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Erythropoietin prevents necrotizing enterocolitis in very preterm infants: a randomized controlled trial.

ABSTRACT: BACKGROUND:Necrotizing enterocolitis (NEC) is one of the most severe complications in very preterm infants, but there are currently no accepted methods to prevent NEC. Studies have shown that erythropoietin (EPO) has the potential to prevent NEC or improve outcomes of preterm NEC. This study aimed to determine whether recombinant human EPO (rhEPO) could protect against NEC in very preterm infants. METHODS:The study was a prospective randomized clinical trial performed among four NICU centers. A total of 1327 preterm infants with gestational age ??32 weeks were admitted to the centers, and 42 infants were excluded leaving 1285 eligible infants to be randomized to the rhEPO or control group. Infants in the rhEPO group were given 500 IU/kg rhEPO intravenously every other day for 2 weeks, while the control group was given the same volume of saline. The primary outcome was the incidence of NEC in very preterm infants at 36 weeks of corrected gestational age. RESULTS:A total of 1285 infants were analyzed at 36 weeks of corrected age for the incidence of NEC. 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). Meanwhile, rhEPO treatment significantly reduced the number of red blood cells transfusion in the confirmed NEC cases (1.2?±?0.4 vs. 2.7?±?1.0, p?=?0.004). Subgroup analyses showed that rhEPO treatment significantly decreased the incidence of confirmed NEC at gestational age??5 (p?=?0.028). CONCLUSION:Repeated low-dose rhEPO treatment is beneficial against NEC in very preterm infants. Trial registration The protocol was registered retrospectively at ClinicalTrials.gov (NCT03919500) on April 18, 2019. https://clinicaltrials.gov/ct2/show/NCT03919500.

SUBMITTER: Wang Y

PROVIDER: S-EPMC7414749 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Erythropoietin prevents necrotizing enterocolitis in very preterm infants: a randomized controlled trial.

Wang Yong Y Song Juan J Sun Huiqing H Xu Falin F Li Kenan K Nie Chunxia C Zhang Xiaoli X Peng Xirui X Xia Lei L Shen Ziyun Z Yuan Xiao X Zhang Shan S Ding Xue X Zhang Yaodong Y Kang Wenqing W Qian Liling L Zhou Wenhao W Wang Xiaoyang X Cheng Xiuyong X Zhu Changlian C

Journal of translational medicine 20200808 1

<h4>Background</h4>Necrotizing enterocolitis (NEC) is one of the most severe complications in very preterm infants, but there are currently no accepted methods to prevent NEC. Studies have shown that erythropoietin (EPO) has the potential to prevent NEC or improve outcomes of preterm NEC. This study aimed to determine whether recombinant human EPO (rhEPO) could protect against NEC in very preterm infants.<h4>Methods</h4>The study was a prospective randomized clinical trial performed among four N ...[more]

PMID: 32771013

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Project description:Background: The pathophysiology of necrotizing enterocolitis (NEC) remains poorly understood.Objective: We assessed the relation between feeding strategies, intestinal microbiota composition, and the development of NEC.Design: We performed a prospective nationwide population-based study, EPIPAGE 2 (Etude Epidémiologique sur les Petits Ages Gestationnels), including preterm infants born at <32 wk of gestation in France in 2011. From individual characteristics observed during the first week of life, we calculated a propensity score for the risk of NEC (Bell's stage 2 or 3) after day 7 of life. We analyzed the relation between neonatal intensive care unit (NICU) strategies concerning the rate of progression of enteral feeding, the direct-breastfeeding policy, and the onset of NEC using general linear mixed models to account for clustering by the NICU. An ancillary propensity-matched case-control study, EPIFLORE (Etude Epidémiologique de la flore), in 20 of the 64 NICUs, analyzed the intestinal microbiota by culture and 16S ribosomal RNA gene sequencing.Results: Among the 3161 enrolled preterm infants, 106 (3.4%; 95% CI: 2.8%, 4.0%) developed NEC. Individual characteristics were significantly associated with NEC. Slower and intermediate rates of progression of enteral feeding strategies were associated with a higher risk of NEC, with an adjusted OR of 2.3 (95% CI: 1.2, 4.5; P = 0.01) and 2.0 (95% CI: 1.1, 3.5; P = 0.02), respectively. Less favorable and intermediate direct-breastfeeding policies were associated with higher NEC risk as well, with an adjusted OR of 2.5 (95% CI: 1.1, 5.8; P = 0.03) and 2.3 (95% CI: 1.1, 4.8; P = 0.02), respectively. Microbiota analysis performed in 16 cases and 78 controls showed an association between Clostridium neonatale and Staphylococcus aureus with NEC (P = 0.001 and P = 0.002).Conclusions: A slow rate of progression of enteral feeding and a less favorable direct-breastfeeding policy are associated with an increased risk of developing NEC. For a given level of risk assessed by propensity score, colonization by C. neonatale and/or S. aureus is significantly associated with NEC. This trial (EPIFLORE study) was registered at clinicaltrials.gov as NCT01127698.

