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Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants

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Authors

Sanjay M Aher1, Arne Ohlsson2

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs


1Neonatology, Dr. Aher's Neocare Hospital, Nashik, India [top]
2Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Canada [top]

Citation example: Aher SM, Ohlsson A. Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD004868. DOI: 10.1002/14651858.CD004868.pub4.

Contact person

Arne Ohlsson

Departments of Paediatrics, Obstetrics and Gynaecology and Institute of Health Policy, Management and Evaluation
University of Toronto
600 University Avenue
Toronto ON M5G 1X5
Canada

E-mail: aohlsson@mtsinai.on.ca

Dates

Assessed as Up-to-date: 01 July 2013
Date of Search: 01 July 2013
Next Stage Expected: 01 July 2015
Protocol First Published: Issue 3, 2004
Review First Published: Issue 3, 2006
Last Citation Issue: Issue 4, 2014

What's new

Date / Event Description
05 July 2013
Updated

We searched the literature on July 1st, 2013, and identified no new trials for inclusion. However, one trial was moved from the review of Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants (Ohlsson 2012) to this review of later EPO treatment (see above).

05 July 2013
New citation: conclusions changed

This update was initiated following feedback from Dr. Robin Ohls. Our inclusion of the study by Dr. Romagnoli and co-workers (Romagnoli 2000) in the early EPO review was questioned by Dr. Robin Ohls, who suggested the study should be included in the late EPO review. We contacted Dr. Romagnoli and he informed us that the mean (± SD) age of the infants when EPO treatment was started was 10 ± 1 days. We therefore moved the study to this Late EPO review.

As expected, when this study (n = 230) was added the results of the meta-analyses changed. The outcome of BPD (defined as need for supplemental oxygen at 28 days of life) is now of borderline statistical significance with an increased risk in the EPO group. Becasue of the very high heterogeneity (I² = 97%) the results should be interpreted with caution.

Our decision to divide the EPO studies into early and late based on initiating EPO treatment at the cut-off of less than/or equal to 7 days of age for early and > 7 days for late treatment with EPO, although somewhat arbitrary, was chosen based on previously published meta-analyses (Garcia 2002; Kotto-Kome 2004) to allow us to compare the results between our reviews and previously published reviews.

In this update there is a trend towards a non-significant increased risk of retinopathy (ROP) of prematurity.

The concern for an increased risk of ROP is real and because of the arbitrary cut-off age for early vs late EPO treatment we decided post hoc to perform a secondary analysis including all studies that reported on ROP stage greater than/or equal to 3 regardless of the age at initiation of EPO treatment. This analysis is included in the updated Early EPO review and shows an increased risk of ROP greater than/or equal to 3 when all studies of EPO regardless of age at initiation of the treatment were included in the analysis.

History

Date / Event Description
10 May 2012
New citation: conclusions changed

The updated searches identified one additional trial for inclusion (20 additional enrolled infants)and identified some for exclusion.

With the inclusion of this trial there was no longer a significant reduction in the total volume (mL/kg) of blood transfused per infant

10 May 2012
Updated

This updates the existing review "Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants" published in the Cochrane Database of Systematic Reviews (Aher 2012b) and updated in February 2010.

26 February 2010
Updated

This review updates the existing review "Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants" published in the Cochrane Database of Systematic Reviews (Aher 2006b).

Updated search found no new trials.

No changes to conclusions.

25 September 2008
Amended

Converted to new review format.

Abstract

Background

Low plasma levels of erythropoietin (EPO) in preterm infants provide a rationale for the use of EPO to prevent or treat anaemia.

Objectives

To assess the effectiveness and safety of late initiation of erythropoietin (EPO) between eight and 28 days after birth, in reducing the use of red blood cell (RBC) transfusions in preterm and/or low birth weight infants.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL in July 2013. Additional searches included the Pediatric Academic Societies Annual Meetings from 2000 to 2013 (Abstracts2View™) and clinical trials registries (ClinicalTrials.gov, Controlled-Trials.com External Web Site Policy, and WHO International Clinical Trials Registry Platform (ICTRP) External Web Site Policy. For this update we moved one study from the early EPO review to this late EPO review.

Selection criteria

Randomised or quasi-randomised controlled trials of late initiation of EPO treatment (started at greater than/or equal to eight days of age) versus placebo or no intervention in preterm (< 37 weeks) and/or low birth weight (< 2500 g) neonates.

Data collection and analysis

We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group.

Results

We include 30 studies (31 comparisons) randomising 1591 preterm infants. Literature searches in 2013 did not identify any new study for inclusion. For this update we moved one study enrolling 230 infants from the early EPO review to this late EPO review.

Most included trials were of small sample size. The meta-analysis showed a significant effect of the use of one or more RBC transfusions (20 studies (n = 1142); typical risk ratio (RR) 0.71, 95% confidence interval (CI) 0.64 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 = 68%; RD I² = 60%). 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%). Three trials enrolling 442 infants reported on ROP (stage greater than/or equal to 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 minimal heterogeneity for this outcome for RR (I² = 18%) but high heterogeneity for RD (I² = 79%). There were no significant differences in other clinical outcomes. There was no reduction in necrotizing enterocolitis in spite of a reduction in the use of RBC transfusions. Long-term neurodevelopmental outcomes were not reported.

Authors' conclusions

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 (div iding one unit of donor blood into many smaller aliquots) may reduce donor exposure.

Plain language summary

Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants

Review question

We reviewed the evidence about the effectiveness and safety of late initiation of erythropoietin treatment between eight and 28 days after birth, in reducing the use of red blood cell (RBC) transfusions in preterm and/or low birth weight infants.

Background

The percentage of circulating red blood cells (hematocrit) falls after birth in all infants. This is particularly true in preterm infants due to their poor response to anaemia and to the amount of blood that is drawn for necessary testing. Low plasma levels of erythropoietin (a substance in the blood that stimulates red blood cell production) in preterm infants provide a rationale for the use of erythropoietin to prevent/treat anaemia.

Search date

The evidence is current to July, 2013.

Study characteristics

To date 1591 infants (between eight and 28 days of age) born preterm have been enrolled in 30 studies of late administration of EPO to reduce the use of red blood cell transfusions and to prevent donor exposure.

Study funding sources

We as reviewers have not received any funding for this review and we have no conflict of interest to declare.

Key findings

The risk of receiving red blood transfusion is reduced following initiation of EPO treatment. However, the overall benefit of EPO is reduced as many of these infants had been exposed to donor blood prior to entry into the trials. Treatment with late EPO did not have any important effects on death or common complications of preterm birth, except for trends in an increased risk for retinopathy of prematurity. Retinopathy of prematurity is a disease of the eye affecting babies born preterm. It is thought to be caused by disorganized growth of retinal blood vessels, which may result in scarring and retinal detachment. Retinopathy of prematurity can be mild and may resolve spontaneously, but it may lead to blindness in serious cases.

Quality of the evidence

The study quality varied and important information regarding the random sequence generation and whether the allocation was concealed or not was often missing. Sample sizes were small and long-term outcomes (18 to 24 months corrected age) were not reported.

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Background

Description of the condition

After birth, the haemoglobin concentration of newborn infants falls to minimal levels of 11 g/dL in term infants by eight to 12 weeks of age, and 7.0 to 10.0 g/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 may be associated with clinical findings that prompt red blood cell transfusions. To our knowledge, the diagnostic accuracy of different clinical signs and laboratory findings has not been studied (Cohen 1998). It is still unknown how low hematocrit levels can fall before clinical signs of anaemia occur and what is the minimum 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 hospitalisations (Widness 1996).

Description of the intervention

Erythropoietin (EPO) and iron effectively stimulate erythropoiesis. Plasma erythropoietin levels in neonates are lower than those of older children and adults. Brown 1983 reported that between two and 30 days of life the mean EPO concentration was 10 mU/mL, as compared to 15 mU/mL in concurrently studied adults. A low plasma EPO level is a key reason that nadir hematocrit values of preterm infants are lower than those of term infants (Dallman 1981; Stockman 1986). Low plasma EPO levels provide a rationale for the 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 are required for adults (Ohls 2000). A 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).

How the intervention might work

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 red blood cell (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 (ROP) (Hesse 1997) and bronchopulmonary dysplasia (BPD).

In preterm infants, iron is needed for erythropoiesis. As neonatal blood volume expands with rapid growth, infants produce large amounts of haemoglobin. Several studies have observed a 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 increase iron demand and the risk of iron deficiency. 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).

EPO has been found to have important non-hematopoietic functions in the brain and other organs during development (Juul 2002). Administration of EPO could potentially have a neuro protective effect in preterm infants, especially in perinatal asphyxia (Dame 2001; Juul 2002). This aspect of EPO use in neonates will be systematically reviewed separately (Yu 2010).

It is likely that additional studies of EPO in preterm or LBW infants have been published since the reviews noted above, which included reports up to October 2002. We have performed a series of Cochrane reviews on the use of EPO in preterm infants, including: Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants (Ohlsson 2012), this review (Late erythropoietin; Aher 2012a), and Early versus late erythropoietin to prevent red blood cell transfusion in preterm and/or low birth weight infants (Aher 2012b). The cut-off of seven days of age or less for 'early' and more than seven days for 'late' treatment with EPO, although somewhat arbitrary, was chosen based on previously published meta-analyses (Garcia 2002; Kotto-Kome 2004), and allowed us to compare the results between our reviews and previously published reviews.

Why it is important to do this review

This review concerns late administration of EPO (starting in infants between eight and 28 days of age, after reaching 40 weeks postmenstrual age (PMA)). The main rationale for such EPO therapy is to avoid exposure of neonates to multiple blood donors and the risks associated with this exposure. It is likely that many sick neonates would have received a transfusion prior to entry into trials enrolling infants more than seven days of age. We carried out a systematic review to evaluate all available studies where EPO was begun after seven days of life, to assess the effect on the use of one or more red blood cell transfusions in preterm/very low birth weight infants.

Objectives

Primary objective

To assess the effectiveness and safety of late initiation of erythropoietin (EPO) between eight and 28 days after birth, in reducing red blood cell (RBC) transfusions in preterm and/or low birth weight infants.

Secondary objective

Subgroup analyses of low (less than/or equal to 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO, and low (less than/or equal to 5 mg/kg/day) and high (> 5 mg/kg/day) doses of supplemental iron in reducing red blood cell transfusions in preterm and/or low birth weight infants.

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Methods

Criteria for considering studies for this review

Types of studies

Randomised or quasi-randomised controlled trials.

Types of participants

Preterm (< 37 weeks) and/or low birth weight (< 2500 g) neonates between eight and 28 days of age.

Types of interventions

Late initiation of EPO, at eight to 28 days of age, using any dose, route, or duration of treatment, versus placebo or no intervention. The use of any dose of supplemental iron.

Types of outcome measures

Primary outcomes
  1. Use of one or more red blood cell transfusions.
Secondary outcomes
  1. The total volume (mL/kg) of blood transfused per infant.
  2. Number of transfusions per infant.
  3. Number of donors to whom the infant was exposed.
  4. Mortality during initial hospital stay (all causes of mortality).
  5. Retinopathy of prematurity (ROP) (any stage and stage greater than/or equal to 3).
  6. Proven sepsis (clinical symptoms and signs of sepsis and positive blood culture for bacteria or fungi).
  7. Necrotising enterocolitis (NEC) (Bell's stage II or more).
  8. Intraventricular haemorrhage (IVH); all grades and grades III and IV.
  9. Periventricular leukomalacia (PVL); cystic changes in the periventricular areas.
  10. Bronchopulmonary dysplasia (BPD) (supplementary oxygen at 28 days of age or at 36 weeks postmenstrual age (PMA) and compatible X-ray).
  11. Sudden infant death after discharge.
  12. 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.
  13. Neutropenia.
  14. Hypertension (as this outcome was frequently reported by trial authors, it has been added since the protocol was published).
  15. Length of hospital stay (days).
  16. Any side effects reported in the trials.

Search methods for identification of studies

Electronic searches

For the original review (Aher 2006b), we searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2006, Issue 2) to identify relevant randomised and quasi-randomised controlled trials. We searched MEDLINE 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. We searched 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].

We ran the same search strategy in February 2010, March 2012 and in July 2013.

Searching other resources

In addition, we performed manual searches of bibliographies and personal files, with no language restrictions. We handsearched abstracts published from the Pediatric Academic Societies' Meetings and the European Society of Pediatric Research Meetings (published in Pediatric Research or electronically) from 1980 to April 2006.

In July 2013 we conducted electronic searches of abstracts from the Annual Meetings of the Pediatric Academic Societies at Abstracts2View™ from 2000 to 2013. Additional searches in July 2013 included clinical trials registries (ClinicalTrials.gov, Controlled-Trials.com External Web Site Policy, and WHO International Clinical Trials Registry Platform (ICTRP) External Web Site Policy).

Data collection and analysis

We used the standard methods of the Cochrane Neonatal Review Group and the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) for data collection and analysis.

Selection of studies

Two review authors assessed all abstracts and published studies identified as potentially relevant by the literature search for inclusion in the review. Each review author extracted data separately onto a data abstraction form. They then compared the information and resolved differences by consensus. One review author (AO) entered the data into Review Manager 5 (RevMan 2012) and the other (SMA) cross-checked the printout against his own data abstraction forms, and corrected errors.

For studies identified as abstracts only, we had planned to contact the primary author to obtain further information. The two studies identified as abstracts did not provide enough information for us to be able to contact the authors (Ahmadpour Kacho 2004; Amin 2004).

This update in 2013 was conducted by both review authors (SMA and AO).

Data extraction and management

The review authors separately extracted, assessed and coded all data for each study using a form that was designed specifically for this review. We replaced any standard error of the mean by the corresponding standard deviation.

Assessment of risk of bias in included studies

We used the standard methods of the Cochrane Neonatal Review Group. We assessed the methodological quality of the studies using the following key criteria: allocation concealment (blinding of randomisation), blinding of intervention, completeness of follow-up, and blinding of outcome measurement/assessment. For each criterion, the assessment was low risk, high risk, or unclear risk of bias. Two review authors separately assessed each study, resolving any disagreement by discussion. This information was added to the Characteristics of included studies table.

For the 2012 and 2013 updates, one review author (AO) evaluated the following issues and entered them into the 'Risk of bias' table, and in 2013 the other review author (SMA) checked the information.

Selection bias

(random sequence generation and allocation concealment)
For each included study, we categorised the risk of selection bias as:

Random sequence generation:

Low risk - adequate (any truly random process e.g. random number table; computer random number generator);
High risk - inadequate (any non-random process e.g. odd or even date of birth; hospital or clinic record number);
Unclear risk - no or unclear information provided.

