Recombinant Human Erythropoietin Improve Neurodevelopmental Outcomes in Extremely Preterm Infants (EPO)

In the ELGAN (Extremely Low Gestational Age Newborn) study, abnormal brain structure and function were associated with intermittent or sustained systemic inflammation (ISSI). Since EPO has anti-inflammatory properties in the kidney and in muscle as well as growth/trophic properties. Based on its potential for neuroprotection, the prospective randomized and masked study was designed to determine whether rhEPO （500u/kg) was also effective in improving developmental outcomes for extremely low gestational age newborns.

Exogenous erythropoietin (EPO) is currently used to reduce or prevent the need for red blood cell transfusions in preterm infants. Just two decades ago, erythropoietin (EPO) receptors were first identified in the brain, and astrocytes were found to be capable of synthesizing EPO . Subsequently, it was found that cultured hippocampal and cerebral cortical neurons exposed to EPO were spared some of the glutamate-induced cell death seen in neurons not exposed to EPO. Thus began the concept that EPO protects the brain against adversity. Several follow-up studies of children who had participated in trials of recombinant EPO for the prevention or treatment of anemia, term newborn encephalopathy,or retinopathy of prematurity have also provided evidence of neuroprotective effects. In the ELGAN (Extremely Low Gestational Age Newborn) study, abnormal brain structure and function were associated with intermittent or sustained systemic inflammation (ISSI) . Since EPO has anti-inflammatory properties in the kidney and in muscle as well as growth/trophic properties, we reasoned that elevated circulating levels might convey information about reduced risk of brain damage in ELGANs. Although major neurodevelopmental disabilities such as cerebral palsy (CP), mental disabilities, and learning and attention deficits during school age figure prominently in the outcomes of ELBW infants, successful neuroprotective interventions have yet to be developed. Investagators designed a prospective, randomized, masked study to evaluate rhEPO during initial hospitalization and follow up, and hypothesized that rhEPO recipients would receive fewer transfusions during initial hospitalization in extremely preterm infants. Based on its potential for neuroprotection, our study was designed to determine whether rhEPO (500 u/kg) was also effective in improving developmental outcomes for extremely low gestational age newborns. The neurodevelopmental outcomes of rhEPO in treating extremely preterm infants are not clear. Investigators propose an early-childhood neurodevelopmental follow-up study to compare long-term effects of the rhEPO as measured by, Bayley Scales of Infant Development III. We plan to follow extremely low gestational age children around 24 months' corrected age (CA) who are enrolled in this study.

In EPO group, The recombinant human erythropoietin (rhEPO) will be given by 500 U/kg/dose intravenously within 72h after birth, and every other day up to 32 weeks of corrected age.

Normal saline is administered the same volume with EPO, intravenously within 72h after birth, and every other day up to 32 weeks of corrected age.

rhEPO is administered 500IU/kg, intravenously within 72h after birth, and every other day up to 32 weeks of corrected age.

Normal salin is administered the same volume with rhEPO intravenously within 72h after birth, and every other day up to 32 weeks of corrected age..

To compare the incidence of MDI<70 via Bayley Scales of Infant Development between the two groups at 2 years old

Retinopathy of prematurity, periventricular leukomalacia,Intraventricular hemorrhage, necrotising enterocolitis and sepsis

To compare the incidence of blindness via auditory brainstem response measurements between the two groups at 2 years old

Inclusion Criteria: Preterm infants admitted to NICU wuth gestational age less than 28 weeks Age less than 3 days; parental informed consent. Exclusion Criteria: Major life-threatening anomalies (brain, cardiac, chromosomal anomalies) Hematologic crises such as DIC, or hemolysis due to blood group incompatibilities Polycythemia (hematocrit > 65); Hypertension Seizures Congenital infection

Rees S, Harding R, Walker D. The biological basis of injury and neuroprotection in the fetal and neonatal brain. Int J Dev Neurosci. 2011 Oct;29(6):551-63. doi: 10.1016/j.ijdevneu.2011.04.004. Epub 2011 Apr 15.