Project description:BackgroundSeveral clinical trials investigated the effects of enteral lactoferrin supplementation on the prevention of sepsis and necrotizing enterocolitis (NEC) in preterm infants, but the efficacy and safety remain disputed. Therefore, we systematically evaluated the effect of enteral lactoferrin supplementation in preterm infants through a meta‑analysis with trial sequential analysis (TSA).MethodsWe searched six databases to identify randomized controlled trials (RCTs) that evaluated the effects of lactoferrin supplementation compared with placebo or no intervention in preterm infants. RevMan version 5.3 software was used to estimate pooled relative risks (RRs) with the random-effects model. TSA, subgroup analyses, and meta-regression analyses were also performed.ResultsNine RCTs with 3515 samples were included. With low to moderate quality of evidence, compared with placebo, enteral lactoferrin supplementation did not significantly decrease the incidences of late-onset sepsis (RR = 0.63, 95% CI: 0.38 to 1.02, P = 0.06), NEC stage II or III (RR = 0.68, 95% CI: 0.30 to 1.52, P = 0.35), all-cause mortality (RR = 0.89, 95% CI: 0.51 to 1.57, P = 0.69), bronchopulmonary dysplasia (RR = 1.01, 95% CI: 0.90 to 1.13, P = 0.92), retinopathy of prematurity (RR = 0.80, 95% CI: 0.49 to 1.32, P = 0.38), invasive fungal infection (RR = 0.27, 95% CI: 0.02 to 3.94, P = 0.34), intraventricular hemorrhage (RR = 1.40, 95% CI: 0.39 to 5.08, P = 0.61), and urinary tract infection (RR = 0.35, 95% CI: 0.11 to 1.06, P = 0.06). Subgroup analysis revealed that lactoferrin significantly reduced the incidence of sepsis in infants with a birth weight below 1500 g (RR = 0.43, 95% CI: 0.22 to 0.84, P = 0.01). TSAs of the primary outcomes showed that the evidence is insufficient and further data is required.ConclusionsLimited evidence suggested that enteral lactoferrin supplementation was associated with a reduction of late-onset sepsis in infants with a birth weight below 1500g, however, did not decrease the incidence of NEC stage II or III, all-cause mortality, and other adverse events in preterm infants. The present evidence was insufficient to inform clinical practice.

Project description:BackgroudThe aim of the study was to evaluate the effect of early parenteral iron supplementation combined erythropoietin for prevention of anemia in preterm infants.MethodsIn total, 96 preterm infants were randomly assigned to 3 groups: a control group receiving standard parenteral nutrition (group 1: n = 31), an iron-supplemented group (group 2: IS, n = 33), and an iron-supplemented combined erythropoietin group (group 3: IS+EPO, n = 32). The primary objective was to assess hemoglobin (Hb) levels. The secondary objectives included assessment of red blood cell counts (RBC), mean cell volume (MCV), serum iron, ferritin, percentages of reticulocyte (RET), total iron binding capacity (TIBC) and oxidative stress, which was assessed by measuring plasma levels of malondialdehyde and superoxide dismutase at baseline and at 2 weeks. The blood routine indices including Hb, RBC, MCV, and percentages of RET were measured at corrected age of 1 and 3 months.ResultsAt 2 weeks of life, the percentages of reticulocyte in group 2 and group 3 were significantly higher than those in group 1 (2.1±0.4, 2.5±0.3, and 1.7±0.3, respectively, P < 0.001, P<0.001), whereas TIBC were significantly lower than those in group 1 (36.7±4.6, 36.0±4.7, and 41.6 ± 5.2 respectively, P = 0.011, P = 0.006). There were no significant differences in RBC counts, the levels of hemoglobin, ferritin, malondialdehyde, and superoxide dismutase among the 3 groups at 2weeks of life. RBC, Hb, MCV, body weight, body length, and head circumference at a corrected age of 1 month did not differ among 3 groups. At corrected age of 3months, more infants in the control group had abnormal Hb and MCV levels (Hb levels: 114.3 ± 21.3, 123.7 ± 31.6, and 125.1 ± 21.2, P = 0.021, P = 0.034, respectively; MCV: 74.1 ± 3.5, 78.3 ± 4.7 and 79.1 ± 5.2, P = 0.017, P = 0.012, respectively), whereas cases of oral iron, cases of breastfeeding, RBC, body weight, body length, and head circumference were not different among 3 groups.ConclusionEarly parenteral iron supplementation combined erythropoietin in preterm infants improved the percentages of reticulocyte, decreased total iron binding capacity, and improved the Hb and MCV levels at 3 months of age. Early parenteral iron supplementations with EPO were beneficial for the preterm infants.

Project description:BackgroundHigh-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established.MethodsIn this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for a total of six doses, followed by a maintenance dose of 400 U per kilogram three times per week by subcutaneous injection through 32 completed weeks of postmenstrual age. Placebo was administered as intravenous saline followed by sham injections. The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. Severe neurodevelopmental impairment was defined as severe cerebral palsy or a composite motor or composite cognitive score of less than 70 (which corresponds to 2 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition.ResultsA total of 741 infants were included in the per-protocol efficacy analysis: 376 received erythropoietin and 365 received placebo. There was no significant difference between the erythropoietin group and the placebo group in the incidence of death or severe neurodevelopmental impairment at 2 years of age (97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence interval, 0.81 to 1.32; P = 0.80). There were no significant differences between the groups in the rates of retinopathy of prematurity, intracranial hemorrhage, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in the frequency of serious adverse events.ConclusionsHigh-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age. (Funded by the National Institute of Neurological Disorders and Stroke; PENUT ClinicalTrials.gov number, NCT01378273.).

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Erythropoietin prevents necrotizing enterocolitis in very preterm infants: a randomized controlled trial.

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Erythropoietin prevents necrotizing enterocolitis in very preterm infants: a randomized controlled trial.

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