EPO Rh4 Study

EPO Rhesus 4 Study

Neonates with hemolytic disease of the newborn (HDN) due to red cell alloimmunization often require top-up (red blood cell) transfusions to treat late anemia during the first three months of life. Late anemia in neonates with HDN may be due to depressed erythropoiesis (hyporegenerative anemia) and/or persisting (intra-marrow) destruction of erythrocytes by remaining antibodies, which is not necessarily associated with parameters of hemolysis. Hyporegenerative anemia occurs in particular in neonates treated with intrauterine red cell transfusions (IUT) due to bone marrow suppression. Approximately 80% of infants with rhesus hemolytic disease (RHD) treated with IUT require at least one top-up transfusion. 
Since more than a decade erythropoietin (EPO) has been applied in small studies and casuistic reports, although it is controversial whether neonates with HDN treated with or without IUT may benefit from this treatment to reduce the risk of delayed anemia and subsequent the need for top-up transfusions. Due to the lack of evidence, routine use of EPO is currently not recommended. To determine a role for EPO in patients treated with IUT, a well-designed randomized controlled clinical trial of sufficient sample size is required.


To evaluate the effect of darbepoetin alfa on the need for top-up transfusions in neonates with HDN due to red cell alloimmunization treated with IUT. Secondary outcomes are number of days of admission for top-up transfusions, reduction in ferritin levels and long-term neurodevelopmental outcome at two years of age using the BSID-III test.

Study design

Randomized controlled trial

Study population

All (near)-term neonates admitted to the Leiden University Medical Center (LUMC) with HDN, treated with IUT.


Treatment with darbepoetin alfa subcutaneously at a dosage of 10 U/kg once a week for a period of 8 weeks (intervention), or “standard care”.

Main study outcome

Number of top-up transfusions required per infant.

Research Staff

Prof. Masja de Haas, MD PhD
Prof. Enrico Lopriore, MD PhD
Isabelle Ree MD


  • Nicaise C, Gire C, Casha P, d'Ercole C, Chau C, Palix C. Erythropoietin as treatment for late hyporegenerative anemia in neonates with Rh hemolytic disease after in utero exchange transfusion. Fetal Diagn Ther. 2002;17:22-24.
  • Patel S, Ohls RK. Darbepoetin Administration in Term and Preterm Neonates. Clin Perinatol. 2015;42(3):557-566.
  • Zuppa AA, Alighieri G, Calabrese V, Visintini F, Cota F, Carducci C, et al. Recombinant human erythropoietin in the prevention of late anemia in intrauterine transfused neonates with Rh-isoimmunization. J Pediatr Hematol Oncol. 2010;32:e95-101.