Erythropoietin Protects Very Preterm Infants Against Necrotizing Enterocolitis and Potential Mechanisms: A Randomized Clinical Trial

Background: To determine whether recombinant human erythropoietin (rhEPO) protects against necrotizing enterocolitis (NEC) and the potential mechanisms in very preterm infants. Methods: The study was a prospective randomized clinical trial performed among 4 NICU centers. Preterm infants with gestational age ≤32 weeks were randomized to rhEPO (500 IU/kg, intravenously every other day for 2 weeks) or control group (the same volume of saline). Primary outcome was the incidence of NEC in very preterm infants at 36 weeks of corrected gestational age. Secondary outcomes were growth and neurodevelopment at 18 months of corrected age in very preterm infants with NEC. Meanwhile, peripheral blood of preterm infants after EPO treatment was collected and the transcriptome was assayed by RNA sequencing. Findings: A total of 1285 infants were analyzed at 36 weeks of corrected age for the incidence of NEC, 84 died (6.5%) and 1030 (80.2%) completed the study at 18 months corrected age. rhEPO treatment significantly decreased the incidence of NEC (stage I, II and III) (12.0% vs. 17.1%, p = 0.010), especially confirmed NEC (stage II and III) (3.0% vs. 5.4%, p = 0.027). Subgroup analyses showed that rhEPO treatment significantly decreased the incidence of NEC in gestational age of <28 weeks (OR = 0.178, 95% CI [0.037-0.865], p = 0.019). And transcriptome analysis showed that rhEPO treatment reduced intestinal inflammation signaling pathway. Interpretation: Repeated low-dose rhEPO treatment is beneficial against NEC in very preterm infants. Trial Registration Number: The trial was registered at ClinicalTrials.gov (NCT02036073). Funding Statement: This study was supported by the national Key Research and Development Program of China (2018YFC1004604), the Department of Science and Technology of Henan Province (134200510023), the Swedish Research Council (2015-02845). Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: This study was approved by the Life Science Ethics Committee of Zhengzhou University and Henan Medical Academy (201201002) in accordance with the Helsinki Declaration. Written informed consent was obtained from the parents of all included infants.