ABO incompatibility is a congenital mismatch between maternal and fetal blood types, that occurs in 15 to 20% of pregnancies. The incompatibility between the mother and the fetus blood antigens of the ABO system is the leading cause of neonatal jaundice and the most common form of HDFN, but clinical severe HDFN will develop only in about 1% of cases of blood types mismatch.

It is thought that the generally milder disease caused by ABO incompatibility is due to the expression of A and B antigens by placenta and other tissues and therefore these antigens may associate with maternal alloantibodies to some extent. Furthermore, the expression of A and B blood group antigens on fetal red cells is not fully developed and so there are fewer antigenic sites on the fetal RBCs surface for the antibodies to bind with.

It must be remembered that individuals naturally begin to make A and/or B antibodies to the antigens that they do not possess at approximately 3–6 months of age. As a result, ABO HDFN can occur with the first pregnancy without any prior foreign antigen exposure, unlike other types of HDFN, is observed almost exclusively in mothers with blood type O and is more common with A fetal blood type.

Mothers with O blood type have naturally occurred immunoglobulins of G class (IgG) against A or B blood types, capable to cross the placenta. During pregnancy, the formation of anti-A, anti-B and anti-A, B titles of the IgG class can be strongly increased.

Both A and B groups patients also develop the respective antibodies to the antigens they do not possess, however they are not normally at risk of HDFN as these antibodies are almost always of IgM class and thus cannot cause fetal or neonatal disease because they do not cross the placenta.

In very rare instances, ABO incompatibility has been implicated as the cause of severe fetal anemia and perinatal morbidity. There is a striking, and yet not understood, difference in the incidence of ABO-mediated HDFN between populations. The incidence is around 0.3–0.8% in the Caucasian population, versus 3– 5% in Black or Asian populations, also with a more severe clinical course.

The mechanism most involved in HDFN is the alloimmunization due to the development of maternal antibodies targeted to an antigen present on the fetal RBC surface, when fetal RBCs enter the maternal blood circulation. The production of maternal antibodies against fetal RBCs antigens is elicited by previous transfusions and FMH.

The alloimmunization rate in the general population varies from 2% to 7%, with an increased likelihood in transfused patients. In pregnancy the rate is estimated to be in the range 0.4% to 1.2%. 

After blood transfusion, 1% to 2% of people develop blood group antibodies; most are of little consequence, however some can induce a severe form of HFDN.  

Alloimmunization due to FMH is an acquired immune-mediated mechanism that typically affects subsequent pregnancies rather than the pregnancy in which the FMH happens.

It has been shown that 75% of women have a FMH during pregnancy or at the time of delivery. In about 50% of these women, the FMH does not exceed 0.1 mL of fetal blood. Less than 1% of women have more than 5 mL, and less than 0.25% have more than 30 mL of fetal blood in their circulations. Some obstetric conditions increase the risk of FMH including antepartum bleeding, toxemia of pregnancy, external version, cesarean section, and manual removal of the placenta. 

Individuals have different antigens on the surface of their RBCs. Some of these antigens are responsible for the development of the immune response, leading to HDFN, whilst many are not. The International Society of Blood Transfusion Working Party for Red Cell Immunogenetics and Blood Group Terminology (ISTB WP) recognizes 43 blood group systems containing 345 red-cell antigens. However, new antigens are constantly discovered and thus the knowledge of potential antigen:antibody complexes continues to increase. The RBC antigens in the different blood group systems are proteins or glycolipids and can have different functions.

The different RBCs antigens, within and among the various blood group systems, have different impact on the antibodies production, but only a minor proportion on these antigens cause red-cell incompatibilities clinically relevant. The most frequently surface antigen of RBCs involved in severe form of HDFN is the Rhesus factor, discovered in the 1940s in Rhesus monkeys. 

The Rh blood group system is the is the second clinically most important after the ABO system. As far as we know to date, the Rh system is made up of 55 surface inherited antigens of which the main are the D, C, c, E and e antigens that are codified by two highly homologous genes, RHD and RHCE. 

The most immunogenic antigen is the D antigen (RhD). A person is considered as Rh-positive (RhD+) or Rh-negative (RhD-) based on the presence or absence of the RhD antigen on RBCs’ surface.  An antigen d has never been proved to exist.  The antigens are inherited in two sets of three, one set from each parent. The most common sets are CDe(R1), c(d)e(r), and cDE(R2) 

Slightly fewer than 50% of Rh-positive people are homozygous for D (i.e., they have inherited a set of antigens containing D from both sets of parents). If a positive mate of an Rh-negative woman is homozygous, all of his children will be Rh-positive whilst if he is heterozygous, the fetus will be Rh- negative or Rh-positive with equal chance.  Only Rh-positive fetuses can cause Rh immunization and the production of anti-D antibodies in RhD-negative women determines erythroblastosis fetalis in RhD-positive fetuses. The D antigen is already present from the sixth/seventh week of gestation and that 0.1 mL of fetal red blood cells D + can alloimmunize an Rh-negative mother. The RhD-positivity varies among the ethnicities: it is reported in 85% of Caucasians, 95% in sub-Saharan Africans, and more than 99.5% in eastern Asians.  

The RhD antigen is the most immunogenic among the antigens of Rh system and anti-D antibody is correlated with the highest risk of fetal mortality and morbidity.  Rhesus antigens other than RhD including c, C, E, and e are often implicated, and can produce severe hemolysis. However, also antigens from Kell, Duffy, MNS, and Kidd blood group systems are known to cause severe form of HDFN. Understanding the different red-cell incompatibilities and antibody production that cause HDFN is important to predict, prevent, monitor and manage pregnancies and neonates at risk of the effects of fetal and neonatal hemolytic disease.

HDFN occurs when the fetus or neonate inherits a RBC antigen from the father that is not present on the mother’s red blood cells. The non-self RBC antigen elicit the maternal production of specific antibody. Maternal IgG antibodies travel across the placenta into the fetal blood stream, bind to the foreign antigen and cause hemolysis and possible anemia. Fetal anemia induces compensatory erythropoiesis, nonetheless this mechanism may be insufficient. Compensation for the anemia results in a hyperdynamic circulation in the fetus causing cardiomegaly and hepatic failure. Liver failure causes decreased protein levels and a reduction in oncotic pressure in the circulation and heart failure causes an increase in venous pressure; the combination of which leads to generalized edema and ascites, known as fetal hydrops, which has a high perinatal mortality rate. 

Hemolysis of the fetal red cells results in raised bilirubin levels. Since bilirubin passes the placenta, excess of bilirubin is cleared via the maternal circulation during pregnancy. After birth, the hemolytic process continues, but the relatively immature liver of the neonate cannot sufficiently conjugate the excess of bilirubin. This may result in severe hyperbilirubinemia and even in irreversible damage to the central nervous system, a condition known as kernicterus. This condition is characterized by bilirubin deposition in the basal ganglia and brain stem nuclei and is correlated with long-term morbidity such as severe form of athetoid cerebral palsy, hearing problems and psychomotor handicaps.