Rhesus Disease

Introduction 

Rhesus disease is a condition where antibodies in a pregnant woman's blood destroy her baby's blood cells. It's also known as haemolytic disease of the foetus and newborn (HDFN).
Rhesus disease doesn't harm the mother, but it can cause the baby to become anaemic and develop a yellow discoloration of the skin and eyes referred to as jaundice.

 

Causes of rhesus disease 

Rhesus disease is caused by a specific mix of blood types between a pregnant mother and her unborn baby.
Rhesus disease can only occur in cases where all of the following happen:

• the mother has a rhesus negative (RhD negative) blood type
• the baby has a rhesus positive (RhD positive) blood type
• the mother has previously been exposed to RhD positive blood and has developed an immune response to it (known as sensitisation)

These are explained in more detail below.

Blood types
There are several different types of human blood, known as blood groups, with the four main ones being A, B, AB and O. Each of these blood groups can either be RhD positive or negative.
Whether someone is RhD positive or RhD negative is determined by the presence of the rhesus D (RhD) antigen. This is a molecule found on the surface of red blood cells.
People who have the RhD antigen are RhD positive, and those without it are RhD negative. In the UK, around 85% of the population are RhD positive.

How blood types are inherited
Your blood type depends on the genes you inherit from your parents. Whether you're RhD positive or negative depends on how many copies of the RhD antigen you've inherited. You can inherit one copy of the RhD antigen from your mother or father, a copy from both of them, or none at all.
You'll only have RhD negative blood if you don't inherit any copies of the RhD antigen from your parents.
A woman with RhD negative blood can have an RhD positive baby if her partner's blood type is RhD positive. If the father has two copies of the RhD antigen, every baby will have RhD positive blood. If the father only has one copy of the RhD antigen, there's a 50% chance of the baby being RhD positive.

Sensitisation
An RhD positive baby will only have rhesus disease if their RhD negative mother has been sensitised to RhD positive blood. Sensitisation occurs when the mother is exposed to RhD positive blood for the first time and develops an immune response to it.
During the immune response, the woman’s body recognises that the RhD positive blood cells are foreign and creates antibodies to destroy them.
In most cases, these antibodies aren't produced quickly enough to harm a baby during the mother's first pregnancy. Instead, any RhD positive babies the mother has in the future are most at risk.

How does sensitisation occur?
During pregnancy, sensitisation can happen if:

• small numbers of foetal blood cells cross into the mother’s blood
• the mother is exposed to her baby's blood during delivery
• there's been bleeding during the pregnancy
• an invasive procedure has been necessary during pregnancy – such as amniocentesis, or chorionic villus sampling (CVS)
• the mother injures her abdomen (tummy)

Sensitisation can also occur after a previous miscarriage or ectopic pregnancy, or if a RhD negative woman has received a transfusion of RhD positive blood by mistake (although this is extremely rare).

How sensitisation leads to rhesus disease
If sensitisation occurs, the next time the woman is exposed to RhD positive blood her body will produce antibodies immediately.
If she's pregnant with an RhD positive baby, the antibodies can lead to rhesus disease when they cross the placenta and start attacking the baby's red blood cells.

Symptoms of rhesus disease 

Rhesus disease only affects the baby, and the mother won't experience any symptoms.
The symptoms of rhesus disease depend on how severe it is. Around 50% of babies diagnosed with rhesus disease have mild symptoms that are easily treatable.

Signs in an unborn baby
 Anaemia because red blood cells are being destroyed faster than usual by the antibodies.
If your baby is anaemic, their blood will be thinner and flow at a faster rate. This doesn't usually cause any noticeable symptoms, but it can be detected with a type of ultrasound scan known as a Doppler ultrasound.
If the anaemia is severe, complications of rhesus disease, such as internal swelling, may be detected during scans.

Signs in a newborn baby
The two main problems caused by rhesus disease in a newborn baby are haemolytic anaemia and jaundice. In some cases, the baby may also have low muscle tone (hypotonia) and they may be lacking in energy.
If a baby has rhesus disease, they won't always have obvious symptoms when they're born. Symptoms can sometimes develop up to three months afterwards.

