Rhesus disease, also known as haemolytic disease of the fetus and newborn (HDFN) is haemolysis occurring in the fetal/neonatal periods, usually as a result of rhesus incompatibility.
🏃♀️ Physiology
Before we look at rhesus incompatibility, let’s remind ourselves on the rhesus blood grouping system:
The system is based on the presence of rhesus (Rh) antigens. There are many different types of rhesus antigens (around 50) but only 5 are clinically important:
- D antigen
- E antigen
- e antigen
- C antigen
- c antigen
Of these 5, the rhesus D antigen (RhD) is the most immunogenicity (i.e. most likely to elicit an immune response).
If an individual has the RhD antigen present on their red blood cell (RBC) surface then they are deemed Rh positive (Rh+) and if it is absent then they are Rh negative (Rh-). The patient’s rhesus status will be indicated with a “+” or “-“ after their ABO blood grouping (e.g. B+ or O-).
Pathophysiology
Let’s look at the primary and secondary immune responses that occur when a Rh- patient is exposed to rhesus factor:
- Primary immune response
An individual who is Rh- and is exposed to rhesus factor (the rhesus antigen) undergoes sensitisation and their immune system will begin to produce IgM antibodies against the rhesus factor. This is the primary immune response. With the primary immune response only a small amount of haemolysis occurs.
- Secondary immune response
If the same individual is exposed to rhesus factor again, a large amount of high-affinity IgG antibodies are produced which attack the Rh+ positive RBCs → major haemolysis.
Sensitisation may occur in Rh- pregnant mothers who are carrying a Rh+ fetus. Sensitisation primarily occurs during delivery of the fetus.
It may also occur in the following instances:
- Miscarriage
- Ectopic pregnancy
- Feto-maternal haemorrhage
- Placental abruption
- Abortion
- Blood transfusions
- Abdominal injury
- Diagnostic investigations - such as amniocentesis and chorionic villus sampling.
Let’s look at a scenario involving baby A and baby B:
Mom is Rh- while dad is Rh+. The rhesus factor has a dominant pattern of inheritance, therefore baby A will most likely be Rh+. During delivery of baby A, mom becomes sensitised to rhesus factors and develops antibodies against it. However, this is a response primarily by IgM. IgM is a large pentameric structure and is unable to pass through the placenta and therefore baby A does not have much destruction of the fetal RBCs.
A few years later mom becomes pregnant again (by the same father) and baby B is also Rh+. This time, however, IgG has already been produced after sensitisation from baby A. IgG is able to pass through the placenta and enter fetal circulation where it destroys the fetal RBCs. This occurs faster than the fetus can produce new RBCs. This is known as haemolytic disease of the fetus (erythroblastosis fetalis) or haemolytic disease of the newborn (erythroblastosis neonatorum). It most commonly occurs with RhD but can occur with other rhesus antigens too.
😷 Presentation
- Neonatal jaundice - due to unconjugated hyperbilirubinaemia secondary to RBC haemolysis
- Fetal anaemia - because of excessive haemolysis
- Kernicterus (bilirubin-induced encephalopathy) - if kernicterus persists, the surviving infant will mots likely have choreoathetoid cerebral palsy.
- Hepatomegaly & splenomegaly - as the liver and spleen are haematopeitic sites that increase RBC production to try to fix the anaemia.
- Immune hydrops fetalis - this occurs in severe cases. The severe anaemia drives the heart to pump more in order to try and deliver more blood to tissues. Over time, the compensatory mechanisms become insufficient to meet the body's oxygen demands. The heart may struggle to maintain an adequate cardiac output, leading to a state of heart failure. This then leads to accumulation of oedema during intrauterine growth → fetal death.
🔍 Investigations
Screening is offered to all mothers at the first antenatal visit. This is done via a rhesus factor blood test to determine of she is Rh+ or Rh-.
If the mother is Rh-, we need to conduct further investigations:
- The father should also go for the rhesus factor blood test.
- If the father is unavailable for testing or if he was tested and he has Rh+ blood, we need to do the following:
- Cell-free fetal nucleic acid testing can be done to determine whether the fetus has Rh+ blood. For this test, doctors test small fragments of the fetus's DNA which are present in the pregnant woman's blood in tiny amounts (usually after 10-11 weeks).
