Effect of Early Erythropoietin on Retinopathy of Prematurity: A Stratified Meta-Analysis
BACKGROUND Recombinant human erythropoietin (rhEPO) lost its role in minimizing red blood cell transfusion in very preterm infants after it had been associated with severe retinopathy of prematurity (ROP). Previous systematic reviews did not stratify ROP by gestation and birth weight (BW). OBJECTIVES The aim of this study was to investigate the effect of early prophylactic rhEPO on ROP in a stratified meta-analysis of randomized controlled trials (RCTs). METHODS The databases EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials were searched in January 2022 and complemented by citation searching. RCTs comparing early rhEPO treatment with no treatment or placebo were selected if they were published in a peer-reviewed journal and reported ROP outcomes. Previously unpublished data were requested from the study authors to allow stratified analyses by gestational age (GA) and BW. Data were extracted and analyzed using the standard methods of the Cochrane Neonatal Review Group. Pre-specified outcomes were "ROP stage ≥3" (primary outcome) and "any ROP." RESULTS Fourteen RCTs, comprising 2,040 infants of <29 weeks of GA, were included for meta-analysis. Data syntheses showed no effects of rhEPO on ROP stage ≥3 or on any ROP, neither in infants of <29 weeks GA, nor in infants of <1,000 g BW, nor in any GA strata. The risk ratio (95% confidence interval) for ROP stage ≥3 in infants of <29 weeks of GA was 1.13 (0.84, 1.53), p = 0.41 (quality of evidence: moderate). CONCLUSIONS The present meta-analysis detected no effects of early rhEPO on ROP in any comparison, but most stratified analyses were limited by low statistical power.
Infants of <29 weeks of gestational age (GA), (14 randomised controlled trials, n= 2,040).
Early recombinant human erythropoietin (rhEPO).
No treatment or placebo.
Data syntheses showed no effects of rhEPO on retinopathy of prematurity (ROP) stage ≥3 or on any ROP, neither in infants of <29 weeks GA, nor in infants of <1,000 g birth weight, nor in any GA strata. The risk ratio for ROP stage ≥3 in infants of <29 weeks of GA was 1.13; 95% confidence interval [0.84, 1.53], (quality of evidence: moderate).
Early erythropoietin for preventing necrotizing enterocolitis in preterm neonates - an updated meta-analysis
European Journal of Pediatrics. 2022;181(5):1821-1833
Previous systematic reviews suggest reduction in necrotizing enterocolitis (NEC) among preterm infants supplemented with erythropoietin (EPO). We aimed to update our 2018 systematic review in this field considering the evidence accumulated over the last 3 years. Randomized controlled trials (RCTs) reporting the effect of early EPO supplementation vs placebo/no EPO supplementation on any stage NEC in preterm infants were included. Fixed effect model was used for meta-analysis. Trial sequential analysis (TSA) was conducted to verify the effects of EPO on NEC after accounting for repeated significance testing. A total of 22 RCTs (n = 5359) were included, of which six were new (n = 2541 additional preterm infants) in comparison to our previous systematic review. EPO significantly decreased the risk of any stage NEC (232/2669 (8.7%) vs 313/2690 (11.6%); RR: 0·76; TSA adjusted 95% CI (0·64, 0·90); p = 0·0008, number needed to treat (NNT) = 34). The risk of definite NEC (≥ Stage II) was also significantly reduced by EPO administration (105/2219 (4.7%) vs 141/2246 (6.3%); RR: 0.77; 95% CI (0.61, 0.98); p = 0.03, NNT: 62). However, the results for definite NEC were no longer significant on sensitivity analyses that included (a) only double-blind RCTs and (b) only prospectively registered trials. The quality of evidence was deemed moderate-to-low for the reported outcomes. CONCLUSION There is moderate to low-quality evidence that early prophylactic EPO reduces any stage and ≥ Stage II NEC in preterm neonates. Prospectively registered, adequately powered, double-blind RCTs are required to confirm these findings. WHAT IS KNOWN • Experimental studies have shown that erythropoietin (EPO) has gastrointestinal trophic effects. • Systematic reviews have shown that early treatment with EPO may decrease the risk of gut injury in preterm or low birth weight infants. WHAT IS NEW • Early EPO supplementation significantly reduced the incidence of any stage NEC and definite NEC in preterm infants < 34 weeks of gestation. • EPO had no significant effect on definite NEC in the analyses that included only double-blinded and prospectively registered RCTs. How might it impact clinical practice in the foreseeable future? • Early prophylactic EPO can be recommended for NEC prevention if its benefits are consistently demonstrated in adequately powered randomized trials with a low risk of bias.