Allocation concealment:

Low risk - adequate (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
High risk - inadequate (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
Unclear risk - no or unclear information provided.

Performance bias

For each included study, we categorised the methods used to blind study personnel from knowledge of which intervention a participant received. (As our study population consisted of neonates they would all be blinded to the study intervention).
Low risk - adequate for personnel (a placebo that could not be distinguished from the active drug was used in the control group);
High risk - inadequate - personnel aware of group assignment;
Uncelar risk - no or unclear information provided.

Detection bias

For each included study, we categorised the methods used to blind outcome assessors from knowledge of which intervention a participant received. (As our study population consisted of neonates they would all be blinded to the study intervention). Blinding was assessed separately for different outcomes or classes of outcomes. We categorised the methods used with regards to detection bias as:
Low risk - adequate; follow-up was performed with assessors blinded to group;
High risk - inadequate; assessors at follow-up were aware of group assignment;
Unclear risk - no or unclear information provided.

Attrition bias

For each included study and for each outcome, we describe the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we re-included missing data in the analyses. We categorised the methods with respect to the risk attrition bias as:
Low risk - adequate (< 10% missing data);
High risk - inadequate (greater than/or equal to 10% missing data);
Unclear risk - no or unclear information provided.

Reporting bias

For each included study, we describe how we investigated the risk of selective outcome reporting bias and what we found. We assessed the methods as:
Low risk - adequate (where it is clear that all of the study's prespecified outcomes and all expected outcomes of interest to the review have been reported);
High risk - inadequate (where not all the study's prespecified outcomes have been reported; one or more reported primary outcomes were not prespecified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
Unclear risk - no or unclear information provided (the study protocol was not available).

Other bias

For each included study, we describe any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as:
Low risk - no concerns of other bias raised;
High risk - concerns raised about multiple checks of the data with the results made known to the investigators, difference in number of infants enrolled in abstract and final publications of the paper;
Unclear - concerns raised about potential sources of bias that could not be verified by contacting the authors. If needed, we planned to explore the impact of the level of bias through undertaking sensitivity analyses.

For the original review, two review authors (SMA, AO) who were not blinded to authors, institution or journal of publication, conducted independent quality assessments.

The 2012 update was conducted by one author (AO) and the current update by both authors (SMA and AO).

Measures of treatment effect

The statistical methods include (typical when applicable) risk ratio (RR), risk difference (RD), number needed to treat for an additional beneficial outcome (NNTB) or number needed to treat to treat for an additional harmful outcome (NNTH) for dichotomous outcomes, and mean difference (MD) for continuous outcomes, all reported with their 95% confidence interval (CI).

Assessment of heterogeneity

We conducted heterogeneity tests including the I² statistic to assess the appropriateness of pooling the data (Higgins 2003). For the 2012 and 2013 updates we classified the different percentages of heterogeneity as up to 25 mild heterogeneity, 25 to 49 low heterogeneity, 50 to 74 moderate heterogeneity and 75 or more high heterogeneity.

Data synthesis

We performed meta-analysis using Review Manager 5 software (RevMan 2012), supplied by The Cochrane Collaboration. For estimates of typical RR and RD, we used the Mantel-Haenszel method. For measured quantities, we used the inverse variance method. All meta-analyses were done using the fixed-effect model.

Subgroup analysis and investigation of heterogeneity

We performed subgroup analyses for low (less than/or equal to 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO, and in addition within those subgroups for no iron, low (less than/or equal to 5 mg/kg/day) and high (> 5 mg/kg/day) doses of supplemental iron (co-intervention).

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Results

Description of studies

For this feedback-initiated update the study by Romagnoli (Romagnoli 2000) was moved from the early EPO review (Ohlsson 2012) to this late EPO review as the infants were of a mean (SD) age of 10 (± 1) days at the initiation of EPO treatment. The study enrolled 230 infants. The 2012 update identified one new study for inclusion. As a result 30 studies (31 comparisons) including 1591 preterm and or low birth weight infants met the inclusion criteria. These studies were performed in 21 countries (Argentina, Australia, Austria, Belgium, Brazil, Canada, Finland, France, Germany, Greece, Israel, Italy, Japan, Norway, South Africa, Spain, Switzerland, Taiwan (Republic of China), the UK, Turkey, the USA). We decided to include studies that enrolled some infants who were less than 8 days at study entry. We made one further deviation from our protocol, as we included studies that enrolled infants beyond 28 days of age. Most of these studies enrolled some infants who were less than 28 days old but the inclusion criteria did not have 28 days of postnatal age as an upper limit. We could not separate data for infants that were under 28 days at enrolment. The inclusion of these studies makes our review more comprehensive. The age at enrolment is stated for each study in the table Characteristics of included studies.

Excluded studies

One study (Ohls 1991) was excluded as it compared an EPO-treated group with a group receiving blood transfusions. Two studies (Messer 1993; Testa 1998) were excluded as they were not randomised controlled trials. Two studies reported only as abstracts were excluded as one study from Saudi Arabia lacked information to ascertain whether the study was a randomised controlled trial or not (Amin 2004) and the other study conducted in Iran did not provide the age of the infants at the time of enrolment (Ahmadpour Kacho 2004). We were unable to contact the authors for additional information. Warwood 2005 was a dose-finding study of darepoetin (longer-acting and more potent than EPO). Infants were randomised to receive either one or four microgram/kg of a single dose of darepoetin, without an untreated control group. Meyer 1996, Bechensteen 1997 and Pathak 2003 also lacked an untreated control group. There were no outcomes of interest in the study by Widness 2006. In the searches in February 2010, we identified two additional studies (Badiee 2006; Pasha 2008). However, as they did not report on any of our prespecified outcomes we excluded them. In the search conducted in 2012, we identified and excluded three additional studies. In Mohammadzadeh 2005 both groups received EPO. Warwood 2011 reported that "only one of the 20 study subjects qualified for and received a subsequent rbc transfusion during the hospitalisation". The authors do not state if the infant who received the transfusion belonged to the darepoetin or the control group. Ohls 2012 compared two dosing schedules; once a week versus three times a week of EPO in infants aged seven days or more.

Included studies

We include 30 studies (31 comparisons) in this review. We treated the report by Giannakopoulou as two separate studies; Under Giannakopoulou 1998a we report on the 32 infants weighing < 1000 g and under Giannakopoulou 1998b we report on the 36 infants weighing 1000 to 1300g. The studies are detailed in the table Characteristics of included studies and are briefly discussed below.

The detailed guidelines used for transfusions are outlined in the Additional Table (Table 1: Transfusion Guidelines).

Akisu 2001 was a single-centre study performed at University of Ege, Izmir Turkey.

  • Objective: To evaluate the effect of EPO on lipid peroxidation and the activities of erythrocyte antioxidant enzymes in very low birth weight (VLBW) infants.
  • Population: Appropriately grown preterm infants with gestational age (GA) < 33 weeks and birthweight < 1500 g.
  • Intervention: The EPO group received high dose of EPO from day 10 of life, totaling 750 IU/kg/week (high dose). Infants in the control group received no placebo. All infants received 3 mg/kg/day (low dose) of elemental iron.
  • Outcomes assessed: Use of one or more red blood cell transfusions.

Al-Kharfy 1996 was a single-centre study performed in Canada.

  • Objective: To determine whether treatment with EPO reduces transfusion requirements in preterm neonates at risk of having bronchopulmonary dysplasia (BDP) and requiring multiple transfusions.
  • Population: Appropriately grown preterm infants with birth weight (BW) < 1250 g and having a 75% probability of having BPD determined on day 10 of life and postnatal age 10 to 17 days.
  • Intervention: The EPO group received EPO 200 IU/kg body weight, by subcutaneous (sc) injection, on Monday, Wednesday and Friday for six weeks (600 IU/kg/week; high dose). The control group received sham injections. Oral ferrous sulphate solution was administered to the EPO group at 6 mg of elemental iron/kg/day (high dose) and the control group received 2 mg of elemental iron/kg/day (low dose).
  • Outcomes assessed: Number of transfusions per infant, mortality, sepsis, retinopathy of prematurity (ROP) (stage greater than/or equal to 3), hypertension, BPD at 28 days of age.

Atasay 2002 was a single-centre study performed in Turkey.

  • Objective: To investigate the effect of early EPO treatment on induction of erythropoiesis and the need for transfusion in VLBW infants with acute neonatal problems.
  • Population: Infants with BW < 1500 g and GA < 32 weeks.
  • Intervention: The EPO group received EPO 600 IU/kg/week (high dose) sc, at seven to ten days and continued over seven to eight weeks. The control group received no EPO, placebo or iron. The EPO group was supplemented with oral iron (ferroglycine sulphate) at the dose of 3 mg/kg/day (low dose).
  • Outcomes assessed: Use of one or more red blood cell transfusion(s).

Bader 1996 was a two-centre study performed in Israel.

  • Objective: To assess whether an iron dose of 6 mg/kg/day is sufficient to maintain serum ferritin at adequate levels (as per authors).
  • Population: Preterm infants with GA < 34 weeks and BW < 1750 g and postnatal age three to five weeks.
  • Intervention: The EPO group received EPO 300 IU/kg/day sc three times a week (900 IU/kg/week; high dose), for a total duration of four weeks. The control group received no placebo or other intervention. Two weeks into the study elemental iron supplementation was begun in both groups at a dose of 6 mg/kg/day (high dose).
  • Outcomes assessed: Use of one or more red blood cell transfusions, side effects, sudden infant death syndrome (SIDS).

Bechensteen 1993 was a four-centre study performed in Norway.

  • Objective: To determine whether VLBW infants respond to EPO with increased erythropoiesis.
  • Population: Preterm infants with BW 900 g to 1400 g at three weeks of age.
  • Intervention: The EPO group received EPO 100 IU/kg three times a week (300 IU/kg/week; low dose) sc from three to seven weeks of age. The control group received neither EPO nor placebo. Oral iron 18 mg/day (high dose) regardless of weight, began at the start of the study (three weeks). If serum iron concentration fell below 16 micromol/L, the dose was increased to 36 mg/day.
  • Outcomes assessed: Use of one or more red blood cell transfusions, mortality, hypertension, neutropenia, side effects.

Bierer 2009 was a single-centre study performed in the USA.

  • Objective: To determine if EPO administration to neonates requiring surgery would stimulate erythropoiesis.
  • Population: Neonates requiring surgery. Post-natal age < 28 days. The majority of infants were preterm and/or low birth weight.
  • Intervention: The EPO group received EPO 200 IU/kg per day or 400 IU/kg sc three times weekly (high dose). The placebo group received an equal volume of normal saline if the infant was on total parenteral nutrition and if not a sham dose was given sc and a BandAid was placed over the sham injection site. Infants received oral iron supplementation when enteral feeds reached 60 mL/kg/day.
  • Outcomes assessed: Volume transfused during hospitalisation (mL/kg), number of donors the infants was exposed to.

Chen 1995 was a single-centre study performed in Taiwan, Republic of China.

  • Objective: To evaluate the safety and efficacy of EPO for the treatment of anaemia of prematurity.
  • Population: Preterm infants with GA less than/or equal to 33 weeks and BW less than/or equal to 1750 g, haemoglobin (Hb) < 10 g/dL and hematocrit (Hct) < 30%.
  • Intervention: The EPO group (A) received 150 IU/kg iv twice a week (300 IU/kg/week; low dose); Group B) received packed washed erythrocyte transfusion, when their Hb levels were < 10 g/dL with signs and symptoms attributed to anaemia or who had a Hb level < 8 g/dL even if asymptomatic; group C did not received EPO or erythrocyte transfusions (three infants excluded from total 19, as they received erythrocyte transfusion later because of frequent episodes of apnoea). All infants received oral elemental iron 3 mg/kg/day (low dose). Group A and C are included in this review.
  • Outcomes assessed: Mortality, adverse effects.

Corona 1998 was a single-centre study performed in Italy.

  • Objective: To evaluate the efficacy of EPO, establish the optimal dose, the age at which to start, the duration of the treatment, any adverse effects and the reduction in red blood cell transfusions.
  • Population: Preterm infants (BW < 1500 g and < 33 weeks GA).
  • Intervention: EPO group A received EPO 150 IU/kg/week sc low dose) ; EPO group B received 300 IU/kg/week sc low dose); the control group (group C) received no treatment. All groups received oral iron 4 mg/kg/day (low dose).
  • Outcomes assessed: Use of one or more red blood cell transfusions, total volume (mL/kg) of blood transfused per infant (means but no standard deviation (SD) provided), side effects.

Donato 1996 was a single-centre study performed in Argentina.

  • Objective: To assess the efficacy of three different doses of recombinant human EPO (rHuEPO) to reduce the need for transfusion in premature infants with BW < 1500 g.
  • Population: Preterm infants with GA < 34 weeks and BW < 1500 g.
  • Intervention: The placebo group (A) received human seroalbumin. The three EPO groups; Group B received EPO 50 IU/kg (150 IU/kg/week; low dose), Group C received EPO 100 IU/kg (300 IU/kg/week; low dose) and Group D received EPO 250 IU/kg (750 IU/kg/week; high dose) sc during eight consecutive weeks. All participants were given oral iron 6 mg/kg/day (high dose) and folic acid (2 mg/day) supplements, starting on day 15 of age and continuing during whole treatment period.
  • Outcomes assessed: Use of one or more red blood cell transfusions, average number of transfusions per infant during treatment, mortality, mean length of hospitalisation time, side effects, hypertension, SIDS.

Emmerson 1993 was a single-centre study performed in the UK.

  • Objective: To investigate the safety and efficacy of EPO for the prevention of anaemia of prematurity.
  • Population: Infants with GA between 27 and 33 weeks.
  • Intervention: The EPO group received low dose EPO (between 50 and 150 IU) twice a week from seven days of age and the placebo group received 4% albumin from seven days of age until discharge home. All infants received iron (6.25 mg) in the form of ferrous glycine sulphate from four weeks of age (high dose).
  • Outcomes assessed: Use of one or more red blood cell transfusions, volume transfused (mL/kg), mortality, hospital stay, SIDS, neutropenia.

Giannakopoulou 1998a and Giannakopoulou 1998b was a single-centre study performed in Greece.

  • Objective: To stimulate erythrocyte production by the use of EPO and thereby decrease the requirement for red blood cell transfusions.
  • Population: Preterm infants with birth weights less than/or equal to 1300 g, postnatal age > 20 days.
  • Intervention: The EPO group received EPO 300 IU/kg body weight, three times a week (900 IU/kg/week; high dose) from 20 days of age for six to eight weeks. The control group did not received any placebo. All infants received oral elemental iron 10 mg/kg/day (high dose).
  • Outcomes assessed: Mortality, side effects, hypertension, neutropenia.
  • We treated this report as two separate studies; Under Giannakopoulou 1998a we report on the 32 infants weighing < 1000 g and under Giannakopoulou 1998b we report on the 36 infants weighing 1000 to 1300g.

