anti-D antibodies in all Rh(D)-negative people at booking
- Give the anti-D immunoglobulin routinely to non-sensitised Rh(D)-negative people:
- At 28 and 34 weeks – either both doses or single doses depending on local factors
- Give anti-D immunoglobulin as soon as possible within 72 hours if any of the following apply, as these may lead to FMH:
- Delivery of an Rh(D) positive infant, even if stillborn
- Any termination of pregnancy
- Any miscarriage >12 weeks
- Any ectopic pregnancy managed surgically
- Procedures including amniocentesis, chorionic villous sampling, foetal blood sampling
- External cephalic version
- Antepartum haemorrhage
- Abdominal trauma
Acute haemolysis in utero
Treatment is performed by a specialist.
- Group O-negative packed cells that are cross-matched with maternal blood may be infused via the umbilical vein at around 16-18 weeks
- Doppler scan monitoring is continued and further transfusions are given. Early delivery may need to be considered.
Acute haemolysis after delivery
The birth should be attended by a specialist. Treatment at birth may require:
- Neonatal resuscitation and transfusion of O-negative blood
- Supportive measures including stabilising temperature, exchange transfusion, phototherapy, and further transfusions may be necessary
Prognosis
- If untreated, HDFN can lead to stillbirth and complications of kernicterus (e.g. learning difficulties, hearing loss, and vision loss), however, treatment is generally effective and these problems are uncommon
- Overall survival is around 90%, however, if hydrops fetalis occurs and does not reverse, survival rates drop to 39%.
