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Darbepoetin alfa to reduce transfusion episodes in infants with haemolytic disease of the fetus and newborn who are treated with intrauterine transfusions in the Netherlands: an open-label, single-centre, phase 2, randomised, controlled trial
Ree, I. M. C., de Haas, M., van Geloven, N., Juul, S. E., de Winter, D., Verweij, E. J. T., Oepkes, D., van der Bom, J. G., Lopriore, E.
The Lancet. Haematology. 2023;10(12):e976-e984
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Editor's Choice
Abstract
BACKGROUND Up to 88% of infants with haemolytic disease of the fetus and newborn who are treated with intrauterine transfusions require erythrocyte transfusions after birth. We aimed to investigate the effect of darbepoetin alfa on the prevention of postnatal anaemia in infants with haemolytic disease of the fetus and newborn. METHODS We conducted an open-label, single-centre, phase 2 randomised controlled trial to evaluate the effect of darbepoetin alfa on the number of erythrocyte transfusions in infants with haemolytic disease of the fetus and newborn. All infants who were treated with intrauterine transfusion and born at 35 weeks of gestation or later at the Leiden University Medical Center, Leiden, Netherlands, were eligible for inclusion. Included infants were randomised by computer at birth to treatment with 10 μg/kg darbepoetin alfa subcutaneously once a week for 8 weeks or standard care (1:1 allocation, in varying blocks of four and six, with no stratification). Treating physicians and parents were not masked to treatment allocation, but the research team, data manager, and statistician were masked to treatment allocation during the process of data collection. The primary outcome was the number of erythrocyte transfusion episodes per infant from birth up to 3 months of life in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT03104426) and has been completed. FINDINGS Between Oct 31, 2017, and April 31, 2022, we recruited 76 infants, of whom 44 (58%) were randomly assigned to a treatment group (20 [45%] were allocated to receive darbepoetin alfa and 24 [55%] were allocated to receive standard care). Follow-up lasted 3 months and one infant dropped out of the trial before commencement of treatment. A significant reduction in erythrocyte transfusion episodes was identified with darbepoetin alfa treatment compared with standard care (median 1·0 [IQR 1·0-2·0] transfusion episodes vs 2·0 [1·3-3·0] transfusion episodes; p=0·0082). No adverse events were reported and no infants died during the study. INTERPRETATION Darbepoetin alfa reduced the transfusion episodes after intrauterine transfusion treatment for haemolytic disease of the fetus and newborn. Treatment with darbepoetin alfa or other types of erythropoietin should be considered as part of the postnatal treatment of severe haemolytic disease of the fetus and newborn. FUNDING Sanquin Blood Supply. TRANSLATION For the Dutch translation of the abstract see Supplementary Materials section.
PICO Summary
Population
Infants with haemolytic disease of the fetus and newborn (n= 44).
Intervention
Darbepoetin alfa once a week subcutaneously for 8 weeks (n= 20).
Comparison
Standard care (n= 24).
Outcome
Follow-up lasted 3 months and one infant in the darbepoetin alfa group dropped out of the trial before commencement of treatment. The primary outcome was the number of erythrocyte transfusion episodes per infant from birth up to 3 months of life in the modified intention-to-treat population. A significant reduction in erythrocyte transfusion episodes was identified with darbepoetin alfa treatment compared with standard care (median 1.0 [IQR 1.0, 2.0] transfusion episodes vs. 2.0 [1.3, 3.0] transfusion episodes). No adverse events were reported and no infants died during the study.
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Effect of Early Erythropoietin on Retinopathy of Prematurity: A Stratified Meta-Analysis
Fischer, H. S., Reibel, N. J., Bührer, C., Dame, C.
Neonatology. 2023;:1-11
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Editor's Choice
Abstract
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.
PICO Summary
Population
Infants of <29 weeks of gestational age (GA), (14 randomised controlled trials, n= 2,040).
Intervention
Early recombinant human erythropoietin (rhEPO).
Comparison
No treatment or placebo.
Outcome
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).
