Bounty

Rhesus Disease - NHS Choices

Rhesus disease – also known as haemolytic disease of the foetus and newborn – is a condition where antibodies in a pregnant woman’s blood destroy her baby's blood cells.

Rhesus disease only happens when the mother has rhesus-negative blood (RhD negative) and the baby in her womb has rhesus-positive blood (RhD positive). The mother must have also been previously sensitised to RhD-positive blood.

Sensitisation happens when a woman with RhD-negative blood is exposed to RhD-positive blood. This could happen during a pregnancy with an RhD-positive baby, or if the woman has a blood transfusion with RhD-positive blood. 

The woman’s body responds to the RhD-positive blood by generating antibodies (infection-fighting protein molecules) that recognise the "alien" blood cells and destroy them. This is known as "sensitisation" the first time it happens.

If sensitisation has already occurred, the next time the woman is exposed to RhD-positive blood her body will start to produce antibodies immediately, and in larger amounts. If she is pregnant with an RhD-positive baby, the antibodies can cross the placenta and cause rhesus disease in the unborn baby. After the baby has been born, the mother's antibodies can remain in the baby for a few months and can continue to attack its red blood cells.

Find out what causes rhesus disease.

Preventing rhesus disease

Rhesus disease is uncommon these days, because the condition can usually be prevented.

All women are offered blood tests as part of their antenatal screening to determine whether their blood is RhD negative or positive. If the mother is RhD negative then she will be offered injections of anti-D immunoglobulin at certain points in her pregnancy when she may be exposed to the baby’s red blood cells. This anti-D immunoglobulin helps to remove the RhD foetal blood cells before they can cause the process of sensitisation.

If a woman has developed anti-D antibodies in a previous pregnancy (she has already become sensitised) then these immunoglobulin injections do not help. The pregnancy will be monitored much more closely than usual, as will the baby after delivery.

Read more about how rhesus disease is prevented.

Treating rhesus disease

If an unborn baby does develop rhesus disease, the treatment will depend on how severe it is. A blood transfusion to the unborn baby may be needed in more severe cases. After delivery, the child is likely to be admitted to a neonatal unit (a hospital unit that specialises in caring for newborn babies). 

Treatment for rhesus disease after delivery includes phototherapy, blood transfusions and a solution of antibodies given through a vein to prevent red blood cells being destroyed (intravenous immunoglobulin).

If rhesus disease is left untreated, severe cases can lead to stillbirth (when a baby dies in the womb before it is born). In other cases, it could lead to learning difficulties, deafness, blindness and cerebral palsy.

Read more about the complications of rhesus disease.

Symptoms

Rhesus disease only affects the baby. It will not cause any symptoms for the mother.

The symptoms of rhesus disease will depend on how severe it is. Around 50% of babies diagnosed with rhesus disease will have mild symptoms that are easily treatable.

Symptoms in an unborn baby

If your baby develops rhesus disease while still in the womb, they may become anaemic, because their red blood cells are being destroyed faster than usual by the antibodies. If your baby is anaemic, their blood will be thinner and flow more quickly. This will be measured using a type of ultrasound scan known as a Doppler ultrasound.

If the anaemia is severe then it can lead to complications, such as swelling or foetal heart failure. Read more about the complications of rhesus disease.

Symptoms 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 be lacking in energy (lethargic).

If a baby has rhesus disease, they won't always have obvious symptoms when they are born. Symptoms can develop up to three months afterwards.

You can read more about how rhesus disease is diagnosed.

Haemolytic anaemia

Haemolytic anaemia occurs when red blood cells (the cells that transport oxygen in the blood) are destroyed. This happens because the antibodies from the woman’s RhD-negative blood have crossed the placenta and are inside her baby’s blood. The antibodies attack the baby’s RhD-positive blood and destroy the red blood cells. In the newborn baby this may cause:

• increased breathing rate
• poor muscle tone
• poor feeding
• jaundice (see below)

Jaundice

Jaundice occurs as a result of haemolytic anaemia. Jaundice in newborn babies will turn the baby’s skin and the whites of their eyes a yellowy colour. In babies with dark skin, it will be noticed mainly in the whites of their eyes. Their body fluids can also often become yellow in colour.

