Sanjay M Aher1, Arne Ohlsson2
Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs
1Neonatal Intensive Care Unit, Kilbil Hospital, Nashik, India
2Departments of Paediatrics, Obstetrics and Gynaecology and Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada
Citation example: Aher SM, Ohlsson A. Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD004865. DOI: 10.1002/14651858.CD004865.pub2.
Departments of Paediatrics, Obstetrics and Gynaecology and Health Policy, Management and Evaluation
University of Toronto
600 University Avenue
Toronto Ontario M5G 1X5
Canada
E-mail: aohlsson@mtsinai.on.ca
| Assessed as Up-to-date: | 23 October 2009 |
|---|---|
| Date of Search: | 09 September 2009 |
| Next Stage Expected: | 23 October 2011 |
| Protocol First Published: | Issue 3, 2004 |
| Review First Published: | Issue 3, 2006 |
| Last Citation Issue: | Issue 3, 2006 |
| Date / Event | Description |
|---|---|
| 23 October 2009 Updated |
This review updates the existing review "Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants" published in the Cochrane Database of Systematic Reviews, Issue 3, 2006 (Aher 2006). Updated search found no new trials. No changes to conclusions. |
| Date / Event | Description |
|---|---|
| 17 September 2008 Amended |
Converted to new review format. |
| 08 May 2006 New citation: conclusions changed |
Substantive amendment |
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.
Randomized or quasi-randomized controlled trials enrolling preterm or LBW infants less than eight days of age. Intervention: Early initiation of EPO (initiated at less than eight days of age) vs. 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 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 and heterogeneity was evaluated using the I-squared test.
Two high quality randomized double-blind controlled studies enrolling 262 infants were identified. A non-significant reduction in the 'use one or more RBC transfusions' [typical RR 0.91 (95% CI 0.78, 1.06)] favouring early EPO was noted. Early EPO administration resulted in a non-significant reduction in the "number of transfusions per infant" 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. Early EPO led to a significant increase in the risk of retinopathy of prematurity (ROP all stages) [(typical RR 1.40 (95% CI 1.05, 1.86)]. 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)]. 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 to 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.
The number of red blood cells falls after birth in preterm infants due to the natural breakdown of erythrocytes and blood letting. Low levels of erythropoietin (EPO), a substance in the blood that stimulates red blood cell production in preterm infants, provide a rationale for the use of EPO to prevent or treat anemia. A total of 262 infants born preterm have been enrolled in two studies of early vs. late administration of EPO to prevent blood transfusions. There were no demonstrable benefits of early vs. late administration of EPO with regards to reduction in the use of red blood cell transfusions, number of transfusions, the amount of red cells transfused or number of donor exposures per infant. However, the use of early EPO compared to late EPO administration increases the risk of retinopathy of prematurity, a serious complication in babies born before term. Currently, there is lack of evidence that either treatment confers any substantial benefits with regard to any donor blood exposure, as many infants enrolled in both studies were exposed to donor blood prior to study entry, and early EPO increases the risk of retinopathy of prematurity. Neither early nor late administration of EPO is recommended.
The haemoglobin concentration falls to minimal levels of 11 gm/dl in term infants by eight to 12 weeks of age and 7.0 to 10.0 gm/dl in preterm infants by six weeks of age (Stockman 1978). This process is called physiologic anaemia of infancy (Strauss 1986). In very low birth weight (VLBW) infants, the hematocrit falls to approximately 24% in infants weighing 1.0 to 1.5 kg and to 21% in infants weighing less than 1.0 kg at birth (Stockman 1986). In extremely low birth weight (ELBW) infants, this decline in hematocrit is not "physiologic", as it is associated with clinical findings that prompt red blood cell transfusions. The diagnostic accuracy of different clinical signs and laboratory findings has not been studied. It is still unknown how low hematocrit levels can fall before clinical signs of anaemia of prematurity occur and what is the minimal hematocrit level acceptable in infants requiring supplemental oxygen (Ohls 2002). Nevertheless, "top-up" transfusions to treat low haemoglobin or low hematocrit levels are frequently used. As many as 80% of VLBW infants and 95% of ELBW infants receive blood transfusions during their hospitalizations (Widness 1996).