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Iron supplementation and the risk of bronchopulmonary dysplasia in extremely low gestational age newborns
Garcia MR, Comstock BA, Patel RM, Tolia VN, Josephson CD, Georgieff MK, Rao R, Monsell SE, Juul SE, Ahmad KA
Pediatric research. 2022
Abstract
BACKGROUND The aim of this study was to determine the relationship between iron exposure and the development of bronchopulmonary dysplasia (BPD). METHODS A secondary analysis of the PENUT Trial dataset was conducted. The primary outcome was BPD at 36 weeks gestational age and primary exposures of interest were cumulative iron exposures in the first 28 days and through 36 weeks' gestation. Descriptive statistics were calculated for study cohort characteristics with analysis adjusted for the factors used to stratify randomization. RESULTS Of the 941 patients, 821 (87.2%) survived to BPD evaluation at 36 weeks, with 332 (40.4%) diagnosed with BPD. The median cohort gestational age was 26 weeks and birth weight 810 g. In the first 28 days, 76% of infants received enteral iron and 55% parenteral iron. The median supplemental cumulative enteral and parenteral iron intakes at 28 days were 58.5 and 3.1 mg/kg, respectively, and through 36 weeks' 235.8 and 3.56 mg/kg, respectively. We found lower volume of red blood cell transfusions in the first 28 days after birth and higher enteral iron exposure in the first 28 days after birth to be associated with lower rates of BPD. CONCLUSIONS We find no support for an increased risk of BPD with iron supplementation. TRIAL REGISTRATION NUMBER NCT01378273. https://clinicaltrials.gov/ct2/show/NCT01378273 IMPACT Prior studies and biologic plausibility raise the possibility that iron administration could contribute to the pathophysiology of oxidant-induced lung injury and thus bronchopulmonary dysplasia in preterm infants. For 24-27-week premature infants, this study finds no association between total cumulative enteral iron supplementation at either 28-day or 36-week postmenstrual age and the risk for developing bronchopulmonary dysplasia.
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Early erythropoietin for preventing necrotizing enterocolitis in preterm neonates - an updated meta-analysis
Ananthan, A., Balasubramanian, H., Mohan, D., Rao, S., Patole, S.
European Journal of Pediatrics. 2022;181(5):1821-1833
Abstract
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.
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Enteral Iron Supplementation in Extremely Preterm Infants and its Positive Correlation with Neurodevelopment; Post Hoc Analysis of the PENUT Randomized Controlled Trial
German KR, Vu PT, Comstock BA, Ohls RK, Heagerty PJ, Mayock DE, Georgieff M, Rao R, Juul SE
The Journal of pediatrics. 2021
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Editor's Choice
Abstract
OBJECTIVES To test whether an increased iron dose is associated with improved neurodevelopment as assessed by the Bayley Scales of Infant Development (BSID-III) among infants enrolled in the Preterm Erythropoietin (Epo) Neuroprotection Trial (PENUT). STUDY DESIGN This is a post hoc analysis of a randomized trial which enrolled infants born at 24 to 28 completed weeks of gestation. All PENUT infants who were assessed with BSID-III at 2 years were included in this study. The associations between enteral iron dose at 60 and 90 days and BSID-III component scores were evaluated using generalized estimating equations models adjusted for potential confounders. RESULTS 692 infants were analyzed (355 placebo, 337 Epo). Enteral iron supplementation ranged 0-14.7 mg/kg/day (IQR 2.1-5.8 mg/kg/day) at day 60, with a mean of 3.6 mg/kg/day in placebo-treated infants and 4.8 mg/kg/day in Epo-treated infants. A significant positive association was seen between BSID-III cognitive scores and iron dose at 60 days, with an effect size of 0.77 BSID points per 50 mg/kg increase in cumulative iron dose (P = .03). Higher iron doses were associated with higher motor and language scores, but did not reach statistical significance. Results at 90 days were not significant. The effect size in the Epo-treated infants compared with placebo was consistently higher. CONCLUSION A positive association was seen between iron dose at 60 days and cognitive outcomes. Our results suggest that increased iron supplementation in preterm infants, at the doses administered in the PENUT Trial, may have positive neurodevelopmental effects, particularly in infants treated with Epo.
PICO Summary
Population
Infants enrolled in the Preterm Erythropoietin Neuroprotection Trial (PENUT), (n= 692).
Intervention
Erythropoietin (Epo), (n= 337).
Comparison
Placebo (n= 355).
Outcome
Enteral iron supplementation ranged 0-14.7 mg/kg/day (IQR 2.1-5.8 mg/kg/day) at day 60, with a mean of 3.6 mg/kg/day in placebo-treated infants and 4.8 mg/kg/day in Epo-treated infants. A significant positive association was seen between BSID-III cognitive scores and iron dose at 60 days, with an effect size of 0.77 BSID points per 50 mg/kg increase in cumulative iron dose. Higher iron doses were associated with higher motor and language scores, but did not reach statistical significance. Results at 90 days were not significant. The effect size in the Epo-treated infants compared with placebo was consistently higher.
