Darbepoetin in Neonatal Encephalopathy (EDEN) Trial

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.