Griffiths 1997 was a study conducted in four neonatal intensive care units (NICU) in Yorkshire, England.

  • Objective: To evaluate the role of EPO in reducing iron supplementation, which may exacerbate free radical change, leading to lung disease.
  • Population: Preterm infants with GA less than/or equal to 32 weeks and/or BW less than/or equal to 1500 g, requirement for mechanical ventilation and/or supplemental oxygen at birth. Postnatal age seven to 14 days.
  • Intervention: The EPO group received 480 IU/kg/week (low dose) and the control group received placebo (4% human albumin) starting at seven to 14 days of age. All infants received oral iron (3.0 mg/kg/day) (low dose) from four weeks after birth.
  • Outcomes assessed: Mortality, BPD (at 36 weeks PMA), number of blood transfusions per infant (medians provided), SIDS


Javier Manchon 1997 was a multi-centre study involving three centres in Barcelona, Spain.

  • Objective: To test the therapeutic effect of EPO on anaemia of prematurity.
  • Population: Preterm infants < 34 weeks GA, who at 28 days after birth had Hb levels < 10.5 g/dL.
  • Intervention: The EPO group received high dose EPO (200 IU/kg/day) three days a week for four weeks and ferrous sulphate 4 mg/kg/day (low dose). The control infants did not receive placebo, EPO or iron.
  • Outcomes assessed: Use of one or more red blood cell transfusions between 30 and 60 days of age.

Juul 2003 was a single-centre study performed in the USA.

  • Objective: To determine whether enterally dosed EPO stimulates erythropoiesis in preterm infants.
  • Population: Preterm infants with BW between 700 to 1500 g and receiving at least 30 mL/kg per day of enteral feeding.
  • Intervention: The EPO group received 1000 IU/kg (enterally) per day divided into two daily feedings (7000 IU/kg/week; high dose), for 14 days. The placebo group received 5% dextrose in water for 14 days. All participants received supplemental iron (iron dextran, 1.0 mg/kg/day, or enteral ferrous sulphate 6 mg/kg/day (high dose)).
  • Outcomes assessed: Phlebotomy loss (mL) and packed red blood cell transfusion volume (mL). Evidence of feeding intolerance and other adverse effects.

Kivivuori 1999 was a four-centre study performed in Helsinki and Espoo, Finland.

  • Objective: To compare oral and intramuscular routes of administration of iron in EPO treated VLBW infants.
  • Population: VLBW infants (birthweight ranged from 625 to 1470 g).
  • Intervention: One EPO group received EPO 300 IU/kg sc three times/week, 900 IU/kg/week (high dose) sc and oral iron 6 mg/kg/day (high dose). Another EPO group received EPO 900 IU/kg/week and weekly im iron 12 mg/kg (high dose). The control group received im iron 12 mg/kg/week but no EPO.
  • Outcomes assessed: Use of one or more red blood cell transfusions. Adverse effects.

Kumar 1998 was a single-centre study performed in the USA.

  • Objective: To evaluate the efficacy and safety of EPO in VLBW infants with anaemia of prematurity.
  • Population: Preterm infants (GA < 32 weeks, BW < 1250 g with anaemia of prematurity.
  • Intervention: The EPO group received 300 IU/kg/dose of EPO sc twice a week (600 IU/kg/week; high dose) for six weeks. The control group received identical volume of placebo suspension (normal saline). All infants received elemental iron 6 mg/kg/day (high dose).
  • Outcomes assessed: Use of one or more red blood cell transfusions, number of erythrocyte transfusions (per infant), entry to discharge duration (days), side effects.

Maier 2002 was a multi-centre study performed in 14 centres in four European countries (Belgium, France, Germany, Switzerland).

  • Objective: To investigate whether EPO reduces the need for transfusions in extremely low birth weight (ELBW) infants and to determine the optimal dose of treatment.
  • Population: Preterm infants with BW 500 to 999 g.
  • Intervention: The EPO group received EPO 200 IU/kg/dose three times a week sc (600 IU/kg/week, high dose). The volume was increased by the equivalent of 50 IU/kg per dose if the hematocrit declined by 6% during any two-week period during the trial, but was withheld if the hematocrit was > 45%. The control group 40 received an identical volume of placebo. Enteral iron 3 mg/kg/day (low dose) was given to all infants from days three to five and was increased at days 12 to 14 to 6 mg/kg/day (high dose) and to 9 mg/kg/day (high dose) at days 24 to 26 of life.
  • Outcomes assessed: Use of one or more red blood cell transfusions, donor exposure, mortality during hospital stay, necrotising enterocolitis (NEC), IVH, periventricular leukomalacia (PVL), ROP, days in oxygen, days in NICU, days in hospital.

Meyer 1994 was a single-centre study performed in South Africa.

  • Objective: To assess the efficacy of EPO in the treatment of anaemia of prematurity.
  • Population: Preterm infants (less than/or equal to 32 weeks GA, weight less than/or equal to 1500 g, postnatal age two to eight weeks, central hematocrit Hct less than/or equal to 35%).
  • Intervention: The EPO group received high dose EPO (200 IU/kg three times a week; 600 IU/kg/week). The control group received an identical volume of placebo. All infants received 3 mg/kg/day of iron (low dose).
  • Outcomes assessed: Use of one or more red blood cell transfusions, sepsis, NEC, SIDS.

Pollak 2001 was a single-centre study conducted in Vienna, Austria.

  • Objective: To test the efficacy and safety of combining intravenous iron in amounts approximately the in-utero accretion rate and the postnatal iron loss with EPO in VLBW infants.
  • Population: Preterm infants < 31 weeks gestation and < 1300 g birthweight not treated with red blood cell transfusions during the study period.
  • Intervention: During a three-day run-in baseline period 9 mg/kg/day of iron poly maltose complex (high dose) was administered to all participants in all groups. This was followed by a treatment period during which participants received: 1) the same oral iron supplementation dose alone (oral iron group - control group); 2) 300 IU/kg/day of EPO iv at three-day intervals (600 IU/kg/week, high dose) along with the same oral iron supplement as the oral iron group (EPO + oral iron group); or 3) 2 mg of intravenous iron sucrose/kg/day + EPO as in group two (iv iron + EPO group). To maintain comparability of iron intake among the three groups, this last group also received EPO and oral iron in an identical manner to the EPO + oral iron group.
  • Outcomes assessed: Mortality, sepsis, ROP, BPD (oxygen dependency at 36 weeks PMA).

Reiter 2005 was a single-centre study performed in the USA.

  • Objective: To determine the effectiveness of a 10-day EPO course in preterm infants.
  • Population: Preterm infants < 32 weeks gestation, hematocrit less than/or equal to 28%, post-conceptual age of < 48 weeks or five months chronological age.
  • Intervention: The EPO group received 300 IU/kg/day (high dose) and 6 mg/kg/day of enteral iron (high dose) versus iron only. Both groups received the intervention for 10 days.
  • Outcomes assessed: Use of one or more red blood cell transfusions, volume of red blood cells required (mL/kg).

Rocha 2001 was a single-centre study performed in Brazil.

  • Objective: To assess the efficacy of EPO for the prevention and treatment of anaemia of prematurity.
  • Population: Preterm infants with GA up to 33 weeks, BW up to 1550 g and postnatal age between 10 and 35 days.
  • Intervention: The two EPO groups received either daily doses of 100 IU/kg of EPO or twice weekly doses of 350 IU/kg (700 IU/kg/week, high dose). The EPO groups were given iron (ferrous sulphate) 3 mg/kg/day enterally, and increased to 6 mg/kg/day in the second week of treatment. In the control group iron supplementation was initiated around the 30th day of life. The control group did not receive any placebo.
  • Outcomes assessed: Mean number of blood transfusions per participant (no SD provided), two or more blood transfusions per participant.

Romagnoli 2000 was a single-centre study performed in Italy.

  • Objective: To assess the effectiveness of rhEPO.
  • Population: Infants with PMA less than/or equal to 30 weeks and those infants of 31 - 34 weeks PMA suffering from respiratory distress syndrome and requiring mechanical ventilation.
  • Intervention: Treated infants received rhEPO doses of 300 IU/kg body weight sc on each Monday, Wednesday and Friday from the 2nd to the 7th week of life (high dose). Iron supplementation (Intrafer-Geymonat) was given at a dose of 1 mg/kg per day iv from the 2nd to the 4th week (low dose); thereafter 12 mg/kg/day orally until the 7th week of life.
  • Outcomes assessed: Retinopathy of prematurity (stage 1 - 2 and stage 3 - 4), IVH (> grade 2), sepsis, NEC, number of infants transfused, number of transfusions per infant.

Ronnestad 1995 was a single-centre study performed in Norway.

  • Objective: To investigate whether EPO given to infants < 32 weeks GA, fed their own mother's milk supplemented with a bovine milk protein and electrolyte fortifier together with moderate iron supplementation, would ameliorate the anaemia and thus reduce the need for bred blood cell transfusions after the second week of life.
  • Population: Preterm infants, < 32 weeks. Age 14 - 22 days.
  • Intervention: The EPO group received EPO 150 IU/kg three times per week (450 IU/kg/week; low dose) or placebo. All infants received 4 mg/kg/day of iron (low dose) as ferrous fumarase.
  • Outcomes assessed: Neutropenia.

Samanci 1996 was a single-centre study performed in Turkey.

  • Objective: To determined whether EPO would prevent anaemia of prematurity and reduce the need for transfusion in infants with VLBW.
  • Population: Preterm infants with GA less than/or equal to 32 weeks, BW of less than/or equal to 1250 g. Post-natal age at the first dose was two to four weeks.
  • Intervention: The EPO group received 200 IU/kg sc three times weekly (600 IU/kg/week, high dose), for four weeks. The control group received an equivalent volume of placebo sc, three times weekly, for four weeks. All infants received oral supplements of elemental iron (3 mg/kg/day) (low dose) during the study period.
  • Outcomes assessed: Use of one or more red blood cell transfusions, number of blood transfusions per infant, NEC, IVH, major adverse events.

Shannon 1991 was a three-centre study performed in the USA.

  • Objective: Not stated.
  • Population: Preterm infants with birth weights less than/or equal to 1250 g.
  • Intervention: The EPO group received EPO 100 IU/kg, twice each week (200 IU/kg/week; low dose) for six weeks. The control group intravenous injections of identical volume of placebo twice each week for six weeks. All infants received 3 mg/kg/day of oral iron (low dose) and continued at the discretion of the attending physician.
  • Outcomes assessed: Use of one or more red blood cell transfusions, mortality, NEC, hypertension, neutropenia, side effects.

Shannon 1992 was a single-centre study performed in the USA.

  • Objective: Not stated.
  • Population: Preterm infants with GA < 33 weeks and BW < 1250 g
  • Intervention: The EPO group received EPO 100 IU/kg, 5 times a week (500 IU/kg/week; high dose. The control group received an identical volume of placebo suspension, five times a week. Oral iron was started in all infants at 3 mg/kg/day (low dose), divided in three doses and given between feedings. The iron dose was increased to 6 mg/kg/day (high dose) for infants who were tolerating full caloric feedings.
  • Outcomes assessed: Use of one or more red blood cell transfusions, major adverse events.

Shannon 1995 was a multi-centre study at 11 centres in the USA.

  • Objective: To assess whether treatment with EPO would stimulate erythropoiesis and thereby reduce the need for erythrocyte transfusions in preterm infants.
  • Population: Preterm infants with GA < 31 weeks with BW of less than/or equal to 1250 g.
  • Intervention: The EPO group received 100 IU/kg/day [from Monday through Friday (500 IU/kg/week; high dose)] for six weeks or until the infants were ready to be discharged home. Doses EPO (or placebo) were adjusted weekly according to changes in body weight. The control group received an identical volume of placebo suspension. Participants received oral iron supplements at study entry to achieve a total enteral intake of 3 mg/kg/day of elemental iron (low dose). Total iron intake was increased to 6 mg/kg/day (high dose) when the infants tolerated full caloric feeding enterally.
  • Outcomes assessed: Use of one or more red blood cell transfusions, mean number of erythrocyte transfusions per infant, mortality, sepsis, NEC, ROP, hypertension, SIDS, side effects.

Whitehall 1999 was a single-centre study conducted in Australia.

  • Objective: To evaluate safety and efficacy of EPO in reducing the need for red cell transfusions in anaemia of prematurity.
  • Population: Infants with GA less than/or equal to 32 weeks.
  • Intervention: Infants in the EPO group received 400 IU/kg every second day x 10 doses (high dose). Infants in the control group received no placebo. Both groups received 3 mg/kg/day of iron (low dose) increased to 6 mg/kg/day (high dose) as tolerated.
  • Outcomes assessed: Total volume (mL/kg) of blood transfused, number of transfusions per infant, mortality during hospital stay.

Yamada 1999a was a single-centre study conducted in Japan.

  • Objective: To assess the efficacy of EPO in the treatment of anaemia of prematurity.
  • Population: Infants with BW 1000 to 1499 g, GA < 33 weeks, haemoglobin < 12 g/dL and oral milk intake > 50 mL/kg/day.
  • Intervention: The EPO group received EPO (200 IU/kg twice a week, low dose) for eight weeks and the control group received no study drug or placebo. All infants received 3 mg/kg/day of oral iron (low dose).
  • Outcomes assessed: Use of one or more red blood transfusions, total volume of blood transfused (mL/infant), number of transfusions per infant, side effects.

Yamada 1999b was a single-centre study conducted in Japan.

  • Objective: To assess the efficacy of EPO in the treatment of anaemia of prematurity.
  • Population: Infants with BW 500 to 999 g, GA < 33 weeks, haemoglobin < 13 g/dL and oral milk intake > 50 mL/kg/day.
  • Intervention: The EPO group received low dose EPO (200 IU/kg twice a week) for eight weeks and the control group received no study drug or placebo. All infants received 3 mg/kg/day of oral iron (low dose).
  • Outcomes assessed: Use of one or more red blood transfusions, total volume of blood transfused (mL/infant), number of transfusions per infant, side effects.