Prophylactic Erythropoietin for Neuroprotection in Very Preterm Infants: A Meta-Analysis Update
Frontiers in pediatrics. 2021;9:657228
A meta-analysis update of randomized controlled trials investigating recombinant human erythropoietin suggests improved neurodevelopmental outcome in preterm infants. There was substantial heterogeneity, which could be ascribed to a single trial. Exclusion of this trial featuring a high risk of bias abolished heterogeneity and any effects of recombinant human erythropoietin treatment.
The effects of monotherapy with erythropoietin in neonatal hypoxic-ischemic encephalopathy on neurobehavioral development: a systematic review and meta-analysis
European review for medical and pharmacological sciences. 2021;25(5):2318-2326
OBJECTIVE Previous systematic review has shown the safety and efficiency of EPO (erythropoietin) for neonatal hypoxic-ischemic encephalopathy (HIE). To date, the evidence is limited that EPO is beneficial to therapeutic hypothermia as an adjuvant. There has not a brief discussion about the neuroprotection effects of EPO without hypothermia. To evaluate the long-term prognosis of HIE treated with EPO alone, we carried out this study that can be a supplement to the previous meta-analysis. MATERIALS AND METHODS 7 databases (including PubMed, EMBASE, Cochrane, CKNI, CBM, WanFang, and VIP) and the ClinicalTrials.gov were retrieved from inception to 1 March 2020. The inclusion criteria were RCTs with EPO treatment without hypothermia. The outcomes were tested by using the Bayley Scales of Infant Development (BSID), including the Bayley Mental Development Index Score (MDI) and the Bayley Psychomotor Development Index Score (PDI). This meta-analysis was done to compare the Risk Ratio (RR) for the scores of BSID less than 70 after over 6 months of follow-up. RESULTS 11 RCTs (1099 newborns) were included, excluding deaths and lost visits, and 917 patients finally were performed the statistical analysis. In neonatal HIE infants, investigation results showed a lower risk of cognitive impairment and psychomotor disability with EPO monotherapy. The pooled event rates of MDI <70 saw a reduction of 36% (95% CI 24%-54%) compared to the control group. There was a decrease of 37% (95% CI 24%-56%) of Psychomotor abnormal (PDI <70) in the EPO group. CONCLUSIONS EPO administration alone could improve the scores of mental and psychomotor in neonates with HIE. However, the level of evidence is low to moderate for the insufficient sample size, so large-scale, multicenter clinical trials are still needed.
Sustained low-dose prophylactic early erythropoietin for improvement of neurological outcomes in preterm infants: A systematic review and meta-analysis
Journal of affective disorders. 2021;282:1187-1192
The aim of this meta-analysis was conducted to assess the effects of different doses of prophylactic rhEPO on neurodevelopmental outcomes and provide reference for rational drug use. The primary outcome was the number of infants with a Mental Developmental Index (MDI) <70 on the Bayley Scales of Infant Development. Five RCTs, comprising 2282 infants, were included in this meta-analysis. Overall, prophylactic rhEPO administration reduced the incidence of infants with an MDI <70, with an odds ratio (95% confidence interval) of 0.55 (0.38-0.79), P <0.05. The low-dose rhEPO subgroup was superior to the placebo subgroup, with an OR (95% CI) of 0.47 (0.25-0.87), P <0.05. However, high-dose rhEPO subgroup had no significant impact on MDI <70 in infants <28 weeks' gestational age. The definitions of the secondary outcome showed that there was no significant effect of rhEPO on cerebral palsy. For neonatal complications, although four studies showed that there were no differences in the pooled results of BPD and ICH events between rhEPO treatment and placebo, the ICH events were significantly lower in the low-dose rhEPO (OR 0.36; 95% CI 0.23-0.59). In addition, in the pooled results of NEC and ROP events, there were significant differences between the two groups (OR 0.63; 95% CI 0.43-0.93) (OR 0.80; 95% CI 0.65-0.98). And the NEC events were significantly lower in the low-dose rhEPO (OR 0.45; 95% CI 0.27-0.73). Sustained low-dose prophylactic early erythropoietin might be more superior than high-dose for improvement of neurological outcomes and several neonatal complications in preterm infants.