EPO and iron effectively stimulate erythropoiesis. Plasma erythropoietin (EPO) levels in neonates are lower than those for older children and adults. Brown and colleagues reported that, between day two and 30 of life, the mean EPO concentration was 10 mIU/ml, as compared to 15 mIU/ml in concurrently studied adults (Brown 1983). A low plasma erythropoietin (EPO) level is a key reason that nadir hematocrit values of preterm infants are lower than those of term infants (Stockman 1986; Dallman 1981). Low plasma EPO levels provide a rationale for use of EPO in the prevention or treatment of anaemia of prematurity. Studies in newborn monkeys and sheep have demonstrated that neonates have a large volume of distribution and more rapid elimination of EPO, necessitating the use of higher doses than required for adults (Ohls 2000). A recent systematic review of EPO administration noted a wide range of doses used, from 90 to 1400 IU/kg/week (Kotto-Kome 2004). Side effects reported in adults include hypertension, bone pain, rash and rarely seizures. Only transient neutropenia has been reported in neonates (Ohls 2000).
The primary goal of EPO therapy is to reduce transfusions. Most transfusions are given during the first three to four weeks of life. The larger or stable preterm infants, who respond best to EPO, receive few transfusions. ELBW infants, who are sick and have the greatest need for RBC transfusions shortly after birth, have not consistently responded to EPO. This suggests that EPO is a more effective erythropoietic stimulator in more mature neonates. ELBW neonates are more likely to need transfusions even if their erythropoiesis is stimulated (Kotto-Kome 2004). In addition, ELBW neonates have a smaller blood volume and the relatively larger phlebotomy volumes that are required during hospital stay often necessitate "early" transfusions. In contrast "late" transfusions are more often given because of anaemia of prematurity (Garcia 2002). Most preterm infants who require blood transfusions will receive their first transfusion in the first two weeks of life (Zipursky 2000). Reducing the number of RBC transfusions reduces the risk of transmission of viral infections and may reduce costs. Frequent RBC transfusions may be associated with retinopathy of prematurity (Hesse 1997) and bronchopulmonary dysplasia.
Preterm infants need iron for erythropoiesis. As neonatal blood volume expands with rapid growth, infants produce large amounts of haemoglobin. Several studies have observed decrease in serum ferritin concentration - an indication of iron deficiency (Finch 1982) - during erythropoietin treatment. The use of higher, more effective doses of erythropoietin might be expected to be particularly likely to increase iron demand and the risk of iron deficiency (Genen 2004). Iron supplementation during erythropoietin treatment has been observed to reduce the risk of the development of iron deficiency (Shannon 1995). The range of iron doses used in EPO treated infants is between 1 mg/kg/day to 10 mg/kg/day (Kotto-Kome 2004).
The efficacy of EPO in anaemia of prematurity has recently been systematically reviewed (Vamvakas 2001; Garcia 2002; Kotto-Kome 2004). Vamvakas et al concluded that there is extreme variation in the results, and until this variation is better understood, it is too early to recommend EPO as standard treatment for the anaemia of prematurity (Vamvakas 2001). Garcia et al concluded that administering EPO to VLBW neonates can result in a modest reduction in late erythrocyte transfusions and that this effect is dependent on the dose of EPO used (Garcia 2002). Kotto-Kome et al concluded that if EPO is begun in the first week of life, a moderate reduction can be expected in the proportion of VLBW neonates transfused. The reduction is less significant for early transfusion than for late transfusion (Kotto-Kome 2004).
Additional studies of EPO in preterm or LBW infants have been published since the reviews noted above, justifying additional reviews. The cutoff of less than eight days of age for early and > 8 days for late treatment with EPO, although somewhat arbitrary, was chosen based on previously published meta-analyses (Garcia 2002; Kotto-Kome 2004).
This review compares early administration of EPO (starting in infants less than eight days of age) versus late administration of EPO (starting > 8 days). The main rationale for this review was to evaluate whether early treatment with EPO in preterm infants is more effective than late treatment to decrease exposure to red blood cell transfusion and the total transfusions required. We performed a systematic review to compare all available studies where EPO was begun during first week of life vs. EPO started after the first week of life to assess the effect on any and total number of erythrocyte transfusions.
To assess the effectiveness and safety of early (before eight days after birth) vs. late (between eight to 28 days after birth) initiation of EPO in reducing red blood cell transfusions in preterm and/or low birth weight infants.
Subgroup analyses:
We planned subgroup analyses within this review for low (< 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO, and low (< 5 mg/kg/day) and high (> 5 mg/kg/day) doses of supplemental iron administered by any route.
