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Alloimmune hemolytic disease of the fetus and newborn is caused by the action of transplacentally transmitted maternal immunoglobulin (Ig) G antibodies on paternally inherited antigens present on fetal red cells but absent on the maternal red cells. Maternal IgG antibodies bind to fetal red cells, causing hemolysis or suppression of erythropoiesis. As a consequence, anemia, extramedullary hematopoiesis, and neonatal hyperbilirubinemia may result, with severe cases resulting in fetal loss or neonatal death or disability. Collaboration among maternal–fetal medicine specialists, hematologists, transfusion medicine physicians, radiologists, and neonatologists has substantially reduced perinatal mortality and morbidity resulting from hemolytic disease of the fetus and newborn. Antenatal diagnostic methods identify at risk fetuses, and assess disease severity in affected fetuses. After birth, phototherapy and exchange transfusions prevent serum bilirubin from rising to levels that could produce bilirubin encephalopathy and resultant brain damage (kernicterus), remove maternal antibody, and replace circulating fetal red blood cells with those negative for the implicated antigen(s). RhIg has successfully prevented alloimmune hemolytic disease resulting from rhesus D sensitization in many at risk infants, but no prophylactic therapy exists as of this writing to prevent alloimmune hemolytic disease resulting from other red cell antibodies. Advances in immunohematology and molecular biology may offer new avenues for prevention and treatment in the future.


Acronyms and Abbreviations:

AAP, American Academy of Pediatrics; anti-D, antibody against D antigen; ccff-DNA, circulating cell-free fetal DNA; DAT, direct antiglobulin test; ΔOD450, change in optical density at 450 nm; FFP, fresh-frozen plasma; FMH, fetomaternal hemorrhage; HDFN, hemolytic disease of the fetus and newborn; HDN, hemolytic disease of the newborn; IAT, indirect antiglobulin test; Ig, immunoglobulin; IUT, intrauterine transfusion; IVIG, intravenous immunoglobulin G; QT-PCR, quantitative polymerase chain reaction; RBC, red blood cell; Rh, rhesus; rHuEPO, recombinant human erythropoietin; RhIg, Rho(D) immunoglobulin; SGA, small for gestational age; TBV, total blood volume; TSB, total serum bilirubin; WB, whole blood.


Alloimmune hemolytic disease of the fetus and newborn (HDFN) is a disorder in which the life span of fetal and/or neonatal red cells is shortened as a result of binding of transplacentally transferred maternal immunoglobulin (Ig) G antibodies on fetal red blood cell (RBC) antigens foreign to the mother, inherited by the fetus from the father. The resulting hemolysis or suppression of erythropoiesis may cause fetal and/or neonatal anemia and significant neonatal jaundice. There are three main classes of alloimmune HDFN, based on the antigen(s) involved: Rh (rhesus), minor red cell antigens (i.e., Kell, Duffy, Kidd antigens) and ABO.


Prior to the development of medical interventions in the 1950s, almost half of all newborn infants with Rh HDFN died or were severely handicapped. Although the clinical condition was described in newborn infants as early as the 1600s, it was only in the 1930s and 1940s that the pathophysiology of Rh HDFN was uncovered. In 1932, Diamond and colleagues1 recognized that the clinical syndromes of stillbirth with unusual erythroblastic activity in the extramedullary ...

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