Birth asphyxia related brain injury occurs in 2.6 (95% CI 2.5 to 2.8) per 1000 live births in
the UK and is the most common cause of death and neurodisability in term babies. The economic
burden to the treasury on support costs of neurodisability from neonatal encephalopathy is
massive (£4 billion per year). In addition, birth asphyxia related (obstetric) claims
accounted for almost half of the NHS litigation expenses in 2016/17 (approx. £2 billion),
increasing by 15% from the previous year. It has been reported that the NHS cost to meet the
complex life-long care needs of babies born with brain damage could be soon over £20m per
child, and this situation is unsustainable to the NHS.The UK Government has recently (October
2016) announced that reducing birth asphyxia related costs is a priority area for the
Government.
The only effective treatment for neonatal encephalopathy is whole-body cooling, with an
estimated saving of £100 million per annum to the UK economy, since its introduction as
standard therapy in the NHS in 2007. Cooling therapy has substantially improved the outcomes
of babies with neonatal encephalopathy in the past decade. However, unacceptably high rate of
adverse outcomes are still seen in cooled babies with moderate or severe neonatal
encephalopathy : death 28% (range 24-38); cognitive impairment 24% (range 21-25); cerebral
palsy 22% (range 13-28); epilepsy 19% (range 15-24); cortical visual impairment 6% (range
1-10), with combined death or moderate/severe disability 48% (range 44- 53), and hence better
treatments and further optimisation of cooling therapy is required. Additionally, cooling
provides a window of opportunity for therapeutic interventions that may arrest or reduce
secondary brain injury and it is unclear whether it provides protection from a sub-acute
chronic injury that may have occurred during the antenatal period.
A key roadblock in clinical translation of over fifteen highly effective neuroprotective
treatments in animal models is the long delay between the intervention and outcome
assessments in neonatal encephalopathy . i.e., the earliest age at which neurodevelopmental
outcome can be accurately assessed is 18 months. Hence, despite having several highly
effective treatments in animal models, no further neuroprotective drugs in neonatal
encephalopathy have been introduced into the NHS in the past ten years.
Erythropoietin (Epo) is a widely used drug for treating anaemia in various age groups,
including newborn infants. Several recent reviews have highlighted Epo as one of the most
promising therapies to augment hypothermic neuroprotection. Epo has both acute effects
(anti-inflammatory, anti-excitotoxic, anti-oxidant, and anti-apoptotic) and regenerative
effects (neurogenesis, angiogenesis, and oligodendrogenesis) essential for the repair of
injury and normal neurodevelopment in animal models. Of the long list of highly effective
drugs in animal models of neonatal encephalopathy and early clinical studies, Epo is the most
promising. It is the only drug with a long therapeutic window, is widely available,
inexpensive, and can be easily administered on a once-a-day dosing schedule. It has been
extensively evaluated in large randomised controlled trials for anaemia of prematurity and
has a proven safety profile in newborn infants. Due to the regenerative effects and the
longer therapeutic window provided by Epo, there is potential to impact the chronic injury
caused to an antenatally compromised foetus.
Although earlier studies have shown benefit with Epo, the time of initiation and duration of
treatment remains uncertain. Moreover, recently published High-Dose Erythropoietin for
Asphyxia and Encephalopathy (HEAL) trial which administered high dose Epo (1000u/kg/day)
within 24 hours of birth and continued until 7 days of age failed to demonstrate the
neuroprotective effect of erythropoietin in moderate and severe encephalopathy as an adjuvant
to therapeutic hypothermia. This result suggest the exposure of the drug during the
therapeutic hypothermia may not be beneficial due to an overlap in the neuroprotective
mechanism. Perhaps a prolonged exposure of Epo following therapeutic hypothermia might be
beneficial.
Another erythropoiesis stimulating agent is Darbepoetin (Darbe) with dual erythropoietic and
potential neuroprotective effects. Darbe is an ideal candidate to augment hypothermic
neuroprotection as it is a long-acting erythropoiesis stimulating agent, allowing prolonged
exposure with less dosing. In preclinical study in rats, darbepoetin alfa crossed the blood
brain barrier and remained stable up to 24 hours. Neuroprotective effects of darbepoetin were
demonstrated following the contusion injury and hemorrhage in rats. The DANCE study
(Darbepoetin Administered to Neonates undergoing Cooling for Encephalopathy) randomised 30
term infants with moderate to severe neonatal encephalopathy to placebo (n=10), 2 μg/kg Darbe
(n=10) or 10 μg/kg Darbe (n=10). At 2 and 10 μg/kg Darbe, t1/2 was 24 and 32 hours. A dose of
10 μg/kg dose achieved an AUC in the neuroprotective range and a terminal t1/2 of 53.4 hours
when compared to the 2 μg/kg dose. No side effects attributable to Darbe were reported. In
another feasibility and safety trial, infants with mild encephalopathy were randomised to
receive Darbepoetin 10 μg/kg single dose within 24 hours and found the drug to be safe with
no reported adverse events.
The EDEN trial is a 2 arm randomised control trial and aims to examine the physiological
effects of Darbepoetin alfa (Darbe) therapy on proton magnetic resonance spectroscopy
thalamic N-acetylaspartate (NAA) level in babies with neonatal encephalopathy undergoing
cooling therapy.
After informed parental consent, a total of 150 babies with HIE (aged <24 hours) undergoing
therapeutic hypothermia will be randomised to one of the following groups
Babies recruited will have electroencephalography (EEG), MR imaging and spectroscopy will be
performed at 1 to 2 weeks of age to examine the brain injury. The neurological outcomes will
be assessed between 18 to 22 months of age. The trial duration will be 4 years, consisting of
a 4 week start up period, 24 month recruitment period, a 18 month follow-up period, and 5
months for data analysis and write up.