- Indirect Coombs test (indirect antiglobulin test) is done periodically throughout the pregnancy, to check if she has anti-D antibodies in her plasma.
- If anti-D antibodies are present in the mother’s blood during pregnancy:
- Doppler ultrasound - done periodically to assess if enough blood is passing to the fetal brain as the fetus is at risk of haemolytic disease of the fetus. If not, there may be anaemia (meaning that haemolysis has taken place).
- After baby is born, blood from the umbilical cord is taken for:
- FBC
- Blood grouping
- Direct Coombs test (direct antiglobulin test) - is done to check for the presence of anti-D antibodies in the baby's circulation, which would indicate haemolytic disease of the newborn.
- During pregnancy, if we suspect that fetal blood has passed into the maternal circulation (fetomaternal haemorrhage), we can do:
- Kleihauer-Betke test - this test involves adding an acid to a sample of maternal blood. Maternal haemoglobin is soluble in the acid and will appear pale (ghost-like). However, if there fetal RBCs present they will be bright and saturated as they are not soluble in the acid. The more severe the haemorrhage, the more fetal RBCs will be present. A positive test suggests that sensitisation is likely to have occurred.
Their are 2 types of Coombs test (antiglobulin test):
- Direct Coombs test/direct antiglobulin test (DAT) - this is used to detect if antibodies or complement system factors have already attached to the surface antigens in-vivo (in the baby). It is used clinically when there is suspected HDN. A positive Coombs test indicates that haemolysis is occurring. This mechanism could be autoimmunity, alloimmunity or a drug-induced immune-mediated mechanism.
- Indirect Coombs test/indirect antiglobulin test (IAT) - this is used to detect in-vitro antibody-antigen reactions. It is used to detect the presence of antibodies in In antenatal care, the IAT is used to screen pregnant women for antibodies that may cause haemolytic disease of the newborn.
Antiglobulin testing can be either direct antiglobulin testing (DAT) or indirect antiglobulin testing (IAT). The principle of DAT is to detect the presence of antibodies attached directly to the RBCs, which takes place by washing a collected blood sample in saline to isolate the patient’s RBCs. IAT, by contrast, is used to detect unbound antibodies (in a recipient) to foreign RBCs with known antigenicity. In DAT and IAT, the presence of agglutination indicates a positive result.
🧰 Management
- Prophylactic anti-D immunoglobulin - given to non-sensitised Rh- mothers. It works by rapidly coating any Rh+ fetal RBCs that have entered the mother’s blood during pregnancy. This prevents sensitisation and the production of antibodies, thus preventing rhesus haemolytic disease. It is offered if it's thought there's a risk that RhD antigens from the baby have entered maternal blood – for example, if there’s been any antepartum haemorrhage, invasive testing (such as amniocentesis) or if the mother has sustained an abdominal injury.
- Termination of pregnancy
- Ectopic pregnancy (If surgically managed)
- External cephalic version
- Antepartum haemorrhage
- Amniocentesis, chorionic villus sampling or foetal blood sampling
- Abdominal trauma
- Vaginal bleeding during pregnancy
- Routine antenatal anti-D prophylaxis - it is recommended for all pregnant Rh- women who haven't been sensitised to the RhD antigen. This is either a 2-dose or 1-dose treatment:
- 2-dose treatment - 1st injection is given during week 28 of gestation and the other is given during week 34.
- 1-dose treatment - injection given between week 28-30 of pregnancy.
Anti-D may also be given in the following circumstances:
After birth though, an additional dose is given within 72 hours of delivery to prevent sensitisation.
- If anaemia is diagnosed in the fetus → fetal blood transfusion may be done. These may be continued until the fetus has matured and can be safely delivered. Blood transfusions can also occur after delivery if needed.
- Corticosteroids - may be given prior to delivery to ensure fetal lung maturation and to reduce the chances of respiratory problems if premature delivery has to be induced.
- Phototherapy - to resolve any jaundice by converting unconjugated bilirubin to its conjugated form which can be excreted through urine and faeces.