Preterm ( < 37 weeks) and/or low birth weight (< 2500 g) neonates less than eight days of age.
Early initiation of EPO (initiated before eight days of age, using any dose, route or duration) vs. late initiation of EPO (initiated between eight to 28 days of age, using any dose, route or duration).
The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2006) was searched to identify relevant randomised and quasi-randomised controlled trials. MEDLINE was searched for relevant articles published from 1966 to November 2005 using the following MeSH terms or text words: (exp Erythropoietin/OR erythropoietin:.mp. OR rhuepo.mp.) AND (anaemia/OR exp anaemia, neonatal/) AND (blood transfusion/OR blood component transfusion/OR erythrocyte transfusion/) AND (infant, newborn/OR infant, low birth weight/OR infant, very low birth weight/OR infant, premature/OR exp Infant, Premature, Diseases) OR (neonate: OR prematur*: OR newborn:).mp. OR newborn infant [age limit]) AND (clinical trial.pt. OR Randomized Controlled Trials/OR (random: OR rct OR rcts OR blind OR blinded OR placebo:).mp. OR (review.pt. OR review, academic.pt.) AND human. EMBASE from 1980 to November 2005 and CINAHL 1982 to November 2005 using the following MeSH terms or text words: (Erythropoietin/OR erythropoietin: OR epo OR epogen OR epoetin: OR (rhuepo).mp. AND (anaemia/OR exp anaemia, neonatal/) AND (blood transfusion/OR exp blood component transfusion/OR erythrocytes/) AND exp Infant, Premature, Diseases/OR infant, newborn/OR infant, low birth weight/OR infant, very low birth weight/OR infant, premature/OR (neonate: OR newborn: OR prematur*:).mp. OR newborn infant [age limit].
In September 2009, we updated the search as follows: The Cochrane Library, MEDLINE (search via PubMed), CINAHL and EMBASE were searched from 2005 to September 2009.
Search terms: erythropoietin OR rhuepo AND anaemia OR anemia AND blood transfusion OR blood component transfusion OR erythrocyte transfusion. Limits: human, infant and clinical trial. No language restrictions were applied. Clinicaltrials.gov was also searched with no date restriction. Search terms: Erythropoietin OR rhuepo AND infant.
In addition to the electronic searches, manual searches of bibliographies and personal files were performed. No language restrictions were applied.
Abstracts published from the Pediatric Academic Societies' Meetings and the European Society of Pediatric Research Meetings (published in Pediatric Research) were hand searched from 1980 to April 2006.
The standard review methods of the Cochrane Neonatal Review Group were used.
All abstracts and published studies identified as potentially relevant by the literature search were assessed for the inclusion in the review by the two review authors.
Each review author extracted data separately on a data abstraction form. The information was then compared and differences were resolved by consensus. One review author (AO) entered data into RevMan and the other (SA) cross checked the printout against his own data abstraction forms and any errors were corrected. For the studies identified as abstract, the primary author was to be contacted to obtain further information.
Quality of included trials was evaluated independently by the review authors, using the following criteria:
Blinding of randomisation; Blinding of intervention; Blinding of outcome measure assessment; Completeness of follow-up. There are three potential answers to these questions yes, no, cannot tell. This information was added to the Characteristics of Included Studies Table.
In addition, the following issues were evaluated and entered into the Risk of Bias table:
1. Sequence generation: Was the allocation sequence adequately generated?
2. Allocation concealment: Was allocation adequately concealed?
3. Blinding of participants, personnel and outcome assessors: Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment?
4. Incomplete outcome data: Were incomplete outcome data adequately addressed?
5. Selective outcome reporting: Are reports of the study free of suggestion of selective outcome reporting?
6. Other sources of bias: Was the study apparently free of other problems that could put it at a high risk of bias?
Statistical analyses were performed using Review Manager software (RevMan 5, Cochrane Collaboration). Categorical data were analyzed using relative risk (RR), risk difference (RD), number needed to treat to benefit (NNTB) or number needed to harm (NNTH) for dichotomous outcomes and mean difference (MD) for continuous data. The 95% Confidence interval (CI) was reported on all estimates.
We examined heterogeneity between trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I2 statistic. If we detected statistical heterogeneity, we planned to explore the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) using post hoc sub group analyses if possible.