Haemolytic anaemia
Haemolytic anaemia occurs when red blood cells are destroyed. This happens when the antibodies from the mother’s RhD negative blood cross the placenta into the baby’s blood. The antibodies attack the baby’s RhD positive blood, destroying the red blood cells.
In the newborn baby, this may cause pale skin, increased breathing rate, poor feeding or jaundice (see below).

Jaundice
Jaundice in newborn babies turns their skin and the whites of their eyes yellow. In babies with dark skin, the yellowing will be most obvious in their eyes or on their palms and soles.
Jaundice is caused by a build-up of a chemical called bilirubin in the blood. Bilirubin is a yellow substance that's made naturally in the body when red blood cells are broken down. It's normally removed from the blood by the liver, so it can be passed out of the body in urine.
In babies with rhesus disease, the liver cannot process the high levels of bilirubin that build up as a result of the baby's red blood cells being destroyed

 

 

 

 

Diagnosing rhesus disease 

Rhesus disease is usually diagnosed during the routine screening tests you're offered during pregnancy.

Blood tests
A blood test should be carried out early on in your pregnancy to test for conditions such as anaemia, rubella, HIV and hepatitis B.
Your blood will also be tested to determine which blood group you are, and whether your blood is rhesus (RhD) positive or negative (see causes of rhesus disease for more information).
If you're RhD negative, your blood will be checked for the antibodies (known as anti-D antibodies) that destroy RhD positive red blood cells. You may have become exposed to them during pregnancy if your baby has RhD positive blood.
If no antibodies are found, your blood will be checked again at 28 weeks of pregnancy and you'll be offered an injection of a medication called anti-D immunoglobulin to reduce the risk of your baby developing rhesus disease (see preventing rhesus disease for more information).
If anti-D antibodies are detected in your blood during pregnancy, there's a risk that your unborn baby will be affected by rhesus disease. For this reason, you and your baby will be monitored more frequently than usual during your pregnancy.
In some cases, a blood test to check the father's blood type may be offered if you have RhD negative blood. This is because your baby won't be at risk of rhesus disease if both the mother and father have RhD negative blood.

Checking your baby's blood type
It's possible to determine if an unborn baby is RhD positive or RhD negative by taking a simple blood test during pregnancy.
Genetic information (DNA) from the unborn baby can be found in the mother's blood, which allows the blood group of the unborn baby to be checked without any risk. It's usually possible to get a reliable result from this test after 11-12 weeks of pregnancy, which is long before the baby is at risk from the antibodies.
If your baby is RhD negative, they're not at risk of rhesus disease and no extra monitoring or treatment will be necessary. If they're found to be RhD positive, the pregnancy will be monitored more closely so that any problems that may occur can be treated quickly.
In the future, RhD negative women who haven't developed anti-D antibodies may be offered this test routinely, to see if they're carrying an RhD positive or RhD negative baby, to avoid unnecessary treatment.

 

Monitoring during pregnancy

If your baby is at risk of developing rhesus disease, they'll be monitored by measuring the blood flow in their brain. If your baby is affected, their blood may be thinner and flow more quickly. This can be measured using a type of ultrasound scan called a Doppler ultrasound.
If a Doppler ultrasound shows your baby’s blood is flowing faster than normal, a procedure called fetal blood sampling (FBS) can be used to check whether your baby is anaemic. This procedure involves inserting a needle through your abdomen (tummy) to remove a small sample of blood from your baby. The procedure is performed under local anaesthetic, usually on an outpatient basis, so you can go home on the same day.
There's a small (usually 1-3%) chance that this procedure could cause you to lose your pregnancy, so it should only be carried out if necessary.
If your baby is found to be anaemic, they can be given a transfusion of blood through the same needle. This is known as an intrauterine transfusion (IUT) and it may require an overnight stay in hospital.
FBS and IUT are only carried out in specialist units, so you may need to be referred to a different hospital to the one where you were going to have your baby.

 

Diagnosis in a newborn baby

If you're RhD negative, blood will be taken from your baby’s umbilical cord when they're born. This is to check their blood group and see if the anti-D antibodies have been passed into their blood. This is called a Coombs test.
If you're known to have anti-D antibodies, your baby’s blood will also be tested for anaemia and jaundice.