Children who were born prematurely, aged between 18-24 months corrected age (n= 2,282, 5 RCTs).
High-dose or low-dose prophylactic erythropoietin (rhEPO).
Overall, prophylactic rhEPO administration reduced the incidence of infants with a mental development index (MDI) <70, with an odds ratio (95% confidence interval) of 0.55 (0.38-0.79). The low-dose rhEPO subgroup was superior to the placebo subgroup, with an OR (95% CI) of 0.47 (0.25-0.87). However, high-dose rhEPO subgroup had no significant impact on MDI <70 in infants <28 weeks' gestational age. There was no significant effect of rhEPO on cerebral palsy. For neonatal complications, although four studies showed that there were no differences in the pooled results of bronchopulmonary dysplasia and intracranial haemorrhage (ICH) events between rhEPO treatment and placebo, the ICH events were significantly lower in the low-dose rhEPO (OR 0.36; 95% CI 0.23-0.59). In addition, in the pooled results of necrotizing enterocolitis (NEC) and retinopathy of prematurity events, there were significant differences between the two groups (OR 0.63; 95% CI 0.43-0.93), (OR 0.80; 95% CI 0.65-0.98). And the NEC events were significantly lower in the low-dose rhEPO (OR 0.45; 95% CI 0.27-0.73).
Clinical outcomes related to the gastrointestinal trophic effects of erythropoietin in preterm neonates: a systematic review and meta-analysis
Advances in Nutrition (Bethesda, Md.). 2018;9((3)):238-246.
Erythropoietin (EPO) plays an important role in the development and maturation of the gastrointestinal tract. Recombinant EPO (rEPO) has been used to prevent anemia of prematurity. The gastrointestinal trophic effects of EPO may reduce feeding intolerance and necrotizing enterocolitis (NEC) in preterm neonates. The aim of this systematic review of randomized controlled trials (RCTs) was to evaluate the effects of rEPO on clinical outcomes such as feeding intolerance, stage II or higher NEC, any stage NEC, sepsis, retinopathy of prematurity, and bronchopulmonary dysplasia in preterm neonates. Twenty-five RCTs (intravenous: 13; subcutaneous: 10; enteral: 2; n = 4025) were eligible for inclusion. Meta-analysis of data from 17 RCTs (rEPO compared with placebo) with the use of a fixed-effects model showed no significant effect of rEPO on stage II or higher NEC (RR: 0.87; 95% CI: 0.64, 1.19; P = 0.39). Meta-analysis of data from 25 RCTs (rEPO compared with placebo) showed that rEPO significantly decreased the risk of any stage NEC [cases/total sample: 120/2058 (5.83%) compared with 146/1967 (7.42%); RR: 0.77; 95% CI: 0.61, 0.97; P = 0.03]. Only one RCT reported on time to full feedings. Meta-analysis of data from 15 RCTs showed a significant reduction in late-onset sepsis after rEPO administration (RR: 0.81; 95% CI: 0.71, 0.94; P = 0.004). Meta-analysis of 13 RCTs showed no significant effect of rEPO on mortality, retinopathy of prematurity, and bronchopulmonary dysplasia. Prophylactic rEPO had no effect on stage II or higher NEC, but it reduced any stage NEC, probably by reducing feeding intolerance, which is often labeled as stage I NEC. Adequately powered RCTs are required to confirm these findings.
Early erythropoiesis-stimulating agents in preterm or low birth weight infants
The Cochrane Database of Systematic Reviews. 2017;((11)):CD004863.