Jaundice is caused by a build-up of a chemical called bilirubin in the blood.

Bilirubin is a yellow substance that is made naturally in the body when red blood cells are broken down. The bilirubin is carried in the bloodstream to the liver where it is removed from the blood so that it can be passed out of the body in urine. If there is too much bilirubin in the blood, or if the liver cannot get rid of it, the excess of bilirubin will cause jaundice.

In newborn babies, the liver might not process the bilirubin as effectively as it can later in life. This is the reason why up to 50% of newborn babies get mild jaundice. However, in rhesus disease, haemolytic anaemia means that more red blood cells than normal are destroyed. This increases the amount of bilirubin that is released into the blood and the baby's liver is unable to deal with it. The bilirubin levels in the baby’s blood remain high, causing jaundice.

Causes

Rhesus disease is caused by a specific mix of blood types between a pregnant mother and her unborn baby.

Rhesus disease is only possible if:

• The mother is rhesus negative (RhD negative).
• The baby is rhesus positive (RhD positive).
• Sensitisation (see below) has previously occurred.

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 antigen (RhD). An antigen is a protein molecule found in blood (see antigens and antibodies below). People who have this antigen are RhD positive, and those without it are RhD negative. In the UK, around 85% of the population are RhD positive.

How are blood types inherited?

Your blood type depends on the genes that you inherit from your parents. Whether you are RhD positive or negative depends on how many copies of the RhD antigen you have inherited. For example, you could inherit one copy of the RhD antigen from your mother or father, a copy from both of them or none at all.

You will be RhD positive if you have inherited either a single copy of the RhD gene (called heterozygote Dd) from one of your parents, or two copies (called homozygote DD); one from each of your parents. To be RhD negative you must have inherited no copies of this gene (called homozygote dd).

If your blood is mixed with a different blood type, it will have a reaction to it. Each type contains different antigens, and, in response to antigens from a different blood type, your blood will produce antibodies.

RhD-positive baby

If a woman who is RhD negative (homozygote dd) has an RhD-positive male partner (heterozygote Dd, or homozygote DD) there is a chance their baby will be RhD positive.

If the male partner has two copies of the D antigen (homozygote DD), the baby will definitely inherit one copy of the D antigen and will be RhD positive.

RhD-negative baby

If the male partner has one copy of the D antigen (heterozygote Dd), there is a 50% chance the baby will be RhD positive, and a 50% chance that they will be RhD negative. An RhD-negative baby will not get rhesus disease because their red blood cells will not have the RhD antigen, so the antibodies will have nothing to recognise and attack.

What are antigens and antibodies?

Antigens are protein molecules found on the surface of red blood cells in plasma. Plasma is the liquid that makes up your blood. Blood groups are identified by the antigens and antibodies that are present in the blood.

Antibodies are your body's natural defence against any foreign antigens that enter your blood. An antibody is a protein that is produced by the body to destroy disease-carrying organisms and toxins. If your blood comes into contact with blood that carries different antigens, your body will produce antibodies to those antigens. The antibodies will destroy the foreign blood cells.

The first time your blood comes into contact with another type of blood and has this response, it is called sensitisation.

Sensitisation

An RhD-positive baby will only have rhesus disease if the RhD-negative mother has been sensitised to RhD-positive blood. 

Sensitisation happens when a mother who is RhD negative is exposed to RhD-positive blood for the first time and has an immune response to it.

During the immune response, the woman’s body recognises that the RhD positive blood cells are foreign and prepares to attack them. Her body does this by designing a specific antibody to target the D antigens in the RhD-positive blood cells. Once the design is ready, her body can start producing the antibody.

However, at this stage there will probably not be enough time to start producing the antibody before the RhD-positive blood is naturally filtered out of her system. Therefore, during sensitisation, it is unlikely that any foreign blood cells will actually be destroyed by the antibodies.

