Mild Encephalopathy in the Newborn Treated With Darbepoetin

Therapeutic hypothermia (TH) is the standard of care for newborns diagnosed with moderate to
severe neonatal encephalopathy (NE) presumably due to hypoxic ischemia. In order to be
eligible for TH an infant must have perinatal acidemia and evidence of moderate or severe
encephalopathy on a standardized neurologic examination (Sarnat). However, the majority of
newborns with perinatal acidemia do not have a neurologic examination abnormal enough to be
classified as moderate or severe NE. In a retrospective review, DuPont et al. found that as
many as 20% of newborns with perinatal academia and mild NE have abnormal short-term outcomes
such as seizures, death from progressive asphyxia insult, brain MRI findings consistent with
NE, abnormal neurologic examination at discharge, gastrostomy tube feeding, or feeding
difficulties. Preliminary data from a prospective trial investigating mild NE (PRIME study,
NCT01747863) found that 39% had either abnormal electroencephalography at < 9h of age, an
abnormal brain MRI finding, or abnormal neurological exam at discharge. Murray et al.
recently reported on 5-year outcomes of infants with mild encephalopathy and showed that 25%
had neurodevelopmental disability. These data suggest that mild NE likely carries a higher
risk of impaired neurological outcome then reported previously. Thus it would appear that
neuroprotective strategies would be beneficial in this group of infants. Preliminary data
suggest that erythropoiesis stimulating agents (ESA) provide neuroprotection, and improve
short and long-term neurologic outcome in neonatal brain injury. ESA may work through several
mechanisms including reduced inflammation, limited oxidative stress, decreased apoptosis and
white matter injury, as well as via pro-angiogenic and neurogenic properties. Darbepoetin
alfa (Darbe), a recombinant human erythropoietin (EPO)-derived molecule has established
safety and pharmacokinetics in newborns. Because Darbe has an extended circulating half-life
with comparable biological activity to EPO, it has the advantage of requiring less frequent
administration

Inclusion Criteria: Infants will be eligible for the MEND trial if they have a gestational
age > 34 weeks by best obstetric estimate, are <24 hours old and have evidence of mild
encephalopathy as defined by Shankaran et al based on a modified Sarnat examination
performed at <6 hours of age.

1. History of an acute perinatal event (abruption, cord prolapsed, severe fetal heart
rate abnormality, or meconium staining)

2. Infant is evaluated for hypothermia therapy and DOES NOT meet clinical criteria for
TH.

3. Infant has an IV for clinical treatment

Exclusion Criteria:

1. Moderate/Severe encephalopathy on modified Sarnat examination at < 6 hours of age

2. Major congenital and/or chromosomal abnormalities

3. Prenatal diagnosis of brain abnormality or hydrocephalus

4. Severe growth restriction (< 3%)

5. Central venous hematocrit >65%, platelet count >600,000/dL, and/or neutropenia
(ANC<500 μL)

6. ECMO

7. Infant judged critically ill and unlikely to benefit from neonatal intensive care by
the attending neonatologist