Three different routes of administration were used; subcutaneous (sc) (Shannon 1992; Bechensteen 1993; Emmerson 1993; Meyer 1994; Yamada 1999a; Yamada 1999b; Ronnestad 1995; Shannon 1995; Al-Kharfy 1996; Bader 1996; Donato 1996; Samanci 1996; Griffiths 1997; Javier Manchon 1997; Corona 1998; Giannakopoulou 1998a; Giannakopoulou 1998b; Kumar 1998; Kivivuori 1999; Whitehall 1999; Romagnoli 2000; Akisu 2001; Rocha 2001; Atasay 2002; Reiter 2005; Bierer 2009), intravenous (iv) (Pollak 2001; Shannon 1991; Chen 1995;) and oral (Juul 2003), iv or sc (Maier 2002). The dose of EPO varied from 150 IU/kg/week (Donato 1996; Corona 1998) to 2100 IU/kg/week (Reiter 2005) when given subcutaneously. When given intravenously, the dose varied from 200 IU/kg/week (Shannon 1991) to 300 IU/kg/week (Chen 1995). Juul 2003 provided 7000 IU/kg/week enterally.

Different EPO preparations were used; Recormon, Boehringer-Mannheim, Germany (Akisu 2001); Eprex (provided by Cilag Zug, Switzerland, Ortho Pharmaceutical Canada Ltd., Janssen-Cilag or Guler Pharmaceutical Corp, Istanbul, Turkey) (Bechensteen 1993; Emmerson 1993; Meyer 1994; Chen 1995; Ronnestad 1995; Al-Kharfy 1996; Bader 1996; Samanci 1996; Griffiths 1997; Giannakopoulou 1998a; Giannakopoulou 1998b; Kivivuori 1999; Whitehall 1999; Atasay 2002 ); Amgen (Shannon 1991), Eogen alpha, Amgen, Inc. Thousand Oaks, CA, USA (Reiter 2005); unnamed products (Shannon 1992; Shannon 1995; Javier Manchon 1997; Corona 1998; Kumar 1998; Yamada 1999a; Yamada 1999b; Romagnoli 2000; Rocha 2001; Juul 2003; Bierer 2009), NeoRecormon, F. Hofman-La Roche, Basel, Switzerland (Maier 2002), Erypo, Janssen-Cilag Pharma, Vienna, Austria (Pollak 2001), and Hemax, Bio Sidus, S. A. (Donato 1996).

Three studies did not state that guidelines for red blood cell transfusions were in place (Shannon 1991; Chen 1995; Akisu 2001). In only one study was it explicit that infants who had received erythrocyte transfusions prior to study entry were excluded (Samanci 1996). For transfusion guidelines see Additional Table (Table 1: Transfusion Guidelines).

Risk of bias in included studies

The assessment of indiv idual studies is presented in the table 'Characteristics of included studies'. All studies were reported as randomised controlled trials. Information on which to base our judgements on whether a study used concealed allocation or not was often not clearly reported. We considered the concealment of allocation to be appropriate in 10 studies (Shannon 1992; Bechensteen 1993; Emmerson 1993; Shannon 1995; Samanci 1996; Al-Kharfy 1996; Griffiths 1997; Romagnoli 2000; Pollak 2001; Maier 2002). In general, the studies were of small sample size ranging from eight (Shannon 1992) to 230 infants (Romagnoli 2000). The studies often lacked a sample size calculation. Most studies did not use a placebo or sham injection, precluding blinding of the intervention and the outcome measure assessment (Bechensteen 1993; Yamada 1999a; Yamada 1999b; Chen 1995; Bader 1996; Javier Manchon 1997; Corona 1998; Giannakopoulou 1998a; Giannakopoulou 1998b; Kivivuori 1999; Whitehall 1999; Romagnoli 2000; Akisu 2001; Pollak 2001; Rocha 2001; Atasay 2002; Reiter 2005).

We performed two post hoc secondary analyses for the primary outcome 'Use of one or more red blood cell transfusions'. In the first, we compared those studies that used concealed allocation (a placebo or sham-injection to blind the intervention) and in which there was blinding of outcome measure assessment to those studies in which this was not evident from the published report. In the second post hoc analysis, we compared the studies that used strict criteria for red blood cell transfusions with those that used no or less strict criteria.

Effects of interventions

For this update one study (Romagnoli 2000) was moved from the early EPO review (Ohlsson 2012) to this late EPO review. This added 230 infants to the review. The review now includes thirty studies (31 comparisons) that randomised 1591 infants. For details of results, see Data and analyses.

Primary Outcome:

Late initiation of erythropoietin (EPO) (8 - 28 days) versus placebo or no intervention (Comparison 1)
The use of one or more red blood cell transfusions (Figure 1) (Outcome 1.1)

A total of 20 studies including 1142 infants reported on the use of one or more red blood cell transfusions following the use of either low or high dose of EPO. There was a significant reduction in the use of one or more red blood cell transfusions (typical risk ratio (RR) 0.71, 95% confidence interval (CI) 0.64 to 0.79; typical risk difference (RD); -0.17, 95% CI -0.22 to -0.12; number needed to treat for an additional beneficial outcome (NNTB); 6, 95% CI 5 to 8). There was moderate heterogeneity for this outcome (for RR; I² = 68.0%; for RD; I² = 60.0%).

Subgroup analyses:

We conducted further analyses including studies that used a high dose of EPO (> 500 IU/kg/week) or a low dose of EPO (less than/or equal to 500 IU/kg/week).

High dose of EPO (Outcome 1.2)

The summary estimates for 14 studies including 912 infants testing a high dose of EPO (Outcome 1.2) were statistically significant with a typical RR of 0.76 (95% CI 0.68 to 0.86), a typical RD of -0.14 (95% CI -0.19 to -0.08) and a NNTB of 7 (95% CI 5 to 13). There was moderate heterogeneity for this outcome for RR (I² = 66%) and for RD (I² = 62%).

We conducted a subgroup analysis for high dose of EPO in combination with high dose of iron (Outcome 1.2.1). Six studies (n = 318) showed a typical RR of 0.74 (95% CI 0.62 to 0.88), a typical RD of -0.16 (95% CI -0.24 to -0.08) and NNTB of 6 (95% CI 4 to 13). There was high heterogeneity for both RR (I² = 79%) and for RD (I² = 78%).

Eight studies of high EPO and low dose of iron (Outcome 1.2.2) (n = 594) showed a typical RR of 0.78 (95% CI 0.67 to 0.91), a typical RD of -0.13 (95% CI -0.20 to -0.05) and NNTB of 8 (95% CI 5 to 20). There was moderate heterogeneity for RR (I² = 58%) and low heterogeneity for RD (I = 38%).


Low dose of EPO (Outcome 1.3)

The summary estimates for seven studies including 239 infants testing a low dose of EPO (Outcome 1.3) were statistically significant with a typical RR of 0.53 (95% CI 0.42 to 0.67), a typical RD of -0.34 (95% CI -0.45 to -0.23) and a NNTB of 3 (95% CI 2 to 4). There was moderate heterogeneity for RR (I² = 59%) and minimal heterogeneity for RD (I² = 14%).

We conducted a subgroup analysis for low dose of EPO in combination with high dose of iron (Outcome 1.3.1). Three studies (n = 77) showed a typical RR of 0.50 (95% CI 0.31 to 0.79), a typical RD of -0.31 (95% CI -0.49 to -0.13) and a NNTB of 3 (95% CI 2 to 8). There was no significant heterogeneity for this outcome for RR (I² = 0%) and RD (I² = 0%).

Four studies (n = 162) evaluated the effectiveness of low dose of EPO in combination with low dose of iron (Outcome 1.3.2). The typical RR was 0.54 (95% CI 0.41 to 0.71), the typical RD was -0.36 (95% CI -0.49 to - 0.22) and the NNTB was 3 (95% CI 2 to 5). There was high heterogeneity (I² = 76%) for RR and moderate heterogeneity for RD (I² = 53%).

Secondary outcomes:

The total volume (mL/kg) of blood transfused per infant (Outcome 1.4)

Five studies including 197 infants reported on the total volume of blood transfused per infant. The typical mean difference (MD) between the groups was not statistically significant, with a typical MD of -1.61 mL/kg (95% CI -5.78 to 2.57) transfused per infant. There was high heterogeneity (I² = 92%). Corona 1998 (n = 60) reported on this outcome but provided only the means with no standard deviation (SD). In the two EPO groups combined the mean was 20 mL/kg and in the control group it was 32 mL/kg (P < 0.01, according to the authors).

Number of red blood cell transfusions per infant (Outcome 1.5)

The number of red blood cell transfusions per infant was reported in 11 studies enrolling 817 infants. The significant typical MD was -0.22 (95% CI -0.38 to -0.06) favouring the EPO group. There was high heterogeneity (I² = 94%). In Griffiths 1997 (n = 42), the median number of blood transfusions was lower for the infants in the EPO group (difference in medians -2 (95% CI -4 to 0)).

Number of donors to whom the infant was exposed (Figure 2) (Outcome 1.6)

Two studies reported on donor exposure in 165 enrolled infants. The significant MD was 0.45 (95% CI 0.20 to 0.69) indicating a higher donor exposure number in the EPO group. There was high heterogeneity for this outcome (I² = 93%).

Mortality during initial hospital stay (all causes of mortality) (Outcome 1.7)

Thirteen studies (14 comparisons) including 767 infants reported on mortality during initial hospital stay. The non significant typical RR was 0.82 (95% CI 0.49 to 1.39) and the typical RD was -0.01 (95% CI -0.05 to 0.02). There was no statistically significant heterogeneity for this outcome for either RR (I² = 0%) or RD (I² = 0%).

Retinopathy of prematurity (ROP) (all stages or stage not reported) (Figure 3) (Outcome 1.8)

Three studies including 404 infants reported on ROP (all stages), with a non significant 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%).

Retinopathy of prematurity (ROP) stage greater than/or equal to 3 (Figure 4) (Outcome 1.9)

Three trials enrolling 442 infants reported on severe ROP (stage greater than/or equal to 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); neither was statistically significant. There was unimportant heterogeneity for this outcome for RR (I² = 18%) but high heterogeneity for RD (I² = 79%).

Proven sepsis (Clinical symptoms and signs of sepsis and positive blood culture) (Outcome 1.10)

Five studies including 551 infants reported on this outcome. The typical RR was 0.75 (95% CI 0.52 to 1.09) and the typical RD was -0.05 (95% CI -0.11 to 0.01), neither statistically significant. There was no heterogeneity for this outcome for either RR (I² = 0%) or RD (I² = 0%).

Necrotising enterocolitis (NEC) (Bell's stage II or higher) (Outcome 1.11)

Six studies including 656 infants reported on NEC. In some studies the stage wa not reported but the results are included in the meta-analyses. The typical RR was 0.88 (95% CI 0.46 to 1.69) and the typical RD -0.01(95% CI -0.04 to 0.03).Neither estimate was statistically significant. There was no heterogeneity for this outcome for either RR (I² = 0%) or RD (I² = 0%).

Intraventricular haemorrhage (IVH); all grades (Outcome 1.12)

Four studies including 454 infants reported on intraventricular haemorrhage (all grades). In Samanci 1996 there were no events in either group and that study is therefore disregarded for the RR. The non-significant typical RR was 0.87 (95% CI 0.53 to 1.42) and typical RD was -0.02 (95% CI -0.07 to 0.04). There was no heterogeneity for either RR (I² = 0%) or RD (I² = 0%). IVH is probably not a relevant outcome in this review as most haemorrhages occur during the first few days of life and infants were enrolled later in these studies.

Periventricular leukomalacia (PVL); cystic changes in the periventricular areas (Outcome 1.13)

One study enrolling 145 infants reported on PVL. The non-significant RR was 4.80 (95% CI 0.57 to 40.05) and the RD was 0.05 (95% CI -0.01 to 0.12). Test for heterogeneity not applicable.

Bronchopulmonary dysplasia (BPD) (supplemental oxygen at 28 days of age) (Figure 4) (Outcome 1.14)

Two studies (n = 285) reported on BPD at 28 days. In Al-Kharfy 1996 all infants in both groups had BPD. The typical RR was 1.25 (95% CI; 1.00 to 1.55) and the RD was 0.10 (95% CI 0.00 to 0.20). There was very high heterogeneity for both RR (I² = 97%) and RD (I² = 88%). Both results were of borderline statistical significance [test for overall effect: Z = 1.99 (P = 0.05)]. The extremely high heterogeneity for this analysis may relate to the fact that in one study all the infants had BPD at 28 days of age. The results should be interpreted with caution.

Bronchopulmonary dysplasia (BPD) (supplemental oxygen at 36 weeks postmenstrual age (PMA)) (Outcome 1.15)

Three studies enrolling 216 infants reported on the use of supplemental oxygen at 36 weeks PMA. The typical RR was 0.89 (95% CI 0.59 to 1.35) and the typical RD was -0.03 (95% CI-0.15 to 0.08); neither was statistically significant. There was moderate heterogeneity for RR (I² = 56%) and for RD (I² = 59%).

Sudden infant death (SIDS) after discharge (Outcome 1.16)

Six studies including 363 infants reported on SIDS. The typical RR was 1.06 (95% CI 0.25 to 4.52) and the typical RD was 0.00 (95% CI -0.03 to 0.04). Neither was statistically significant. There was no heterogeneity for either RR (I² = 0%) or RD (I² = 0%).

Neutropenia (Outcome 1.17)

Five studies (six comparisons) enrolling 164 infants reported on neutropenia. The typical RR was 0.28 (95% CI 0.05 to 1.54) (in only two studies did the outcome of interest occur), and the typical RD was -0.04 (-0.11 to 0.03); neither was statistically significant. There was no heterogeneity for RR (I² = 0%) and for RD (I² = 0%).

Hypertension (Outcome 1.18)

Seven studies (eight comparisons) including 363 infants reported on hypertension. The RR was 1.20 (95% CI 0.46 to 3.14) and the RD 0.01 (95% CI -0.04 to 0.05); neither was statistically significant. There was no statistically significant heterogeneity for either RR (I² = 21%) or RD (I² = 0%).

Length of hospital stay (days) (Outcome 1.19)

Length of hospital stay was reported in two studies enrolling 55 infants. There was no significant difference between the groups with a typical MD of -0.35 days (95% CI -12.83 to 12.13). There was no heterogeneity (I² = 0%).

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

Long-term neurodevelopmental outcomes were not reported in any study.

Any side effects reported in the trials

There were no serious side effects reported in most of the trials that specifically reported on adverse events (Shannon 1991; Shannon 1992; Bechensteen 1993; Yamada 1999a; Yamada 1999b; Chen 1995; Shannon 1995; Bader 1996; Donato 1996; Samanci 1996; Corona 1998; Giannakopoulou 1998a; Giannakopoulou 1998b; Kumar 1998; Kivivuori 1999; Rocha 2001; Juul 2003). Griffiths 1997 reported a total of 41 different types of adverse events, with infection (positive blood cultures), pneumonia, and patent ductus arteriosus being the most common.