Korzeniewski SJ, Allred E, Logan JW, Fichorova RN, Engelke S, Kuban KC, O'Shea TM, Paneth N, Holm M, Dammann O, Leviton A; ELGAN study investigators. Elevated endogenous erythropoietin concentrations are associated with increased risk of brain damage in extremely preterm neonates. PLoS One. 2015 Mar 20;10(3):e0115083. doi: 10.1371/journal.pone.0115083. eCollection 2015.

Moore EM, Bellomo R, Nichol AD. Erythropoietin as a novel brain and kidney protective agent. Anaesth Intensive Care. 2011 May;39(3):356-72. doi: 10.1177/0310057X1103900306.

Ohls RK, Kamath-Rayne BD, Christensen RD, Wiedmeier SE, Rosenberg A, Fuller J, Lacy CB, Roohi M, Lambert DK, Burnett JJ, Pruckler B, Peceny H, Cannon DC, Lowe JR. Cognitive outcomes of preterm infants randomized to darbepoetin, erythropoietin, or placebo. Pediatrics. 2014 Jun;133(6):1023-30. doi: 10.1542/peds.2013-4307. Epub 2014 May 12.

Zhu C, Kang W, Xu F, Cheng X, Zhang Z, Jia L, Ji L, Guo X, Xiong H, Simbruner G, Blomgren K, Wang X. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics. 2009 Aug;124(2):e218-26. doi: 10.1542/peds.2008-3553. Epub 2009 Jul 27.

Brown MS, Eichorst D, Lala-Black B, Gonzalez R. Higher cumulative doses of erythropoietin and developmental outcomes in preterm infants. Pediatrics. 2009 Oct;124(4):e681-7. doi: 10.1542/peds.2008-2701. Epub 2009 Sep 28.

Leviton A, Kuban KC, Allred EN, Fichorova RN, O'Shea TM, Paneth N; ELGAN Study Investigators. Early postnatal blood concentrations of inflammation-related proteins and microcephaly two years later in infants born before the 28th post-menstrual week. Early Hum Dev. 2011 May;87(5):325-30. doi: 10.1016/j.earlhumdev.2011.01.043. Epub 2011 Feb 18.

O'Shea TM, Shah B, Allred EN, Fichorova RN, Kuban KCK, Dammann O, Leviton A; ELGAN Study Investigators. Inflammation-initiating illnesses, inflammation-related proteins, and cognitive impairment in extremely preterm infants. Brain Behav Immun. 2013 Mar;29:104-112. doi: 10.1016/j.bbi.2012.12.012. Epub 2013 Jan 4.

Lee SH, Li C, Lim SW, Ahn KO, Choi BS, Kim YS, Moon IS, Kim J, Bang BK, Yang CW. Attenuation of interstitial inflammation and fibrosis by recombinant human erythropoietin in chronic cyclosporine nephropathy. Am J Nephrol. 2005 Jan-Feb;25(1):64-76. doi: 10.1159/000084275. Epub 2005 Mar 2.

Contaldo C, Lindenblatt N, Elsherbiny A, Hogger DC, Borozadi MK, Vetter ST, Lang KS, Handschin AE, Giovanoli P. Erythropoietin requires endothelial nitric oxide synthase to counteract TNF-[alpha]-induced microcirculatory dysfunction in murine striated muscle. Shock. 2011 Mar;35(3):315-21. doi: 10.1097/SHK.0b013e3181fd0700.

Milne S, McDonald J, Comino EJ. The use of the Bayley Scales of Infant and Toddler Development III with clinical populations: a preliminary exploration. Phys Occup Ther Pediatr. 2012 Feb;32(1):24-33. doi: 10.3109/01942638.2011.592572. Epub 2011 Aug 4.