BACKGROUND Preterm infants have low plasma levels of erythropoietin (EPO), providing a rationale for the use of erythropoiesis-stimulating agents (ESAs) to prevent or treat anaemia and to provide neuro protection and protection against necrotising enterocolitis (NEC). Darbepoetin (Darbe) and EPO are currently available ESAs. OBJECTIVES To assess the effectiveness and safety of ESAs (erythropoietin (EPO) and/or Darbe) initiated early (before eight days after birth) compared with placebo or no intervention in reducing red blood cell (RBC) transfusions, adverse neurological outcomes, and feeding intolerance including necrotising enterocolitis (NEC) in preterm and/or low birth weight infants. Primary objective for studies that primarily investigate the effectiveness and safety of ESAs administered early in reducing red blood cell transfusions:To assess the effectiveness and safety of ESAs initiated early in reducing red blood cell transfusions in preterm infants. Secondary objectives:Review authors performed subgroup analyses of low (≤ 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO and the amount of iron supplementation provided: none, low (≤ 5 mg/kg/d), and high (> 5 mg/kg/d). Primary objective for studies that primarily investigate the neuro protective effectiveness of ESAs:To assess the effectiveness and safety of ESAs initiated early in reducing adverse neurological outcomes in preterm infants. Primary objective for studies that primarily investigate the effectiveness of EPO or Darbe administered early in reducing feeding intolerance:To assess the effectiveness and safety of ESAs administered early in reducing feeding intolerance (and NEC) in preterm infants. Other secondary objectives:To compare the effectiveness of ESAs in reducing the incidence of adverse events and improving long-term neurodevelopmental outcomes. SEARCH METHODS We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE via PubMed (1966 to 10 March 2017), Embase (1980 to 10 March 2017), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to 10 March 2017). We searched clinical trials databases, conference proceedings, and reference lists of retrieved articles for randomised and quasi-randomised controlled trials. SELECTION CRITERIA Randomised and quasi-randomised controlled trials of early initiation of EAS treatment versus placebo or no intervention in preterm or low birth weight infants. DATA COLLECTION AND ANALYSIS We used the methods described in the Cochrane Handbook for Systematic Reviews of Interventions and the GRADE approach to assess the quality of evidence. MAIN RESULTS This updated review includes 34 studies enrolling 3643 infants. All analyses compared ESAs versus a control consisting of placebo or no treatment.Early ESAs reduced the risk of 'use of one or more [red blood cell] RBC transfusions' (typical risk ratio (RR) 0.79, 95% confidence interval (CI) 0.74 to 0.85; typical risk difference (RD) -0.14, 95% CI -0.18 to -0.10; I2 = 69% for RR and 62% for RD (moderate heterogeneity); number needed to treat for an additional beneficial outcome (NNTB) 7, 95% CI 6 to 10; 19 studies, 1750 infants). The quality of the evidence was low.Necrotising enterocolitis was significantly reduced in the ESA group compared with the placebo group (typical RR 0.69, 95% CI 0.52 to 0.91; typical RD -0.03, 95% CI -0.05 to -0.01; I2 = 0% for RR and 22% for RD (low heterogeneity); NNTB 33, 95% CI 20 to 100; 15 studies, 2639 infants). The quality of the evidence was moderate.Data show a reduction in 'Any neurodevelopmental impairment at 18 to 22 months' corrected age in the ESA group (typical RR 0.62, 95% CI 0.48 to 0.80; typical RD -0.08, 95% CI -0.12 to -0.04; NNTB 13, 95% CI 8 to 25. I2 = 76% for RR (high heterogeneity) and 66% for RD (moderate); 4 studies, 1130 infants). The quality of the evidence was low.Results reveal increased scores on the Bayley-II Mental Development Index (MDI) at 18 to 24 months in the E
Recombinant human erythropoietin in neonates: guidelines for clinical practice from the French Society of Neonatology . French
Archives de Pediatrie. 2015;22((10)):1092-7.
OBJECTIVE 1/To assess the effectiveness and safety of EPO in reducing red blood cell (RBC) transfusions in preterm infants. 2/To provide guidelines for clinical practice in France. METHODS 1/This systematic evidence review is based on PubMed search, Cochrane library. 2/Using French National Authority for Health methods concerning guidelines for clinical practice. RESULTS Early EPO reduced the risk of RBC transfusions, donor exposure, and the number of transfusions in very preterm infants (LE2). Late EPO reduced the risk of RBC transfusions and the number of transfusions in very preterm infants (LE2). There is no difference between the effectiveness of early and late EPO (LE2). There is no difference between high-dose and low-dose EPO (LE2). The level of evidence is too low to recommend the intravenous route. EPO has no impact on the rate of bronchopulmonary dysplasia, necrotizing enterocolitis (LE3), and retinopathy of prematurity (LE2). The level of evidence is too low to recommend EPO for neuroprotection in very preterm or term infants. CONCLUSIONS EPO to reduce RBC transfusion in very preterm infants is recommended (Level A). The optimal time to start therapy is unknown (Level B). The recommended dose is 750IU/kg/week via three subcutaneous injections for 6weeks (Level B).Copyright © 2015 Elsevier Masson SAS. All rights reserved.