Secondary (post hoc) analyses:

In an attempt to further explore the heterogeneity observed in the primary outcome and subgroup analyses, we performed a post hoc analysis comparing the results of studies that we judged as high quality with those that we identified as of lower quality or could not precisely define their quality because of lack of information. We also compared the results of studies that used strict criteria for red blood cell transfusions to those that used no criteria or less strict criteria.

Use of one or more blood transfusions (secondary analysis based on quality) (Outcome 1.20)

For five high-quality studies enrolling 357 infants, the typical RR was 0.84 (95% CI 0.73 to 0.96); the typical RD was -0.12 (95% CI -0.21 to -0.03). For 15 studies of uncertain quality enrolling 785 infants, the typical RR was 0.63 (95% CI 0.54 to 0.73) and the typical RD was -0.20 (-0.26 to -0.14). The summary effect size was larger in the studies of poor quality. There was moderate heterogeneity for the high-quality studies (I² = 58% for both RR and RD) as well as for the studies of uncertain quality which had higher heterogeneity (I² = 71% for RR and 61% for RD).

Use of one or more blood transfusions (secondary analysis based on criteria for red blood cell transfusions) (Outcome 1.21)

We considered 15 studies enrolling 963 infants to have used strict (although variable) guidelines for red blood cell transfusions, and three studies enrolling 97 infants to have used no criteria or less strict criteria. We excluded two studies for which we were unable to translate the text regarding possible transfusion guidelines (Yamada 1999a; Yamada 1999b). For the 15 studies using strict red blood cell transfusion guidelines, the typical RR was 0.76 (95% CI 0.68 to 0.85) and the typical RD was -0.15 (95% CI -0.20 to -0.09); NNTB 7 (95% CI 5 to 11). There was moderate heterogeneity for RR (I² = 64%) and RD (I² = 56%). For the studies using no criteria or less strict criteria, the typical RR was 0.25 (95% CI 0.08 to 0.77) and the typical RD was -0.21 (95% CI -0.36 to -0.07); NNTB 5 (95% CI 3 to 14). There was no heterogeneity for the studies using no criteria or less strict criteria for RR (I² = 0%) and RD (I² = 0%). The summary effect size was larger for the studies that did not use strict guidelines for red blood cell transfusions compared to those that did.

Funnel plot

A funnel plot for the primary outcome 'Use of one or more red blood cell transfusions' was asymmetric, with a relative absence of smaller studies not having a protective effect (see Figure 5).

Enterally-dosed EPO

One study (Juul 2003) using enterally-dosed EPO found that the intervention did not significantly influence erythropoiesis or iron utilisation when given for a two-week period, nor did it elevate the serum EPO concentration in preterm or term infants. The authors concluded that enterally-dosed EPO is not an effective substitute for parenteral administration (Juul 2003).

Discussion

Summary of main results

In this update we have moved the study Romagnoli 2000 from the early erythropoietin (EPO) review (Ohlsson 2012) to this late EPO review as infants started treatment with EPO at a mean (SD) age of 10 (± 1) days. The literature searches in March/May 2012 identified one additional trial (Bierer 2009) and a few for exclusion (See Characteristics of excluded studies). The searches in 2013 did not identify any new trials. The current review includes 30 studies (31 comparisons) meeting our inclusion criteria. These studies included a total of 1591 preterm and/or low birth weight infants and reported on at least one of the outcomes of interest for this systematic review.

The results show that late administration of erythropoietin reduces the use of one or more blood transfusions following study entry. These results were quite consistent (overlapping confidence intervals) when including studies that used both low and high doses of EPO in combination with low and high doses of iron.

With the inclusion of Romagnoli 2000 in which there was a statistically significant increase in retinopathy of prematurity (ROP) at all stages and at stage 3 or higher, the overall estimates in the meta-analyses now show a trend towards increase for both these outcomes. Three studies including 404 infants reported on ROP (all stages), 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). This outcome was not statistically significantly different between the groups. There was high heterogeneity for this outcome for both RR ( I² = 83%) and RD (I² = 82%). Three trials enrolling 442 infants reported on severe ROP (stage 3 or higher). 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); neither was statistically significant. There was minimal heterogeneity for this outcome for RR (I² = 18%) but high heterogeneity for RD (I² = 79%). As the cut-off for early EPO treatment versus late EPO treatment was set arbitrarily at 8 completed days of initiation of treatment, we thought it justified to include all studies that have reported on ROP in secondary analyses. Details of these analyses are presented in the 2014 update of the early EPO review (Ohlsson 2012). We combined all studies that reported on ROP at stage 3 or higher regardless of at what age the EPO treatment was initiated. We included seven studies from the early EPO review and three studies from the late EPO review that reported on this outcome. A total of 10 studies enrolling 1303 infants reported on this outcome. There was a significantly increased risk of ROP stage 3 or higher [typical RR 1.48 (95% CI 1.02 to 2.13); typical RD 0.03 (95% CI 0.00 to 0.06) (P = 0.04 for RR and 0.03 for RD); number needed to treat for an additional harmful outcome (NNTH) 33 (95% CI 17 to infinity)]. There was no heterogeneity for RR (1² = 0%) and moderate (I² = 50%) for RD.

Overall completeness and applicability of evidence

The number needed to treat for an additional beneficial outcome (NNTB) to avoid one red blood cell transfusion was low (range 3 to 8, for different combinations of EPO and iron). The clinical importance of this finding is lessened by the fact that any donor exposure was not avoided, as many infants required red blood cell transfusions prior to study entry. Only two studies reported on donor exposure. In the study by Bierer 2009 there was a statistically significant increase in the number of donors the infants were exposed to but not in the study by Maier 2002. In the meta analysis of the two studies a significant difference in the typical mean difference for number of transfusions was noted indicating a higher donor exposure number in the EPO group. There was very high heterogeneity for this outcome (I² = 93% ), reducing the importance of the finding. In addition, in the 2012 and 2013 updates there was no statistically significant reduction in the total volume (mL/kg) of blood transfused per infant. There was a small reduction in the mean number of transfusions (0.2) per infant.

The need for intravenous, intramuscular or subcutaneous injections with EPO/iron treatment in the neonatal period is associated with repeated painful stimuli and could potentially have adverse long-term effects. This has not been addressed in any study.

Quality of the evidence

The study quality varied and important information regarding the random sequence generation and whether the allocation was concealed or not was often missing. No study was reported according to the 'Consort' statement (CONSORT 2012). Sample sizes were small and long-term outcomes (18 to 24 months corrected age) were not reported. In only one study (Samanci 1996) did the authors state that infants were not eligible to enter the study if they had previously received a red blood cell transfusion. Most studies followed guidelines for red blood cell transfusions, although these varied between the studies.

For the primary outcome of 'use of one or more blood transfusions' the typical risk ratio (RR) for five high quality studies was 0.84 (95% CI 0.73 to 0.96). For 15 studies of uncertain quality, the typical RR was 0.63 (95% CI 0.54 to 0.73). The CIs for these analyses are not overlapping, indicating that there are statistically significant differences in the effect sizes between studies that could be ascertained as being of high quality and studies of uncertain quality. There was a reduction in heterogeneity when the high quality studies were analysed separately. Studies of higher quality often show lower effect sizes (Schulz 1995). Judging the quality of a study depends to a large extent on the information published, and obtaining additional information from the authors may change the evaluations. The typical effect size for studies that used strict red blood cell transfusion guidelines was smaller (RR 0.76) than for studies that used no or less strict criteria (RR 0.25).

Of concern is the finding of moderate heterogeneity for the primary outcome, including all combinations of low and high EPO and low and high iron treatment. The heterogeneity remained for indiv idual combinations of EPO and iron. The heterogeneity could possibly be explained by the fact that the studies were conducted in 21 countries, with presumably different care practices. Of note, the control rates for red blood cell transfusions varied markedly between studies. As noted in the Additional Table 1, there was large variation in the guidelines for red blood cell transfusions. The results of these post hoc analyses should therefore be interpreted with caution.

Potential biases in the review process

As outlined in Figure 5; Funnel plot of comparison: 1 Late initiation of EPO (8 - 28 days) vs placebo or no intervention, outcome: 1.1 Use of one or more red blood cell transfusions (low and high dose of EPO) there is a paucity of smaller studies not having a protective effect. It is possible that such studies have been conducted and that the results have not been published.

Several studies were supported by pharmaceutical companies and some authors were employed by such companies.

We are not aware of any potential biases in our own review process.

Agreements and disagreements with other studies or reviews

Systematic reviews of the efficacy of EPO in anaemia of prematurity have been published (Vamvakas 2001; Garcia 2002; Kotto-Kome 2004). Vamvakas 2001 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. Garcia 2002 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. Kotto-Kome 2004 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. Direct comparisons regarding the results of this systematic overview and previous reviews (Vamvakas 2001; Garcia 2002; Kotto-Kome 2004) are not appropriate as our review includes a much larger sample of studies.

Authors' conclusions

Implications for practice

Late EPO administration results in a reduction in the use of one or more red blood cell transfusions following initiation of therapy. It minimally reduces the number of red blood cell transfusions per infant. It is not associated with reductions in mortality or other neonatal morbidities. The use of late EPO is not associated with any short-term serious side effects except for a possible association with retinopathy of prematurity (ROP) stage 3 or higher. A large proportion of extremely low birth weight/preterm neonates require red blood cell transfusions during the first few days of life, when neither early nor late EPO administration could possibly have an impact. The decision to use late EPO will depend on the baseline rate of red blood cell transfusions in this population in a specific neonatal intensive care unit, the costs, the associated pain, and the values assigned to the clinical outcomes. Other means of reducing the need for red blood cell transfusions should be considered, including reduced blood sampling and the use of 'satellite packs' from directed or universal donors.

Implications for research

There is no need for further research to assess the effectiveness of the late use of EPO in reducing red blood cell transfusions. Its effectiveness has been established in populations that were exposed to donor blood prior to study entry, minimising the clinical importance of this effect. Future research should focus on strategies to minimise red blood cell donor exposure (using multiple aliquots from a properly tested single donor) during the first week of life, when the likelihood of need for red blood cell transfusions is at its peak. Such strategies in combination with late EPO treatment may reduce further donor exposure in early infancy. All ongoing and planned studies should monitor the incidence of retinopathy of prematurity.

Acknowledgements

We are thankful to Dr Rolf Maier, Zentrum für Kinder und Jugendmedizin, Philipps-Universität, Marburg, who provided us with additional information regarding his study.
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 express our gratitude to Ms Marie Sirdevan, Perinatal Pharmacist, Pharmacy, Mount Sinai Hospital, Toronto, Ontario, Canada, who helped interpreting two papers written in Japanese. We are thankful to Dr Jaques Belik, the Hospital for Sick Children (SickKids), Toronto, Ontario, Canada, who translated part of one paper from Spanish to English. We are thankful to Dr Robin Ohls, University of New Mexico, Albuquerque, New Mexico, USA, who drew to our attention our misclassification of the study by Romagnoli and co-workers. We are thankful to Dr Constantion Romagnoli, Division of Neonatology, Catholic University of Rome, Rome, Italy, who provided us with additional information regarding his study.

Ms Yolanda R Brosseau, Managing Editor, Cochrane Neonatal Review Group conducted the literature searches in 2012. She and Ms Colleen M Ovelman, Trials Search Co-ordinator and Webmaster, Cochrane Neonatal Review Group, conducted the literature searches in July 2013.

Contributions of authors

Sanjay M Aher (SMA) and Arne Ohlsson (AO) contributed equally to all sections of the protocol for this review. The literature search of databases 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; designed and agreed upon data collection forms; conducted quality assessments and abstracted and compared data independently. One review author (AO) entered the data into RevMan 5 and the other review author (SMA) checked for accuracy. One review author (AO) wrote the full review and the other review author (SMA) read and made changes. Both review authors made changes following feedback from the editors of the review group.

Sanjay M Aher (SMA) and Arne Ohlsson (AO) wrote the original review.

The February 2010 update was conducted centrally by the Cochrane Neonatal Review Group staff (Yolanda Montagne, Diane Haughton, and Roger Soll). That update was reviewed and approved by AO, who completed the 'Risk of bias' tables.

The 2012 update was conducted by AO and approved by SMA.

The current update in 2013 was conducted by both authors (SMA and AO).

Declarations of interest

  • None noted

Differences between protocol and review

In our objectives we state that neonates enrolled between eight and 28 days of age were to be included. In the studies that we identified some infants were less than 8 days at study entry and some were older than 28 days. When most of the enrolled infants were 8 days or older we included the studies in this Late EPO review and not in the Early EPO review. The inclusion of these studies makes our review more comprehensive. The age at enrolment is stated for each study in the table Characteristics of included studies. Hypertension was frequently reported by trial authors, and therefore it has been added as an outcome since the protocol was published.

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Characteristics of studies

Characteristics of included studies

Akisu 2001

Methods

Randomised controlled study, single centre, University of Ege, Izmir, Turkey

Study period: Not stated

Funding sources: Not stated

Declarations of interest: None reported

Participants

40 AGA preterm infants with GA < 33 weeks and birth weight < 1500 g were enrolled on day 10 of life

Interventions

Infants assigned to the treatment group (n = 20) received r-HuEPO (Recormon, Boehringer-Mannheim, Germany) sc 3 times per week, totaling 750 IU/kg/week (high dose)
20 infants were assigned to the control group with no placebo given
All infants received 3 mg/kg/day (low dose) of elemental iron
All infants received poly-vitamin supplements, vitamin D and folate

Outcomes

Exposure of a proportion of infants to one or more red blood cell transfusions

Notes

Unknown whether infants who had received blood transfusions prior to study entry were included or not
This study focused on lipid peroxidation and antioxidant enzyme activities in preterm infants
Guidelines for transfusion were not stated.

