Erythropoietin Protects Very Preterm Infants Against Necrotizing Enterocolitis

Zhengzhou Children's Hospital, China, The First Affiliated Hospital of Zhengzhou University, Women and Children Health Care Center of Luoyang, China, Göteborg University

This study evaluates the effect of repeated low-dose erythropoietin (EPO) treatment on necrotizing enterocolitis (NEC) in very preterm infants. Half of participants will receive EPO, while the other half will receive a placebo.

NEC is one of the most severe complications in preterm neonates and is associated with high morbility and mortality. Studies have reported that EPO treatment decreases the incidence and severity of experimental NEC in animal models. Evidence from previous clinical studies about the effect of EPO treatment against NEC have all been hampered by small numbers of patients. The study is to investigate whether repeated low-dose EPO protects against NEC. Preterm infants with gestational age ≤32 weeks who are admitted to neonatal intensive care units within 72 hours after birth are randomized to EPO (500IU/kg, intravenously every other day for 2 weeks) or control group (the same volume of saline). Primary outcome is the incidence of NEC at 36 weeks of corrected age. Secondary outcome is growth and neurodevelopment at 18 months of corrected age in infants with NEC.

Infants in the EPO group are given EPO 500IU/kg dissolved in 2 ml saline intravenously every other day for 2 weeks starting within 72 hours after birth.

Infants in the control group are given normal saline intravenously with the same volume as EPO every other day for 2 weeks.

Infants in EPO group are administered 500IU/kg intravenously within 72 hours after birth every other day for 2 weeks.

To compare the incidence of low height in patients with NEC between EPO and control groups via the Standardized Growth Curve for Chinese Children at 18 months of corrected age.

To compare the incidence of low weight in patients with NEC between EPO and control group via the Standardized Growth Curve for Chinese Children at 18 months of corrected age.

To compare the incidence of low head circumference in patients with NEC between EPO and control group via the Standardized Growth Curve for Chinese Children at 18 months of corrected age.

To compare the incidence of MDI<70 in patients with NEC between EPO and control group via Bayley Scales of Infant Development (second edition) at 18 months of corrected age.

To compare the incidence of cerebral palsy in patients with NEC between EPO and control group at 18 months of corrected age.

To compare the incidence of blindness in patients with NEC between EPO and control group via visual acuity at 18 months of corrected age.

To compare the incidence of deafness in patients with NEC between EPO and control group via auditory brainstem response measurement at 18 months of corrected age.

To investigate different mRNA expression between EPO and control group, peripheral venous blood of preterm infants after EPO treatment will be collected in both EPO group and control group, and the transcriptome of the premature infant blood will be assayed by RNA sequencing.

Inclusion Criteria: Preterm infants with gestation age ≤ 32weeks Within 72 hours after birth Written informed consent obtained from parents Exclusion Criteria: Genetic or metabolic diseases Congenital abnormalities Polycythemia Intracranial hemorrhage grade III/IV Unstable vital signs (such as respiration and circulation failure)

De-identified individual participant data for all primary and secondary outcome measures will be made available.

Data access requests will be assessed by sponsor. Requestors will be required to sign a Data Access Agreement.

Sun H, Song J, Kang W, Wang Y, Sun X, Zhou C, Xiong H, Xu F, Li M, Zhang X, Yu Z, Peng X, Li B, Xu Y, Xing S, Wang X, Zhu C. Effect of early prophylactic low-dose recombinant human erythropoietin on retinopathy of prematurity in very preterm infants. J Transl Med. 2020 Oct 19;18(1):397. doi: 10.1186/s12967-020-02562-y.

Wang Y, Song J, Sun H, Xu F, Li K, Nie C, Zhang X, Peng X, Xia L, Shen Z, Yuan X, Zhang S, Ding X, Zhang Y, Kang W, Qian L, Zhou W, Wang X, Cheng X, Zhu C. Erythropoietin prevents necrotizing enterocolitis in very preterm infants: a randomized controlled trial. J Transl Med. 2020 Aug 8;18(1):308. doi: 10.1186/s12967-020-02459-w.