losartan-potassium and Retinopathy-of-Prematurity

Anemia of prematurity affects the majority of preterm infants, particularly extremely low birthweight infants. Anemia of prematurity arises from both innate and iatrogenic causes and results in more than 80% of extremely preterm infants receiving red blood cell transfusions during the first month after birth. Multiple randomized controlled trials were conducted to evaluate the effect of using lower versus higher transfusion thresholds based on hemoglobin levels. These trials showed no difference in the primary outcome of neurodevelopmental impairment at 2 years of age between lower and higher thresholds. However, some uncertainties about transfusion thresholds remain. This review elaborates the following: 1) the etiology, prevention, and treatment of anemia of prematurity with a focus on red blood cell transfusions, 2) the history of randomized controlled trials on the treatment of anemia of prematurity, and 3) limitations of the evidence and remaining questions about thresholds for red blood cell transfusions in preterm infants.

Topics: Anemia; Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Extremely Low Birth Weight; Infant, Extremely Premature; Infant, Newborn; Retinopathy of Prematurity

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).. 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).. 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 Previously unpublished data were requested from the study authors to allow stratified analyses by gestational age (GA) and BW.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.". 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).. 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.

Topics: Anemia, Neonatal; Birth Weight; Erythropoietin; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Retinopathy of Prematurity; Risk Factors

Retinopathy of prematurity (ROP) is a leading cause of vision impairment and blindness in premature infants. Oxidative stress is implicated in its pathophysiology. NADPH oxidase (NOX), a major enzyme responsible for reactive oxygen species (ROS) generation in endothelial cells, has been studied for its involvement in physiologic and pathologic angiogenesis. Erythropoietin (EPO) has gained interest recently due to its tissue protective and angiogenic effects, and it has been shown to act as an antioxidant. In this review, we summarize studies performed over the last five years regarding the role of various NOXs in physiologic and pathologic angiogenesis. We also discuss the effect of EPO in tissue and vasoprotection, and the intersection of EPO and NOX-mediated oxidative stress in angiogenesis and the pathophysiology of ROP.

Topics: Endothelial Cells; Erythropoietin; Humans; Infant; Infant, Newborn; Infant, Premature, Diseases; NADP; NADPH Oxidases; Neovascularization, Pathologic; Retinopathy of Prematurity

Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia.. To assess the effectiveness and safety of early versus late initiation of EPO in reducing red blood cell (RBC) transfusions in preterm and/or low birth weight (LBW) infants.. Randomised or quasi-randomised controlled trials enrolling preterm or LBW infants less than eight days of age.. Early initiation of EPO (initiated at less than eight days of age) versus late initiation of EPO (initiated at eight to 28 days of age).. The standard methods of the CNRG were followed. Weighted treatment effects included typical risk ratio (RR), typical risk difference (RD), number needed to treat to benefit (NNTB), number needed to treat to harm (NNTH) and mean difference (MD), all with 95% confidence intervals (CI). A fixed-effect model was used for meta-analyses and heterogeneity was evaluated using the I-squared (I. No new trials were identified in March of 2012. Two high quality randomised double-blind controlled studies enrolling 262 infants were identified. A non-significant reduction in the 'Use of one or more RBC transfusions' [two studies 262 infants; typical RR 0.91 (95% CI 0.78 to 1.06); typical RD -0.07 (95% CI -0.18 to 0.04; I. The use of early EPO did not significantly reduce the 'Use of one or more RBC transfusions' or the 'Number of transfusions per infant" compared with late EPO administration. The finding of a statistically significant increased risk of ROP (any grade) and a similar trend for ROP stage > 3 with early EPO treatment is of great concern.

Topics: Anemia, Neonatal; Epoetin Alfa; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic; Retinopathy of Prematurity

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. Darbepoetin (Darbe) and EPO are currently available ESAs.. To assess the effectiveness and safety of late initiation of ESAs, between eight and 28 days after birth, in reducing the use of red blood cell (RBC) transfusions in preterm or low birth weight infants.. We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2018, Issue 5), MEDLINE via PubMed (1966 to 5 June 2018), Embase (1980 to 5 June 2018), and CINAHL (1982 to 5 June 2018). We searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.. Randomised or quasi-randomised controlled trials of late initiation of EPO treatment (started at ≥ eight days of age) versus placebo or no intervention in preterm (< 37 weeks) or low birth weight (< 2500 grams) neonates.. We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of the evidence.. We include 31 studies (32 comparisons) randomising 1651 preterm infants. Literature searches in 2018 identified one new study for inclusion. No new on-going trials were identified and no studies used darbepoetin.Most included trials were of small sample size. The meta-analysis showed a significant effect on the use of one or more RBC transfusions (21 studies (n = 1202); typical risk ratio (RR) 0.72, 95% confidence interval (CI) 0.65 to 0.79; typical risk difference (RD) -0.17, 95% CI -0.22 to -0.12; typical number needed to treat for an additional beneficial outcome (NNTB) 6, 95% CI 5 to 8). There was moderate heterogeneity for this outcome (RR I² = 66%; RD I² = 58%). The quality of the evidence was very low. We obtained similar results in secondary analyses based on different combinations of high/low doses of EPO and iron supplementation. There was no significant reduction in the total volume (mL/kg) of blood transfused per infant (typical mean difference (MD) -1.6 mL/kg, 95% CI -5.8 to 2.6); 5 studies, 197 infants). There was high heterogeneity for this outcome (I² = 92%). There was a significant reduction in the number of transfusions per infant (11 studies enrolling 817 infants; typical MD -0.22, 95% CI -0.38 to -0.06). There was high heterogeneity for this outcome (I² = 94%).Three studies including 404 infants reported on retinopathy of prematurity (ROP) (all stages or stage not reported), with a typical RR 1.27 (95% CI 0.99 to 1.64) and a typical RD of 0.09 (95% CI -0.00 to 0.18). There was high heterogeneity for this outcome for both RR (I² = 83%) and RD (I² = 82%). The quality of the evidence was very low.Three trials enrolling 442 infants reported on ROP (stage ≥ 3). The typical RR was 1.73 (95% CI 0.92 to 3.24) and the typical RD was 0.05 (95% CI -0.01 to 0.10). There was no heterogeneity for this outcome for RR (I² = 18%) but high heterogeneity for RD (I² = 79%). The quality of the evidence was very low.There were no significant differences in other clinical outcomes including mortality and necrotising enterocolitis. For the outcomes of mortality and necrotising enterocolitis, the quality of the evidence was moderate. Long-term neurodevelopmental outcomes were not reported.. Late administration of EPO reduces the use of one or more RBC transfusions, the number of RBC transfusions per infant (< 1 transfusion per infant) but not the total volume (mL/kg) of RBCs transfused per infant. Any donor exposure is likely not avoided as most studies included infants who had received RBC transfusions prior to trial entry. Late EPO does not significantly reduce or increase any clinically important adverse outcomes except for a trend in increased risk for ROP. Further research of the use of late EPO treatment, to prevent donor exposure, is not indicated. Research efforts should focus on limiting donor exposure during the first few days of life in sick neonates, when RBC requirements are most likely to be required and cannot be prevented by late EPO treatment. The use of satellite packs (dividing one unit of donor blood into many smaller aliquots) may reduce donor exposure.

Topics: Age Factors; Anemia, Neonatal; Bronchopulmonary Dysplasia; Cause of Death; Drug Administration Schedule; Erythrocyte Transfusion; Erythropoietin; Hematinics; Hospital Mortality; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic; Retinopathy of Prematurity; Time Factors

Currently the question of whether to maintain a higher hemoglobin level by transfusing more liberally, as opposed to a more restrictive strategy with lower hemoglobin maintenance levels, has not been answered. We review summarized conclusions of a Cochrane systematic review and meta-analysis of 614 infants in 4 randomized controlled trials (RCT) pooling data. This suggests potential benefits of higher hemoglobin levels, i.e., a possible improved cognition of infants at 18-21 months' corrected age and a reduction of apnea. However, the data on cognition is hypothesis generating as it derives from a post hoc analysis from a single trial in 451 infants. Moreover, the data on apnea need confirmation in larger trials. The effect of adding data of cognitive 2-year outcomes of 1,744 infants from 2 RCT, which will be reported soon, should expand our understanding. This new data will need to be integrated with the older generation of RCTs but also with emerging suggestions from observational data on potential risks of blood transfusions. We discuss some of these warnings from observational studies. Finally, we ask whether we are ready to individualize blood transfusion to physiological measures made in individual infants, and we point to some current difficulties hindering this step.

Topics: Anemia, Neonatal; Apnea; Erythrocyte Transfusion; Erythropoietin; Evidence-Based Practice; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic; Retinopathy of Prematurity

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.

Topics: Bronchopulmonary Dysplasia; Enterocolitis, Necrotizing; Erythropoietin; Gastrointestinal Tract; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Retinopathy of Prematurity; Sepsis

Erythropoietin (EPO) administration prevents anemia of prematurity and may be associated with a significant increase in the risk of retinopathy of prematurity (ROP) in preterm infants. Nonetheless, early EPO treatment may prevent damage following retinal neovascularization. The aim of this meta-analysis was to elucidate whether EPO administration increases the risk of ROP.. We searched MEDLINE, PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), and the Cochrane Central Register of Controlled Trials with no language restrictions. Randomized controlled trials that reported the association between EPO treatment in preterm infants and ROP were eligible. All of the included studies were stratified into two groups according to the age of initiation of EPO treatment: before 8 days of age (early EPO), and 8-28 days of age (late EPO).. Thirteen studies were identified that included a total of 1999 preterm infants. EPO administration did not increase the risk of ROP of any stage or Stage ≥3 (any relative risk: 0.99, 95% confidence interval: 0.84-1.16, p = 0.89; Stage ≥3 relative risk: 1.34, 95% confidence interval: 0.90-1.99, p = 0.15). This trend remained unchanged in both the early and late EPO groups. There did not seem to be any evidence of publication bias for outcomes as the funnel plots were symmetrical.. EPO administration did not significantly increase the risk of ROP of any stage reported or Stage ≥3. Further clinical trials investigating the impact of EPO on ROP in premature infants should include all confounding factors to clarify this important issue.

Topics: Erythropoietin; Hematinics; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Retinopathy of Prematurity; Risk

We performed a meta-analysis to study the association between erythropoietin (EPO) and the development of retinopathy of prematurity (ROP) in preterm newborn infants. Studies were identified through PubMed (1966-) and ISI databases (1965-) literature searches. Results and effect sizes are expressed as odds ratio (OR) with 95 % confidence intervals (CI). Fourteen studies identified to the meta-analysis, including 3,484 preterm newborn infants. A total of 563 of 1,221 babies treated with EPO had ROP (46.1 %) vs. 420 of 1,134 babies without EPO (37.0 %). No significant difference was found in the ROP risk between the two groups, with the OR 1.592 (95 % CI 0.901-2.812). A total of 192 of 1,298 babies treated with EPO had severe ROP (stage 3-4) (14.8 %) vs. 166 of 1,199 babies without EPO (13.8 %). The OR was 1.203 (95 % CI 0.763-1.896). No significant publication bias was found. Sensitivity analyses showed the results were robust.. Our meta-analysis indicates that EPO treatment is not associated with the development of ROP in preterm infants. But this conclusion should be confirmed by further high-quality researches.

Topics: Erythropoietin; Hematinics; Humans; Infant, Newborn; Infant, Premature; Models, Statistical; Odds Ratio; Retinopathy of Prematurity

Retinopathy of prematurity occurs because the retina of a preterm infant at birth is incompletely vascularized, and if the postnatal environment does not match the in utero environment that supported retinal development, the vessels and neural retina will not grow normally. Risk factors determined from many clinical studies and animal studies fall into 2 categories: prenatal factors and postnatal factors.