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

No information provided

Blinding (performance bias and detection bias) High risk

The control group did not receive a placebo

Incomplete outcome data (attrition bias) Low risk

Outcomes reported for all randomised infants

Selective reporting (reporting bias) Unclear risk

The protocol for the study was not available to us and therefore we can not ascertain if there were deviations from the protocol

Other bias Low risk

Appears free of other biases

Al-Kharfy 1996

Methods

A double-blind (sham-injection in the placebo group), randomised, control trial, single centre, Canada

Study period: March 1992 to May 1994

Funding sources: Supported by a grant from the Vancouver Foundation

Declarations of interest: None reported

Participants

55 preterm infants with birth weight < 1250 g, appropriate for GA, postnatal age 10 - 17 days, Hct less than 45% and a > 75% probability of having BPD, determined at 10 days of age by the predictive score of Sinkin et al. were included
Infants were randomly assigned, within 250 g birth weight strata and between 10 and 17 days of age
41 infants received the 6-week treatment schedule

Interventions

Infants assigned to the treatment group (n = 27) received r-HuEPO (Eprex, Ortho Pharmaceutical, Canada Ltd), in a dosage of 200 IU/kg body weight, by sc injection, on Monday, Wednesday and Friday for 6 weeks (600 IU/kg/week; high dose)
In control infants (n = 28), because of a desire to avoid repeated sc placebo injections, sham injections were given and an adhesive dressing was applied to the sham injection site. The care of the infant was then handed back to nursery personnel unaware of treatment assignment
Vitamin E (25 IU/day) and folic acid (0.05 mg/day) began when enteral feeding reached 50% of total fluid intake
Oral ferrous sulphate solution was administered to the treatment group at 6 mg of elemental iron/kg/day (high dose) and the control group received 2 mg of elemental iron/kg/day

Outcomes

Number of transfusions per infant
Mortality
Sepsis
ROP (stage = 3)
Hypertension
BPD (at 28 days)

Notes

Unclear whether infants who had received blood transfusions prior to study entry were included or not
This study exclusively enrolled those infants, who were predicted to have > 75% probability of having BPD and requiring multiple transfusions
All enrolled infants were included in the data analyses
Sham injections were given in the control group
Erythrocyte transfusions were in accordance with the guidelines developed by the Canadian Paediatric Society Fetus and Newborn Committee

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Low risk

Blinding of randomisation - yes (numbered sealed envelopes)

Blinding (performance bias and detection bias) Low risk

Sham-injection was given in the placebo group

Blinding of outcome measure assessment - yes

Incomplete outcome data (attrition bias) Low risk

Outcomes reported on all randomised infants

Selective reporting (reporting bias) Unclear risk

The protocol for the study was not available to us so we could not judge if there were deviations from the protocol

Other bias Low risk

Appears free of other bias

Atasay 2002

Methods

Prospective, randomised, placebo controlled trial, single centre, Turkey

Study period: October 1997 to February 1999

Funding sources: None stated

Declarations of interest: None reported

Participants

27 VLBW infants, with birth weight < 1500 g, GA < 32 weeks and postnatal age 7 - 10 days

Interventions

14 infants received 600 IU/kg/week (high dose) rHuEPO (Cilag AG Schafhausen, Switzerland), by sc route, at 7 - 10 days and continued over 7 - 8 weeks
13 infants were assigned to control group (no EPO or placebo)
Infants in the study group were supplemented with oral iron (ferroglycine sulphate) at the dose of 3 mg/kg/day (low dose)

Outcomes

Exposure of a proportion of infants to one or more red blood cell transfusions

Notes

Infants were enrolled at age 7 - 10 days. We decided to include this study in the late EPO systematic review, although some infants may have been < 8 days old at enrolment
Unknown if infants who had received blood transfusions prior to study entry were included or not
Transfusion guidelines were followed
The authors did not provide information on the mean age of the infants at enrolment
Strict transfusion criteria were used in this trial

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

No information provided

Blinding (performance bias and detection bias) Unclear risk

Blinding of intervention not stated
Blinding of outcome measure assessment not stated

Incomplete outcome data (attrition bias) Low risk

Outcomes reported for all randomised infants

Selective reporting (reporting bias) Unclear risk

The protocol for the study was not available to us so we could not judge if there were deviations from the protocol

Other bias Low risk

Appears free of other bias

Bader 1996

Methods

Randomised, controlled clinical trial, 2 centres, Israel,

Study period: January 1, 1992 to December 31, 1992

Funding sources: None stated

Declarations of interest: CILAG int. supplied rHuEPO

Participants

29 preterm infants (birth weight < 1750 g, GA < 34 weeks and postnatal age of 3 - 5 weeks, mean postnatal age 34 ± 14 days)

Interventions

15 infants received 300 IU/kg/day of rHuEPO (Eprex, Cilag Int.) sc to lateral aspect of right arm 3 times a week (900 IU/kg/week; high dose), for a total duration of 4 weeks
14 infants received no placebo or other intervention
All infants received enteral vitamin E (25 IU/day), vitamin A and D (400 and 1500 IU/day) and folic acid
Two weeks into the study elemental iron supplementation was begun in both groups at a dose of 6 mg/kg/day (high dose)

Outcomes

Exposure of a proportion of infants to one or more red blood cell transfusions
SIDS
Side effects

Notes

Unclear whether infants who had received blood transfusions prior to study entry were included or not
Criteria for blood transfusion were in place

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

No information provided - infants were randomly assigned

Blinding (performance bias and detection bias) High risk

Blinding of intervention - no; no placebo was used
Blinding of outcome measure assessment - no

Incomplete outcome data (attrition bias) Low risk

Outcomes reported on all randomised infants

Selective reporting (reporting bias) Unclear risk

The protocol for the study was not available to us so we could not judge if there were deviations from the protocol

Other bias Low risk

Appears free of other bias

Bechensteen 1993

Methods

Randomised, open, controlled study, 4 participating centres

Study period: Dates not reported

Funding sources: Cilag provided financial support and provision of Eprex

Declarations of interest: One of the authors (AGB) was a recipient of a research fellow-ship from the Norwegian Cancer Society. The financial support of Semper AB, Sweden was acknowledged for the preparation of freeze dried human milk protein

Participants

29 preterm infants (birth weight 900 - 1400 g, AGA) at 3 weeks of age

Interventions

14 infants received rHuEPO (Eprex, Cilag), 100 IU/kg 3 times a week (300 IU/kg/week; low dose) sc from 3 to 7 weeks of age
15 infants received neither EPO nor placebo
Oral iron 18 mg/day (high dose) regardless of weight, began at the start of the study (3 weeks). If serum iron concentration fell below 16 micromol/L, the dose was increased to 36 mg/day

Outcomes

Exposure of a proportion of infants to one or more red blood cell transfusions
Mortality
Hypertension
Neutropenia
Side effects

Notes

Infants receiving blood transfusions < 96 hours before start of study were excluded
Indications for blood transfusions were 1) Hb < 80 g/L or 2) at the discretion of the clinician caring for the infant according to symptoms and signs
This study concentrates more on different haematological parameters rather than the need for RBC transfusions

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Low risk

Prenumbered sealed envelopes were used

Blinding (performance bias and detection bias) High risk

Blinding of intervention - no
Blinding of outcome measure assessment -no

Incomplete outcome data (attrition bias) Low risk

Outcomes reported on all randomised infants

Selective reporting (reporting bias) Unclear risk

The protocol for the study was not available to us so we could not judge if there were deviations from the protocol

Other bias Low risk

Appears free of other bias

Bierer 2009

Methods

Randomised, placebo controlled study, 1 centre, the USA

Study period: August 2001 to May 2005

Funding sources: Supported by grants from national Institues of Health HD00988 and M01 RR 00997

Declarations of interest: None reported

Participants

20 infants; 10 infants in the EPO group (BW (SEM) 2034 ± 308 g, 8 ± 2 days old); 10 infants in the placebo group (BW (SEM) 2400 ±184 g, 7 ±2 days old)

Interventions

The EPO group received EPO 200 IU/kg per day or 400 IU/kg sc 3 times weekly (high dose). The placebo group received an equal volume of normal saline if the infant was on total parenteral nutrition and if not a sham dose was given sc and a BandAid was placed over the sham injection site. Infants received oral iron supplementation (dose not specified) when enteral feeds reached 60 mL/kg/day. Dosing continued until the infant reached study day 14 unless the infant was discharged from the hospital or died before the end of the study period.

Outcomes

Volume transfused during hospitalisation (mL/kg)

Number of transfusion per infant

Number of donors the infants was exposed to

Notes

We included this study in our Late EPO review as most infants would have been > 7 days and would have weighed < 2500g on study entry.

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

A random number list was used.

Allocation concealment (selection bias) Low risk

EPO or placebo was dispensed from the pharmacy in total parenteral nutrition iv administration or in syringes for sc dosing. If iv access was not present, EPO was administered sc. For infants randomised to receive placebo, iv administration consisted of TPN with placebo (an equal volume of normal saline) added, whereas sc administration consisted of sham dosing, followed by placement of a BandAid over the sham injection site

Blinding (performance bias and detection bias) Low risk

Outcome data reported for all randomised infants

Incomplete outcome data (attrition bias) Unclear risk
Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Chen 1995

Methods

Randomised, controlled clinical trial, single centre, Taiwan, Republic of China

Study period: June 1992 to May 1994

Funding sources: None reported

Declarations of interest: none reported

Participants

67 preterm infants (birth weight less than/or equal to 1750 g and GA less than/or equal to 33 weeks
Mean age at entry Group A 22.3 ± 6.6 days; Group C 22.3 ± 6.6. days

Interventions

26 infants (Group A) received rHuEPO (Eprex, Cilag Zug, Switzerland) 150 mg/kg iv twice a week (300 IU/kg/week; low dose) for 4 weeks
25 infants (Group B) received packed washed erythrocyte transfusion, 10 to 15 mL/kg, during a 2 - 4 hour period when their Hb levels were less than 10 g/dL with signs and symptoms attributed to anaemia or who had a Hb level less than 8 g/dL even if asymptomatic.
16 infants (Group C) did not receive rHuEPO or erythrocyte transfusions (3 infants excluded from total 19, as they received erythrocyte transfusion later because of frequent episodes of apnoea)
All infants received oral elemental iron 3 mg/kg/day (low dose) and vitamin E 5 mg/kg/d

Outcomes

Mortality
Side effects

Notes

Unknown whether infants who had received blood transfusions prior to study entry were included or not
Strict guidelines for transfusions were not in place (transfusions were given based on frequent episodes of apnoea)
We compared Groups A and C based on intention-to-treat in this systematic review

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

No information provided

Blinding (performance bias and detection bias) High risk

Blinding of intervention - no
Blinding of outcome measurement - no

Incomplete outcome data (attrition bias) Low risk

Outcomes reported for all randomised infants

Selective reporting (reporting bias) Low risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other sources of bias

Corona 1998

Methods

Randomised, controlled clinical trial, single centre, Italy

Study period: Not reported

Funding sources: None reported

Declarations of interest: None reported

Participants

60 preterm infants (birth weight < 1500 g and < 33 weeks GA)
Postnatal age (days) group A 10.1 ± 2; group B 9.5 ± 3; Group C 9.8 ± 2

Interventions

20 infants (group A) received rHuEPO (unnamed product) 150 IU/kg/week sc (low dose)
22 infants (group B) received 300 IU/kg/week sc
18 infants (group C) received no treatment
All groups received oral iron 4 mg/kg/day

Outcomes

Exposure of a proportion of infants to one or more red blood cell transfusions
Total volume (mL/kg) of blood transfused per infant (no SD provided)
Side effects

Notes

Unknown whether infants who had received blood transfusions prior to study entry were included or not
Infants were included after the first week of life the mean (SD) postnatal age was 10.1 (2) days in group A; 9.5 (3) in group B and 9.8 (2) in group C
Some infants my have been < 8 days old, but we included this study in the Late EPO review as most infants were greater than/or equal to 8 days
Transfusion guidelines were in place

We combined the two groups of infants that received EPO (n = 42) and compared that combined group to the group (n = 18 infants) that did not receive any treatment

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

No information provided - infants were divided into 3 groups

Blinding (performance bias and detection bias) High risk

Blinding of intervention - no
Blinding of outcome measurement - no

Incomplete outcome data (attrition bias) Low risk

Outcomes reported for all randomised infants

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Donato 1996

Methods

Prospective, randomised, placebo-controlled trial, single centre

Study period: Argentina, July 1991 to June 1993

Funding sources: This work was supported by Bio Sidus S.A.

Declarations of interest: See funding resources

Participants

32 preterm infants with GA < 34 weeks and birth weight < 1500 g
Age at enrolment was 21 to 35 days of life
Mean postnatal age at enrolment (days) group A. 27.0 ± 3.2; Group B 27.6 ± 3.6; Group C 29.7 ± 5.8; Group D 32.1 ± 7.7

Interventions

32 preterm infants were randomly assigned to receive:
1. Group A (n = 9) placebo (human seroalbumin) sc
2. Group B (n = 8) rHuEPO (HEMAX, Bio Sidus, S.A.) at dose of 50 IU/kg sc (150 IU/kg/week; low dose)
3. Group C (n = 8) rHuEPO at dose of 100 IU/kg sc (300 IU/kg/week; low dose)
4. Group D (n = 7) rHuEPO at dose of 250 IU/kg sc (750 IU/kg/week; high dose), sc 3 days per week during 8 consecutive weeks
All infants were given oral iron 6 mg/kg/day (high dose) and folic acid (2 mg/day) supplements, starting on day 15 of age and continuing during whole treatment period

Outcomes

Exposure of a proportion of infants to one or more red blood cell transfusions

Average number of transfusions per infant during treatment
Mortality
Mean length of hospitalisation (days)
Side effects

Hypertension

SIDS

Notes

Transfusion criteria were followed in this study

We combined the results for the three EPO groups (Group B, Group C and Group D; total n = 23) regardless whether high or low dose of EPO was used and compared to the results for the placebo group (Group A; n = 9). In separate analyses we compared the low dose EPO groups (Group B; n = 8 and group C; n = 8) to the placebo group (Group A) and the high dose EPO group (Group D; n = 7) to the placebo group (Group A; n = 9). All infants were given high dose of iron.

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

No information provided - "randomly assigned"

Blinding (performance bias and detection bias) Low risk

Blinding of intervention - yes - placebo-controlled
Blinding of outcome measure assessment - yes

Incomplete outcome data (attrition bias) Low risk

Outcomes reported on all randomised infants

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Emmerson 1993

Methods

Randomised, double-blind, placebo-controlled trial, 1 centre in the UK

Study period: Not stated

Funding sources: This study was supported by Cilag Ltd.

Declarations of interest: See founding sources

Participants

24 infants with GA between 27 and 33 weeks
Postnatal age > 7 days
Mean (SE) age (days) at first dose; EPO group 9 (0.4); Placebo group 8 (0.6)
One infant in the EPO group was withdrawn at 14 days of age to enable transfer to another hospital for maternal reasons

Interventions

16 infants were randomly assigned to receive r-HuEpo sc (Eprex, Cilag, Ltd). The first 9 infants received 50 IU/Kg of EPO, the next 9 infants received 100 IU/kg, and the final 6 infants received 150 IU/kg of r-HuEpo or placebo (4% albumin) twice a week sc after 7 days of age twice weekly sc 300 IU/kg/week (low dose) into the buttock commencing after 7 days of age and administered until the infant was discharged home. All infants received iron (6.25 mg) in the form of ferrous glycine sulphate from four weeks of age (high dose).

