Effective combined immunotherapy for severe hemolytic disease of the fetus

Maternal anti-Kell and anti-Rhesus D-alloimmunization cause severe hemolytic disease of the fetus and newborn (HDF) by crossing the placenta, leading to anemia and hydrops fetalis. Early-onset HDF from anti-K and anti-RhD alloimmunization often requires multiple, early intrauterine transfusions (IUTs), with higher complication rates and decreased sensitivity after the first intervention. Mortality remains high.

We report the successful treatment of three pregnant women with high-titer red cell alloantibodies-two with anti-K and one with anti-RhD-during the first trimester, a period with otherwise limited therapeutic options. We applied a novel triple therapy consisting of immunoadsorption (IA), high-dose intravenous immunoglobulin (IVIG), and rituximab (Rtx) (IIR). This approach resulted in a marked reduction of antibody titers: anti-D decreased from 1:1024 to 1:16, and anti-K from 1:8192 and 1:2048 to 1:32, respectively. One patient presented at 19 weeks of gestation with fetal hydrops, severe anemia, and thrombocytopenia. IIR reduced the need for invasive procedures (intrauterine transfusions) and led to resolution of fetal thrombocytopenia. In the remaining two high-risk cases, IIR prevented the onset of fetal anemia. All neonates were delivered healthy and without anemia.

This case series presents a novel, safe personalized prophylactic and therapeutic approach that may delay anemia onset and reduce invasive procedures in high-risk patients with limited options and resulted in healthy neonates without apparent comorbidities.