Topics: Erythropoietin; Humans; Infant; Infant, Newborn; Infant, Premature; Insulin-Like Growth Factor I; Oxygen; Retina; Retinopathy of Prematurity; Vascular Endothelial Growth Factor A

Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia.. To assess the effectiveness and safety of early initiation of EPO in reducing red blood cell (RBC) transfusions in preterm and/or low birth weight infants.. The Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE, CINAHL, abstracts from scientific meetings published in Pediatric Research and reference lists of identified trials and reviews were searched through July 2009. Searches were repeated in March 2012 including searches of Pediatric Academic Societies Annual meetings 2000 to 2012 (Abstracts2View(TM)) and clinical trials registries (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp).. Randomised or quasi-randomised controlled trials of early (< eight days of age) initiation of EPO treatment versus placebo or no intervention in preterm and/or low birth weight neonates.. Data collection and analysis were accomplished using the methods of the Neonatal Cochrane Review Group.. The May 2012 update did not identify any new studies for inclusion. A number of randomised controlled trials were excluded as they compared one EPO dosing regimen with another, did not provide the numbers of infants randomised to the EPO and the placebo group, or the dose of EPO was not stated. The update includes 27 studies that enrolled 2293 preterm infants. Early EPO reduced the risk of the "use of one or more RBC transfusions" [typical risk ratio (RR); 0.80 (95% confidence interval (CI) 0.75 to 0.86); typical risk difference (RD) -0.13, (95% CI -0.17 to -0.09); number needed to benefit (NNTB) = eight, (95% CI 6 to 11); 16 studies, 1,825 infants].There was moderate heterogeneity for this outcome [RR (P = 0.004; I(2) = 56.7%); RD (P = 0.003; I(2) = 56.0%)].A total of six studies enrolling 515 infants reported on the total volume of red blood cells transfused per infant. The significant typical mean difference (MD) was a reduction of 6 mL/kg of blood transfused (mL/kg) per infant (95% CI -11 to - 1). There was moderate heterogeneity for this outcome (P = 0.02; I(2) = 63.0%). The results from 14 studies enrolling 1131 infants reported on the number of red blood cell transfusions per infant. The significant typical MD for number of red blood cell transfusions per infant was -0.33, (95% CI -0.48 to -0.18). There was high heterogeneity for this outcome (P = 0.00001, I(2) = 78%). Two studies enrolling 188 infants reported on the number of donors to whom the infant was exposed; the MD was significantly reduced -0.63, (-1.07 to -0.19). There was no heterogeneity for this outcome (P = 0.59; I(2) = 0%).There was a significant increase in the risk of stage ≥ 3 retinopathy of prematurity (ROP) in the early EPO group [typical RR; 1.65, (95% CI 1.12 to 2.43); typical RD; 0.05 (95% CI 0.01 to 0.08); number needed to harm (NNTH); 20, (95% CI 13 to 100); eight studies, 984 infants]. There was no heterogeneity for this outcome for RR (P = 0.87; I(2) = 0%), but there was moderate heterogeneity for RD (P = 0.006; I(2) = 65%). The rates for mortality and other neonatal morbidities were not significantly changed by early EPO treatment nor were neurodevelopmental outcomes at 18 to 22 months in the small number of infants tested to-date.. Early administration of EPO reduces the use of RBC transfusions and the volume of RBCs transfused. These small reductions are of limited clinical importance. Donor exposure is probably not avoided since most studies included infants who had received RBC transfusions prior to trial entry. There was a significant increase in the rate of ROP (stage ≥ 3). Early EPO does not significantly decrease or increase any of the other important adverse outcomes. Ongoing research should deal with the issue of ROP and evaluate the current clinical practice that will limit donor exposure. Due to the limited benefits and the increased risk of ROP, early administration of EPO is not recommended. Evidence is lacking for the possible neuro protective role of EPO in preterm infants. This topic will be reviewed in separate Cochrane reviews for preterm and term and late preterm infants.

Topics: Age Factors; Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic; Retinopathy of Prematurity; Time Factors

Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia.. To assess the effectiveness and safety of early versus late initiation of EPO in reducing red blood cell (RBC) transfusions in preterm and/or low birth weight (LBW) infants.. The standard search of the Cochrane Neonatal Review Group (CNRG) was performed in 2006 and updated in 2009. Updated search in September 2009 as follows: The Cochrane Library, MEDLINE (search via PubMed), CINAHL and EMBASE were searched from 2005 to September 2009. The searches were repeated in March 2012. The Pediatric Academic Societies' Annual meetings were searched electronically from 2000 to 2012 at Abstracts2View(TM) as were clinical trials registries (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp).. Randomised or quasi-randomised controlled trials enrolling preterm or LBW infants less than eight days of age.. Early initiation of EPO (initiated at less than eight days of age) versus late initiation of EPO (initiated at eight to 28 days of age).. The standard methods of the CNRG were followed. Weighted treatment effects included typical risk ratio (RR), typical risk difference (RD), number needed to treat to benefit (NNTB), number needed to treat to harm (NNTH) and mean difference (MD), all with 95% confidence intervals (CI). A fixed-effect model was used for meta-analyses and heterogeneity was evaluated using the I-squared (I(2)) test.. No new trials were identified in March of 2012. Two high quality randomised double-blind controlled studies enrolling 262 infants were identified. A non-significant reduction in the 'Use of one or more RBC transfusions' [two studies 262 infants; typical RR 0.91 (95% CI 0.78 to 1.06); typical RD -0.07 (95% CI -0.18 to 0.04; I(2) = 0% for both RR and RD] favouring early EPO was noted. Early EPO administration resulted in a non-significant reduction in the "number of transfusions per infant" compared with late EPO [typical MD - 0.32 (95% CI -0.92 to 0.29)]. There was no significant reduction in total volume of blood transfused per infant or in the number of donors to whom the infant was exposed. Early EPO led to a significant increase in the risk of retinopathy of prematurity (ROP) (all stages) [two studies, 191 infants; typical RR 1.40 (95% CI 1.05 to 1.86); typical RD 0.16 (95% CI 0.03 to 0.29); NNTH 6 (95% CI 3 to 33)]. There was high heterogeneity for this outcome (I(2) = 86% for RR and 81% for RD). Both studies (191 infants) reported on ROP stage ≥ 3. No statistically significant increase in risk was noted [typical RR 1.56 (95% CI 0.71 to 3.41); typical RD 0.05 (-0.04 to 0.14)] There was no heterogeneity for this outcome (0% for both RR and RD). No other important favourable or adverse neonatal outcomes or side effects were reported.. The use of early EPO did not significantly reduce the 'Use of one or more RBC transfusions' or the 'Number of transfusions per infant" compared with late EPO administration. The finding of a statistically significant increased risk of ROP (any grade) and a similar trend for ROP stage ≥ 3 with early EPO treatment is of great concern.

Topics: Age Factors; Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic; Retinopathy of Prematurity

Topics: Animals; Antioxidants; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Models, Animal; Oxygen; Retinal Vessels; Retinopathy of Prematurity; Vascular Endothelial Growth Factor A

Erythropoietin (EPO) is a glycoprotein that regulates many functions of an organism: It stimulates the production of red blood cells and it has angiogenic and neuroprotective properties in newborn infants. Retinopathy of prematurity (ROP) is a frequent cause of visual impairment in preterm newborn infants and it has two distinct phases in which hypoxia-induced angiogenic factors are involved. The relationship between EPO and ROP is derived from the observation of studies done on the haematopoietic effect of EPO. The first observations suggested that a precocious treatment with EPO increases the risk of ROP, while the most recent reports suggested that the late treatment with high doses of rhEPO can increase the risk of ROP. All these studies were not designed to demonstrate the relationship between EPO and ROP. Further studies specifically designed should be performed. New ongoing studies on the neuroprotective role of EPO should consider this objective. In the mean time the use of EPO in the neonatal period should be cautious, mainly in very low birth weight infants.

Topics: Age Factors; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Recombinant Proteins; Retinopathy of Prematurity; Signal Transduction

Retinopathy of prematurity (ROP) is a potentially blinding disease of premature infants and despite timely treatment some infants develop retinal detachment and sight loss. Current treatment utilises laser therapy which causes destruction of treated retinal tissue resulting in field loss. There is considerable research work ongoing on neovascular eye disease which is likely to result in antiangiogenic approaches that will arrest the development of ROP by specifically targeting the involved molecular mediators. Some of these new therapeutic interventions have entered clinical trials. This article reviews new information available on the molecular pathogenesis of ROP which may result in novel treatments for ROP; it does not discuss the well-known role of oxygen in the development of ROP.

Topics: Erythropoietin; Granulocyte Colony-Stimulating Factor; Humans; Infant, Newborn; Insulin-Like Growth Factor I; Oxidative Stress; Protein Isoforms; Retinopathy of Prematurity; Vascular Endothelial Growth Factor A

Erythropoientin (Epo), a glycoprotein hormone, plays an important role in erythropoiesis and neuroprotection. Recently,Epo is also considered to have protective effects against hyperoxic lung injury, retinopathy of prematurity and neonatal necrotizing enterocolitis. Recombinant human erythropietin (rhEpo) as Epo gene cloning drug has been widely used in neonatal clinical practice.

Topics: Enterocolitis, Necrotizing; Erythropoietin; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Infant, Newborn, Diseases; Recombinant Proteins; Retinopathy of Prematurity

The history of retinopathy of prematurity (ROP) gives a prime example of how dangerous the uncontrolled introduction of a new medical treatment--particularly in the field of neonatology--may be. The most important risk factors for the development of ROP are the immaturity of premature infants as well as uncontrolled and/or inadequate treatment with oxygen. In comparison to the fetus, the premature infant is exposed to a nonphysiologically high oxygen concentration. This hyperoxia leads to formation of aggressive oxygen radicals on the one hand and, on the other hand, to temporarily reduced production of growth factors such as vascular endothelial growth factor and erythropoietin, which both play an important role in the pathogenesis of ROP. The most important measure to prevent ROP is restrictive and carefully monitored oxygen treatment. Medical treatment to prevent ROP includes injection of D-penicillamine and retinol, but the available data are still limited, particularly with regard to the long-term effects of this treatment. A higher oxygenation in prethreshold ROP does not lead to recovery of ocular findings, but it increases the incidence of pulmonary complications. A reduction of light intensity in neonatal intensive care units proved not to be efficient for preventing ROP. To avoid blindness, standardized screening of the risk group is needed.

Topics: Erythrocyte Transfusion; Erythropoietin; Gestational Age; Humans; Hyperoxia; Infant, Newborn; Iron Overload; Mass Screening; Oxygen Inhalation Therapy; Recombinant Proteins; Referral and Consultation; Retinopathy of Prematurity; Risk Factors

Hematocrit falls after birth in preterm infants due to physiological factors and blood letting. Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anemia.. To assess the effectiveness and safety of early initiation of EPO (initiated before eight days after birth) in reducing red blood cell transfusions in preterm and/or low birth weight infants.. Subgroup analyses of low (< 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO and, within these subgroups, analyses of the use of low (< 5 mg/kg/day) and high (> 5 mg/kg/day) doses of supplemental iron, in reducing red blood cell transfusions in these infants.. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, CINAHL, abstracts from scientific meetings published in Pediatric Research and reference lists of identified trials and reviews were searched in November 2005. No language restrictions were applied.. Randomised or quasi-randomized controlled trials of early initiation of EPO treatment (started before 8 days of age) vs. placebo or no intervention in preterm (< 37 weeks) and/or low birth weight (< 2500 g) neonates. For inclusion, the studies needed to provide information on at least one outcome of interest.. Data were abstracted by the two authors on pre-tested data collection forms. Data were entered by one review author (AO) and checked for accuracy by the other (SA). Data were analysed using RevMan 4.2.8. The statistical methods included 'typical' relative risk (RR), risk difference (RD), number needed to treat to benefit (NNTB) and needed to treat to harm (NNTH) for dichotomous outcomes and weighted mean difference (WMD) for continuous outcomes reported with their 95% confidence intervals (CI). A fixed effects model was used for meta-analyses. Heterogeneity tests, including the I(-)squared (I(2)) statistic, were performed to assess the appropriateness of pooling the data.. Twenty-three studies enrolling 2074 preterm infants in 18 countries were included in the review. All studies except one applied transfusion guidelines. The quality of the trials varied. Most trials were of small sample size. Only one study clearly stated that infants were excluded if they had received red blood cell transfusion prior to study entry (Arif 2005). A total of 16 studies, including 1825 infants reported on the primary outcome of "use of one or more red cell transfusions". The summary estimates were significant [typical RR; 0.80 (95% CI 0.75, 0.86); typical RD; -0.13 (95% CI -0.17, -0.09); typical NNTB; 8 (95% CI 6, 11)]. There was statistically significant heterogeneity [for RR (p< 0.004), I(2) = 56.7%; for RD (p = 0.003), I(2 ) = 56.0%]. Similar results were obtained in secondary analyses based on different combinations of high doses of EPO and high and low iron supplementation. There were insufficient data to draw conclusions for low doses EPO in combination with high or low dose of iron. Two studies (n = 188) reported a significant reduction in the number of donors to whom the infant was exposed [typical WMD; -0.63 (95% CI -1.07, -0.19)]. A significant reduction in the total volume (ml/kg) of blood transfused per infant [typical WMD; -6 ml (95% CI -1, -11)] and in the number of transfusions per infant [typical WMD -0.27 (95% CI -0.12, -0.42 )] was noted. There was a significant increase in the risk of stage > 3 retinopathy of prematurity (ROP) in the EPO group [typical RR; 1.71 (95% CI 1.15, 2.54); typical RD; 0.05 (95% CI 0.01, 0.09); NNTH; 20 (95% CI 11, 100)]. The non-significant results for ROP (any stage reported) showed a similar trend. The increased risk for ROP may be associated with use of higher doses of supplemental of iron in the EPO group than in the control group. The rates for mortality, sepsis, intraventricular haemorrhage, periventricular leukomalacia, necrotizing enterocolitis, bronchopulmonary dysplasia, neutropenia, hypertension, length of hospital stay or long-term neurodevelopmental outcomes were not significantly change by the administration of EPO.. Early administration of EPO reduces the use one or more red blood cell transfusions, the volume of red blood cells transfused, and the number of donors and transfusions the infant is exposed to following study entry. The small reductions are of limited clinical importance. Any donor exposure is likely not avoided as most studies included infants, who had received red cell transfusions prior to trial entry. There was a significant increase in the rate of ROP (stage >3). Animal data and observational studies in humans support a possible association between treatment with EPO and the development of ROP. EPO does not significantly decrease or increase any of the other important neonatal adverse outcomes including mortality. The incidence of ROP should be ascertained in the studies that have already been conducted but did not report on this outcome. Any ongoing research should deal with the issue of ROP and evaluate the current clinical practice that will limit donor exposure through satellite units. Research efforts should focus on limiting donor exposure (to as few donors as possible) during the first few days of life in sick neonates, when red blood cell transfusions are most likely to be required and cannot be prevented by early (or late) EPO treatment. Due to the limited benefits and the increased risk of ROP, early administration of EPO is not recommended.

