Hemolytic disease of newborn caused by rhesus incompatibility

Rhesus blood group and rhesus antigens


The rhesus blood group system is the most important blood group system next to the ABO system. Just as the A and B antigens found on red blood cell surface, rhesus antigens are surface antigens expressed on the surface of red blood cells. There are more than forty different antigens in the rhesus system; however, only five of these are common in human population.

The five different rhesus antigens commonly expressed among human populations are:

  1. C antigen
  2. D antigen
  3. E antigen
  4. c antigen
  5. e antigen

Allelic forms of rhesus antigens


 The allelic forms of the rhesus antigens are C/c, D/d, and E/e antigens. The d allelic form is very rare, occurring only in about 15% of human population.

Humans express more than five rhesus antigens


Studies show that several variations and combinations of the five principle genes exist, and their products antigens number over 50 rhesus antigens. Because of these vast variations in rhesus antigens, the rhesus blood group system is arguably the most complex of all red blood group systems.

Therefore, about 50 rhesus antigens exist but most rhesus-related incompatibilities are due to the five principle antigens (C, D, E, c, e rhesus antigens).

Moreover, among the five commonly implicated rhesus antigens, the D antigen is the most immunogenic and most potent in inducing extremely strong immune reactions. Consequently, individuals that express D antigens are positive for rhesus (Rh+) whereas individuals who lack the D antigen are negative for rhesus (Rh). Consequently, the term ‘D positive’ and ‘D negative’ refers to the presence or absence of ‘D antigens’ on the surfaces of red blood cells. Never forget that ‘D positive means Rh+ and ‘D negative’ means Rh.

Rhesus inheritance


Rhesus gene is a dominant gene hence if either of the parents happens to be Rh+; the child will definitely be Rh+ regardless of the rhesus status of the other parent. Therefore, the baby of an Rh+ father and an Rh father is Rh+ and the baby of an Rh father and an Rh+ mother will be Rh+.

Rhesus antibodies


In contrast to the ABO system, in the rhesus system, individuals who are Rh do not develop anti-Rh antibodies in their plasma. However, when Rh individuals encounter Rh+ red blood cells, they develop anti-Rh antibodies, in their plasma, against the Rh antigens. Moreover, the production of Rh antibodies occurs mostly during transfusion and pregnancy.

Thus, humans develop rhesus antibodies in their plasma after prior exposure to the rhesus antigens. The first exposure sensitizes and immunizes the system providing the stimulus for formation of anti-rhesus antibodies. Antibodies formed during rhesus incompatibility reactions are predominantly IgG subtype. Rhesus antibodies are responsible for hemolytic disease of the newborn.

Hemolytic diseases of newborn that result from rhesus incompatibility


Since the rhesus gene is dominant, a baby of a Rh+ father and a Rh mother is Rh+. As pregnancy progresses, the Rh+ blood form the fetus can enter into the mother’s Rh circulation.

The rhesus antigens expressed on fetal red blood cells are foreign antigens (immunogens) that trigger the production of Rh antibodies by the mother.

The Rh antibodies produced are mainly IgG subtype, and recall that IgG antibodies can cross the placental barrier to enter into fetal circulation.

Chances are that the Rh antibodies the mother generates will cross into fetal circulation and bind to rhesus antigens on fetal red blood cells. Binding of Rh antibodies (produced by the mother) to fetal red blood cells cause hemolysis of fetal red blood cells.

The first child only sensitizes the mother to produce rhesus antibodies


The first child born to the rhesus incompatible mother is often free of the signs of incompatibility reactions that define hemolytic disease of newborn. During pregnancy, placental cells separate fetal blood from maternal blood. Thus, the placental barrier prevents fetal blood from crossing into maternal circulation. However, at delivery, the feto-maternal placental barrier tears and breaks loose allowing a considerable amount of fetal blood to enter into the mother’s circulation.

Fetal red blood cells entering into the mother system carry Rhesus antigens (i.e. are Rh+) and triggers the production of rhesus antibodies.

Because the first encounter between fetal blood and maternal blood occurs during delivery, the first child is free of the symptoms of hemolytic disease of newborn. However, the first child succeeds in making the mother generate an army of anti-rhesus antibodies. The second and subsequent fetus will suffer varying degrees of incompatibility reactions due to the rhesus antibodies present in the mother before the conception of the second child.

Subsequent children will suffer hemolytic disease of newborn


No complications arising from incompatibility reactions develop during first pregnancy (the sensitizing pregnancy). However, during second and subsequent pregnancies, maternal anti-rhesus antibodies cross the placenta into fetal blood. In the fetal blood, the anti-rhesus antibodies bind to rhesus antigens on red blood cells of fetus and cause the lysis of the fetal red blood cells.

Complications that result from hemolytic disease of newborn


Anemia and jaundice: anti-rhesus antibodies (from the mother) react to rhesus antigens on fetal red blood cells, causing the lysis of fetal red blood cells. Thus, hemolysis, which is the destruction of red blood cells, occurs in the fetus. Excessive hemolysis results in jaundice and anemia in the fetus.

Erythroblastosis fetalis: anemia stimulates fetal bone marrow to increase its production and release of red blood cells. Under this stimulation, bone marrow begins to release immature red blood cells into fetal circulation, a condition called Erythroblastosis fetalis because erythroblasts will become significantly present in fetal circulation.

Kernicterus: excessive destruction of red blood cells (hemolysis) results in elevated bilirubin levels in newborns causing kernicterus. Kernicterus is a condition of considerable brain damage that results from the deposition of uncongugated bilirubin mainly in the basal ganglia and certain nuclei of the brainstem. Normally, bilirubin binds to albumin in plasma and is unable to cross the blood-brain barrier. Nevertheless, when bilirubin levels become too high, bilirubin crosses the blood-brain barrier into brain tissues where it causes damage.

Mechanism of anti-rhesus antibodies mediated hemolysis


Anti-rhesus antibodies mediated hemolysis is principally mediated by IgG. Rhesus-specific IgG antibodies bind to rhesus antigens on the surface of red blood cells. The antibodies bind to rhesus antigens using their Fc region.

The bound antibodies act as opsonins that compel macrophages in liver and spleen to engulf the antibody-RBC complex destroying the red blood cells.

Can the first child suffer hemolytic disease of newborn?


Of course, it is possible for the first child to suffer the complications associated with hemolytic disease of newborn. It can happen that the mother already has anti-rhesus antibodies to the rhesus antigens. This can occur due to transfusion of Rh+ blood her either prior to the pregnancy or during the pregnancy.

ABO incompatibility reactions between mother and fetus are also possible


Besides rhesus incompatibility, ABO incompatibility reactions between mother and fetus can equally cause hemolytic disease of newborn. However, in contrast to the reactions due to rhesus incompatibility, ABO incompatibility reactions between mother and fetus are often mild. Usually, fetus with blood group A or B carried by mother with blood group O may develop hemolytic disease of newborn.

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