Aetiology

Three genes are thought to encode for the Rh blood groups. Two of these genes are located on the short arm of chromosome 1: RhD and RhCE.[15] Study of the RhD gene has revealed significant heterogeneity that may result in a lack of expression of the RhD phenotype. RhD pseudogene has all 10 exons of the RhD, but the gene is not transcribed into a messenger RNA product due to the presence of a stop codon in the intron between exons 3 and 4. Therefore, no RhD protein is synthesised, and the patient is serologically RhD-negative.[16]

Rh incompatibility is caused by destruction of fetal red blood cells (RBCs) from transplacental passage of maternally derived immunoglobulin G antibodies. Passage of fetal cells into the maternal circulation and fetomaternal haemorrhage (FMH) is a frequent occurrence, detectable in 65% of pregnancies either antenatally or in the early postnatal period.[17] Sensitisation of an RhD-negative mother with as little as 0.1 mL of RhD-positive fetal RBCs may elicit a primary immune response.[17][18][19]

Placental trauma of varying degrees may lead to sensitising FMH. FMH increases throughout pregnancy (3% first trimester, 43% second trimester, and 64% third trimester).[17][18][19]​ FMH has been found in 1% to 6% of external cephalic versions.[20][21][22]​​ Small amounts of FMH (>0.1 mL) are potentially immunising and occur in 2% of patients undergoing amniocentesis.[23][24]​​ The incidence of FMH at the time of chorionic villus sampling is about 14%.[25] Other invasive procedures, such as cordocentesis, can also cause FMH. Primary prevention of RhD sensitisation can be accomplished with appropriate use of RhD immunoprophylaxis in these clinical settings.[23]​​

An episode of threatened, spontaneous, or induced abortion can sensitise RhD-negative patients, but the risk of RhD alloimmunisation is very low with pregnancy loss before 12 weeks’ gestation.[26][27]​ Alloimmunisation has been reported after ectopic pregnancy, and 24% of patients with ruptured ectopic pregnancy have fetal RBCs detectable in the maternal circulation.[28]​ The risk of RhD alloimmunisation is low in complete molar pregnancy because of absent or incomplete vascularisation of villi and absence of D antigen. Conversely, a partial mole should be viewed as a risk factor for sensitisation.[23]​​​[26][29]

Pathophysiology

Exposure of an RhD-negative mother to RhD-positive fetal red blood cells (RBCs) results in the generation of B lymphocyte clones that recognise the foreign RBC antigen and promote production of immunoglobulin G (IgG). Memory B lymphocytes await the reappearance of RBCs containing the respective antigen, usually in a subsequent pregnancy. When challenged by these antigenic RBCs, the lymphocytes differentiate into plasma cells and produce IgG. Maternal IgG crosses the placenta and attaches to fetal RBCs that have expressed the antigen. These RBCs are then sequestered by macrophages in the fetal spleen, where extravascular haemolysis occurs, producing fetal anaemia. The fetus attempts to compensate by increasing extramedullary haematopoiesis. This results in hepatosplenomegaly, portal hypertension, cardiac compromise, tissue hypoxia, hypoviscosity, and increased brain perfusion. Extreme fetal haemoglobin deficits of ≥70 g/L (≥7 g/dL) can ultimately lead to hydrops fetalis (collection of fluid in serous compartments) and intrauterine fetal death, unless corrected by intrauterine fetal transfusion or neonatal exchange transfusion following delivery.[17][26][30]

Classification

Clinical classification[2]

  • Rhesus D (RhD) red blood cell (RBC) alloimmunisation

  • Haemolysis caused by RhD antigen

  • Non-RhD RBC alloimmunisation

  • Haemolysis caused by other, atypical RBC antigens (Kell, Rhc, Kidd, Duffy)

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