Two studies enrolling 268 infants were identified (Donato 2000; Maier 2002). For details of the studies see table "Characteristics of Included Studies". One non-randomized study was excluded (Rudzinska 2002). For transfusion guidelines see Additional table (Table 1 Transfusion guidelines).
Donato 2000: This was a blinded multicenter randomized placebo controlled study conducted in seven private hospitals in Buenos Aires, Argentina between July 1996 to October 1997.
Maier 2002: This was a blinded multicenter randomized placebo controlled study conducted in 14 centres in four European countries (Belgium, France, Germany, Switzerland) between May 1998 to June 1999. An early EPO, a late EPO and a control group were studied. The early EPO and late EPO groups were eligible for inclusion in this review.
Both included studies (Donato 2000; Maier 2002) were randomized double-blind controlled studies with concealed allocation. Donato et al. (Donato 2000) report that infants were assigned to one of the two groups at birth through a central randomization process. Placebo and EPO were indistinguishable before and after reconstitution. Parents, investigators, and nurses were unaware of each patient's treatment group. Maier et al. (Maier 2002) concealed the allocation by means of numbered sealed envelopes. To assure blinding and to avoid placebo injections, sham injections were given to the late EPO group prior to starting treatment with EPO. In both studies, outcomes were assessed by individuals unaware of treatment assignment. Sample size calculations were performed in both studies. Six infants with significant protocol violations were excluded from the study by Donato et al (Donato 2000). The group assignment was not reported, but it is likely that the excluded infants were equally distributed between the groups as 57 infants remained in each group. In the study by Maier et al (Maier 2002), no infant was withdrawn from the early EPO and late EPO groups. Followup was complete for the study by Maier (Maier 2002), but not in the study by Donato (Donato 2000). (See Table "Characteristics of included studies"). Both studies were industry funded (Donato 2000; Maier 2002). We obtained unpublished data from the authors of both studies.
PRIMARY OUTCOME:
Outcome 01.01: Use of one or more red blood cell transfusions
Both studies reporting on 262 infants assessed the use of one or more red blood cell transfusions. Neither found a significant effect. The meta-analysis did not find a significant effect [typical RR 0.91 (95% CI 0.78, 1.06); typical RD -0.07 (95% CI -0.18, 0.04)]. This result was consistent across studies.
SECONDARY OUTCOMES:
Outcome 01.02: The total volume (ml/kg) of red blood cells transfused per infant
Donato et al (Donato 2000) reported on this outcome in 144 infants. They did not find a significant effect [MD 30 ml/kg (95% CI -13.4, 13.6)].
We obtained unpublished data from Maier et al. (Maier 2002). They reported on the volume of red blood cells transfused in ml/kg/day. They did not find a significant effect [MD -0.80 ml/kg/day (95% CI -1.88, 0.28)].
Outcome 01.03: Number of red blood cell transfusions per infant
Both studies reporting on 262 infants assessed the number of red blood cell transfusions per infant. Neither found a significant effect. The meta-analysis did not find a significant effect [typical WMD -0.32, 95% CI -0.92, 0.29)]. This result was consistent across studies.
Outcome 01.04: Number of donors to whom the infant was exposed
Maier (Maier 2002) reported on this outcome in 148 infants. They did not find a significant effect [MD -0.20; (95% CI -0.67, 0.27)].
Outcome 01.05: Mortality during initial hospital stay (all causes)
Both studies reporting on 262 infants assessed mortality during initial hospital stay. Neither found a significant effect. The meta-analysis did not find a significant effect [typical RR 0.76 (95% CI 0.39, 1.51); RD - 0.03, (95% CI -0.11, 0.05)]. This result was consistent across studies.
Outcome 01.06: Retinopathy of prematurity (all stages)
We obtained unpublished data from both lead authors of the studies included in this review for this outcome. Both studies assessed retinopathy of prematurity in a total of 191 infants. Donato et al reported on the rate of ROP in infants examined during the first year of life. Maier et al reported on the worst stage of ROP during the study. There was a significant increase in the incidence of ROP (all stages) in the study by Donato et al (Donato 2000), but not in the study by Maier et al (Maier 2002). The meta-analysis found a significant effect [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 (RR p = 0.007; I2 = 86%; RD p = 0.02; I2 = 81%).
