2 Clinical need and practice
2.1 Human red blood cells carry many antigens on their surfaces. The most important of these antigens belong to the ABO system and the rhesus (Rh) system. The D antigen is the most important antigen of the rhesus system. People with the rhesus D (RhD) antigen are referred to as RhD positive, and those without it as RhD negative. A baby inherits its blood type from both parents. Therefore a mother who is RhD negative can carry a baby who is RhD positive. During pregnancy small amounts of fetal blood can enter the maternal circulation (an event called feto–maternal haemorrhage or FMH). The presence of fetal RhD-positive cells in her circulation can cause a mother who is RhD negative to mount an immune response, producing a template for the production of antibodies as well as small amounts of antibodies against the RhD antigen (anti-D antibodies). This process is called sensitisation or alloimmunisation.
2.2 Sensitisation can happen at any time during pregnancy, but is most common in the third trimester and during childbirth. Sensitisation can follow events in pregnancy known to be associated with FMH, such as medical interventions (chorionic villus sampling, amniocentesis or external cephalic version), terminations, late miscarriages, antepartum haemorrhage and abdominal trauma. It can also occur in the absence of an observed potentially sensitising event. The risk of sensitisation is affected by the ABO blood type of the fetus, with a lower risk if it is incompatible with the mother's ABO type. Sensitisation depends on the volume of fetal blood entering the mother's circulation and the magnitude of the mother's immune response. The risk of sensitisation is greatest in the first pregnancy and decreases with each subsequent pregnancy. Once sensitisation has occurred it is irreversible.
2.3 The process of sensitisation has no adverse health effects for the mother and usually does not affect the pregnancy during which it occurs. However, if the mother is exposed to the RhD antigen during a subsequent pregnancy, the immune response is quicker and much greater. The anti-D antibodies produced by the mother can cross the placenta and bind to RhD antigen on the surface of fetal red blood cells. These antibody-coated fetal red blood cells are removed from the fetal circulation. Fetal anaemia results if the red blood cells are removed faster than they are produced. Severe anaemia can lead to fetal heart failure, fluid retention and swelling (hydrops), and intrauterine death. Before birth, anaemia and hydrops can be managed with intrauterine transfusions, but this carries a 2% risk of fetal loss. When red blood cells are broken down, bilirubin is released. In utero this is cleared by the placenta and is not harmful. However, after birth the neonatal liver cannot cope with the excess production of bilirubin, and this leads to jaundice (haemolytic disease of the newborn or HDN). Low levels of jaundice are not harmful but, if left untreated, higher levels can result in damage to specific areas of the neonatal brain, causing permanent brain damage (kernicterus). This can lead to a range of neurodevelopmental problems, such as cerebral palsy, deafness, and motor and speech delay. Postnatal jaundice can be treated with phototherapy and exchange transfusion.
2.4 The risk of sensitisation can be reduced by administering anti-D immunoglobulin to women in situations in which FMH is likely (after delivery, miscarriage, abortion, invasive procedures or abdominal trauma). Potentially sensitising events introduce a quantity of fetal RhD antigen into the maternal circulation. The anti-D immunoglobulin administered neutralises this fetal antigen. In addition, anti-D immunoglobulin can be administered routinely in the third trimester as prophylaxis against small amounts of FMH that can occur in the absence of observable sensitising events. This is known as routine antenatal anti-D prophylaxis (RAADP). The use of anti-D immunoglobulin for RAADP is in addition to the administration of anti-D immunoglobulin following potentially sensitising events, and its use in either indication is not affected by prior use in the other.
2.5 The incidence of HDN depends on the proportion of the population that is RhD negative. This proportion varies between ethnic groups and is highest in the white population; in the UK, approximately 16% of the white population is RhD negative. For 2005, it was estimated that approximately 65,000 RhD-positive babies were born in the UK to women who were RhD negative (10% of all births). Without RAADP, but with the use of anti-D immunoglobulin after sensitising events, 1% of these women (approximately 650) would have become sensitised. Of these, approximately 550 would go on to have a further pregnancy. Taking into account subsequent pregnancies, it is estimated that about 520 affected pregnancies in England and Wales per year would require close monitoring because the mother is RhD negative and has been sensitised. Between 10% and 12% of these babies would require intrauterine transfusions. It is estimated that fetal anaemia and HDN would lead to approximately 37 fetal or neonatal deaths, 21 children with minor developmental problems and eight children with major developmental problems.
2.6 RAADP can be given as two doses of anti-D immunoglobulin of 500 IU (one at 28 weeks and one at 34 weeks gestation), as two doses of anti-D immunoglobulin of 1000–1650 IU (one at 28 weeks and one at 34 weeks gestation), or as a single dose of 1500 IU either at 28 weeks or between 28 and 30 weeks gestation. RAADP is not used uniformly throughout the NHS. In 2005, a survey of obstetric units reported that 75% offered RAADP, and of these 81% used one of the two-dose regimens. RAADP is usually administered by community midwives or at antenatal clinics.