If you are worried that your pre-term infant might develop encephalopathy, and are considering giving him neuroprotective treatment with recombinant human erythropoietin (rhEPO), don’t! It’s no use and does not provide any benefit.

According to a trial published in the Journal of the American Medical Association (JAMA), on May 17th, 2016, an early dose of rhEPO is not significant in reducing the risk of encephalopathy and neurodevelopmental risks, in very pre-term infants.

Prophylactic administration of high-dosages of rhEPO has sparked considerable interest among clinicians and parents of pre-term infants. Studies and experiments in neonatal animal models have vouched for the efficacy of rhEPO. Their findings entail a significant decrease in both acute and long-term sequelae of brain injury with the prophylactic administration of erythropoietin.

Randomized clinical trials, involving adults with stroke, multiple sclerosis or schizophrenia, have also expanded on the neuroprotective properties of rhEPO. However, limited data and reports are available, regarding the benefits of prophylactic rhEPO administration and the neurodevelopmental outcome in preterm infants. Moreover, the available reports and data are contentious.

Attempting to substantiate, or negate, the evidence available from earlier studies, the current study undertook the challenge with the main objective to determine whether prophylactic high-dosages of rhEPO provide benefits in terms of neurodevelopmental outcome among preterm two-year old infants.

 Study Design, Settings and Participants

The randomized, double-blind, and multicenter trial enrolled 448 preterm Swiss infants born between born 26 weeks, 0 days and 31 weeks, 6 days gestation. Neurodevelopmental assessment was done after two years for each infant in 2014. The mean age of the cohort at the time was 23.6 months.

All infants were randomized to two arms — the rhEPO arm i.e., 228 infants; and the placebo arm i.e., 220 infants. Infants received rhEPO (3000 IU/kg) and placebo (isotonic saline, 0.9%) IN at 3 hours, 12-18 hours and 36-42 hours following birth.

The primary outcome of the study was the assessment of cognitive development at two years. Higher values of the Mental Development Index (MDI) indicated better function. Secondary outcomes included an assessment of motor development, hearing or visual impairment, cerebral palsy and anthropometric growth parameters.

Results

The final analysis did not reveal significant difference on the MDI scale between the rhEPO group (93.5) and the placebo group (94.5). No differences were found between groups in the secondary outcomes.

Interpretation

The researchers concluded that an early prophylactic use of high-dose rhEPO neither lowered the risk of encephalopathy nor improved neurological development in very pre-term infants at two years. A follow-up is recommended for cognitive problems that have not hitherto manifested themselves in pre-term infants.

Pre-Term Infants and Risk of Brain Injury

Besides death, premature infants are at a heightened risk of brain injury. Even the smallest and sickest baby that thrives is prone to developing lifelong neurodevelopmental problems. Striding through life comes at a high cost for such babies i.e., carrying a >50% risk of disability at school age if they weighed <1,000 g at birth.

In fact, such babies have the highest incidence of cerebral palsy i.e., they constitute the fastest growing subgroup of children with cerebral palsy. Cerebral palsy is a group of neurological disorders characterized by a permanent defect in the body movement, muscle coordination, and balance. It appears either in infancy or early childhood.

rhEPO Benefits

Erythropoietin, a cytokine, regulates red blood cell production in the body. Cytokines are molecules produced by immune cells that help in cell-to-cell communication in immune responses, and facilitate the movement of killer cells towards sites of inflammation, infection and trauma.

Cytokines also have a direct vasoactive effect i.e., they expand blood vessels, thereby regulating blood circulation (hemodynamics), and providing a proangiogenic effect i.e., stimulation of vascular endothelial growth factor secretion that triggers cell-division (mitosis) and motility of endothelial cells.

The protective effects of erythropoietin have made it the center of attention for researchers. Over time, erythropoietin has received considerable attention, such as being employed in animal studies of neurological disorders.

Experimental data obtained from such studies and trials indicate that rhEPO can lower the detrimental effects of glutamate toxicity. Glutamate is an excitatory neurotransmitter that has a role in the normal development of learning and memory. High concentration of glutamate can lead to over-excitation of the nerve cell.

Erythropoietin has neuroprotective and neurotrophic effects — it upregulates the brain-derived neurotrophic factor – a group of proteins that facilitate growth, survival, and differentiation of developing and mature neurons. This particular effect of erythropoietin renders it most significant in clinical research.

Other beneficial effects of erythropoietin include:

  • Modulation of intracellular calcium metabolism
  • Production of antiapoptotic factors i.e., factors preventing programmed cell death (apoptosis)
  • Inflammation attenuation
  • Inhibition of nitric oxide-mediated injury

All of these factors have been reported to contribute to brain injury, the risk of which is highest in pre-term infants.