The next time RhD-positive blood cells enter the woman’s blood, the design will be ready and the correct antibodies can be produced straight away. This time, enough antibodies will be produced to start destroying the foreign blood cells. If this occurs, the baby will develop rhesus disease.

How does sensitisation occur?

The most likely time that RhD-positive blood cells could have entered the mother’s blood is during an earlier pregnancy with a baby who was RhD positive.

During pregnancy, sensitisation can happen if:

• Small numbers of foetal blood cells cross into the mother’s blood during a normal pregnancy.
• Blood of the mother and baby come into contact during delivery.
• There has been bleeding in the pregnancy.
• An invasive procedure has been necessary during pregnancy – such as amniocentesis, or chorionic villus sampling (CVS).
• The mother has had an abdominal injury.

Sensitisation can also occur after a previous miscarriage, or ectopic pregnancy, or if an RhD negative woman has received a transfusion of RhD positive blood.

Diagnosis

As part of your pregnancy, you should be offered several routine screening tests. Before having a screening test your GP or midwife will discuss it with you. You don't have to have a test if you don't want it.

Blood testing

A blood test will be used early on in your pregnancy so that the sample can be tested for conditions such as:

• anaemia 
• rubella 
• HIV
• hepatitis B

Your blood will also be tested to determine which ABO blood group you are, and whether your blood is rhesus (RhD) positive or negative.

If you are RhD negative, a test will be carried out to make sure your blood is not producing antibodies (known as anti-D antibodies). This rules out the possibility that you have already been sensitised. Your blood will be checked again at 28 weeks of pregnancy. You will be offered routine administration of anti-D prophylaxis to help prevent sensitisation occurring.

Diagnosis in an unborn baby

If you develop anti-D antibodies during your pregnancy, or if you have antibodies present from a previous pregnancy, there is a risk your baby will be affected and become anaemic before it is born. For this reason, you and your baby will be monitored more frequently than usual during pregnancy.

Your baby will be monitored by measuring the blood flow in their brain. If your baby is anaemic, their blood will be thinner and flow more quickly. Your baby’s blood flow can be measured using a type of ultrasound scan called a Doppler ultrasound.

If a Doppler ultrasound shows that your baby’s blood is flowing at a higher speed than normal, a procedure called foetal blood sampling (FBS) can be used to check whether your baby is anaemic. In FBS, a needle is inserted through your abdomen and is used to take a small sample of blood for testing, either from your baby’s umbilical cord, or from the umbilical vein as it passes through their liver. The procedure is performed under local anaesthetic, usually on an outpatient basis (where you do not have to stay in hospital overnight).

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). After a transfusion, you may need to stay overnight.

FBS and IUT are only available in some hospitals. Therefore, if you need to have one of these procedures, your GP may refer you to a different hospital from the one where you were going to have your baby.

Read more about how rhesus disease is treated.

Diagnosis in a newborn baby

If you are RhD negative, after the birth of your baby blood will be taken from the baby’s umbilical cord to check the blood group and to see whether there is any evidence that anti-D antibodies have crossed the placenta. This is called a Coombs test. If you are known to have anti-D antibodies, your baby’s blood will also be tested for anaemia and jaundice.

Foetal DNA tests

If you are RhD negative and have been sensitised to RhD-positive blood, you are at risk of having a pregnancy affected by rhesus disease if the baby is RhD positive. This will be determined by the father’s blood group.

In some cases, there is only a 50% chance that the unborn baby will be RhD positive, and at risk of rhesus disease. In the other 50% of cases, the baby is RhD negative, like their mother, and safe from the antibodies.   

It is now possible to test the rhesus blood group of the unborn baby by taking a simple blood test during pregnancy. Genetic information (DNA) from the unborn baby can be found in their mother's blood and this allows the blood group of the unborn baby to be determined without any risk. It is usually possible to obtain a reliable result from this test by 11 to 12 weeks of gestation, long before the baby is at risk from the antibodies.

If the unborn baby is RhD negative, you can be reassured that your baby is not at risk from the antibodies.