Outcome 01.07: Retinopathy of prematurity (stage > 3)
We obtained unpublished data from both lead authors of the studies included in this review for this outcome. Both studies assessed this outcome in a total of 191 infants. Donato et al reported on the rate of ROP in infants examined during the first year of life. Maier et al reported on the worst stage of ROP during the study. Neither found a significant effect. The meta-analysis did not find a significant effect [typical RR 1.56 (95% CI 0.71, 3.41); typical RD 0.05 (95% CI -0.04, 0.14). This result was consistent across studies.
Proven sepsis (Clinical symptoms and signs of sepsis and positive blood culture) (No outcome table).
No data for this outcome were reported
Outcome 01.08 Necrotizing enterocolitis (NEC) (Bell's stage II or more)
Maier (Maier 2002) reported on this outcome in 148 infants. The study did not find a significant effect [RR 1.00 (95% CI 0.37, 2.71); RD 0.00 (95% CI -0.09, 0.09)].
Outcome 01.09: Intraventricular haemorrhage (IVH); all grades and grades III and IV
Both studies (n = 262) reported on the incidence of IVH grade III and IV. Neither found a significant effect. The meta-analysis did not find a significant effect [typical RR 1.33 (95% CI 0.84, 2.13); typical RD 0.06 (95% CI -0.04, 0.16)]. The results were consistent across studies.
Outcome 01.10: Periventricular leukomalacia (PVL); cystic changes in the periventricular areas
Maier (Maier 2002) reported on PVL in 148 infants. The study did not find a significant effect [RR 0.09 (95% CI 0.01, 1.62); RD -0.07 (95% CI -0.13, -0.01)].
Length of hospital stay (No outcome table)
Maier (Maier 2002) reported on the length of hospital stay. The median (quartiles) number of days in hospital was 87 days (73, 107) in the early EPO group and 90 days (68, 110) in the late group. There was no statistically significant difference (p = 0.94) across three groups including a control group (87 days; 69, 108).
Outcome 01.11: Bronchopulmonary dysplasia (BPD) (supplementary oxygen at 28 days of age or at 36 weeks postmenstrual age and compatible X-ray)
Maier (Maier 2002) reported on the need for oxygen at 36 weeks postmenstrual age in 148 infants. The study did not find a significant effect [RR 0.90 (95% CI 0.53, 1.54); RD -0.03 (95% -0.17, 0.12).
Outcome 01.12: Sudden infant death after discharge
Donato (Donato 2000) reported no deaths in either group after a follow-up period of 9 to 24 months after discharge.
Long term outcomes assessed at any age beyond one year of age by a validated cognitive, motor, language, or behavioural/school/social interaction/adaptation test (No outcome table).
No data for these outcomes were reported.
Neutropenia (No outcome table)
Donato (Donato 2000) reported that the incidence of neutropenia was similar in the two groups, but did not provide any data. Maier (Maier 2002) reported that neutrophil counts did not differ between groups, but did not provide any data.
Any side effects reported in the trials (No outcome table)
Donato (Donato 2000) stated "No clinical adverse effect attributable to EPO, oral iron, or folic acid administration was observed".
Outcome 01.13: Weight gain during the study period (This outcome was not included in the protocol for this review)
In the study by Donato (Donato 2000), the MD for weight gain during the entire study period was 6.0 g (95% CI -137.37, 149.37) comparing the early EPO group to the late EPO group. In the study by Maier (Maier 2002), the median weight gain was 890 g in the early EPO group and 872 g in the late EPO group during the first nine weeks of life. Quartiles were not provided.
Outcome 01.14: Thrombocytosis (This outcome was not included in the protocol for this review)
Donato (Donato 2000) reported on thrombocytosis (platelet count > 500 x 109/L) in 114 infants. The study did not show a significant effect [RR 1.06 (95% CI 0.61, 1.84); RD 0.02 (95% CI -0.15, 0.19)].
In the study by Maier (Maier 2002) the median increase in platelet count during the study was 118 x 109/L in the early EPO group, 155x109/L in the late EPO group and 186 x 109/L in the control group. A p-value was not reported.
Subgroup analyses
We planned subgroup analyses within this review for low (< 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO, and low (< 5 mg/kg/day) and high (> 5 mg/kg/day) doses of supplemental iron administered by any route. However, both included studies used high dose of EPO and high dose of iron, and therefore subgroup analyses were not performed.
