Haemolytic disease is likely to occur when maternal antibodies develop against fetal red blood cells. Red cells not infrequently cross from the fetus to the mother, either antenatally or at some intrapartum event and, if they are antigenically different from the mother’s red cells, there may be a maternal immune response with antibody production. IgG antibodies may cross in the opposite direction, back to the fetus, leading to haemolysis, anaemia, high-output cardiac failure and fetal death. There are numerous known red cell antigens but the rhesus D antigen accounts for approximately 85% of haemolytic disease.

Maternal rhesus alloimmunization exemplifies the achievements of systematic scientific and clinical research. In just 40 years, it has been possible to unravel the pathophysiology, devise useful treatments and introduce an effective means to prevent a condition which had previously caused extensive fetal morbidity and mortality. Among populations with access to an anti-D prophylaxis programme, the fully developed clinical condition of haemolytic disease of the newborn is rare.

The blood group system

Blood groups are determined by antigens on the erythrocyte cell wall. In the ABO system, the letter O is used to refer to those who lack both the A and B antigens. If the mother is group O and the fetus has paternally inherited the A or B antigen, the mother may, if exposed, develop antibodies to these fetal cells. In practice these antibodies rarely cause significant haemolytic disease and no antenatal investigations are warranted.

The next most important system is the rhesus system, which comprises at least 40 antigens, the most important of which are C, D and E. C and E have immunologically distinct isoforms which are designated ‘c’ and ‘e’, but it seems unlikely that a ‘d’ isoform exists. If there is a ‘d’ antigen, it seems to have little if any immunogenic potential and the notation ‘d’ is used to indicate the absence of ‘D’. A parent contributes one or other antigen (e.g. C or c) to the offspring from each of these three alphabetically designated pairs. An individual can therefore be homozygous or heterozygous for any of the six (e.g. Cde/cDE, cde/cdE). Those who carry the D antigen, which is inherited as an autosomal dominant, are referred to as rhesus D positive whether in the homozygous or heterozygous form.

Any of the rhesus antigens are capable of stimulating antibody formation but the D antigen is by far the most immunogenic, followed by c and E. If a rhesus negative mother has a rhesus positive baby and is at some stage sensitized to the baby’s red cells, there is a chance of anti-D antibodies developing against the fetal cells. These antibodies may cross back to the fetus and lead to fetal haemolytic anaemia.

There are other significant antigens in addition to the ABO and rhesus systems. Many of these (e.g. Ce, Fya, Jka, Cw) are poorly developed on the red cell surface and usually stimulate only low levels of antibody production, often of the IgM category (which does not cross the placenta). Some, however, will cause significant haemolytic disease.

One notable exception is the anti-Kell antibody, which has the potential to cause significant fetal anaemia and along with anti-RhD, and anti-Rhc are the most commonly reported antibodies in cases requiring intrauterine transfusion. Kell alloimmunization differs from RhD alloimmunization in that the anaemia is not solely due to haemolysis – erythroid suppression has an important role. In addition, past obstetric history cannot be relied on to predict the severity of disease in the current or subsequent pregnancies. Fortunately, the incidence of Kell alloimmunization is low (0.1–0.2%). Since only 9% of the Caucasian population is Kell-positive, the majority being heterozygous, the number of cases of haemolytic disease of the newborn is small.

Pathophysiology of haemolytic disease

Exposure to a foreign antigen leads to an antigen-specific antibody response, initially of IgM antibodies, which do not cross the placenta. On subsequent exposure, for example in a second pregnancy, the already primed Β cells produce a much larger response, this time of IgG antibodies, which do cross the placenta. In the fetal circulation, an antibody–antigen complex is formed on the red cell membrane, which provokes phagocytosis of the cell by the reticuloendothelial system and results in fetal haemolysis. This will lead to anaemia unless there is sufficient compensatory haemopoiesis from the marrow, spleen and liver.

Increasing anaemia causes progressive fetal hypoxia and acidosis leading to hepatic and cardiac dysfunction. Generalized oedema of skin develops, as well as ascites, pericardial and pleural effusions. This syndrome is known as ‘immune hydrops fetalis’ and it is potentially fatal.

Red cell haemolysis results in increased production of bilirubin, most of which passes across the placenta to the mother and is cleared by the maternal system. The fetus therefore does not become jaundiced antenatally, but after delivery its own liver is unable to metabolize bilirubin sufficiently quickly and the neonatal bilirubin level rises (Fig. 39.1). If untreated, the bilirubin can rise to levels, which endanger the nervous system and bilirubin deposition in the basal ganglia leads to a condition known as ‘kernicterus’.

Fig. 39.1Baby delivered at 37 weeks because of high anti-D levels.

The bilirubin level rose steeply in the first 24 h but, with phototherapy, exchange transfusion was avoided.

Although most fetal bilirubin is readily cleared, some also passes into the fetal urine and then into the amniotic fluid. The level of amniotic bilirubin is therefore an indicator of the severity of the haemolysis.

Incidence

The incidence varies widely. Before the availability of anti-D prophylaxis, rhesus haemolytic disease was common in populations where there was a high prevalence of Rh(D)-negative individuals and where high parity caused an accumulation of alloimmunized women. In the UK, 17% of the population is Rh(D)-negative; 55% of Caucasian males are heterozygous for the RhD antigen. Assuming random mating without intervention, around two-thirds of Rh(D)-negative mothers would be expected to carry a rhesus-positive fetus. Approximately 10% of pregnant women are therefore at risk of developing anti-D antibodies.

Since the effective use of prophylactic anti-D, the perinatal mortality from haemolytic disease has fallen from around 46/100 000 to 1.9/100 000. Newly sensitized cases are detected at a rate of approximately 1/1000 maternities.