In the future, non-sensitised RhD-negative women may be offered this test to see if they are carrying a RhD-positive or RhD-negative baby. Women carrying a RhD-negative baby will not need to be given anti-D immunoglobulin for prevention.

Read more about how rhesus disease is prevented.

Treatment

Rhesus disease may be mild, moderate or severe and this will affect what treatment is needed. In more severe cases, treatment may need to begin before the birth of the baby. Phototherapy and blood transfusions are the most common treatment options.

Around 50% of babies with rhesus disease will have a mild case that does not usually require much treatment. However, your baby will need to be monitored on a regular basis as in some babies the symptoms of anaemia may be delayed.

Around 25% of affected babies have moderate symptoms. Phototherapy is often needed and blood transfusions may be used to speed up the removal of bilirubin (a substance created when red blood cells break down) from the body.

Around 25% of babies with rhesus disease will have a severe case and the baby will often need neonatal intensive care (NIC). Intensive phototherapy will be needed and a blood transfusion will be required.

Rhesus disease does not affect the mother physically, but there may be preventative treatment offered during or after the mother’s first pregancy. Read more about preventing rhesus disease.

Phototherapy

Phototherapy is treatment with light and it has been used since the early 1970s. The newborn baby will be placed under a halogen or fluorescent lamp with their eyes covered.

Fibre-optic phototherapy devices that use a blanket containing optical fibres have also been developed. The baby lies on the blanket and the light travels through the optical fibres and shines onto their back. In both methods of phototherapy, the aim is to expose the baby’s skin to as much light as possible.

Phototherapy lowers the bilirubin levels in the baby’s blood by photo-oxidation. This process adds oxygen to change a substance (in this case, the bilirubin) using the energy from light. The bilirubin is converted into a substance that dissolves easily in water. This makes it easier for the baby’s liver to break down the bilirubin and remove it from the blood.

If rhesus disease is confirmed, phototherapy should be started soon after birth because the bilirubin levels in the blood can rise quickly. If enough phototherapy is used, there may be less need for a blood transfusion.

During phototherapy your baby should be kept hydrated, because more water is lost through their skin and more urine is produced as their body expels the bilirubin. Your baby may need to have intravenous hydration (where water is given into a vein) if they cannot drink enough themselves.

Blood transfusions

Your doctor will decide whether the level of bilirubin in the blood is high enough to need a transfusion. Depending on the severity of your baby’s jaundice or anaemia, your baby may need to have more than one blood transfusion.

During a blood transfusion, some of your baby’s blood will be 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 catheter). This process has two benefits:

• It removes some of the bilirubin that is present in the baby’s blood.
• It removes the antigens that were passed from the mother into the baby.

Removing the antigens means that red blood cells will no longer be broken down. The replacement blood does not contain bilirubin and therefore the overall levels of bilirubin in the blood will decrease. It is also possible for the baby to have a transfusion of just red blood cells to top up those they already have.

Intrauterine blood transfusion

In more severe cases, your baby may develop rhesus disease while still in the womb and they may need to be given a blood transfusion before birth (intrauterine foetal blood transfusion (IUT). Even if the disease doesn't cause anaemia before birth, it is likely that your baby will be born a bit early.

Your baby may require more than one IUT, depending on how severely they are affected by rhesus disease. Transfusions can be repeated every two to four weeks until your baby is mature enough to be delivered (usually 34 weeks). An IUT may decrease the need for phototherapy after birth, but more blood transfusions could still be necessary.

Intravenous immunoglobulin

Intravenous immunoglobulin is also called IVIG. The immunoglobulin is a solution of antibodies (proteins produced by the immune system to fight against disease-carrying organisms) that is obtained from healthy donors. Intravenous means injected into a vein.

IVIG may be used alongside multiple sessions of phototherapy if the level of bilirubin in your baby’s blood is continuing to rise at a rapid hourly rate. The IVIG works by preventing the destruction of red blood cells, so that the level of bilirubin in your baby’s blood will stop rising.