Topics: Age Factors; Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic; Retinopathy of Prematurity

Hematocrit falls after birth in preterm infants due to physiological factors and frequent blood letting. Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia.. To assess the effectiveness and safety of early (before 8 days after birth) versus late (between 8 - 28 days after birth) initiation of EPO in reducing red blood cell transfusions in preterm and/or low birth weight infants.. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2006) was searched. Electronic and manual searches were conducted in November 2005 of MEDLINE, EMBASE and CINAHL, personal files, bibliographies of identified trials and abstracts by the Pediatric Academic Societies' and the European Society of Pediatric Research Meetings published in Pediatric Research.. Randomized or quasi-randomized controlled trials.. Preterm (< 37 weeks gestational age) or low birth weight infants (< 2500 g) less than eight days of age.. Early initiation of EPO (initiated at < 8 days of age) vs. late initiation of EPO (initiated at 8 - 28 days of age). Outcomes; At least one of the following outcomes were reported: Use of one or more red blood cell transfusions; Total volume (ml/kg) of blood transfused per infant; Number of transfusions per infant; Number of donors to whom the infant was exposed; Mortality during initial hospital stay (all causes); and common outcomes associated with preterm birth.. The standard methods of the Cochrane Neonatal Review Group were followed independently by the authors to assess study quality and report outcomes. Weighted treatment effects, calculated using RevMan 4.2.8 included typical relative risk (RR), typical risk difference (RD), number needed to treat to benefit (NNTB), number needed to treat to harm (NNTH) and mean difference (MD), all with 95% confidence intervals (CI). A fixed effect model was used for meta-analyses. Heterogeneity tests including the I-squared (I(2)) test were performed to assess the appropriateness of pooling the data.. Two high quality randomized double-blind controlled studies enrolling 262 infants were identified (Donato 2000; Maier 2002). Both studies used well defined, but not identical, criteria for blood transfusions. Between 14 and 32% of the enrolled infants had received blood transfusions prior to study entry. A non-significant reduction in the 'use one or more red blood cell transfusions' [typical RR 0.91 (95% CI 0.78, 1.06); typical RD - 0.07 (95% CI -0.18, 0.04)] favouring early EPO was noted. Both studies (n = 262) reported on "number of transfusions per infant"; early EPO administration resulted in a non-significant reduction compared to late EPO [typical WMD - 0.32 (95% CI -0.92, 0.29)]. There was no significant reduction in total volume of blood transfused per infant or in the number of donors to whom the infant was exposed. Retinopathy of prematurity (ROP) (all stages) was assessed in 191 infants. Early EPO led to a significant increase in the risk of ROP [(typical RR 1.40 (95% CI 1.05, 1.86); typical RD 0.16 (95% CI 0.03, 0.29); NNTH 6 (95% CI 3 -33)]. There was statistically significant heterogeneity for this outcome. Both studies (n = 191) reported on ROP stage > 3. No statistically significant increase in risk was noted [typical RR 1.56 (95% CI 0.71, 3.41); typical RD was 0.05 (95% CI - 0.04, 0.14)]. There was no statistically significant heterogeneity for this outcome for either RR or for RD. No other important favourable or adverse neonatal outcomes or side effects were reported.. The use of early EPO did not significantly reduce the primary outcome of "use of one or more red blood cell transfusions", or "number of transfusions per infant" compared to late EPO administration. Currently there is lack of evidence that early EPO vs. late EPO confers any substantial benefits with regard to any donor blood exposure as a large proportion (14 - 30 %) of infants enrolled in these studies were exposed to donor blood prior to study entry. The finding of a statistically significant increased risk of ROP (any grade) and a similar trend for ROP stage > 3 with early EPO treatment is of great concern. No further studies comparing early vs. late administration of EPO are warranted.

Topics: Age Factors; Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Randomized Controlled Trials as Topic; Retinopathy of Prematurity

Very preterm infants are at risk of developing retinopathy of prematurity (ROP). Recombinant human erythropoietin (rhEPO) is routinely used to prevent anemia in preterm infants; however, the effect of rhEPO on ROP development is still controversial. The purpose of this study was to evaluate the effect of early prophylactic low-dose rhEPO administration on ROP development in very preterm infants.. A total of 1898 preterm infants born before 32 weeks of gestation were included. Preterm infants received rhEPO (n = 950; 500 U/kg, rhEPO group) or saline (n = 948, control group) intravenously within 72 h of birth and then once every other day for 2 weeks.. The total incidence of ROP was not significantly different between the two groups (10.2% vs. 13.2%, p = 0.055). Further analysis showed that rhEPO group had lower rates of type 2 ROP than the control group (2.2% vs. 4.1%, RR 0.98; 95% CI 0.96-1.00; p = 0.021). Subgroup analysis found that rhEPO treatment significantly decreased the incidence of type 2 ROP in infant boys (1.8% vs. 4.3%, p = 0.021) and in those with a gestational age of 28-29. Repeated low-dose rhEPO administration has no significant influence on the development of ROP; however, it may be effective for type 2 ROP in infant boys or in infants with gestational age > 28 weeks and birth weight > 1500 g. Trial registration The data of this study were retrieved from two clinical studies registered ClinicalTrials.gov (NCT02036073) on January 14, 2014, https://clinicaltrials.gov/ct2/show/NCT02036073 ; and (NCT03919500) on April 18, 2019. https://clinicaltrials.gov/ct2/show/NCT03919500 .

Topics: Anemia; Erythropoietin; Humans; Infant; Infant, Newborn; Infant, Premature; Male; Recombinant Proteins; Retinopathy of Prematurity

The Preterm Erythropoietin (Epo) Neuroprotection (PENUT) Trial sought to determine the safety and efficacy of early high-dose Epo as a potential neuroprotective treatment. We hypothesized that Epo would not increase the incidence or severity of retinopathy of prematurity (ROP).. A total of 941 infants born between 24-0/7 and 27-6/7 weeks' gestation were randomized to 1,000 U/kg Epo or placebo intravenously for 6 doses, followed by subcutaneous or sham injections of 400 U/kg Epo 3 times a week through 32 weeks post-menstrual age. In this secondary analysis of PENUT trial data, survivors were evaluated for ROP. A modified intention-to-treat approach was used to compare treatment groups. In addition, risk factors for ROP were evaluated using regression methods that account for multiples and allow for adjustment for treatment and gestational age at birth.. Of 845 subjects who underwent ROP examination, 503 were diagnosed with ROP with similar incidence and severity between treatment groups. Gestational age at birth, birth weight, prenatal magnesium sulfate, maternal antibiotic exposure, and presence of heart murmur at 2 weeks predicted the development of any ROP, while being on high-frequency oscillator or high-frequency jet ventilation (HFOV/HFJV) at 2 weeks predicted severe ROP.. Early high-dose Epo followed by maintenance dosing through 32 weeks does not increase the risk of any or severe ROP in extremely low gestational age neonates. Gestational age, birth weight, maternal treatment with magnesium sulfate, antibiotic use during pregnancy, and presence of a heart murmur at 2 weeks were associated with increased risk of any ROP. Treatment with HFOV/HFJV was associated with an increased risk of severe ROP.

Topics: Erythropoietin; Female; Gestational Age; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Male; Pregnancy; Retinopathy of Prematurity; Risk Factors

To investigate the safety and short term outcome of high dose recombinant human erythropoietin (rhEpo) given shortly after birth and subsequently over the first 2 days for neuroprotection to very preterm infants.. Randomized, double masked phase II trial. Preterm infants (gestational age 26 0/7-31 6/7 weeks) were given rhEpo (nt = 229; 3000 U/kg body weight) or NaCl 0.9% (nc = 214) intravenously at 3, 12-18, and 36-42 hours after birth.. There were no relevant differences between the groups for short-term outcomes such as mortality, retinopathy of prematurity, intraventricular hemorrhage, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. At day 7-10, we found significantly higher hematocrit values, reticulocyte, and white blood cell counts, and a lower platelet count in the rhEpo group.. Early high-dose rhEpo administration to very premature infants is safe and causes no excess in mortality or major adverse events.. ClinicalTrials.gov: NCT00413946.

Topics: Bronchopulmonary Dysplasia; Developmental Disabilities; Dose-Response Relationship, Drug; Double-Blind Method; Enterocolitis, Necrotizing; Erythropoietin; Europe; Hematocrit; Humans; Hypoxia-Ischemia, Brain; Infant, Newborn; Infant, Premature; Intracranial Hemorrhages; Leukocyte Count; Leukomalacia, Periventricular; Neuroprotective Agents; Platelet Count; Recombinant Proteins; Reticulocyte Count; Retinopathy of Prematurity; Sepsis

Premature infants are at risk of developing encephalopathy of prematurity, which is associated with long-term neurodevelopmental delay. Erythropoietin was shown to be neuroprotective in experimental and retrospective clinical studies.. To determine if there is an association between early high-dose recombinant human erythropoietin treatment in preterm infants and biomarkers of encephalopathy of prematurity on magnetic resonance imaging (MRI) at term-equivalent age.. A total of 495 infants were included in a randomized, double-blind, placebo-controlled study conducted in Switzerland between 2005 and 2012. In a nonrandomized subset of 165 infants (n=77 erythropoietin; n=88 placebo), brain abnormalities were evaluated on MRI acquired at term-equivalent age.. Participants were randomly assigned to receive recombinant human erythropoietin (3000 IU/kg; n=256) or placebo (n=239) intravenously before 3 hours, at 12 to 18 hours, and at 36 to 42 hours after birth.. The primary outcome of the trial, neurodevelopment at 24 months, has not yet been assessed. The secondary outcome, white matter disease of the preterm infant, was semiquantitatively assessed from MRI at term-equivalent age based on an established scoring method. The resulting white matter injury and gray matter injury scores were categorized as normal or abnormal according to thresholds established in the literature by correlation with neurodevelopmental outcome.. At term-equivalent age, compared with untreated controls, fewer infants treated with recombinant human erythropoietin had abnormal scores for white matter injury (22% [17/77] vs 36% [32/88]; adjusted risk ratio [RR], 0.58; 95% CI, 0.35-0.96), white matter signal intensity (3% [2/77] vs 11% [10/88]; adjusted RR, 0.20; 95% CI, 0.05-0.90), periventricular white matter loss (18% [14/77] vs 33% [29/88]; adjusted RR, 0.53; 95% CI, 0.30-0.92), and gray matter injury (7% [5/77] vs 19% [17/88]; adjusted RR, 0.34; 95% CI, 0.13-0.89).. In an analysis of secondary outcomes of a randomized clinical trial of preterm infants, high-dose erythropoietin treatment within 42 hours after birth was associated with a reduced risk of brain injury on MRI. These findings require assessment in a randomized trial designed primarily to assess this outcome as well as investigation of the association with neurodevelopmental outcomes.. clinicaltrials.gov Identifier: NCT00413946.