The main objective of this review was to assess whether early vs. late treatment with EPO would reduce the receipt of one or more red blood cell transfusions. Two high quality placebo controlled multicenter trials conducted in Argentina and in four European countries were identified for this review. These two studies included a total of 262 preterm infants with very low/extremely low birth weight, who were enrolled at approximately three days of age. The dose of EPO varied from 750 to 1250 IU/kg/week (high dose). All infants received supplemental iron (high dose). Both studies used well defined, although not identical, criteria for red blood cell transfusions (see Additional table; Table 1 Transfusion guidelines). In the study by Maier et al (Maier 2002), more than 30% of the enrolled infants had received red blood transfusions prior to study entry. In the study by Donato et al (Donato 2000), 14% had received red blood cell transfusions prior to enrolment.
Early treatment with EPO did not significantly reduce the risk for an infant of receiving a red blood cell transfusion compared to late treatment. There was no statistically significant heterogeneity for this or any of the other effectiveness outcomes of interest, justifying the combination of the results from the two studies when possible. There was no significant reduction in the number of transfusions per infant nor in the number of donors to whom the infant was exposed.
The results for other secondary outcomes included in this review reached statistical significance only for PVL and ROP. PVL was reported in one study (Maier 2002). There was a statistically significant reduction for RD but not for RR (there was no case of PVL in the early EPO group). We consider this finding of borderline statistical significance.
A total of 191 infants of 268 infants enrolled were assessed for ROP (all stages, and stage > 3). The lack of outcome ascertainment in a large number of infants is of concern. There was a statistically significant increased risk of ROP (any stage reported). The typical RR was 1.45 (95% CI 1.08, 1.95), the typical RD was 0.18 (95% CI 0.05, 0.31) and the NNTH was 6 (95% CI 3 -20). There was statistically significant heterogeneity for this outcome. The heterogeneity is likely at least in part due to differences in the rates of ROP and the different times in the life of the infants when ROP was assessed. There were no striking differences in the dose of EPO or iron used in the two studies. The transfusion guidelines were most strict in the study by Donato et al (Donato 2000). The outcome of ROP (stage > 3) was assessed in the same population as all stages of ROP. The meta-analysis did not find a significant effect [typical RR 1.56 (95% CI 0.71, 3.41); typical RD 0.05 (95% CI -0.04,0.14)]. This result was consistent across studies. The increased risk of ROP is of concern. The results are similar to the Cochrane review of "Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants" (Ohlsson 2006) No other important neonatal adverse outcomes or side effects were noted.
The results of this systematic review should be considered in conjunction with our other two Cochrane reviews that have been conducted "Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants" (Ohlsson 2006) and "Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants" (Aher 2006a). In our review of "Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants" (Ohlsson 2006), we noted an increased risk of ROP. Based on current evidence, an increased risk of developing ROP with early EPO cannot be excluded. For detailed discussion of the potential association with ROP and EPO, please refer to the Cochrane review of "Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants" (Ohlsson 2006).
Other systematic reviews of EPO do not address the issue of early vs. late treatment. The trials included in this review (Donato 2000; Maier 2002) were not included in the meta-analyses by Vamvakas et al (Vamvakas 2001) and Garcia et al (Garcia 2002). Kotto-Kome et al (Kotto-Kome 2004) included both trials in their meta-analysis of the effect of early EPO on early and late erythrocyte transfusions, but did not compare the effectiveness of early vs. late EPO administration. None of these meta-analyses included analyses on the incidence of ROP.
Early treatment with EPO did not confer any major benefits compared to late EPO treatment. The major obstacle to reduce any donor exposure during the hospital stay is that as many as one third of these infants will require a red blood cell transfusion prior to the initiation of treatment with EPO. In the study by Maier et al (Maier 2002), 12 of the 14 centers used satellite packs of the original red cell pack to reduce donor exposure in both groups. The use of satellite packs and conservative transfusion guidelines reduces the exposure to multiple donors during the hospitalization for preterm infants.
It is unlikely that long-acting EPO [Aranesp (Darbepopoietin alfa, Amgen)] would confer any benefits with regards to any donor exposure, but could reduce the number of injections the infant would require (Ohls 2004). To date, only a dose finding trial has been published (Warwood 2005). The authors concluded based on pharmacodynamic and pharmacokinetic findings that darbepoetin dosing in neonates would require a higher unit dose/kg and a shorter dosing interval than are generally used for anemic adults (Warwood 2005).
Currently there is lack of evidence that early EPO confers any substantial benefits compared to late administration of EPO, particularly with regard to any donor blood exposure, as a large proportion of infants enrolled in both studies were exposed to donor blood prior to study entry. There is a concern of an increased risk of ROP following early administration of EPO, and such treatment is not recommended.