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Transfusions and neurodevelopmental outcomes in extremely low gestation neonates enrolled in the PENUT Trial: a randomized clinical trial
Vu PT, Ohls RK, Mayock DE, German KR, Comstock BA, Heagerty PJ, Juul SE
Pediatric research. 2021;:1-8
Abstract
BACKGROUND Outcomes of extremely low gestational age neonates (ELGANs) may be adversely impacted by packed red blood cell (pRBC) transfusions. We investigated the impact of transfusions on neurodevelopmental outcome in the Preterm Erythropoietin (Epo) Neuroprotection (PENUT) Trial population. METHODS This is a post hoc analysis of 936 infants 24-0/6 to 27-6/7 weeks' gestation enrolled in the PENUT Trial. Epo 1000 U/kg or placebo was given every 48 h × 6 doses, followed by 400 U/kg or sham injections 3 times a week through 32 weeks postmenstrual age. Six hundred and twenty-eight (315 placebo, 313 Epo) survived and were assessed at 2 years of age. We evaluated associations between BSID-III scores and the number and volume of pRBC transfusions. RESULTS Each transfusion was associated with a decrease in mean cognitive score of 0.96 (95% CI of [-1.34, -0.57]), a decrease in mean motor score of 1.51 (-1.91, -1.12), and a decrease in mean language score of 1.10 (-1.54, -0.66). Significant negative associations between BSID-III score and transfusion volume and donor exposure were observed in the placebo group but not in the Epo group. CONCLUSIONS Transfusions in ELGANs were associated with worse outcomes. We speculate that strategies to minimize the need for transfusions may improve outcomes. IMPACT Transfusion number, volume, and donor exposure in the neonatal period are associated with worse neurodevelopmental (ND) outcome at 2 years of age, as assessed by the Bayley Infant Scales of Development, Third Edition (BSID-III). The impact of neonatal packed red blood cell transfusions on the neurodevelopmental outcome of preterm infants is unknown. We speculate that strategies to minimize the need for transfusions may improve neurodevelopmental outcomes.
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The effects of monotherapy with erythropoietin in neonatal hypoxic-ischemic encephalopathy on neurobehavioral development: a systematic review and meta-analysis
Liu TS, Yin ZH, Yang ZH, Wan LN
European review for medical and pharmacological sciences. 2021;25(5):2318-2326
Abstract
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.
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Early Biomarkers of Hypoxia and Inflammation and Two-Year Neurodevelopmental Outcomes in the Preterm Erythropoietin Neuroprotection (PENUT) Trial
Wood TR, Parikh P, Comstock BA, Law JB, Bammler TK, Kuban KC, Mayock DE, Heagerty PJ, Juul S
EBioMedicine. 2021;72:103605
Abstract
BACKGROUND In the Preterm Erythropoietin (Epo) NeUroproTection (PENUT) Trial, potential biomarkers of neurological injury were measured to determine their association with outcomes at two years of age and whether Epo treatment decreased markers of inflammation in extremely preterm (<28 weeks' gestation) infants. METHODS Plasma Epo was measured (n=391 Epo, n=384 placebo) within 24h after birth (baseline), 30min after study drug administration (day 7), 30min before study drug (day 9), and on day 14. A subset of infants (n=113 Epo, n=107 placebo) had interferon-gamma (IFN-γ), Interleukin (IL)-6, IL-8, IL-10, Tau, and tumour necrosis factor-α (TNF-α) levels evaluated at baseline, day 7 and 14. Infants were then evaluated at 2 years using the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III). FINDINGS Elevated baseline Epo was associated with increased risk of death or severe disability (BSID-III Motor and Cognitive subscales <70 or severe cerebral palsy). No difference in other biomarkers were seen between treatment groups at any time, though Epo appeared to mitigate the association between elevated baseline IL-6 and lower BSID-III scores in survivors. Elevated baseline, day 7 and 14 Tau concentrations were associated with worse BSID-III Cognitive, Motor, and Language skills at two years. INTERPRETATION Elevated Epo at baseline and elevated Tau in the first two weeks after birth predict poor outcomes in infants born extremely preterm. However, no clear prognostic cut-off values are apparent, and further work is required before these biomarkers can be widely implemented in clinical practice. FUNDING PENUT was funded by the National Institute of Neurological Disorders and Stroke (U01NS077955 and U01NS077953).
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Prophylactic Erythropoietin for Neuroprotection in Very Preterm Infants: A Meta-Analysis Update
Fischer HS, Reibel NJ, Bührer C, Dame C
Frontiers in pediatrics. 2021;9:657228
Abstract
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.
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Sustained low-dose prophylactic early erythropoietin for improvement of neurological outcomes in preterm infants: A systematic review and meta-analysis
Liang L, Yu J, Xiao L, Wang G
Journal of affective disorders. 2021;282:1187-1192
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Editor's Choice
Abstract
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.
PICO Summary
Population
Children who were born prematurely, aged between 18-24 months corrected age (n= 2,282, 5 RCTs).
Intervention
High-dose or low-dose prophylactic erythropoietin (rhEPO).
Comparison
Placebo.
Outcome
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).