Topics: Brain; Brain Diseases; Double-Blind Method; Epoetin Alfa; Erythropoietin; Humans; Infant; Infant, Newborn; Infant, Premature; Magnetic Resonance Imaging; Neuroprotective Agents; Recombinant Proteins; Retinopathy of Prematurity

Erythropoietin has been shown to be protective against hypoxic-ischemic and inflammatory injuries in cell culture, animal models of brain injury, and clinical trials of adult humans. The rationale for our study was that early administration of high-dose recombinant human erythropoietin may reduce perinatal brain injury (intraventricular hemorrhage and periventricular leukomalacia) in very preterm infants and improve neurodevelopmental outcome. We investigated whether administration of high-dose recombinant human erythropoietin to very preterm infants shortly after birth and subsequently during the first 2 days is safe in terms of short-term outcome.. This was a randomized, double-masked, single-center trial with a 2:1 allocation in favor of recombinant human erythropoietin. Preterm infants (gestational age: 24 to 31 weeks) were given recombinant human erythropoietin or NaCl 0.9% intravenously 3, 12 to 18, and 36 to 42 hours after birth.. The percentage of infants who survived without brain injury or retinopathy was 53% in the recombinant human erythropoietin group and 60% in the placebo group. There were no relevant differences regarding short-term outcomes such as intraventricular hemorrhage, retinopathy, sepsis, necrotizing enterocolitis, and bronchopulmonary dysplasia. For 5 infants who were in the recombinant human erythropoietin group and had a gestational age of <26 weeks, withdrawal of intensive care was decided (3 of 5 with severe bilateral intraventricular hemorrhage, 2 of 5 with pulmonary insufficiency); no infant of the control group died. Recombinant human erythropoietin treatment did not result in significant differences in blood pressure, cerebral oxygenation, hemoglobin, leukocyte, and platelet count.. No significant adverse effects of early high-dose recombinant human erythropoietin treatment in very preterm infants were identified. These results enable us to embark on a large multicenter trial with the aim of determining whether early high-dose administration of recombinant human erythropoietin to very preterm infants improves neurodevelopmental outcome at 24 months' and 5 years' corrected age.

Topics: Apgar Score; Brain Diseases; Cerebral Hemorrhage; Developmental Disabilities; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Erythropoietin; Female; Follow-Up Studies; Gestational Age; Humans; Infant, Newborn; Infant, Premature, Diseases; Infant, Very Low Birth Weight; Intensive Care Units, Neonatal; Male; Maximum Tolerated Dose; Probability; Recombinant Proteins; Reference Values; Retinopathy of Prematurity; Risk Assessment; Survival Analysis; Treatment Outcome

Comparing a group of infants treated with recombinant erythropoietin and iron supplementation to a group of control infants, no difference was observed concerning the transfusion need. The incidence of retinopathy of prematurity was significantly higher in the treated group. These data need to be confirmed in randomized controlled studies.

Topics: Blood Transfusion; Erythropoietin; Ferric Compounds; Ferritins; Hematocrit; Humans; Incidence; Infant, Newborn; Recombinant Proteins; Respiratory Distress Syndrome, Newborn; Retinopathy of Prematurity; Severity of Illness Index

Anemia and retinopathy of prematurity (ROP) are common comorbidities experienced by preterm infants, yet the role of anemia on the pathogenesis of ROP remains unclear. Reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) is a sensitive technique for estimating the gene expression changes at the transcript level but requires identification of stably expressed reference genes for accurate data interpretation. This is particularly important for oxygen induced retinopathy studies given that some commonly used reference genes are sensitive to oxygen. This study aimed to identify stably expressed reference genes among eight commonly used reference genes in the neonatal rat pups' retina upon exposure to cyclic hyperoxia-hypoxia, anemia, and erythropoietin administration at two age groups (P14.5 and P20) using Bestkeeper, geNorm, and Normfinder, three publicly available, free algorithms, and comparing their results to the in-silico prediction program, RefFinder.. The most stable reference gene across both developmental stages was Rpp30, as predicted by Genorm, Bestkeeper, and Normfinder. RefFinder predicted Tbp to be the most stable across both developmental stages. At P14.5, stability varied by prediction program; at P20, RPP30 and MAPK1 were the most stable reference genes. Gapdh, 18S, Rplp0, and HPRT were predicted as the least stable reference genes by at least one of the prediction algorithms.. Expression of Rpp30 is the least affected by experimental conditions of oxygen induced retinopathy, phlebotomy induced anemia and erythropoietin administration at both timepoints of P14.5 and P20.

Topics: Anemia; Animals; Erythropoietin; Gene Expression Profiling; Humans; Infant, Newborn; Infant, Premature; Oxygen; Rats; Real-Time Polymerase Chain Reaction; Reference Standards; Retina; Retinopathy of Prematurity; RNA, Messenger

Retinopathy of prematurity (ROP) is a major morbidity in preterm infants causing visual impairment including blindness. Prevention and timely treatment are critical. We investigated the potential role of red blood cell (RBC) transfusions as risk factor for ROP development.. Retrospective cohort study of data from 68 tertiary level neonatal intensive care units in Germany. Preterm infants born at 22 + 0 to 28 + 6 weeks of gestation between January 2009 and December 2021 were enrolled.. We included n = 12 565 infants. Prevalence of any ROP was 49.2% with most infants being diagnosed with stage 1 (21.5%) and 2 disease (17.2%). ROP stage 3 was present in 10.2%, stage 4 in 0.3%, and ROP requiring treatment in 6.6%. Infants with ROP had significantly more frequently a history of RBC transfusions. Adjusting for confounders, RBC transfusions were associated with increased odds of ROP (OR 1.4, p < 0.001), ROP progression (OR 2.1, p < 0.01) and ROP requiring treatment (OR 3.6, p < 0.001). Restrictive transfusion approaches correlated with decreased (OR 0.7, p < 0.001), liberal regimes with increased odds (OR 1.2, p = 0.001).. The present study confirmed an association of RBC transfusions and ROP. Our findings emphasise the need for anaemia prevention and critical re-evaluation of transfusion practices in preterm infants.

Topics: Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Gestational Age; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Retinopathy of Prematurity; Retrospective Studies; Risk Factors

Endogenous erythropoietin (EPO) concentrations vary widely in preterm infants and may be associated with perinatal risk factors and neurological outcomes. Erythropoietin is elevated in fetal hypoxia but is also a potential neuroprotectant.. In a prospective study of 27 infants ≤ 30 weeks gestation, serum erythropoietin concentrations were measured during the first month of life, on day 1 and weeks 1, 2, and 4, and related to perinatal risk factors and outcomes including retinopathy of prematurity and cerebral injury evaluated near term-equivalent post menstrual age using magnetic resonance imaging with quantitative scoring.. Lower birth weight was associated with higher EPO concentrations throughout the first 2 weeks of life (r = -0.6, p < 0.01). Higher day 1 and week 1 EPO concentrations were associated with lower Apgar score at 1 minute (r = - 0.5) and 5 minutes (r = -0.7), respectively (p < 0.01). Higher day 1 EPO concentrations and 2-week area under the curve were associated with increased risk (p = 0.01) and severity (r = 0.5, p < 0.02) of retinopathy of prematurity. Higher EPO concentrations at 2 weeks were associated with increased total brain injury score (r = 0.5, p < 0.05).. Elevated endogenous erythropoietin concentrations in the first two weeks of life are associated with lower birth weight and increased risk of adverse outcomes.

Topics: Age Factors; Apgar Score; Brain Injuries; Erythropoietin; Female; Humans; Infant, Low Birth Weight; Infant, Newborn; Infant, Newborn, Diseases; Infant, Premature; Infant, Premature, Diseases; Male; Pregnancy; Prospective Studies; Retinopathy of Prematurity

Retinopathy of prematurity (ROP) is a developmental retinal vaso-proliferative disease and a leading cause of blindness in children. Early gestational age, low birth weight and unregulated oxygen exposure are the main risk factors for the development of ROP. There are conflicting reports of a possible association between recombinant Erythropoietin (rhEPO) use and an increased risk for the development of ROP.. To determine whether rhEPO is an independent risk factor for the development of severe ROP among preterm infants with a gestational age of 23 to 32 weeks and a birth weight <1500 g.. We performed a retrospective study of risk factors for ROP on a cohort of 1762 premature infants born between 2009 and 2014, half of whom received rhEPO. To examine the association between treated ROP and rhEPO, a propensity score (PS) analysis was performed using the inverse probability of treatment weighted (IPTW) approach.. The incidence of treated ROP was 7.3% (129/1762). PS analysis did not show an association between rhEPO and severe ROP needing treatment or ROP stage 2 or higher, in either the whole population or in the subgroup of babies born at 23 to 28 weeks gestation, in whom the incidence of severe ROP was the highest. Of 117 patients treated for Type 1 or worsening stage 3 ROP, 17 were first diagnosed after NICU discharge.. Our study showed no association between Erythropoietin use and severe ROP and highlights the importance of Ophthalmology follow up after hospital discharge.

Topics: Child; Erythropoietin; Gestational Age; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Retinopathy of Prematurity; Retrospective Studies; Risk Factors

Preterm infants with anaemia are treated with recombinant human erythropoietin (rhEPO). It is debated whether rhEPO treatment is a risk factor for retinopathy of prematurity (ROP). We evaluated longitudinal EPO and haemoglobin levels, blood transfusions and neonatal morbidities as risk factors for severe ROP.. This prospective study included 78 Swedish infants, born <28 weeks gestational age (GA), screened for ROP. We tested serum EPO levels on postnatal days 1, 7, 14 and 28 and at postmenstrual ages 32, 36 and 40 weeks. Haemoglobin levels and blood transfusions were recorded during postnatal weeks 1-4. Anaemia was defined as haemoglobin ≤110 g/L.. During postnatal week 1, infants with severe ROP requiring treatment (28%) more frequently developed anaemia (42.9% versus 8.0%, P = 0.003) and had higher mean EPO levels (postnatal day 7: 14.2 versus 10.8 mIU/mL, P = 0.003) compared to infants with no or less severe ROP not requiring treatment. In multivariable analyses, GA and anaemia during week 1 remained significant risk factors, but elevated EPO level postnatal day 7 was no longer significant.. Among infants born <28 weeks GA, anaemia during week 1 was a significant risk factor for severe ROP requiring treatment but not elevated EPO levels.

Topics: Anemia; Blood Transfusion; Erythrocyte Transfusion; Erythropoietin; Female; Gestational Age; Hemoglobins; Humans; Infant; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Logistic Models; Longitudinal Studies; Male; Multivariate Analysis; Prospective Studies; Retinopathy of Prematurity; Risk Factors

Thrombocytosis is more prevalent in pediatric than in adult patients and is associated with complications or worsened outcomes after vascular events. This study aimed to determine the prevalence of thrombocytosis in very preterm infants who had not received human recombinant erythropoietin treatment (rHuEPO) and its relationship with other hematological parameters and clinical complications.. We performed a retrospective study of hematological and clinical data of very preterm infants who were admitted to our unit in their first 48 hours of life and stayed for longer than 1 week.. Thrombocytosis was prevalent (32.6% of patients) in very preterm infants (≤32 weeks of gestational age, n = 193) who had not received rHuEPO. The platelet count was positively correlated with calendar age. Infants with thrombocytosis were significantly more premature (28.0 ± 2.1 versus 29.6 ± 2.2 weeks) and had a lower birth weight (1036 ± 304 versus 1303 ± 304) than those without thrombocytosis. Thrombocytosis was associated with retinopathy of prematurity after adjusting for gestational age and comorbidities, but not with other prematurity-associated complications.. Late asymptomatic thrombocytosis is common in very preterm infants at approximately 1 month of postnatal age and it may be associated with retinopathy of prematurity.

Topics: Erythropoietin; Follow-Up Studies; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Prognosis; Recombinant Proteins; Retinopathy of Prematurity; Retrospective Studies; Spain; Thrombocytosis

In this case-control study, the erythropoietin (EPO) promoter variant s1617640, linked to high intravitreal EPO concentrations and increased risk of diabetic retinopathy, was not associated with severe retinopathy of prematurity. This finding was observed both in infants with and without recombinant EPO administration.

