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Rhesus D incompatibility

Extracted from Survival Guide to Midwifery, 2nd Edition (2012) Diane M. Fraser and Margaret A. Cooper, Oxford; Churchill Livingstone: 2012. Courtesy Elsevier

Rhesus (RhD) isoimmunisation causes haemolytic disease of the newborn (HDN). Few antibodies to blood group antigens other than those in the Rh system cause severe HDN; fetal transfusion is unusual for multiple maternal antibody isoimmunisation without anti-D. ABO incompatibility (See ABO incompatibility) is possibly the most frequent cause of mild to moderate haemolysis in neonates.

RhD incompatibility can occur when a woman with Rh-negative blood type is pregnant with a fetus with Rh-positive blood type.

  • The placenta normally prevents fetal blood entering the maternal circulation. However, during pregnancy or birth, small amounts of fetal Rh-positive blood cross the placenta and enter the circulation of the mother, who has Rh-negative blood.
  • The woman's immune system reacts by producing anti-D antibodies that cause sensiisation.
  • In subsequent pregnancies these maternal antibodies can cross the placenta and destroy fetal erythrocytes.
  • Usually, sensitisation occurs during the first pregnancy or birth, leading to extensive destruction of fetal red blood cells during subsequent pregnancies.


Rh isoimmunisation can result from any procedure or incident where maternal blood leaks across the placenta or from the inadvertent transfusion of Rh-positive blood to the woman.

Prevention of RhD isoimmunisation

This is by routine antenatal anti-D immunoglobulin (Ig) prophylaxis, within 72 hours of birth or after any other sensitising event. Anti-D Ig is a human plasma-based product that prevents the production of anti-D antibodies by the mother.

Administration of anti-D Ig

Anti-D Ig is administered to Rh-negative women who are pregnant with, or have given birth to, an Rh-positive baby. It destroys any fetal cells in the mother's blood before her immune system produces antibodies. The process for non-sensitised women is:

1. Women who are Rh-negative are screened for Rh antibodies (indirect Coombs' test). A negative test shows an absence of antibodies or sensitisation 2. Blood is retested at 28 weeks of pregnancy. In countries where antenatal prophylaxis is routine (at 28 and 34 weeks' gestation), the first injection of anti-D Ig is given just after this blood sample is taken 3. Where a policy of routine antenatal anti-D Ig prophylaxis is not in place, blood is retested for antibodies at 34 weeks of pregnancy 4. When anti-D Ig prophylaxis is given at 28 weeks, blood is not retested, as it is difficult to distinguish passive anti-D Ig from immune anti-D 5. Following the birth, cord blood is tested for confirmation of Rh type, ABO blood group, haemoglobin and serum bilirubin levels and the presence of maternal antibodies on fetal red cells (direct Coombs' test). Again, a negative test indicates an absence of antibodies or sensitisation. The postnatal dose of anti-D Ig is still given if passive anti-D Ig is present 6. A Kleihauer acid elution test is also carried out on an anticoagulated maternal blood sample immediately after birth to estimate the number of fetal cells in a sample of maternal blood 7. Anti-D Ig must always be given as soon as possible, and in any case within 72 hours of any sensitising event and the birth. Anti-D Ig is injected into the deltoid muscle, from which absorption is optimal

Dose of anti-D Ig

Research evidence for the optimal dose is still limited but the doses listed below are recommended:

  • 500 IU anti-D Ig at 28 and 34 weeks' gestation for women in their first pregnancy
  • At least 500 IU for all non-sensitised Rh-negative woman following the birth of a Rh-positive infant
  • 250 IU following sensitising events up to 20 weeks' gestation
  • At least 500 IU following sensitising events after 20 weeks' gestation
  • Larger doses for traumatic events and procedures such as caesarean birth, stillbirths and intrauterine deaths, abdominal trauma during the third trimester, or manual removal of the placenta (dose calculated on 500 IU of anti-D Ig suppressing immunisation from 4 ml of RhD-positive red blood cells)
  • Larger doses for any other instance of inadvertent transfusion of Rh-positive red blood cells, e.g. from an incorrect blood transfusion of Rh-positive blood platelets


Ethical and legal issues

Anti-D Ig is a human plasma-based product. To give informed consent to its use, women need to know the possible consequences of treatment, as opposed to non-treatment, with anti-D Ig.

Management of RhD isoimmunisation

Effects of RhD isoimmunisation

  • Destruction of fetal RBCs results in anaemia, possibly oedema and congestive cardiac failure.
  • Fetal bilirubin levels also increase as more red cells are destroyed, with possible neurological damage as bilirubin is deposited in the brain.
  • Lesser degrees of destruction result in haemolytic anaemia, while extensive haemolysis can cause hydrops fetalis and death in utero.


Antenatal monitoring and treatment of RhD isoimmunisation

Depending on the severity of Rh isoimmunisation, monitoring and treatment can include the following:

  • Women who are Rh-negative are screened for Rh antibodies (indirect Coombs' test). A positive test indicates the presence of antibodies or sensitisation.
  • Red blood cells (RBCs) obtained by chorionic villus sampling (using an immune rosette technique) can be Rh phenotyped as early as 9-11 weeks' gestation.
  • Maternal blood is retested frequently to monitor any increase in antibody titres. Sudden and unexpected rises in serum anti-D levels can result in hydrops fetalis.
  • If antibody titres remain stable, ongoing monitoring is continued.
  • If antibody titres increase, Doppler ultrasonography of the middle cerebral artery peak systolic velocity is used rather than amniocentesis to detect fetal anaemia.
  • Changes in fetal serum bilirubin levels are observed.
  • The fetus is closely monitored by ultrasonography for oedema and hepatosplenomegaly.
  • Intravenous immunoglobulin (IVIG) has the potential to maintain the fetus until intrauterine fetal transfusion (IUT) can be performed. IVIG works by blocking Fc-mediated antibody transport across the placenta, blocking fetal red cell destruction and reducing maternal antibody levels.
  • IUT can be used from about 20 weeks of gestation to reduce the effects of haemolysis until the fetus is capable of survival outside the uterus.
  • Early delivery depends on the ongoing severity of the haemolysis and the condition of the fetus.


Postnatal treatment of RhD isoimmunisation

  • Babies with mild to moderate haemolytic anaemia and hyperbilirubinaemia may require careful monitoring but less aggressive management.
  • Babies with hydrops fetalis are pale and have oedema and ascites; in some cases they may be stillborn.
  • Management of surviving infants aims to prevent further haemolysis, reduce bilirubin levels, remove maternal Rh antibodies from the baby's circulation and combat anaemia.
  • In some cases phototherapy can be effective but exchange transfusion is often required, and packed cell transfusion may be needed to increase Hb levels.
  • Infants are at risk of ongoing haemolytic anaemia.

See also Antenatal care

Further reading

Qyreshi H, Massey E, Kirwan D, et al, for the British Committee for Standards in Haematology (BCSH). (2014) BCSH guideline for the use of anti-D immunoglobulin for the prevention of haemolytic disease of the fetus and newborn. Transfusion Medicine. Doi: 10.1111/tme.12091;jsessionid=194D2DDC31A900F6DB2DFA4E80763A73.f01t04?v=1&t=in5vdwtk&s=f606f8aab9110d24853ae7ff986107fa674eb1c8

Willacy H. (2012) Haemolytic Disease of the Newborn (Professional reference).

NICE (2008) Routine anti-D prophylaxis for women who are rhesus D negative. Technology appraisal 156.

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