Hemolytic disease and reticulocytopenia of the newborn attributable to maternal immunoglobulin G anti‐M reacting optimally at cold temperatures

Abstract

Background: Hemolytic disease of the fetus and newborn (HDFN) attributable to anti-M is rare, although case reports implicate anti-M in varying severities of HDFN, including fetal hydrops and intrauterine death. Case Description: We describe the case of a newborn with HDFN associated with an atypical immunoglobulin (Ig) G anti-M that reacted best at cold temperatures. The maternal antibody detected in pregnancy was not reactive at 37°C, and a direct antiglobulin test (DAT) on red blood cells (RBCs) from the newborn was negative, suggesting an anti-M that should not have been clinically relevant. However, the infant developed hyperbilirubinemia (bilirubin level, 17.6 mg/dL), hemolytic anemia (hemoglobin nadir, 5.5 g/dL), and reticulocytopenia. Laboratory testing demonstrated the presence of an IgG anti-M in maternal and neonatal samples reacting best at 4°C. This passively acquired IgG anti-M provoked hemolytic anemia in the infant and likely suppressed erythropoiesis, resulting in reticulocytopenia with prolonged anemia. He was treated for IgG anti-M HDFN with 10 intravenous Ig infusions and 10 days of oral prednisone followed by a taper. He required seven transfusions with M− RBCs. His hemoglobin level normalized at 3 months of age. Follow-up at 2 years revealed no hematologic or neuro-developmental concerns. Conclusion: To our knowledge, this is the second report of HDFN attributable to an IgG anti-M reacting preferentially at cold temperature with no 37°C reactivity. Clinically relevant IgG anti-M may elude standard testing. Early recognition and testing for cold-reacting IgG anti-M should be considered for newborns with hemolysis, a negative DAT, and prolonged anemia.

Allo‐anti‐M: Detection peaks around 2 years of age, but may be attenuated by red blood cell transfusion

“…26 A subsequent case of a low titer, cold reactive anti-M IgG causing ADFN with reticulocytopenia was recently reported in the USA. 28 Similarly, ADFN with ineffective erythropoiesis is reported with anti-Ge3 antibodies against glycophorin C. 29 This study has some limitations. As a retrospective survey, it relied on post-transfusion data collection that was not necessarily part of routine care.…”

“… 26 A subsequent case of a low titer, cold reactive anti‐M IgG causing ADFN with reticulocytopenia was recently reported in the USA. 28 Similarly, ADFN with ineffective erythropoiesis is reported with anti‐Ge3 antibodies against glycophorin C. 29 …”

Analysis of anti-M antibody status and blood transfusion strategy in Hunan, China

“…Production of the antibodies is caused by diversity of antigens and immunity between maternal and fetal immunity, blood transfusion, and transplantation and immune and hematological diseases ( 16 ). An accidental antibody is an immune response against a foreign erythrocyte antigen; anti-M antibody is a common accidental antibody in pregnant women, which can cause HDFN ( 17 ). For neonatal hemolytic diseases with negative direct antiglobulin test (DAT), since MNS and other antigens are expressed on erythroid progenitor cells and anti-M destroys erythroid progenitor cells rather than mature RBCs, the hemolysis related tests may be negative even though the anemia is severe at birth.…”

“…In recent years, it has been reported in some Southeast Asian countries, Suzhou and Henan, and anti-M antibody is a relatively common accidental antibody. The type of anti-M antibody is mainly IgM in Southeast Asia and Henan, while the type of anti-M antibody is mainly IgG in Suzhou ( 4 , 17 , 26 ). Attention should be paid to the detection of anti-M antibodies in normal work.…”