Randomized controlled trial on the use of EPO to reduce top-up transfusions in neonates with red blood cell alloimmunization treated with intrauterine transfusions.

The mainstay of antenatal treatment of fetal anemia due to red cell
alloimmunization is (serial) IUT. The mainstay of postnatal treatment in HDN is
(1) intensive phototherapy and exchange transfusion to treat hyperbilirubinemia
and prevent kernicterus, and (2) top-up transfusions to treat anemia. Up to 80%
of infants with HDN treated with IUT require at least one top-up transfusions
for late anemia during the first 3 months of life.
Several risk factors for late anemia have been reported, including serial IUT
(due to bone marrow suppression), severity of HDN, reduced use of exchange
transfusions during the neonatal period and reduced survival of transfused red
blood cells. Finally, erythropoietin deficiency is also considered as a
possible contributing factor to late anemia.
EPO has been increasingly used in neonates to prevent or reduce neonatal anemia
without short or long-term adverse effects. Several small studies and casuistic
reports suggest that neonates with HDN may benefit from treatment with EPO to
reduce the risk of delayed anemia and subsequent top-up transfusions. However,
other authors found that EPO may be less effective than expected. Due to the
lack of evidence, routine use of EPO is currently not recommended. To determine
a role for EPO in this group of patients, a well-designed randomized controlled
clinical trial of sufficient sample size is required. Potentially, EPO
stabilizes the hemoglobin levels of these infants and thus prevents top-up
transfusions and extra admissions, creating a more stable and natural postnatal
course for patients with HDN.

The primary objective of this study is to investigate whether darbepoetin alfa
is effective in reducing the incidence of late anemia in infants with HDN
treated with IUT and therefore in decreasing the number of top-up transfusion
required per infant. As secondary objectives the percentage of infants that
require top-up transfusions will be assessed, as well as the number of days of
admission for top-up transfusions, occurrence of hypertension and high ferritin
levels and, as exploratory otoc long-term neurodevelopmental outcome at 2 years
of age using the BSID-III test.

Randomized controlled trial. Included neonates will be randomized at birth to
treatment with EPO (intervention group) or *standard of care*, 1:1 allocation.
In the treatment group, EPO (darbepoetin alfa) is administered subcutaneously
at a dosage of 10 mcg/kg once a week, starting at day 7, for a period of 8
weeks. Treatment is administered during weekly home visits. Concomitant therapy
with folate (0.25 mg/day) is given in both groups (standard practice).
Concomitant iron therapy is given if ferritin level drops below 75 microg/l.19
Weekly routine measurements of complete blood counts (including hemoglobin
level and reticulocyte count) will be performed in both groups (standard
practice). EPO is discontinued if hemoglobin level is >= 13 g/dL after at least
4 weeks of treatment with EPO. Monthly measurements of liver enzymes (aspartate
aminotransferase (ASAT), alanine aminotransferase (ALAT), gamma-glutamyl
transferase (γGT) and lactate dehydrogenase (LDH)) will also be performed in
all groups (standard practice). In addition, EPO-level will be determined at
the start of the treatment with EPO. The number of top-up transfusions received
during the first 3 months of life and hemoglobin levels prior to the top-up
transfusion are recorded. After initial discharge from the LUMC, top-up
transfusions are performed when hemoglobin levels fall below 7.2 g/dL or when
hemoglobin is between 7.2 and 8.8 g/dL if clinical symptoms of anemia
(lethargy, feeding difficulties or failure to thrive) are present.

At two years of age a physical and neurological examination and an assessment
of cognitive and neurological development using the Dutch version of the Bayley
Scales of Infant Development, third edition (BSID-III) will be performed
(standard practice). BSID-III scores provide mental developmental indexes (MDI)
and psychomotor development indexes (PDI).

Darbepoetin alfa subcutaenous injection once a week for a period of 8 weeks
after birth, dosage 10mcg/kg.

The burden to the intervention group seem small, though cannot be neglected as
the intervention group receives weekly subcutaneous injections for a period of
8 weeks. However, these injections seem of minor burden compared to the weekly
(routine) blood draw. Risks are considered mild as no severe adverse effects
have been reported in term neonates.