Outcomes

Exposure of a proportion of infants to one or more red blood cell transfusions

Volume transfused (mL/kg)

Mortality

Hospital stay

SIDS

Neutropenia

Notes

Transfusion guidelines were followed
Unknown if infants who had received transfusions prior to study entry were included or not
One infant in the EPO group was withdrawn at 14 days of age to enable transfer to another hospital for maternal reasons and was not included in the analyses

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

No information provided

Blinding (performance bias and detection bias) Low risk

Blinding of intervention - yes - placebo-controlled
Blinding of outcome measure assessment - yes

Incomplete outcome data (attrition bias) Low risk

Outcomes reported on all randomised infants

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Giannakopoulou 1998a

Methods

Randomised controlled trial, single centre, Greece,

Study period: Period not stated

Funding sources: None reported

Declarations of interest: None stated

Participants

36 preterm infants with birth weights 1000 - 1300 g,
32 preterm infants with birth weight < 1000 g
Postnatal age > 20 days
divided into 4 groups
Groups 1 and 3 were controls and Groups 2 and 4 were treatment groups
one infant in Group 2 died and one infant from Group 1 was excluded because of severe infection

Interventions

24 infants received rHuEPO (Eprex, Cilag, Schafhausen, Switzerland) from day 20 of life sc at a dose of 300 IU/kg body weight, 3 times a week (900 IU/kg/week; high dose) for 6 - 8 weeks (n = 24)
24 control infants did not received any treatment.
All received oral elemental iron 10 mg/kg/day (high dose), folic acid 1 mg/day and vitamin E 15 mg/day

Outcomes

Mortality
Hypertension
Neutropenia
Side effects

Notes

Unknown whether infants who had received blood transfusions prior to study entry were included or not
Guidelines for blood transfusions were in place
Under Giannakopoulou 1998a we report on the 32 infants weighing < 1000 g

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

No information provided

Blinding (performance bias and detection bias) High risk

Blinding of intervention - no
Blinding of outcome measures - no

Incomplete outcome data (attrition bias) Low risk

Outcomes reported for all randomised infants

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Giannakopoulou 1998b

Methods

See above

Participants

See above

Interventions

See above

Outcomes

See above

Notes

Under Giannakopoulou 1998b we report on the 36 infants weighing 1000 - 1300 g

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

No information provided

Blinding (performance bias and detection bias) High risk

Blinding of intervention - no
Blinding of outcome measures - no

Incomplete outcome data (attrition bias) Low risk

Outcomes reported for all randomised infants

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Griffiths 1997

Methods

A multi centre, randomised, placebo-controlled, double-blind study, 4 NICUs in Yorkshire, the UK

Study period: June 1993 - December 1994

Funding sources: One of the authors (GG) was funded by the Yorkshire Regional health Authority

Declarations of interest: None reported

Participants

43 preterm infants with GA < 32 weeks and/or birth weight < 1500 g, requirement for mechanical ventilation and/or supplemental oxygen on day 7 to 14 after birth

Interventions

21 infants received R-HuEpo (Eprex; Cilag UK) EPO 480 IU/kg/week (low dose) sc and 21 infants received placebo (4% human albumin) sc
The first injection was given on the day of randomisation, and then twice weekly until the infant either (a) reached 40 weeks PMA, (b) was transferred to another hospital (not in the study), (c) did not require any mechanical ventilation/oxygen for a period of more than a week, (d) had local adverse reactions/complications related to the trial solution, or (e) had PCV > 60%. All infants received oral iron (3.0 mL/kg/day) (low dose) from 4 week after birth.

Outcomes

Mortality, BPD (at 36 weeks PMA)

SIDS
Median number of blood transfusions

Notes

Infants who received blood transfusions prior to study entry were not excluded
Transfusion guidelines were in place
One infant who received treatment was ineligible and was subsequently withdrawn and excluded from the analysis

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Low risk

Stratified randomisation was used. Blinding was maintained throughout the study

Blinding (performance bias and detection bias) Low risk

Blinding of intervention yes
Blinding of outcome measure assessment - yes

Incomplete outcome data (attrition bias) Low risk

Outcomes reported on all randomised infants except 1 infant who received treatment but was ineligible and was subsequently withdrawn and excluded from the analysis

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Javier Manchon 1997

Methods

A multi centre, randomised, controlled study, 3 centres in Barcelona, Spain

Study period: Not stated

Funding sources: None reported

Declarations of interest: none reported

Participants

Population: Preterm infants < 34 weeks GA, who at 28 days after birth had haemoglobin levels < 10.5 g/dL

Interventions

15 infants received 200 IU EPO/kg sc (unnamed product) 3 days a week for 4 weeks (600 IU/kg/week; high dose) and ferrous sulphate 4 mg/kg/day (low dose)
13 control infants did not receive placebo, EPO or iron

Outcomes

Exposure of a proportion of infants to one or more red blood cell transfusions between 30 and 60 days of age

Notes

Infants were included if they had received blood transfusions prior to randomisation
Transfusion guidelines were similar in all 3 centres (details not provided)

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

No information provided

Blinding (performance bias and detection bias) High risk

Blinding of intervention - no
Blinding of outcome measure assessment - no

Incomplete outcome data (attrition bias) Low risk

Outcomes reported on all randomised infants

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Juul 2003

Methods

A prospective, blinded, placebo-controlled study, single centre, USA

Study period: Period not stated

Funding sources: Supported by the National Institues of health, grants M01-RR-00037 and RR00082

Declarations of interest: None reported

Participants

36 preterm infants with birth weight between 700 to 1500 g and receiving at least 30 mL/kg per day of enteral feeding. 32 infants completed the study
The mean (SD) GA (weeks) at birth was 27.8 ± 1.8 in the EPO group and 28.8 ± 2.1 in the placebo group
Mean (SD) corrected GA (weeks) at study entry was 31.6 ± 2.0 in the EPO group and 31.9 ± 1.6 in the placebo group

Infants in the EPO group ranged from 2 to 8 weeks postnatal age at study entry (with a median of 4 weeks), whereas placebo-treated infants ranged from 1 to 7.4weeks postnatal age (with a median of 2 weeks). Overall, the median age at study entry was 2.8 weeks of age.

Interventions

15 infants received rEpo (unnamed product) 1000 IU/kg per day divided into 2 daily feedings (7000 IU/kg/week; high dose), for 14 days.
17 infants received placebo (D5W) for 14 days.
All subjects received supplemental iron (iron dextran, 1.0 mg/kg/day administered in the hyperalimentation solution, or enteral ferrous sulphate 6 mg/kg per day (high dose))

Outcomes

Phlebotomy loss (mL) and PRBC transfusion volume (mL)
Evidence of feeding intolerance and other adverse effects

Notes

This is the only study which used oral EPO
The results of this study are not included in the meta-analyses

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

No information provided

Blinding (performance bias and detection bias) Low risk

Blinding of intervention - yes
Blinding of outcome measure assessment - yes

Incomplete outcome data (attrition bias) High risk

Information on 4 infants is missing. 36 infants were enrolled and 32 completed the study

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Kivivuori 1999

Methods

An open randomised study, four centres; three in Helsinki and one in Espoo, Finland

Study period: Not stated

Funding sources: None reported

Declarations of interest: Cilag A.G. supplied the erythropoietin and Vifor International supplied parenteral iron preparation

Participants

45 VLBW infants (4 excluded - see notes)
41 infants included
Birthweight ranged from 625 - 1470 g
The infants were randomised to 3 groups
One group (n = 14) received rHuEPO and oral iron (mean GA 30.1 ± 0.7 weeks), one group (n = 14) received rHuEPO and im iron ( mean GA 28.8 ± 0.5 weeks), one group (n = 13) received no rHuEPO and im iron (mean GA 29.1 ± 0.6 weeks)
Infants who were weaned from the respirator by 2 weeks of age were eligible

Interventions

14 infants received rHuEPO (Cilag A.G., Schafhausen, Switzerland) 300 IU/kg sc 3 times/week, 900 IU/kg/week (high dose) sc and oral iron 6 mg/kg/day (high dose)
14 infants received 900 IU/kg/week of rhuEPO and weekly im iron 12 mg/kg (high dose)
13 infants received im iron 12 mg/kg/week but no rHuEPO

Outcomes

Exposure of a proportion of infants to one or more red blood cell transfusions
Side effects

Notes

Unknown whether infants who had received blood transfusion prior to study entry were included or not
4 infants were excluded after randomisation; 1 weighed > 1500 g, 1 had intestinal "obstipation", 1 had highly elevated serum transferrin saturation (96%), 1 accidentally received a high dose of parenteral iron (43 mg/kg)
We include the infants in the im iron group in the high-dose iron analyses
The transfusion policies (not stated) were the same in all hospitals

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

No information provided

Blinding (performance bias and detection bias) High risk

Blinding of intervention - no; open randomised study
Blinding of outcome measure assessment - no

Incomplete outcome data (attrition bias) High risk

Complete follow-up - no; 4 infants were excluded after randomisation (see above)

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Kumar 1998

Methods

Randomised, double-blind, placebo- controlled trial, single centre, USA

Study period: Period not stated

Funding sources: None reported

Declarations of interest: None reported

Participants

30 infants (GA < 32 weeks, birth weight < 1250 g with anaemia of prematurity)
Mean (SD) postnatal age (days) at entry was 40.3 (20.4) in the EPO group and 36.5 (16.6) in the placebo group)

Interventions

300 IU/kg/dose of rHuEPO (unnamed product) sc injection twice a week (600 IU/kg/week; high dose) for 6 weeks (n = 15)
Identical volume of placebo suspension (normal saline) (n = 15)
Infants received elemental iron 6 mg/kg/d (high dose)

Outcomes

Exposure of a proportion of infants to one or more red blood cell transfusions
Number of erythrocyte transfusions (per infant)
Entry to discharge duration (days)
Side effects

Notes

Infants who had received transfusions prior to randomisation were included
Transfusion guidelines were followed

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

No information provided; infants were randomly assigned

Blinding (performance bias and detection bias) Low risk

Blinding of intervention - yes
Blinding of outcome measure assessment - yes

Incomplete outcome data (attrition bias) Low risk

Outcomes reported for all infants randomised

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Maier 2002

Methods

Randomised controlled study, 14 centres in four European countries (Belgium, France, Germany, Switzerland)

Study period: May 1998 to June 1999

Funding sources: The study was supported by F. Hoffman-La Roche, Basel, Switzerland

Declarations of interest: One of the authors (FG) was employed by F. Hoffman-La Roche

Participants

148 infants with BW 500 - 999 g
Exclusion criteria: cyanotic heart disease, major congenital malformation requiring surgery, administration of investigational drug during pregnancy, GA greater than/or equal to 30 completed weeks
The early EPO group started treatment at 3 - 5 days of age and the late EPO group 3 weeks later (at 24 to 26 days of age)

Interventions

Infants were randomised to 3 groups (see notes for the control group). In the early EPO group 74 infants (median and quartiles for GA; 26 (25 to 28) weeks for BW 778 (660, 880) g) received 250 IU/kg iv or sc of rHuEPO on Mondays, Wednesdays and Fridays (NeoRecormon, F. Hofman-La Roche, Basel Switzerland) (750 IU/week iv or sc, high dose) starting at days 3 - 5 of life.
In the late EPO group 74 infants received the same treatment 3 weeks later
Treatment in both groups continued until days 65 to 68 of life. rHEPO was given iv in both groups as long as the infant had an iv line in place and sc thereafter. The late EPO group received sham injections until EPO was given.
Enteral iron 3 mg/kg/day was given to all infants from days 3 - 5 and was increased at days 12 - 14 to 6 mg/kg/day and to 9 mg/kg/day at days 24 - 26 of life (high dose)

A third group (control group, n =71) was included in this trial.

Outcomes

Exposure of a proportion of infants to one or more red blood cell transfusions
Donor exposure
Mortality during hospital stay
NEC
IVH
PVL
ROP
Days in oxygen
Days in NICU
Days in hospital

Notes

Sample size calculation was performed
Transfusion guidelines were followed
Industry funded (F. Hoffman-La Roche, Basel Switzerland)
24 (32%) of the infants in the early EPO group and 23 (31%) in the late EPO group received 1 - 3 transfusions before they entered the study.
A third group (control group, n =71) was included in this trial. One infant in the control group was excluded from all evaluations because the parents withdrew consent a few hours after randomisation before the start of the treatment phase.

We compared the late EPO group (n = 74) to the control group (n = 71).

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Low risk

Numbered sealed envelopes

Blinding (performance bias and detection bias) Low risk

Blinding of intervention - yes
Blinding of outcome-measure assessment - yes

Incomplete outcome data (attrition bias) Low risk

One infant in the control group was excluded from all evaluations because the parents withdrew consent a few hours after randomisation before the start of the treatment phase.

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Meyer 1994

Methods

Randomised, double-blind, placebo-controlled study, single centre, South Africa

Study period: Not stated

Funding sources: Funding for the study was obtained from Janssen's Pharmaceutica

Declarations of interest: See funding resources

Participants

80 preterm infants (< 32 weeks GA, birth weight < 1500 g, postnatal age 2 to 8 weeks.

Interventions

40 infants received rHuEPO (Eprex) sc 3 times a week at a dose of 200 IU/kg/dose (600 IU/kg/week, high dose). The volume was increased by the equivalent of 50 IU/kg per dose if the Hct declined by 6% during any 2-week period during the trial, but was withheld if the Hct was > 45%.
40 infants received an identical volume of placebo
Infants received 3 mg/kg/day of iron (low dose)

Outcomes

Exposure of a proportion of infants to one or more red blood cell transfusions
Sepsis
NEC
SIDS

Notes

Previous blood transfusion was not an exclusion criterion
Transfusion guidelines were followed

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

A computerised random numbers generator was used

Allocation concealment (selection bias) Unclear risk

No information provided

Blinding (performance bias and detection bias) Low risk

Blinding of intervention - yes
Blinding of outcome measure assessment - yes

Incomplete outcome data (attrition bias) Low risk

Three infants were early withdrawals from the trial. One infant in the placebo group completed 4 days in the trial before features of necrotizing enterocolitis became apparent. The infant died one week later; the entry data were included in the analysis. A second infant from the placebo group completed 39 days in the study before dying from intraventricular haemorrhage associated with a previous ventriculoperitoneal shunt. One infant in the treatment group developed group B streptococcal septicaemia and meningitis at the age of 30 days; the symptoms began on day 19 of the study. The infant subsequently died of complications at one year of age. The observations obtained for the last 2 infants up to the time of the intercurrent event were included in the results.