The impact of either early or late administration of EPO on 'any donor exposure' is likely to be minimal, as many infants would have been exposed to donor blood during the first few days of life, when they are most likely to receive a red blood cell transfusion; a time period during which EPO treatment could not possibly prevent donor exposure. Any ongoing study of EPO should carefully monitor the incidence of ROP and data/safety monitoring committees should be informed of its occurrence. Further studies to compare early vs. late administration of EPO are not justified. Research should focus on reducing blood letting and the use of satellite packs from the same donor, should red blood cell transfusions be necessary.
We would like to thank Ms. Elizabeth Uleryk, Chief Librarian, the Hospital for Sick Children (SickKids,) Toronto, Ontario, Canada for developing the search strategy. We are thankful to Dr. Hugo Donato, Buenos Aires, Argentina, and to Dr. Rolf Maier, Zentrum für Kinder- und Jugendmedizin, Philipps-Universität, Marburg, Germany, who provided us with unpublished data regarding their studies.
The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.
Sanjay Aher (SA) and Arne Ohlsson (AO) contributed equally to all sections of the protocol for this review. The literature search was conducted with the help of an experienced librarian. Both review authors identified potentially eligible studies from the printouts and agreed on which trials to include. Data collection forms were designed and agreed upon by the two review authors. Quality assessments were conducted and data were abstracted by both review authors independently and compared. One review author (AO) entered the data into RevMan 4.2.8 and the other review author (SA) checked for accuracy. One review author (AO) wrote the full review and the other review author (SA) read and made changes. Changes were made by both review authors following feedback from the editors of the review group.
The September 2009 update was conducted centrally by the Cochrane Neonatal Review Group staff (Yolanda Montagne, Roger Soll, Diane Haughton) and approved by AO.
| Methods | Randomized placebo controlled study |
|---|---|
| Participants | 120 infants with BW < 1250 g and GA < 32 weeks were included |
| Interventions | Infants were randomized to two groups: In the early EPO group 57 infants (mean GA 27.7 wk +/- SD 2.4; mean BW 916 +/- SD 217) received rHuEPO (Hemax, Bio Sidus S.A, Buenos Aires, Argentina) [1250 IU/kg/week i.v. (high dose)] starting before 72 hours of life and until day 14 of life. In the late EPO group 57 infants (mean GA 27.9 weeks +/- SD 2.5; mean BW 972 +/- SD 206 received placebo (human seroalbumin) throughout this period. Starting on the third week of life, both groups received rHuEPO 750 IU/kg/week, divided in 3 doses s. c. during 6 weeks. All infants were given oral iron 6mg/kg/day as ferrous sulfate (high dose), starting as soon as enteral feedings were initiated and continuing during the entire treatment period |
| Outcomes | Use of one or more red blood cell transfusions |
| Notes | Sample size calculation was performed |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Unclear | Randomized placebo controlled study |
| Allocation concealment? | Yes | Blinding of randomization - yes |
| Blinding? | Yes | Blinding of intervention - yes |
| Incomplete outcome data addressed? | No | Completeness of follow-up - no 6 infants (group not stated, but likely to be 3 infants in each group) with significant protocol violations were excluded |
| Free of selective reporting? | No | 6 infants (group not stated, but likely to be 3 infants in each group) with significant protocol violations were excluded |
| Free of other bias? | Yes |
| Methods | Randomized controlled study |
|---|---|
| Participants | 148 infants with BW 500 - 999 g |
| Interventions | Infants were randomized to 3 groups (see notes for the control group). In the early EPO group 74 infants [median and quartiles for GA; 26 (25, 28) weeks for BW 778 (660, 880) g] received 250 IU/kg of rHEPO on Mondays, Wednesdays and Fridays (NeoRecormon, F. Hofman-La Roche, Basel Switzerland) (750 IU/week, high dose) starting at days 3-5 of life. |
| Outcomes | Use of one or more red blood cell transfusions |
| Notes | Sample size calculation was performed |
| Item | Judgement | Description |
|---|---|---|
| Adequate sequence generation? | Unclear | Randomized controlled study |
| Allocation concealment? | Yes | Blinding of randomization - yes |
| Blinding? | Yes | Blinding of intervention - yes |
| Incomplete outcome data addressed? | Yes | One of the randomized infants (control group) was excluded from all evaluations because the parents withdrew consent a few hours after randomization before the start of treatment phase |
| Free of selective reporting? | Yes | |
| Free of other bias? | Yes |
BW = birth weight
GA = gestational age
g = grams
i.v. = intravenously
s.c. subcutaneously
Reference | Indications |
|---|---|
Indications for transfusion followed slightly modified criteria described in a previous study (Shannon 1995). | |
Infants on assisted ventilation or > 40% of inspired oxygen were not transfused unless Hct dropped below 0.40. Spontaneously breathing infants were not transfused unless Hct dropped below 0.35 during the first 2 weeks of life, 0.30 during the 3rd to 4th weeks, and 0.25 thereafter. Transfusion was allowed when life threatening anaemia or hypovolaemia was diagnosed by the treating neonatologist, or surgery was planned. Twelve of the 14 centres used satellite packs of the original red cell pack to reduce donor exposure. The amount of packed red cells transfused was not reported. |
Donato H, Vain N, Rendo P, Vivas N, Prudent L, Larguia M, et al. Effect of early versus late administration of human recombinant erythropoietin on transfusion requirements in premature infants: results of a randomized, placebo-controlled, multicenter trial. Pediatrics 2000;105:1066-72.