Topics: Case-Control Studies; Erythropoietin; Female; Follow-Up Studies; Genetic Markers; Humans; Infant, Newborn; Infant, Premature; Male; Promoter Regions, Genetic; Recombinant Proteins; Retinopathy of Prematurity; Retrospective Studies; Severity of Illness Index

To explore the association between concentrations of endogenous erythropoietin (EPO) in blood the first 2 weeks of life and neonatal disorders in extremely low gestational age newborns (ELGANs).. Prospective cohort study.. Neonatal care units at 14 participating hospitals in the USA.. 867 children born before the 28th week of gestation from the ELGAN study cohort.. EPO blood concentrations were measured on postnatal days 1, 7 and 14. The following neonatal characteristics and disorders were registered: blood gases, early and late respiratory dysfunction, pulmonary deterioration, retinopathy of prematurity (ROP), necrotising enterocolitis (NEC) and bronchopulmonary dysplasia (BPD). We calculated the gestational age-adjusted ORs for having each disorder associated with an EPO blood concentration in the highest or lowest quartile, compared with infants whose EPO concentration was in the middle two quartiles on the corresponding day.. Newborns whose day-1 EPO was in the highest quartile were at increased risk for early and persistent respiratory dysfunction during the first 2 weeks of life, and NEC requiring surgery. The lowest EPO quartile on day 1 was associated with a decreased risk of moderate BPD. The association between low EPO and decreased risk of respiratory complications persisted on day 7. On day 14, being in the highest EPO quartile was associated with increased risk of ROP, and BPD not requiring ventilation assistance.. EPO blood concentrations in extremely preterm newborns during the first 2 weeks of life convey information about increased risks of bowel, lung and retinal diseases.

Topics: Bronchopulmonary Dysplasia; Enterocolitis, Necrotizing; Erythropoietin; Gestational Age; Humans; Infant, Extremely Premature; Infant, Premature, Diseases; Prospective Studies; Respiratory Distress Syndrome, Newborn; Retinopathy of Prematurity; Risk Factors; Time Factors

Topics: Erythropoietin; Female; Hematinics; Humans; Male; Retinopathy of Prematurity

To investigate the changes in plasma concentrations of vascular endothelial growth factor (VEGF), insulin growth factor (IGF-1), erythropoietin, pigment epithelium-derived factor, and IgG1 after bevacizumab intravitreal injection in infants with retinopathy of prematurity.. Eleven eyes from six infants who received intravitreal injection of bevacizumab were enrolled in this study. At preinjection and postinjection 1, 2, 3, 4, 5, 6, 7, and 8 weeks, 0.5 mL of blood was collected from each infant. The plasma concentrations of VEGF, insulin growth factor, erythropoietin, pigment epithelium-derived factor, and IgG1 were measured by enzyme-linked immunosorbent assay. Five patients received simultaneous bilateral bevacizumab injection; one patient received unilateral injection.. Of the infants who received intravitreal bevacizumab injection, two were males and four were females. The mean gestational age was 26 ± 2 weeks. The mean birth weight was 870 g. The mean plasma VEGF concentration before bevacizumab injection was 2.05 ± 3.00 ng/mL; plasma level decreased significantly to 0.16 ± 0.10 ng/mL and to 0.14 ± 0.14 ng/mL (P = 0.028) after 1 week and 2 weeks, respectively. Moreover, the plasma concentrations of VEGF did not return to the original level in any of the samples until 8 weeks after the injection. However, mean plasma IgG1, erythropoietin, insulin growth factor, and PEDF concentrations did not change significantly during the interval between preinjection and any other follow-up time points.. Intravitreal bevacizumab injections significantly reduce plasma VEGF concentration in infants with retinopathy of prematurity over a 7-week period.

Topics: Angiogenesis Inhibitors; Bevacizumab; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Eye Proteins; Female; Gestational Age; Humans; Immunoglobulin G; Infant, Newborn; Infant, Very Low Birth Weight; Insulin-Like Growth Factor I; Intravitreal Injections; Male; Nerve Growth Factors; Retinopathy of Prematurity; Serpins; Vascular Endothelial Growth Factor A

Exogenous human erythropoietin (EPO) artificially synthesised through recombinant DNA technology (rHuEPO) is currently used as a substitute for blood transfusion in preterm and low birth weight neonates. The objective of this study is to determine whether the use of rHuEPO is associated with an increased severity of retinopathy of prematurity (ROP) in preterm neonates.. This retrospective review studies neonates who were admitted to a tertiary perinatal unit and screened for ROP during the 10-year period from January 2003 to December 2012.. : During the 10-year period, 688 preterm neonates underwent ROP screening, with 198 identified as having ROP. The incidence of stage 1 ROP was 51.5% (102/198), followed by 35.9% (71/198) for stage 2, and 12.6% (25/198) for stage 3 and greater. Plus disease was seen in 14 neonates (7.1%). Treatment (laser photocoagulation) was administered in 64% of neonates (16/25) with stage 3 of the disease and above because of progression to threshold ROP. Twenty-six (13%) of the neonates received rHuEPO treatment. There were no statistically significant differences in birth weight (910.4 vs 885 g; P=0.71), gestational age (26.5 vs 25.8 weeks; P=0.09), and duration of ventilation (512 vs 501.4 h; P=0.92) between neonates who did not receive rHuEPO compared with those who were treated with rHuEPO. Multivariate regression analysis showed that the use of EPO was associated with increased severity of ROP.. EPO therapy appears to increase the risk of development and worsening of ROP.

Topics: Anemia, Neonatal; Birth Weight; Epoetin Alfa; Erythropoietin; Female; Gestational Age; Hematinics; Humans; Infant, Newborn; Infant, Premature; Laser Coagulation; Male; Recombinant Proteins; Retinopathy of Prematurity; Retrospective Studies; Risk Factors; Severity of Illness Index

Neovascularization and vaso-obliteration are vision-threatening events that develop by interactions between retinal vascular and glial cells. A high-salt diet is causal in cardiovascular and renal disease, which is linked to modulation of the renin-angiotensin-aldosterone system. However, it is not known whether dietary salt influences retinal vasculopathy and if the renin-angiotensin-aldosterone system is involved. We examined whether a low-salt (LS) diet influenced vascular and glial cell injury and the renin-angiotensin-aldosterone system in ischemic retinopathy.. Pregnant Sprague Dawley rats were fed LS (0.03% NaCl) or normal salt (0.3% NaCl) diets, and ischemic retinopathy was induced in the offspring. An LS diet reduced retinal neovascularization and vaso-obliteration, the mRNA and protein levels of the angiogenic factors, vascular endothelial growth factor, and erythropoietin. Microglia, which influence vascular remodeling in ischemic retinopathy, were reduced by LS as was tumor necrosis factor-α. Macroglial Müller cells maintain the integrity of the blood-retinal barrier, and in ischemic retinopathy, LS reduced their gliosis and also vascular leakage. In retina, LS reduced mineralocorticoid receptor, angiotensin type 1 receptor, and renin mRNA levels, whereas, as expected, plasma levels of aldosterone and renin were increased. The aldosterone/mineralocorticoid receptor-sensitive epithelial sodium channel alpha (ENaCα), which is expressed in Müller cells, was increased in ischemic retinopathy and reduced by LS. In cultured Müller cells, high salt increased ENaCα, which was prevented by mineralocorticoid receptor and angiotensin type 1 receptor blockade. Conversely, LS reduced ENaCα, angiotensin type 1 receptor, and mineralocorticoid receptor expression.. An LS diet reduced retinal vasculopathy, by modulating glial cell function and the retinal renin-angiotensin-aldosterone system.

Topics: Adaptor Protein Complex 1; Aldosterone; Animals; Animals, Newborn; Aquaporin 4; Body Weight; Cells, Cultured; Diet, Sodium-Restricted; Disease Models, Animal; Drinking Behavior; Ependymoglial Cells; Epithelial Sodium Channels; Erythropoietin; Gliosis; Hematocrit; Ion Transport; Ischemia; Kidney Glomerulus; MAP Kinase Signaling System; Microglia; Phosphorylation; Potassium Channels, Inwardly Rectifying; Protein Processing, Post-Translational; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System; Retinal Ganglion Cells; Retinal Neovascularization; Retinopathy of Prematurity; Sodium; Sodium Chloride, Dietary; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Retinopathy of prematurity (ROP) is a multifactorial disease with evidence of many associated risk factors. Erythropoietin has been reported to be associated with this disorder in a murine model, as well as in humans in some single-center reports. We reviewed the data from two large tertiary NICUs in Italy to test the hypothesis that the use of erythropoietin may be associated with the development of the most severe stages of ROP in extremely low birth weight (ELBW) neonates.. Retrospective study by review of patient charts and eye examination index cards on infants with birth weight <1000g admitted to two large tertiary NICUs in Northern Italy (Sant'Anna Hospital NICU in Torino, and Ca' Foncello Hospital Neonatology in Treviso) in the years 2005 to 2007. Standard protocol of administration of EPO in the two NICUs consisted of 250 UI/kg three times a week for 6-week courses (4-week in 1001-1500g infants). Univariate analysis was performed to assess whether the use of EPO was associated with severe (threshold) ROP. A control, multivariate statistical analysis was performed by entering into a logistic regression model a number of neonatal and perinatal variables that - in univariate analysis - had been associated with threshold ROP.. During the study period, 211 ELBW infants were born at the two facilities and survived till discharge. Complete data were obtained for 197 of them. Threshold retinopathy of prematurity occurred in 26.9% (29 of 108) of ELBW infants who received erythropoietin therapy, as compared with 13.5% (12 of 89) of those who did not receive erythropoietin (OR 2.35; 95% CI 1.121-4.949; p=0.02 in univariate analysis, and p=0.04 at multivariate logistic regression after controlling for the following variables: birth weight, gestational age, days on supplemental oxygen, systemic fungal infection, vaginal delivery). Use of erythropoietin was not significantly associated with other major sequelae of prematurity (intraventricular hemorrhage, bronchopulmonary dysplasia, necrotizing enterocolitis). © 2014 Elsevier Ireland Ltd. All rights reserved.. Use of erythropoietin is an additional, independent predictor of threshold ROP in ELBW neonates. Larger prospective, population-based studies should further clarify the extent of this association.

Topics: Case-Control Studies; Cohort Studies; Erythropoietin; Female; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Intensive Care Units, Neonatal; Italy; Male; Retinopathy of Prematurity; Retrospective Studies

Inhibiting VEGF improves adult retino/choroido-vascular diseases, but can lead to recurrent intravitreous neovascularization (IVNV), avascular retina (AVA), and retinal detachment in preterm infants with retinopathy of prematurity (ROP). We sought to understand causes of late-onset IVNV and AVA following anti-VEGF using an ROP model.. In the Penn model of ROP, postnatal day (p)12 pups received 1 μL intravitreal VEGFA164 antibody (anti-VEGF; 25-100 ng) or IgG control in each eye. Analyses included lectin-stained percent IVNV and AVA; VEGF protein, erythropoietin, phosphorylated extracellular signal-related kinases and signal transducer and activator of transcription-3 (p-STAT3); and immunohistochemistry of retinal sections for p-VEGFR2. Western blots of human retinal microvascular endothelial cells (hRMVECs) stimulated with VEGF or erythropoietin were analyzed for p-STAT3. Statistical analysis was performed with one-way ANOVA or two-tailed t-tests.. At p18, 50 ng anti-VEGF reduced IVNV, and at p25, caused increased IVNV and AVA compared with controls. VEGF and p-VEGFR2 labeling increased following 100 ng anti-VEGF. Following 50 ng anti-VEGF, reduced p-STAT3 and increased erythropoietin occurred at p18. Erythropoietin or VEGF stimulated hRMVEC proliferation and STAT3 activation. In vivo, anti-VEGF reduced pup growth.. Increases in erythropoietin and angiogenic signaling following anti-VEGF may account for recurrent IVNV. Anti-VEGF reduced pup growth. Research is needed regarding safety, dose, and type of antiangiogenic treatment for ROP.