 

Treating rhesus disease 

Treatment for rhesus disease depends on how severe the condition is. In more severe cases, treatment may need to begin before the baby is born.
Around half of all cases of rhesus disease are mild and don't usually require much treatment. However, your baby will need to be monitored regularly, in case serious problems develop.
In more severe cases, a treatment called phototherapy is usually needed and blood transfusions may help to speed up the removal of bilirubin (a substance created when red blood cells break down) from the body.
In the most serious cases, a blood transfusion may be carried out while your baby is still in the womb and a medication called intravenous immunoglobulin may be used when they're born if phototherapy isn't effective.
If necessary, the baby may be delivered early using medication to start labour (induction) or a caesarean section, so treatment can start as soon as possible. This is usually only done after about 34 weeks of pregnancy.

Phototherapy
Phototherapy is treatment with light. It involves placing the newborn baby under a halogen or fluorescent lamp with their eyes covered.
Alternatively, they may be placed on a blanket containing optical fibres through which light travels and shines onto the baby's back (fibre optic phototherapy).
The light absorbed by the skin during phototherapy lowers the bilirubin levels in the baby’s blood through a process called photo-oxidation. This means that oxygen is added to the bilirubin, which helps it to dissolve in water. This makes it easier for the baby’s liver to break down the bilirubin and remove it from the blood.
During phototherapy, fluids will usually be given into a vein (intravenous hydration) because more water is lost through your baby's skin and more urine is produced as the bilirubin is expelled.
Using phototherapy can sometimes reduce the need for a blood transfusion.

Blood transfusions
In some cases, the levels of bilirubin in the blood may be high enough to require one or more blood transfusions.
During a blood transfusion, some of your baby’s blood is removed and replaced with blood from a suitable matching donor (someone with the same blood group). A blood transfusion normally takes place through a tube inserted into a vein (intravenous cannula).
This process helps to remove some of the bilirubin in the baby’s blood and also removes the antibodies that cause rhesus disease.
It's also possible for the baby to have a transfusion of just red blood cells to top up those they already have.

Blood transfusion to an unborn baby
If your baby develops rhesus disease while still in the womb, they may need to be given a blood transfusion before birth. This is known as intrauterine foetal blood transfusion.
An intrauterine foetal blood transfusion requires specialist training and is not available in all hospitals. You may therefore be referred to a different hospital for the procedure.
A needle is usually inserted through the mother's abdomen (tummy) and into the umbilical cord, so donated blood can be injected into the baby. An ultrasound scanner is used to help guide the needle to the right place.
Local anaesthetic is used to numb the area, but you'll be awake during the procedure. A sedative may be given to keep you relaxed and your baby may also be sedated to help stop them moving during the procedure.
You may need more than one intrauterine foetal blood transfusion. Transfusions can be repeated every two to four weeks until your baby is mature enough to be delivered. They may even reduce the need for phototherapy after birth, but further blood transfusions could still be necessary.
There's a small risk of miscarriage during an intrauterine foetal blood transfusion, so it's usually only used in particularly severe cases.

Intravenous immunoglobulin
In some cases, treatment with intravenous immunoglobulin (IVIG) is used alongside phototherapy if the level of bilirubin in your baby’s blood continues to rise at an hourly rate.
The immunoglobulin is a solution of antibodies (proteins produced by the immune system to fight against disease-carrying organisms) taken from healthy donors. Intravenous means that it's injected into a vein.
Intravenous immunoglobulin helps to prevent red blood cells being destroyed, so the level of bilirubin in your baby’s blood will stop rising. It also reduces the need for a blood transfusion.
However, it does carry some small risks. It's possible that your baby may have an allergic reaction to the immunoglobulin, although it's difficult to calculate how likely this is or how severe the reaction will be.
Concerns over possible side effects, and the limited supply of intravenous immunoglobulin, mean that it's only used when the bilirubin level is rising rapidly, despite phototherapy sessions.
Intravenous immunoglobulin has also been used during pregnancy, in particularly severe cases of rhesus disease, as it can delay the need for treatment with intrauterine foetal blood transfusions.




 

Complications of rhesus disease 

Although rhesus disease is rare and most cases are successfully treated, there are some risks to both unborn and newborn babies.