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| Outcome or Subgroup | Studies | Participants | Statistical Method | Effect Estimate |
|---|---|---|---|---|
| 1.1 Use of one or more red blood cell transfusions | 2 | 262 | Risk Ratio (M-H, Fixed, 95% CI) | 0.91 [0.78, 1.06] |
| 1.2 Total volume of red blood cells transfused per infant | 2 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.2.1 Total volume of red blood cells transfused (ml/kg) | 1 | 114 | Mean Difference (IV, Fixed, 95% CI) | 0.30 [-13.04, 13.64] |
| 1.2.2 Total volume of red cells transfused (ml/kg/day) | 1 | 148 | Mean Difference (IV, Fixed, 95% CI) | -0.80 [-1.88, 0.28] |
| 1.3 Number of red blood cell transfusions per infant | 2 | 262 | Mean Difference (IV, Fixed, 95% CI) | -0.32 [-0.92, 0.29] |
| 1.4 Number of donors the infant was exposed to | 1 | 148 | Mean Difference (IV, Fixed, 95% CI) | -0.20 [-0.67, 0.27] |
| 1.5 Mortality during initial hospital stay (all causes) | 2 | 262 | Risk Ratio (M-H, Fixed, 95% CI) | 0.76 [0.39, 1.51] |
| 1.6 Retinopathy of prematurity (all stages) | 2 | 191 | Risk Ratio (M-H, Fixed, 95% CI) | 1.40 [1.05, 1.86] |
| 1.7 Retinopathy of prematurity (stage >/= 3) | 2 | 191 | Risk Ratio (M-H, Fixed, 95% CI) | 1.56 [0.71, 3.41] |
| 1.8 NEC | 1 | 148 | Risk Ratio (M-H, Fixed, 95% CI) | 1.00 [0.37, 2.71] |
| 1.9 IVH | 2 | 262 | Risk Ratio (M-H, Fixed, 95% CI) | 1.33 [0.84, 2.13] |
| 1.9.1 Grade III/IV | 2 | 262 | Risk Ratio (M-H, Fixed, 95% CI) | 1.33 [0.84, 2.13] |
| 1.10 PVL | 1 | 148 | Risk Ratio (M-H, Fixed, 95% CI) | 0.09 [0.01, 1.62] |
| 1.11 BPD (oxygen at 36 weeks) | 1 | 148 | Risk Ratio (M-H, Fixed, 95% CI) | 0.90 [0.53, 1.54] |
| 1.12 Sudden infant death after discharge | 1 | 114 | Risk Ratio (M-H, Fixed, 95% CI) | Not estimable |
| 1.13 Weight gain (grams) during the study period (from entry to exit from study) | 1 | 114 | Mean Difference (IV, Fixed, 95% CI) | 6.00 [-137.37, 149.37] |
| 1.14 Thrombocytosis (platelet count > 500 x 10 to the 9th /L) | 1 | 114 | Risk Ratio (M-H, Fixed, 95% CI) | 1.06 [0.61, 1.84] |
This review is published as a Cochrane review in The Cochrane Library, Issue 1, 2010 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review. |