Topics: Animals; Antibodies; Biomarkers; Blotting, Western; Body Weight; Case-Control Studies; Disease Models, Animal; Erythropoietin; Humans; Infant, Newborn; Neovascularization, Pathologic; Rats; Rats, Sprague-Dawley; Retina; Retinopathy of Prematurity; STAT3 Transcription Factor; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2

This study aims to investigate the incidence and the relative risk factors of retinopathy of prematurity (ROP) and posterior-ROP (P-ROP): ROP in Zone I and posterior Zone II, as well as to analyze the occurrence of surgical treatment of ROP and to evaluate the short term outcome of the disease in Italy.. It is a prospective multicenter observational study; all infants with a birth weight (BW) ≤ 750 g and/or a gestational age (GA) ≤27 weeks born between January 1st 2008 and December 31st 2009 in 25 III level Italian neonatal intensive care units were eligible for the study.. 421 infants were examined: 265 (62.9%) developed ROP and 102 (24.2%) P-ROP.. P-ROP is the most aggressive type of ROP. It associates with lower GA and sepsis. Obstetricians and Neonatologists must focus on the reduction of severe preterm births and on the prevention of neonatal early and late onset sepsis in order to reduce the incidence of P-ROP.

Topics: Birth Weight; Erythropoietin; Female; Gestational Age; Humans; Infant, Newborn; Intensive Care Units, Neonatal; Intracranial Hemorrhages; Italy; Laser Therapy; Male; Multivariate Analysis; Prospective Studies; Retinopathy of Prematurity; Sepsis

The role of growth factors in the pathogenesis of retinopathy of prematurity (ROP) is known. To better understand this issue, the authors investigated vascular endothelial growth factor (VEGF), insulin-like growth factor 1 (IGF-1), and erythropoietin (EPO) levels in the cord blood of premature newborns.. IGF-1, VEGF, and EPO levels were measured in cord blood samples obtained from 93 infants less than 32 weeks of gestational age at birth, and their predictive value in the development of ROP was investigated.. The mean birth age and mean birth weight were 32.2 ± 1.5 weeks and 1,678 ± 326 g, respectively, in infants without ROP and 29.6 ± 2.3 weeks and 1,384 ± 343 g, respectively, in infants with ROP. Multivariate logistic regression analysis showed that only the gestational age and the serum VEGF at birth were independently associated with the risk of developing ROP (P = .002, Exp[B] = 0.514, CI = 95%: 0.341-0.775; P = .028, Exp[B] = 0.999, CI = 95%: 0.997-1.00).. Serum VEGF levels at birth were lower in infants who later developed ROP. This may have a predictive value for ROP and contribute to the pathogenesis, because affected infants may be more susceptible to extrauterine hyperoxic insult.

Topics: Erythropoietin; Female; Fetal Blood; Humans; Infant, Newborn; Insulin-Like Growth Factor I; Logistic Models; Male; Predictive Value of Tests; Retinopathy of Prematurity; Vascular Endothelial Growth Factor A

Retinopathy of prematurity (ROP) is a leading cause of blindness in children and is, in its most severe form, characterized by uncontrolled growth of vision-threatening pathologic vessels. Propranolol, a nonselective β-adrenergic receptor blocker, was reported to protect against pathologic retinal neovascularization in a mouse model of oxygen-induced retinopathy (OIR). Based on this single animal study using nonstandard evaluation of retinopathy, clinical trials are currently ongoing to evaluate propranolol treatment in stage 2 ROP patients who tend to experience spontaneous disease regression and are at low risk of blindness. Because these ROP patients are vulnerable premature infants who are still in a fragile state of incomplete development, the efficacy of propranolol treatment in retinopathy needs to be evaluated thoroughly in preclinical animal models of retinopathy and potential benefits weighed against potential adverse effects.. Retinopathy was induced by exposing neonatal mice to 75% oxygen from postnatal day (P) 7 to P12. Three routes of propranolol treatment were assessed from P12 to P16: oral gavage, intraperitoneal injection, or subcutaneous injection, with doses varying between 2 and 60 mg/kg/day. At P17, retinal flatmounts were stained with isolectin and quantified with a standard protocol to measure vasoobliteration and pathologic neovascularization. Retinal gene expression was analyzed with qRT-PCR using RNA isolated from retinas of control and propranolol-treated pups.. None of the treatment approaches at any dose of propranolol (up to 60 mg/kg/day) were effective in preventing the development of retinopathy in a mouse model of OIR, evaluated using standard techniques. Propranolol treatment also did not change retinal expression of angiogenic factors including vascular endothelial growth factor.. Propranolol treatment via three routes and up to 30 times the standard human dose failed to suppress retinopathy development in mice. These data bring into question whether propranolol through inhibition of β-adrenergic receptors is an appropriate therapeutic approach for treating ROP.

Topics: Administration, Oral; Adrenergic beta-Antagonists; Angiopoietin-1; Angiopoietin-2; Animals; Animals, Newborn; Cell Proliferation; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Gene Expression Profiling; Humans; In Vitro Techniques; Infant, Newborn; Injections, Intraperitoneal; Injections, Subcutaneous; Mice; Oxygen; Propranolol; Receptors, Adrenergic, beta; Receptors, Vascular Endothelial Growth Factor; Retina; Retinal Neovascularization; Retinopathy of Prematurity; Reverse Transcriptase Polymerase Chain Reaction; RNA; Up-Regulation; Vascular Endothelial Growth Factor A

Prolyl hydroxylases (PHDs) are oxygen sensors that stabilize hypoxia-inducible factors (HIFs) to induce proinflammatory, vasopermeability, and proapoptotic factors. These may be potential targets to reduce the complications of ischemic retinopathies.. Oxygen-induced ischemic retinopathy (OIR) was generated as a model for retinopathy of prematurity (ROP) by placing 7-day-old mice in 75% oxygen for 5 days and returning them to the relative hypoxia of room air for 5 days. Neovascularization (NV) and avascular areas were assessed on retinal flat-mounts by image analysis. Blood-retinal barrier breakdown was assessed using ³H-mannitol as a tracer. Apoptosis was detected with TUNEL staining. HIF-1α and VEGF were quantified using Western blot analysis and ELISA.. PHD1-deficient mice demonstrated reduced hyperoxia-associated vascular obliteration during oxygen-induced ischemic retinopathy. This was associated with subsequent reduced avascularity, vascular leakage, and pathologic NV during the hypoxic phase, which could be accounted for by a reduced expression of HIF-1α and VEGF. Apoptosis in the retina was also reduced in PHD1-depleted mice after 2 days in hyperoxia.. PHD1 deficiency is associated with a reduction of ischemia-induced retinal NV. The regulatory mechanism in this model appears to be: PHD1 depletion prevents HIF-1α degradation in hyperoxia, which induces VEGF, thus preventing hyperoxia-related vessel loss. Without a vessel deficiency, there would not be relative hypoxia when the mice are returned to room air and there would be no need to initiate angiogenesis signaling. Blocking PHD1 may be beneficial for ischemic retinopathies and inflammatory and neurodegenerative disorders.

Topics: Animals; Animals, Newborn; Apoptosis; Blood-Retinal Barrier; Blotting, Western; Capillary Permeability; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; In Situ Nick-End Labeling; Infant, Newborn; Mice; Mice, Knockout; Oxygen; Procollagen-Proline Dioxygenase; Reperfusion Injury; Retinal Neovascularization; Retinal Vessels; Retinopathy of Prematurity; Vascular Endothelial Growth Factor A

In addition to its hematopoietic effects, erythropoietin causes an increased release of endothelin-1 and the stimulation of angiogenesis and thereby it may have possible role in development of retinopathy of prematurity (ROP). Our objective was to determine if an association exists between recombinant human erythropoietin (rhEPO) treatment and the development of ROP. Our case-control study involved 85 very low birthweight infants with birthweights <1500 g born during 2003 and 2004. All the infants were divided into two groups on the basis of whether they got rhEPO or not. The rhEPO was given at the dose of 200 to 250 units/kg/dose three times a week for 10 doses. Further duration of rhEPO therapy was decided on the basis of the clinical response. Ophthalmological examinations were done at the age of 5 to 6 weeks and were repeated 1 to 4 weeks after the first examination according to the severity of the ROP disease during their in-hospital stay. Of 85 infants, 56 (66%) received rhEPO and 29 (34%) did not. In the rhEPO-treated group, 12 infants (21%) had ROP; in the non-rhEPO group, 11 infants (38%) developed ROP. This difference is not statistically significant (odds ratio = 2.63; P = 0.10). There was no correlation between the use of rhEPO and the stage of ROP (random sample = -0.01; P = 0.89). There was no significant difference in the incidence of plus, prethreshold, or threshold disease and the treatment required for ROP between the rhEPO-treated and the nontreated group. The study showed there is no significant difference in the incidence and severity of ROP between the rhEPO-treated and nontreated group.

Topics: Case-Control Studies; Endothelin-1; Erythropoietin; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Neovascularization, Physiologic; Recombinant Proteins; Retinopathy of Prematurity; Severity of Illness Index

To evaluate associations between conditions of maternal new-onset gestational hypertension (mHTN) and the features imparting risk of severe retinopathy of prematurity (ROP) in preterm infants.. Hospital databases and charts of all preterm inborn infants at the University of North Carolina from 1996 to 2007 were retrospectively reviewed. The presence or absence of mHTN (e.g., pre-eclampsia) and infant factors (birthweight, gestational age, erythropoietin use, and zone and stage of ROP) were analyzed for independence of association.. Of the 5143 infants, 323 had ROP and 76 had mothers with mHTN. Infants with ROP were more likely to have mothers with mHTN and to be younger and smaller at birth. At initial examination, more infants of mothers with mHTN had vascularization into the lower zones than did infants of mothers without mHTN (P < 0.001). However, at the examination in which the most severe ROP was present, there was no association between mHTN and ROP stage (P = 0.2342). Analysis of stage and zone together showed that infants born to mothers with mHTN were more likely to have ROP at initial examination, after adjustment for gestational age, but not for birth weight. The use of erythropoietin was not associated with ROP zone or stage, even after adjustment for maternal condition, infant birth weight, or gestational age.. Although larger avascular areas or higher severity scores were associated with mHTN after adjustment for gestational age at initial examination, no associations were found between mHTN and ROP severity score at the examination when ROP was most severe. There were no associations between ROP severity and treatment with erythropoietin.

Topics: Anemia, Neonatal; Erythrocyte Transfusion; Erythropoietin; Female; Gestational Age; Humans; Hypertension, Pregnancy-Induced; Infant, Low Birth Weight; Infant, Newborn; Pregnancy; Recombinant Proteins; Retinopathy of Prematurity; Retrospective Studies; Risk Factors

Erythropoietin (EPO) stimulates angiogenesis and may favour the appearance of retinopathy of prematurity (ROP). The objective was to determine if EPO+Fe administered from the 5th day of life could be an independent risk factor for ROP appearance and its severity.. The study included 718 preterm newborns with a birth weight ≤1,500g or a gestational age ≤32 weeks (and 6 days), admitted between 2001 and 2008. During these years, the target SaO₂ was between 88% and 93%. EPO treatment began at 5-7 days of life, with a dose of 250 UI/Kg, 3 times a week, subcutaneously, together with Fe, 5-6mg/kg/day, both until 34 weeks of corrected age or discharge.. A total of 493 preterms (68.7%) did not have ROP, 139 (19.4%) had a grade 1 ROP, 50 (7.0%) a grade 2 ROP and 36 (5.0%) a grade 3 ROP. Laser therapy was required by 27 severe ROP was associated with lower birth weight and gestational age, more neonatal morbidity and a more aggressive treatment (duration of oxygen supplements or mechanical ventilation, number of blood transfusions). Risk factors independently and significantly associated with any ROP grade were: lower birth weight, no caesarean section, EPO administration and need for blood transfusion. EPO administration increased the risk of ROP by 2.4, but this only happened in case of grade 1 ROP (OR: 5.50).. EPO+Fe administration is associated and perhaps stimulates the appearance of grade 1 ROP.

