Alloimmune neonatal neutropenia: Presentation of three cases and review of the literature

We report on three cases of isolated prolonged neutropenia that occurred in preterm neonates and were all due to maternal alloimmunization.

Case 1: Male, gestational age 35+3 weeks, birth weight 1650g. The first postnatal white blood cell count (WBCC) showed leukocytopenia of 6860/µl and neutropenia of 686/µl. Subsequently, the leucocyte and neutrophil numbers further decreased to minimum levels of 3190/µl and 120/µl, respectively. From day 14 to 17, both the total WBCC and the neutrophil count showed a progressive increase towards their normal ranges. Case 2: Male, gestational age 35+3 weeks, birth weight 2410g. The first hematologic examination after birth showed leukocytopenia of 7100/µl and neutropenia of 639/µl. Afterwards, the total WBCC decreased to a minimum of 4100/µl, and the neutrophil count to 276/µl. From day 20 of life, the neutrophils were restored to their normal range. Case 3: Male, gestational age 32+6 weeks, birth weight 1730g. Immediately after birth, leukocytopenia of 8680/µl and neutropenia of 520/µl were found. In the following, a moderate further decrease in the WBCC to 5000/µl was observed while the neutrophils fell to 67/µl. The normalization of the total WBCC and the neutrophil count started at day 23 of life.

After excluding common causes of neonatal leukopenia/neutropenia such as bacterial/viral infections, Alloimmune Neonatal Neutropenia (ANN) should be taken into consideration. In this uncommon, yet potentially life-threatening disorder, fetal neutrophil antigens inherited from the father induce the formation of maternal IgG antibodies. In contrast to typical rhesus incompatibility, anti-neutrophil alloimmunization already occurs during the first pregnancy. The antibodies cross the placenta and cause severe neutropenia which may “hide“ behind an apparently normal total WBCC. The mother has normal blood cell counts and no clinical history of recurrent infections. The Granulocyte Immuno Fluorescence Test (GIFT) and the Granulocyte Agglutination Test (GAT) allow to detect specific alloantibodies in maternal serum. In our cases, HNA (Human Neutrophil Antigen) 1a and 1b antibodies were found to have caused the otherwise unexplained neutropenia in the preterm neonates. The overall incidence of ANN amounts to one to six per thousand live births. The clinical course ranges from mild, self-limiting infection to overwhelming sepsis. In cases of severe bacterial infection, mortality is up to 60%.

Even though distinct preventive or therapeutic guidelines are missing, correct diagnosis of ANN may help to identify neonates at increased risk of early and potentially fatal infections.