Erythropoietin in perinatal hypoxic-ischemic encephalopathy: a systematic review and meta-analysis

Background: Erythropoietin (EPO) appears to confer neuroprotection to the injured brain. Randomized clinical trials (RCTs) have demonstrated its safety in neonates with hypoxic-ischemic encephalopathy (HIE); however, the evidence is unclear. The objective of this study was to examine the role of EPO in perinatal HIE by a systematic review and meta-analysis. Methods: Database search included Embase, MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Cochrane Central Register of Controlled Trials (CENTRAL). RCTs reporting a death, neurodevelopmental outcomes or brain injury were included. Two authors extracted the data independently from included studies and assessed the level of evidence (LOE). Results: Six RCTs (EPO= 5 and darbepoetin alpha =1) involving 454 neonates were included. A trend toward a lower risk of death was identified in infants treated with EPO [EPO with or without hypothermia: five RCTs, 368 participants, relative risk (RR) 0.74, 95% confidence interval (CI) 0.47E19, LOE - low; EPO without hypothermia: four RCTs, 318 participants, RR 0.89, 95% CI 0.49-1.32, LOE - low]. EPO treatment without hypothermia compared to placebo resulted in a reduced risk of cerebral palsy (two RCTs, 230 participants, RR 0.447, 95% CI 0.27-0.80, LOE - moderate) and moderate to severe cognitive impairment (two RCTs, 226 participants, RR 0.49, 95% CI 0.28 0.85, LOE - moderate). A reduced risk of brain injury was identified in EPO treated infants (EPO with or without hypothermia, two RCTs, 148 participants, RR 0.70, 95% CI 0.53 0.92, LOE - moderate). Conclusion: EPO administration in neonates with perinatal HIE reduces the risk of brain injury, cerebral palsy and cognitive impairment. The evidence is limited to suggest its role as an adjuvant to hypothermia. Larger powered trials are underway to overcome this limitation.