Topics: Erythropoietin; Female; Humans; Infant, Newborn; Infant, Premature; Iron; Male; Recombinant Proteins; Retinopathy of Prematurity; Retrospective Studies; Risk Factors; Time Factors

To identify and quantify risk factors related to red blood cell transfusion in premature babies weighing<1,500g who received erythropoietin (EPO). Secondly, to assess the relationship between retinopathy of prematurity and rh-EPO.. Prospective descriptive study of infants admitted to the Reina Sofía University Hospital between January 2006 and March 2009. Infants reviewed had a birth weight<1,500g and gestational age<32 weeks. Infants were administered rh-EPO 750IU/kg/week subcutaneously 3 days/week/ 6 weeks. We used univariate and multivariate logistic regressions with PASW Statistics 18 for Windows.. Data were obtained from 110 infants, with a mean birth weight of 1154grs and mean gestational age of 29.3 weeks. Risk factors (OR; 95% CI) for being transfused were: male sex (4.41; 1.24-15.66), GA (1.64; 1.14-2.36, 1 week), Hb level on admission (1.45; 1.04-2.04; 1g/dl), late onset sepsis (7.75; 2.21-21.11), late onset treatment with rh-EPO (6.27; 1.22-32.35). All surgically treated infants with patent ductus arteriosus ligation or necrotizing enterocolitis needed transfusion. There is no relationship between rh-EPO administration and retinopathy of prematurity (ROP), but there was a relationship with transfusion.. Premature infants with the lower gestational age, being male, a lower Hb level on admission and late onset sepsis are those with the greatest risk for blood transfusion.

Topics: Blood Transfusion; Erythropoietin; Female; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Male; Prospective Studies; Recombinant Proteins; Retinopathy of Prematurity; Risk Factors; Transfusion Reaction

Erythropoietin (EPO), an oxygen-regulated hormone stimulating erythrocyte production, was recently found to be critical for retinal angiogenesis. EPO mRNA expression levels in retina are highly elevated during the hypoxia-induced proliferation phase of retinopathy. The authors investigated the inhibition of retinal EPO mRNA expression with RNA interference as a potential strategy to suppress retinal neovascularization and to prevent proliferative retinopathy.. The authors used a mouse model of oxygen-induced retinopathy. Retinal EPO and Epo receptor (EpoR) expression during retinopathy development were quantified with real-time RT-PCR in whole retina and on laser-captured retinal vessels and neuronal layers. Retinal hypoxia was assessed with an oxygen-sensitive hypoxyprobe. A small interference RNA (siRNA) targeting EPO or control negative siRNA was injected intravitreally at postnatal (P) day 12, P14, and P15 during the hypoxic phase, and the effect on neovascularization was evaluated in retinal flatmounts at P17.. Retinal EPO mRNA expression in total retina was suppressed during the initial phase of vessel loss in retinopathy and was significantly elevated during the hypoxia-induced proliferative phase in all three neuronal layers in the retina, corresponding to an increased level of retinal hypoxia. EpoR mRNA expression levels also increased during the second neovascular phase, specifically in hypoxia-induced neovascular vessels. Intravitreous injection of EPO siRNA effectively inhibited approximately 60% of retinal EPO mRNA expression and significantly suppressed retinal neovascularization by approximately 40%.. Inhibiting EPO mRNA expression with siRNA is effective in suppressing retinal neovascularization, suggesting EPO siRNA is a potentially useful pharmaceutical intervention for treating proliferative retinopathy.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Erythropoietin; Fluorescent Antibody Technique, Indirect; Gene Expression Regulation; Humans; Infant, Newborn; Injections; Mice; Microscopy, Confocal; Oxygen; Receptors, Erythropoietin; Retinal Neovascularization; Retinal Vessels; Retinopathy of Prematurity; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA, Messenger; RNA, Small Interfering; Vitreous Body

To determine the vitreous levels of erythropoietin and vascular endothelial growth factor (VEGF) in eyes with retinopathy of prematurity (ROP) and to study the correlation between the 2 levels.. Retrospective case-control study.. Forty eyes of 27 infants with stage 4 ROP (4A, 30 eyes; 4B, 10 eyes) were studied. Five eyes of 4 patients with congenital cataract were used as controls.. The eyes with ROP were classified by the vascular activity into 3 groups: highly vascular-active ROP (n = 16), moderately vascular-active ROP (n = 10), and mildly vascular-active ROP (n = 14). Eyes with highly vascular-active ROP initially received an intravitreal injection of 0.5 mg bevacizumab and underwent vitrectomy approximately 1 week after the injection. The eyes in the other groups underwent vitrectomy without bevacizumab. Undiluted vitreous samples were obtained at the beginning of vitrectomy, and the vitreous concentrations of erythropoietin and VEGF were measured by enzyme-linked immunosorbent assay.. The vitreous concentrations of erythropoietin and VEGF were determined and compared among the 4 groups.. The vitreous level of erythropoietin was significantly higher (P<0.05) in the highly and moderately vascular-active ROP eyes than in control eyes. The median concentration of erythropoietin was 744.6 mIU/ml in the highly vascular-active ROP eyes, 729.9 mIU/ml in the moderately vascular-active ROP eyes, 478.0 mIU/ml in the mildly vascular-active ROP eyes, and 0 mIU/ml in control eyes. The vitreous VEGF level was significantly higher (P<0.05) in the moderately vascular-active ROP eyes than in control eyes. The median concentration of VEGF was 44.7 pg/ml in the highly vascular-active ROP eyes that had received an intravitreal bevacizumab injection, 360.8 pg/ml in the moderately vascular-active ROP eyes, 0 pg/ml in the mildly vascular-active ROP eyes, and 11.4 pg/ml in control eyes. There was a significant positive correlation (r = 0.410; P = 0.047) between the erythropoietin and VEGF levels in moderately and mildly vascular-active ROP eyes.. The elevated level of erythropoietin and its correlation with the VEGF level in eyes with stage 4 ROP suggest that not only VEGF but also erythropoietin may contribute to the pathogenesis of ROP.. The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bevacizumab; Case-Control Studies; Combined Modality Therapy; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Female; Gestational Age; Humans; Infant, Extremely Low Birth Weight; Infant, Low Birth Weight; Infant, Newborn; Injections; Laser Coagulation; Male; Retinopathy of Prematurity; Retrospective Studies; Vascular Endothelial Growth Factor A; Vitrectomy; Vitreous Body

To observe the effect of inhibition of retinal neovascularization by small-interference RNA (siRNA) targeting erythropoietin (EPO).. Three siRNAs against EPO were designed and synthesized. Then they were transfected to NIH/3T3 cells by liposomes. RT-PCR and Western blot were used to evaluate the efficacy of siRNA in attenuating EPO expression in NIH/3T3 cells. One-week-old C57BL/6J mice were exposed to 75 +/- 2% oxygen for 5 days, then they were returned to room air to induce retinal neovascularization. The siRNA type shown as most powerful in reducing EPO expression in vitro was intravitreally injected in the treatment group. Retinal neovascularization was evaluated by angiography with injection of fluorescein-dextran and quantification of neovascular proliferative retinopathy after 5 days in room air. Moreover, RT-PCR and immunoblot analysis were used to determine whether local administration of siRNA could affect the expression of EPO in murine retinas.. Among the 3 designed siRNAs (named siEPO1-3), siEPO2 is the most efficient in inhibiting EPO expression. In this murine model of oxygen-induced retinopathy, retinal neovascularization in the eyes with siEPO2 injection was significantly reduced compared with that of the contralateral control eyes. Similarly, histological analysis indicates that the number of neovascular nuclei protruding into the vitreous cavity was decreased compared to the control eyes. Furthermore, the expression of EPO in the retinas injected with siEPO2 was dramatically decreased.. siRNA against EPO could inhibit experimental retinal neovascularization by reducing EPO expression in the retinas of mice. It may provide a powerful and novel therapeutic tool for ischemia-induced retinal diseases.

Topics: Animals; Animals, Newborn; Base Sequence; Blotting, Western; Cell Culture Techniques; Dextrans; Disease Models, Animal; Erythropoietin; Fluorescein Angiography; Fluoresceins; Gene Expression Regulation; Humans; Infant, Newborn; Injections; Mice; Mice, Inbred C57BL; Molecular Sequence Data; NIH 3T3 Cells; Oxygen; Retinal Neovascularization; Retinopathy of Prematurity; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; RNA, Small Interfering; Transfection; Vitreous Body

Preterm infants are at high risk of brain injury, and high-dose recombinant erythropoietin (rEpo) may be therapeutic. However, the effect of rEpo on the development of retinopathy of prematurity (ROP) is unknown. We hypothesized that (1) rEpo would cross the blood-eye barrier and (2) early rEpo would modulate ROP in a rat model. Epo concentrations were measured by ELISA from the plasma and the homogenized eye tissue at timed intervals after rEpo injection. Flat-mounted retinas were prepared from rats given rEpo (0, 5000, or 30,000 U/kg i.p. qid x 3) on postnatal d (P) 1-3 that were raised in room air (RA) or cyclic oxygen exposure (COE) with O2 cycling every 24 h between 50% and 10% for 14 d. Photomicrographs of the fluorescein- or ADPase-stained P20 retinas were examined. rEpo penetrated into the eye in a dose- and time-dependent manner. COE increased retinal vascular pathology and decreased vessel density compared with RA controls. The 30,000 U/kg dose of rEpo increased the ROP clock hour scores, but only in ADPase-stained tissues. In contrast, 5000 U/kg rEpo did not change the incidence or severity of ROP by any measure. High-dose rEpo may protect against preterm brain injury with minimal impact on ROP.

Topics: Analysis of Variance; Animals; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Erythropoietin; Fluorescein Angiography; Humans; Infant, Newborn; Neuroprotective Agents; Oxygen; Rats; Recombinant Proteins; Retina; Retinopathy of Prematurity

Topics: Erythropoietin; Humans; Infant, Newborn; Retinal Neovascularization; Retinopathy of Prematurity; Vascular Endothelial Growth Factor A; Vitreous Body

Recombinant human erythropoietin (rhEPO) is used for the treatment of anemia of prematurity. However, it has also been found to have properties similar to vascular endothelial growth factor (VEGF), the major angiogenic factor implicated in the pathogenesis of retinopathy of prematurity (ROP). We sought to determine whether rhEPO is an independent risk factor for the development of ROP.. Data were analyzed from 264 infants admitted to the Loma Linda University Children's Hospital neonatal intensive care unit in 1994 and 2002. The data included demographic characteristics, incidence of major morbidities, rhEPO treatment, number of red blood cell transfusions received, and incidence and severity of ROP. A multiple logistic regression model was used to determine the relation of the studied risk factors to the incidence (any stage) and severity (threshold ROP requiring cryotherapy or laser photocoagulation) of ROP.. The risk of developing ROP increased among infants who received >20 doses of rhEPO was higher compared with those who received < or =20 doses (OR, 3.53; 95% CI, 1.59, 7.85). These infants were also more likely to require laser photocoagulation (OR, 4.31; 95% CI, 1.99, 9.33). The age at which rhEPO was started was also a significant risk factor, with those starting rhEPO after 20 days of age having almost fourfold the risk of ROP compared with those starting it on or before 20 days of age (OR, 3.57; 95% CI, 1.59, 8.03).. rhEPO was found to be a significant independent risk factor for the development of ROP.

Topics: Age Factors; Anemia, Neonatal; Birth Weight; California; Dose-Response Relationship, Drug; Erythropoietin; Follow-Up Studies; Humans; Incidence; Infant, Newborn; Models, Statistical; Prognosis; Recombinant Proteins; Regression Analysis; Retinopathy of Prematurity; Retrospective Studies; Risk Factors

Topics: Animals; Awards and Prizes; Child; Child, Preschool; Disease Models, Animal; Erythropoietin; Humans; Infant, Newborn; Insulin-Like Growth Factor I; Ophthalmology; Retinal Vessels; Retinopathy of Prematurity; Societies, Medical; United States; Vascular Endothelial Growth Factor A

To evaluate the frequency and severity of retinopathy of prematurity in extremely low-birth-weight (ELBW) infants who received recombinant human erythropoietin (rHuEPO), and to compare the frequency of blood cell transfusions these infants required with a matched control group who did not receive rHuEPO.. Retrospective cohort analysis.. Level III neonatal intensive care unit in a large academic medical center.. One hundred thirty-eight ELBW infants who received rHuEPO and 138 ELBW infants who did not (control group) but who were matched by birth weight, gestational age, sex, and year of birth and who survived to the first ophthalmologic examination.. The rHuEPO was started before the 8th day of life in 115 (83%) of the 138 infants. Stages III-V retinopathy of prematurity occurred with similar frequency in both groups of infants (rHuEPO group 19% [26 infants] vs control group 20% [27 infants], p>0.05). Infants in the rHuEPO group received fewer transfusions on average during their hospitalization compared with those in the control group (4.2 vs 6.1 transfusions, p<0.01).. Use of rHuEPO for prevention or treatment of anemia of prematurity in ELBW infants does not increase the frequency of severe retinopathy of prematurity and reduces the number of transfusions.