IVIG significantly reduces the need for a blood transfusion, however, it does carry some small risks.

It is possible that your baby may have an allergic reaction to the IVIG, but it is difficult to calculate how likely this is or how severe the reaction will be. It is also possible for a virus to be transferred through the donated immunoglobulin, although the process to screen donors should prevent this.

Concerns over possible side effects, and the limited supply of IVIG, mean that IVIG is only used when the bilirubin level is rising rapidly, despite multiple phototherapy sessions.

IVIG has also been used during pregnancy, in particularly severe cases of rhesus disease. It can help delay the point during pregnancy at which IUTs become necessary.

Complications

Advancements in prevention and treatment mean that rhesus disease is now rare. However, there are still some risks to both unborn and newborn babies.

Unborn babies

If rhesus disease causes severe anaemia in the foetus, it can also cause:

• foetal heart failure
• fluid retention
• swelling (oedema)
• stillbirth (when a baby dies in the womb before being born)

Intrauterine transfusions (IUT) are used to treat anaemia in a foetus. Although IUT has a low complication rate, occasionally the baby can become distressed during the procedure and need to be delivered. Sometimes, pre-term labour (labour that begins before the 37th week of pregnancy) can occur after an IUT. There is also a 2% risk of miscarriage or stillbirth after an IUT.

Newborn babies

Rhesus disease makes the body produce excessive amounts of bilirubin. Without prompt treatment, a build-up of bilirubin in the brain can lead to a neurological condition called kernicterus. This can lead to complications such as deafness, blindness, brain damage, learning difficulties or even death. It is important that high levels of bilirubin are treated immediately.

Blood transfusions

The risk of catching an infection from the blood that is 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.

However, an adverse reaction to the blood is possible or there may be a problem with the transfusion itself. For example, the catheter (the tube) that is used to deliver the blood could become dislodged, causing a haemorrhage (heavy bleeding) or a blood clot. These risks are small and do not outweigh the benefits of treating a baby with anaemia.

Prevention

Rhesus disease can be avoided if sensitisation is prevented. If an RhD-negative woman has not been sensitised to RhD-positive blood, an injection of anti-D immunoglobulin can prevent her being sensitised.

Anti-D immunoglobulin

Sensitisation is avoided by administering anti-D immunoglobulin. The anti-D immunoglobulin neutralises any foetal RhD-positive antigens that have entered the mother’s blood. If the antigens have been neutralised, the mother’s blood will not start to produce antibodies.

You will be offered anti-D immunoglobulin after a potentially sensitising event, during which some foetal RhD antigens may have entered your blood. For example, if you experience any bleeding during your pregnancy, if you have an invasive procedure (such as amniocentesis) or experience any abdominal injury, anti-D immunoglobulin may be administered.

Anti-D immunoglobulin can also be administered routinely during the third trimester of your pregnancy. It is more likely for small amounts of foetal blood to pass into your blood during this time even if there have been no noticeable sensitising events. 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

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

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

There does not seem to be any difference in terms of the clinical effectiveness between the one-dose or two-dose treatments. Your primary care trust (PCT) 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 RhD-negative women who have not been sensitised to the RhD antigen. If you are RhD negative and routine tests carried out during your pregnancy show that sensitisation has not occurred, you will be offered RAADP. RAADP will not work if you’ve already been sensitised; instead you will be closely monitored and have regular blood tests and ultrasound scans.

Read more about how rhesus disease is diagnosed.

If rhesus disease starts to develop it will be treated either in the foetus or after birth, depending on when it is diagnosed.

Read more about how rhesus disease is treated.

Anti-D immunoglobulin after birth

After giving birth, a sample of your baby's blood will be taken from the umbilical cord. If your baby is RhD positive and you have not already been sensitised, you will 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 will prevent sensitisation because your blood will not have a chance to produce antibodies. This will significantly decreasing 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 taken from the donor blood will be carefully screened, there is a small risk that an infection could be transferred through the blood. However, the evidence in support of RAADP shows that the benefits of preventing sensitisation far outweigh these small risks.