Unborn babies
If rhesus disease causes severe anaemia in an unborn baby, it can lead to:

• foetal heart failure
• fluid retention and swelling (foetal hydrops)
• stillbirth 

Blood transfusions given to a baby in the womb (intrauterine transfusions [IUT]), can be used to treat anaemia in an unborn baby. However, this treatment also carries some risks of complications. It can lead to an early labour that begins before the 37th week of pregnancy and there's a 2% risk of miscarriage or stillbirth.

Newborn babies
Rhesus disease causes a build up of excessive amounts of a substance called bilirubin. Without prompt treatment, a build-up of bilirubin in the brain can lead to a neurological condition called kernicterus. This can lead to deafness, blindness, brain damage, learning difficulties or even death.
Treatment for rhesus disease is usually effective in reducing bilirubin levels in the blood, so these complications are uncommon.

Blood transfusions
The risk of developing an infection from the blood used in blood transfusions is low, because all the blood is carefully screened. The blood used will also be matched to the baby’s blood type, so the likelihood of your baby having an adverse reaction to the donated blood is also low.
However, there may be a problem with the transfusion itself. For example, the tube (catheter) used to deliver the blood can become dislodged, causing heavy bleeding (haemorrhage) or a blood clot.
Generally, the risks associated with blood transfusions are small and don't outweigh the benefits of treating a baby with anaemia




 

Preventing rhesus disease 

Rhesus disease can largely be prevented by having an injection of a medication called anti-D immunoglobulin.
This can help to avoid a process known as sensitisation, which is when a woman with RhD negative blood is exposed to RhD positive blood and develops an immune response to it.
Blood is known as RhD positive when it has a molecule called the RhD antigen on the surface of the red blood cells.

Anti-D immunoglobulin
The anti-D immunoglobulin neutralises any RhD positive antigens that may have entered the mother’s blood during pregnancy. If the antigens have been neutralised, the mother’s blood won't produce antibodies.
You'll be offered anti-D immunoglobulin if it's thought there's a risk that RhD antigens from your baby have entered your blood – for example, if you experience any bleeding, if you have an invasive procedure (such as amniocentesis) or if you experience any abdominal injury.
Anti-D immunoglobulin is also administered routinely during the third trimester of your pregnancy if your blood type is RhD negative. This is because it's likely that small amounts of blood from your baby will pass into your blood during this time.
This routine administration of anti-D immunoglobulin is called routine antenatal anti-D prophylaxis, or RAADP (prophylaxis means a step taken to prevent something from happening).

Routine antenatal anti-D prophylaxis (RAADP)
There are currently two ways you can receive RAADP:

• a one-dose treatment: where you receive an injection of immunoglobulin at some point during weeks 28 to 30 of your pregnancy
• a two-dose treatment: where you receive two injections; one during the 28th week and the other during the 34th week of your pregnancy

There doesn't seem to be any difference in the effectiveness between the one-dose or two-dose treatments. Your local clinical commissioning group (CCG) may prefer to use a one-dose treatment, because it can be more efficient in terms of resources and time.

When will RAADP be given?
RAADP is recommended for all pregnant RhD negative women who haven't been sensitised to the RhD antigen, even if you previously had an injection of anti-D immunoglobulin.
As RAADP doesn't offer lifelong protection against rhesus disease, it will be offered every time you become pregnant if you meet these criteria.
RAADP won't work if you’ve already been sensitised. In these cases, you'll be closely monitored so treatment can begin as soon as possible if problems develop.

Anti-D immunoglobulin after birth
After giving birth, a sample of your baby's blood will be taken from the umbilical cord. If you're RhD negative and your baby is RhD positive, and you haven't already been sensitised, you'll be offered an injection of anti-D immunoglobulin within 72 hours of giving birth.
The injection will destroy any RhD positive blood cells that may have crossed over into your bloodstream during the delivery. This means your blood won't have a chance to produce antibodies and will significantly decrease the risk of your next baby having rhesus disease.

 

Complications from anti-D immunoglobulin

Some women are known to develop a slight short-term allergic reaction to anti-D immunoglobulin, which can include a rash or flu-like symptoms.
Although the anti-D immunoglobulin, which is made from donor plasma, will be carefully screened, there's a very small risk that an infection could be transferred through the injection.
However, the evidence in support of RAADP shows that the benefits of preventing sensitisation far outweigh these small risks.
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