Topics: Anemia, Neonatal; Birth Weight; Blood Transfusion; Cohort Studies; Erythropoietin; Female; Gestational Age; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Male; Pregnancy; Pregnancy Outcome; Recombinant Proteins; Retinopathy of Prematurity; Retrospective Studies; Risk Assessment

Oxygen-induced retinopathy (OIR) in the mouse, like the analogous human disease retinopathy of prematurity, is an ischemic retinopathy dependent on oxygen-induced vascular obliteration. We tested the hypothesis that chemically overriding the oxygen-induced downregulation of hypoxia-inducible factor (HIF) activity would prevent vascular obliteration and subsequent pathologic neovascularization in the OIR model. Because the degradation of HIF-1alpha is regulated by prolyl hydroxylases, we examined the effect of systemic administration of a prolyl hydroxylase inhibitor, dimethyloxalylglycine, in the OIR model. Our results determine that stabilizing HIF activity in the early phase of OIR prevents the oxygen-induced central vessel loss and subsequent vascular tortuosity and tufting that is characteristic of OIR. Overall, these findings imply that simulating hypoxia chemically by stabilizing HIF activity during the causative ischemia phase (hyperoxia) of retinopathy of prematurity may be of therapeutic value in preventing progression to the proliferative stage of the disease.

Topics: Aerobiosis; Amino Acids, Dicarboxylic; Animals; Basic Helix-Loop-Helix Transcription Factors; Disease Models, Animal; Enzyme Inhibitors; Erythropoietin; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Infant, Newborn; Kidney; Liver; Mice; Oxygen; Procollagen-Proline Dioxygenase; Retina; Retinopathy of Prematurity; Vascular Endothelial Growth Factor A

Erythropoietin (Epo) is an erythropoietic, neurotropic, and angiogenic factor, and may be involved in retinal development. Studies in adult diabetic retinopathy patients reveal significantly elevated vitreal Epo concentrations. It is unknown whether Epo plays a similar role in retinopathy of prematurity. We sought to determine whether Epo is present in the normally developing human eye. Fetal serum and vitreous samples were obtained from 12 to 24 wk gestation. RNA was extracted from isolated retina for Epo mRNA and hypoxia inducible factor-1alpha (HIF) mRNA determination by real-time polymerase chain reaction. Fetal serum was isolated from the umbilical cord. Serum and vitreous samples were analyzed for Epo protein by enzyme-linked immunosorbent serologic assay. In fetal retina, Epo mRNA increased with increasing gestational age, while HIF mRNA remained constant. Epo protein increased with increasing gestation in both vitreous and serum. At each gestational group measured (12-14, 15-17, 18-20, and 21-24 wk), Epo concentrations were significantly greater in vitreous than in serum (p < 0.05). Epo mRNA and protein concentrations increase with increasing gestational age and are greater in the vitreous than serum. We speculate that changes in Epo production following preterm delivery might affect retinal vascular development.

Topics: Aging; Erythropoietin; Eye; Gestational Age; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Infant, Newborn; Retina; Retinopathy of Prematurity; RNA, Messenger; Vitreous Body

Retinopathy of prematurity (ROP) is a multifactorial disease affecting the developing retinal vasculature and remains an important cause of blindness in very preterm infants. Rush disease, or aggressive posterior ROP (AP-ROP), progresses rapidly to stage 5 disease without exhibiting the classical course that includes stages 1-3. We describe an infant with minimal exposure to oxygen who developed AP-ROP that led to bilateral retinal detachments and a poor visual outcome, despite following current recommended screening guidelines.

Topics: Adrenal Cortex Hormones; Adult; Continuous Positive Airway Pressure; Erythropoietin; Female; Humans; Hypertension, Pregnancy-Induced; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature; Light Coagulation; Male; Neonatal Screening; Oxygen; Pregnancy; Respiratory Distress Syndrome, Newborn; Retinopathy of Prematurity

Topics: Anemia, Neonatal; Animals; Disease Progression; Dose-Response Relationship, Drug; Erythropoietin; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Prognosis; Recombinant Proteins; Retinopathy of Prematurity; Risk Factors

To investigate the inheritance of susceptibility to oxygen-induced retinopathy in the rat with the use of formal backcross analysis.. Neonatal offspring of inbred albino Fischer 344 (F344) and pigmented Dark Agouti (DA) crosses and F1xF344 and F1xDA backcrosses were exposed to alternating 24-hour cycles of hyperoxia (80% oxygen in air) and normoxia (21% oxygen in air) for 14 days. Retinal avascular area was analyzed by staining with Griffonia simplicifolia isolectin B4, a marker of vascular endothelial cells. Expression of erythropoietin (EPO) mRNA in retinas was quantified by real-time reverse-transcription polymerase chain reaction.. Oxygen-exposed offspring of two F344xDA F1 crosses showed retinal avascular areas and ocular and coat pigmentation that were similar to those of the DA strain. Mean retinal avascular area was 73%. Offspring of two DAxF1 backcrosses were similar to F344xDA F1 pups, with pigmented eyes and coats and a mean retinal avascular area of 76%. In contrast, offspring of two F344xF1 backcrosses exhibited a range of eye and coat pigmentation. Mean retinal avascular area of pigmented offspring of the F344xF1 backcrosses was 71% (P < 0.001 compared with F344 rats). Mean avascular area of albino offspring of the F344xF1 backcrosses was 27% (P > 0.05 compared with F344 rats). The normalized expression of EPO mRNA was 3.01 +/- 1.00 in retinas from pigmented F344xF1 backcross offspring compared with 1.31 +/- 0.69 for albino offspring (P < 0.001).. Segregation of the susceptibility trait to oxygen-induced retinopathy in the DA and F344 rat strains is associated with pigmentation and erythropoietin expression and can be modeled using an autosomal dominant pattern of inheritance.

Topics: Animals; Animals, Newborn; Disease Models, Animal; Endothelium, Vascular; Erythropoietin; Female; Genetic Predisposition to Disease; Humans; Hyperoxia; Inbreeding; Infant, Newborn; Oxygen; Pedigree; Plant Lectins; Rats; Rats, Inbred F344; Retina; Retinal Vessels; Retinopathy of Prematurity; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Skin Pigmentation

Retinopathy of prematurity is a complication of premature birth that varies in its severity. The incidence and severity of retinopathy of prematurity at our perinatal center in a regional referral hospital changed substantially during 1995 to 1998 and presented us with an opportunity to examine whether there was a protective effect on risk of retinopathy associated with exposure to recombinant erythropoietin.. We undertook a retrospective cohort study. From January 1995 through December 1998, charts of infants weighing<1500 g, who were 30 weeks' gestation or less, and who were admitted and survived to the first eye examination at 6 weeks were reviewed. Primary and secondary risk factors were recorded from the first 6 weeks of life. Of the eligible infants, 327 of 390 (84%) had complete records and retinal examinations. The probability for progression of retinopathy was estimated by logistic regression multivariate analysis using the continuation-ratio model.. The overall incidence of retinopathy of prematurity was 36%. Recombinant erythropoietin exposure, as total 6-week dose, was independently associated with an increased risk for progression of retinopathy, OR=1.27 per 500 units/kg (95%CI=1.04, 1.55, P=0.02). Postnatal day of recombinant erythropoietin initiation also was associated with retinopathy risk but did not reach conventional statistical significance, OR=1.07 (CI=1.00, 1.14, P=0.07).. These findings identify an association between cumulative recombinant erythropoietin exposure, used to reduce blood transfusions in premature infants, and an increased risk for retinopathy of prematurity. The nonhematopoietic properties of erythropoietin may account for the above findings, however further evaluation with confirmation is required.

Topics: Disease Progression; Erythropoietin; Female; Gestational Age; Humans; Incidence; Infant; Infant, Newborn; Infant, Very Low Birth Weight; Male; Maternal Age; Multivariate Analysis; Recombinant Proteins; Retinopathy of Prematurity; Retrospective Studies; Risk Factors

Topics: Analysis of Variance; Diabetic Retinopathy; Erythropoietin; Humans; Infant, Newborn; Infant, Very Low Birth Weight; Retinal Neovascularization; Retinopathy of Prematurity; Risk Factors

An HLF (HIF-1alpha-like factor)/HIF-2alpha-knockout mouse is embryonic lethal, preventing investigation of HLF function in adult mice. To investigate the role of HLF in adult pathological angiogenesis, we generated HLF-knockdown (HLF(kd/kd)) mice by inserting a neomycin gene sandwiched between two loxP sequences into exon 1 of the HLF gene. HLF(kd/kd) mice expressing 80-20% reduction, depending on the tissue, in wild-type HLF mRNA were fertile and apparently normal. Hyperoxia-normoxia treatment, used as a murine model of retinopathy of prematurity (ROP), induced neovascularization in wild-type mice, but not in HLF(kd/kd) mice, whereas prolonged normoxia following hyperoxic treatment caused degeneration of retinal neural layers in HLF(kd/kd) mice due to poor vascularization. Cre-mediated removal of the inserted gene recovered normal HLF expression and retinal neovascularization in HLF(kd/kd) mice. Expression levels of various angiogenic factors revealed that only erythropoietin (Epo) gene expression was significantly affected, in parallel with HLF expression. Together with the results from intraperitoneal injection of Epo into HLF(kd/kd) mouse, this suggests that Epo is one of the target genes of HLF responsible for experimental ROP.

Topics: Animals; Antibodies; Basic Helix-Loop-Helix Transcription Factors; Disease Models, Animal; Electroretinography; Erythropoietin; Female; Gene Expression Regulation; Gene Targeting; Genetic Vectors; Helix-Loop-Helix Motifs; Humans; Hyperoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Immunohistochemistry; In Situ Nick-End Labeling; Infant, Newborn; Integrases; Mice; Mice, Knockout; Retina; Retinal Neovascularization; Retinopathy of Prematurity; RNA, Messenger; Tissue Distribution; Trans-Activators; Transcription Factors; Vimentin; Viral Proteins

The aim of our study was to assess frequency of ROP in VLBW and ELBW treated with rhEPO in preventing anemia. In 36 newborns with birth weight 480 to 1490 g (median 1032 g) and 24 to 32 weeks of gestational age (median 28.0 weeks) we have estimated concentration of cord erythropoietin. According this concentration we have divided our material into two groups. In first group of 22 newborns with cord concentration of EPO < 10 mU/ml we started early erythropoietin (rhEPO) therapy which was continued by 6 weeks. Second group of 14 no early usage newborns had cord EPO concentration > 10 mU/ml. In second group the control level of serum EPO was measured in 15th day of life. In newborns from second group in which the EPO concentration during two weeks decreased below 10 mU/ml we started to use rhEPO as a late usage. First oculistic consultation took place in the 5th week of life according to the screening performed in our country. In the first group (n = 22) with early EPO treatment retinopathy was recognized in 15 preterm newborns (68.2%). Eight of them (53.3%) had advanced form of retinopathy ROP (III lub III+) and were undergone a laserotherapy. In the group of late usage of rhEPO (n = 14) 8 newborns (57.1%) had signs of retinopathy, but only 3 of them (37.5%) required laserotherapy because of advanced form of ROP (III lub III+).

Topics: Combined Modality Therapy; Erythropoietin; Humans; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight; Laser Therapy; Recombinant Proteins; Retinopathy of Prematurity; Retrospective Studies

The role of blood transfusions and iron intake in the pathogenesis or retinopathy of prematurity (ROP) is controversial.. To evaluate the influence of packed red cell (PRC) transfusions and iron intake on ROP incidence.. Prospective observational study.. Forty-five preterm infants with birthweight <1250 g were studied. After ophthalmological study, they were divided into group A (n=24) that included newborns without ROP, and group B (n=21) that included newborns with ROP.. Logistic regression analysis demonstrated that gestational age (OR 0.61; 95% C.I. 0.41-0.90), transfusion volume during the first week (OR 1.16; 95% C.I. 1.03-1.3) and during the first 2 months of life (OR 2.93; 95% C.I. 1.52-5.62), and iron intake during the first week of life (OR 1.15; C.I. 1.01-1.32) and during the first 2 months of life (OR 2.93; 95% C.I. 1.52-5.62) were associated with the development of ROP.. Our study showed that gestational age, blood transfusion volume and iron load by transfusions are associated with the risk of occurrence of ROP in infants with a birthweight of less than 1250 g.

Topics: Erythropoietin; Gestational Age; Humans; Infant, Newborn; Infant, Premature; Iron; Iron, Dietary; Logistic Models; Ophthalmoscopy; Prospective Studies; Retinopathy of Prematurity; Transfusion Reaction