Rhesus Disease in Pregnancy

Epidemiology

The percentage of the population who are RhD negative varies between ethnic groups. It is most common in the white population, and in the UK approximately 16% of the population are RhD negative. According to the National Institute of Clinical Excellence (NICE), in 2005, an estimated 65 000 RhD-positive babies were born to RhD-negative women (10% of all births).

The science

Blood is grouped according to both ABO and Rhesus genotypes. The Rhesus system consists of three linked gene pairs: C/c, D/d and E/e, coding for Rhesus antigens on the surface of red blood cells. The inheritance follows the Mendelian pattern, with one allele inherited from each parent. D is dominant to d, so individuals who are DD or Dd will express the D antigen and are D Rhesus positive.

Individuals who are homozygous recessive are Rhesus D negative and their immune system will recognize the D antigen as foreign. Rhesus antigens appear on the surface of red blood cells. Of the antigens, D is most common and is the focus of antenatal screening and prevention. ABO blood group incompatibility can also cause haemolytic disease of the newborn, but this is usually mild.

If a Rhesus-negative mother is carrying a Rhesus (D)-positive foetus, exposure to the foetal antigen in the maternal bloodstream causes an immune response and production of red cell antibodies. This sensitization is irreversible. It commonly occurs at delivery and will therefore cause problems only if there are subsequent pregnancies. However, it can occur as a complication of miscarriage or threatened miscarriage, procedures or bleeding in pregnancy (see Box 1).

This first exposure produces IgM antibodies, which do not cross the placenta. However, the B cells are now primed and any repeat exposure will cause them to produce IgG antibodies which do cross the placenta and reach the foetal circulation.

Once there, the antibodies destroy foetal red blood cells and cause a haemolytic anaemia. In utero, this can be treated using foetal exchange transfusions, although each transfusion carries a 2% risk of miscarriage.

Haemolytic disease of the newborn ranges in severity from mild neonatal jaundice to intrauterine death. In mild cases, phototherapy can be used to break down bilirubin to water-soluble products which can be excreted by the kidneys. In more severe cases, when cord haemoglobin is low or cord bilirubin high at delivery, exchange transfusion is used. Severe haemolysis is characterized by hydrops foetalis: oedema, hepatosplenomegaly, ascites, pleural and pericardial effusions and may be fatal.

The maternal immunological response causing Rhesus disease can be prevented by removing the foreign D antigens from the maternal bloodstream whenever exposure to foetal blood might have occurred. This can be done by giving anti-D immunoglobulin, which binds to foetal red blood cells resulting in effective neutralization of the antigens.

Anti-D is given as an intramuscular injection; it is generally safe but does carry a small risk of local or generalized allergic reaction. It is derived from donor blood so, as with all blood products, there is a small risk of blood-borne infection.

Testing for FMH

FMH at delivery is very common. Studies have shown that approximately 99% of women have a FMH of less than 4 ml at delivery. Of the larger FMHs, 50% occur after normal deliveries. However, there are certain events which increase the risk of larger FMHs (see Box 1).

It is important to quantify the size of the FMH because the standard 1000–1500 international unit (IU) dose of anti-D will not cover the 0.3% of women with a FMH greater than 15 ml. The recommended policy in the UK is that a blood sample is taken from the woman within 2 hours of delivery for Kleihauer screening (which detects foetal haemoglobin). If this test suggests that there has been a large FMH, then additional anti-D is administered.

Routine antenatal screening

NICE guidance on antenatal care recommends that women are tested for blood type and Rhesus status early in pregnancy. All women should receive testing for atypical red cell antibodies in early pregnancy and at 28 weeks. If this test is positive, referral to a specialist centre is indicated. It is important to counsel women about the results of Rhesus status tests (Box 2).

Routine prevention

In non-sensitized Rhesus-negative mothers, NICE recommends antenatal anti-D prophylaxis. This can be given as two doses of 500 IU anti-D immunoglobulin at 28- and 34-week gestation or as a single, larger dose between 28- and 30-week gestation. It is also important that anti-D is given after delivery (immediately or up to 72 hours afterwards) if the blood group of the baby is RhD positive or unknown.

Prophylaxis following sensitizing events before delivery

Sensitization due to FMH can occur at any time during pregnancy and is most common in the third trimester and during childbirth. Box 3 gives a summary of potentially sensitizing events. It is essential that following a potentially sensitizing event, additional anti-D prophylaxis is given to Rhesus-negative women.

It is recommended that a dose of 250IU anti-D immunoglobulin should be given following sensitization events up to 20-week gestation. For all events after 20-week gestation, at least 500 IU anti-D immunoglobulin should be administered. This should be followed by a test to identify those women with FMH greater than 4 ml, and then additional anti-D must be given as required.

Prophylaxis following abortion

Management of alloimmunization

The main principles of managing isoimmunization are identification of women at risk of foetal haemolysis and anaemia, assessing severity of foetal anaemia and then blood transfusion in utero and/or on delivery.