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Pollak 2001

Methods

Randomised, unmasked, controlled study, single centre study conducted in Vienna, Austria

Study period: August 1995 to May 1997

Funding sources: The study was supported by the March and Dimes Birth defects Foundation (Grant FY 95-0220); by Vifor International, St Gallen, Switzerland; by Janssen-Cilag Pharma, Vienna, Austria, by the Verein zur Förderung der wissenschaftlichen Forschung auf dem Gebiet der Neonatologie und Kinderintenzivmedicin; and by the red Bull Company, Salzburg, Austria

Declarations of interest: See funding resources

Participants

38 preterm infants with GA < 31 weeks and weight < 1300 g at birth.
Infants who had received red blood cell transfusions 3 days before study entry or during the study were excluded. 9 infants were disqualified (see 'Notes'). Age at entry > 7 days

Interventions

The 21-day study consisted of a 3-day run-in baseline period during which 9 mg/kg/day of iron poly maltose complex (IPC; Ferrum Hausmann Syrup, Vifor International, St Gallen, Switzerland) supplementation was administered to all participants in all groups. This was followed by an 18-day treatment period during which participants received: 1) the same oral iron supplementation dose alone (oral iron group, n = 9); 2) 300 IU/kg/day (> 600 IU/kg/week; high dose) of r-HuEPO (Erypo, Janssen-Cilag Pharma, Vienna, Austria) as an iv bolus infusion administered at 3-day intervals along with the same oral iron supplement as the oral iron group (EPO + oral iron group, n = 10); or 3) 2 mg of iv iron sucrose/kg/day (Venofer, Vifor International) diluted in 0.9% of sodium chloride to a final concentration of 2 mg/mL and infused daily over 2 hours (iv iron + EPO group, n = 10). To maintain comparability of iron intake among the 3 groups, this last group also received EPO and oral iron in an identical manner as the EPO + oral iron group

Outcomes

Mortality

Sepsis

BPD at 36 weeks

ROP (stage not provided)
Hospital stay

Notes

Transfusion guide lines were in place
Of the 38 study participants who began the study, 9 were disqualified during the treatment period (3 infants with sepsis or sepsis-like episodes, 2 with NEC, 2 who received blood transfusions, and 2 for a protocol violation)

In a secondary analysis a diagnostic nomogram was used by Kasper et al to characterise and differentiate iron status in anaemic very low birth weight infants (Pollak 2001). In this secondary study no outcomes of interest for this review were included.

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Low risk

Randomisation was performed by drawing sequentially numbered sealed envelopes in blocks of 6 for each stratification group

Blinding (performance bias and detection bias) High risk

Unmasked trial

Incomplete outcome data (attrition bias) Low risk

Of the 38 study participants who began the study, 9 were disqualified during the treatment period (see above)

Disqualified infants were replaced by the next eligible infant in the stratification group

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Reiter 2005

Methods

Randomised, controlled study, single centre, the USA

Study period: Not stated

Funding sources: Supported by Grant Number M01 RR000069 General Clinical Research Centers Program National Centers for Research Resources NIH

Declarations of interest: No conflict of interests with any of the authors

Participants

60 preterm infants with GA at birth < 32 week, Hct less than/or equal to 28%, < 48 weeks conceptual age or 5 months chronological age

Interventions

30 infants received EPO (Eogen alpha, Amgen Inc., Thousand Oaks, CA) at 300 IU/kg per day sc for 10 days (2100 IU/kg/week; high dose) and oral elemental iron at 6 mg/kg/day (high dose). The control group (n = 30) received only supplemental iron in the same dose. 7 infants in the EPO group and 5 in the control group had received EPO prior to study entry.

Outcomes

Exposure of a proportion of infants to one or more red blood cell transfusions
Volume of red blood cells transfused (mL/kg)

Notes

Transfusion guidelines were in place and followed

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

It is uncertain whether there was concealed allocation to the two study groups (A clinical research nurse assigned infants to a study group using a random number table)

Allocation concealment (selection bias) Unclear risk

A clinical research nurse assigned infants to a study group using a random number table

Blinding (performance bias and detection bias) High risk

There was no placebo

Incomplete outcome data (attrition bias) Low risk

Three infants were withdrawn from the initial data analysis: 1 from the EPO group and 2 from the control group because post-treatment laboratory variables were not obtained

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Rocha 2001

Methods

Randomised, controlled study, single centre study in Brazil

Study period: March 1995 to December 1996

Funding sources: None reported

Declarations of interest: None reported

Participants

45 preterm infants with GA less than/or equal to 33 weeks, BW less than/or equal to 1550 g, postnatal age 10 - 35 days

Interventions

In Group 1) 15 infants received daily doses of 100 IU/kg of EPO sc (unnamed product) (700 IU/kg/week - high dose); in Group 2) 15 infants received 350 IU/kg of EPO sc twice weekly (700 IU/kg/week - high dose); in Group 3) 15 infants did not receive EPO
Groups 1 and 2 were given iron (ferrous sulphate) 3 mg/kg/day enterally and was increased to 6 mg/kg/day in the second week of treatment
In Group 3 iron supplementation was initiated around the 30th day of life

Outcomes

Short-term side effects
Mean number of blood transfusions per infant, but no SD provided
Excessive blood transfusions defined as greater than/or equal to 2 blood transfusions per infant (This was not an outcome identified in our protocol)

Notes

Although stated to be a randomised controlled trial in the abstract this is uncertain as in the text the authors write:"...each of the patients was systematically placed into on of the three existing groups...". Three infants (one from group 2 and two from group 3) were not included due to intercurrent diseases (2 cases of severe sepsis and one case of necrotizing enterocolitis). The authors do not state in which groups the specific diseases occurred.
The name of the manufacturer of EPO was not provided
"Data collection was interrupted after a sample size calculation revealed that the number of patients studied so far would have to be at least doubled in order to obtain a statistical difference between the two groups of preterm infants who used EPO in different posology"
The authors were satisfied when "a statistical difference regarding excessive blood transfusions was found between the two treated groups and the control group"
It is unknown whether infants who had received blood transfusions prior to study entry were included or not
Transfusion guidelines were followed

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

"...each of the patients were systematically placed in one of the three existing groups" (for groups see interventions above)

Blinding (performance bias and detection bias) High risk

No placebo was used

Incomplete outcome data (attrition bias) Low risk

Three infants (one from group 2 and two from group 3) were not included due to intercurrent diseases (2 cases of severe sepsis and one case of necrotizing enterocolitis)

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias High risk

We have serious concerns about possible 'other bias' as noted under 'Notes' above.

Romagnoli 2000

Methods

Randomised, double-blind, controlled clinical trial, single centre, Rome Italy, 3-year period ending December 1998

Participants

230 infants with gestational age < 30 weeks and 31 - 34 weeks with RDS and requiring mechanical ventilation. Infants were 7 days old, when randomised

Study period: Not reported

Funding sources: None reported

Declarations of interest: None declared

Interventions

115 infants received EPO (unnamed product) 300 IU/kg sc, 3 times a week (900 IU/kg/week, high dose) from the 2nd to the 7th week and iron 1 mg/kg/day iv (high dose)
115 infants did not receive EPO, placebo or iron

Outcomes

Use of one or more red blood cell transfusions
Number of blood transfusions per infant
ROP (all stages, stages 1 - 2, 3 - 4, and the need for cryotherapy)
NEC
IVH > grade III - IV
Chronic lung disease at 28 days
Sepsis

Notes

It is not stated whether infants who had received blood transfusions prior to study entry were included
Protocol was used to administer transfusions during study period. We obtained information from Dr Romagnoli stating that the mean (SD) age when the treatment started was 10 (± 1) days. We therefore moved this study from the Early EPO to the Late EPO review

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Random number

Allocation concealment (selection bias) Low risk

Opening of numbered, sealed envelopes, on the 7th day of life

Blinding (performance bias and detection bias) High risk

Blinding of intervention: no

Blinding of outcome-measure assessment: no (the outcome of ROP was)

Incomplete outcome data (attrition bias) Low risk

Complete follow-up: yes

Selective reporting (reporting bias) Unclear risk

The protocol for the study was not available to us and therefore we can not ascertain if there were deviations from the protocol. This study was reported as a 'Research letter' format allowing for a limited number of details

Other bias Unclear risk

This study was reported in a 'Research letter' format allowing only for few details. We obtained information from the Editorial office of the European Journal of Pediatrics, that 'Research letters' are peer-reviewed.

Ronnestad 1995

Methods

Randomised, double-blind, placebo-controlled trial, single Centre, Norway

Study period: Period not stated

Funding sources: The study was financially supported by the National Public Health Society

Declarations of interest: Recombinant human erythropoietin was provided by Cilag, Norway

Participants

24 preterm infants, < 32 weeks, between 14 and 22 days of age

Interventions

24 preterm infants were randomly assigned, to receive sc either rHuEPO (Eprex, Cilag) (n = 12) 150 IU/kg 3 times per week (450 IU/kg/week; low dose) or placebo (n = 12). Treatment was started between day 14 and 22 and continued for 6 weeks or alternatively until haemoglobin concentration exceeded 13.0 g/100 mL after 4 weeks of treatment.
All infants were fed their own mother's milk 150 - 180 mL/kg/day, supplemented with a bovine milk protein and electrolyte fortifier. Additionally, they received vitamin E 25 mg/kg/day, a multivitamin formula (Multibionata) 0.5 mL/day and folic acid 100 mcg/day
Iron supplementation 4 mg/kg/day (low dose) as ferrous fumarase was started at study entry

Outcomes

Neutropenia

Notes
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

No information provided - infants were randomly assigned

Blinding (performance bias and detection bias) Low risk

Blinding of intervention - yes; a placebo-treated group was in place
Blinding of outcome measure assessment - yes

Incomplete outcome data (attrition bias) Low risk

Outcomes reported on all randomised infants

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Samanci 1996

Methods

Randomised, double-blind, controlled clinical trial, single centre, University of Istanbul, Turkey

Study period: September 1993 to March 1994

Funding sources: None reported

Declarations of interest: Recombinant human erythropoietin was manufactured by Cilag AG, Switzerland and provided by Güler Pharmaceutical Corp, Instanbul, Turkey

Participants

24 preterm infants with GA less than/or equal to 32 weeks, birth weight of less than/or equal to 1250 g and postnatal age at the first dose was 2 - 4 weeks.

Interventions

12 infants received r-HuEPO (Cilag AG, Switzerland, provided by Guler Pharmaceutical Corp, Istanbul, Turkey) at a dose of 200 IU/kg, sc, 3 times weekly (600 IU/kg/week, high dose), for 4 weeks.
12 infants received an equivalent volume of placebo sc, 3 times weekly, for 4 weeks
All infants received oral supplements of elemental iron (3 mg/kg/day) (low dose) and vitamin E, 25 IU/day, during the study period

Outcomes

Exposure of a proportion of infants to one or more red blood cell transfusions
Number of blood transfusions per infant
IVH

NEC
Side effects

Notes

Infants who received erythrocyte transfusions before study entry were excluded
Guidelines for erythrocyte transfusions were developed and followed

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

A random number table was used

Allocation concealment (selection bias) Unclear risk

No information provided

Blinding (performance bias and detection bias) Low risk

A placebo was used

Incomplete outcome data (attrition bias) Low risk

Outcomes reported on all infants randomised

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Shannon 1991

Methods

Multicentre, randomised, double-blind, controlled clinical trial, 3 centres, USA,

Study period: Study period not stated

Funding sources: Supported by a grant from the R. W. Johnson Pharmaceutical Research Institute, and by grants from the National Institues of Health (DK 32094 and M01RR01271, Pediatric Clinical Research Center)

Declarations of interest: None reported

Participants

20 preterm infants, including 2 pairs of twins
Participants were stratified at entry into 2 groups: a) "large" (birth weight 901 to 1250 g) and b) "small" (birth weight less than/or equal to 900 g)
10 small and 10 large babies were entered into the trial
Within these two subgroups 5 infants each were randomly assigned to receive either r-HuEPO or placebo
Postnatal age 10 to 35 days

Interventions

10 infants received iv injections of r-HuEPO (Amgen) at a dose of 100 IU/kg, twice each week (200 IU/kg/week; low dose) for 6 weeks.
10 infants received iv injections of identical volume of placebo twice each week for 6 weeks.
All infants received 3 mg/kg/day of oral iron (low dose) and continued at the discretion of the attending physician.
All infants received supplemental vitamin E (5 IU/day).

Outcomes

Exposure of a proportion of infants to one or more red blood cell transfusions
Mortality
NEC
Hypertension
Neutropenia
Side effects

Notes

Unknown whether infants who had received transfusions prior to randomisation were included or not
Infants with more complicated courses had large amounts of blood removed for laboratory tests
Transfusions were administered at the discretion of the attending physician

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

No information provided; infants were randomly assigned

Blinding (performance bias and detection bias) Low risk

A placebo was used

Incomplete outcome data (attrition bias) Low risk

Outcomes reported for all infants randomised

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Shannon 1992

Methods

A double-blind, randomised, pilot study, single centre, USA

Study period: October to December 1991

Funding sources: Supported by a grant from the R. W. Johnson Pharmaceutical Research Institute, and by grants from the National Institues of Health (DK 32094 and M01RR01271, Pediatric Clinical Research Center)

Declarations of interest: None reported

Participants

8 preterm infants with GA < 33 weeks and birth weight <1250 g
Postnatal age (range) 8 - 28 days

Interventions

4 infants received sc injections of r-HuEPO (unnamed product) at a dose of 100 IU/kg, 5 times a week (500 IU/kg/week; high dose)
4 infants received identical volume of placebo suspension, 5 times a week.
Oral iron was started in all infants at 3 mg/kg/day (low dose), divided in 3 doses and given between feedings
The iron dose was increased to 6 mg/kg/day for infants who were tolerating full caloric feedings
Infants also received 1 mL/day of multivitamins and vitamin E (15 IU per day

Outcomes

Exposure of a proportion of infants to one or more red blood cell transfusions
Major adverse events

Notes

This was a pilot study
Unclear if infants were included if they had received transfusions prior to randomisation
Guidelines for red blood cell transfusions were in place

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

No information provided; infants were randomly assigned

Blinding (performance bias and detection bias) Low risk

An identical-looking placebo was used

Incomplete outcome data (attrition bias) Low risk

Outcomes reported on all infants randomised

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Shannon 1995

Methods

Multicentre, randomised, double-blind, controlled clinical trial, 11 centres, USA

Study period: October 1991 to October 1993

Funding sources: This work was supported, in part, by the R.W. Johnson Pharmaceutical Research Institute. Additional support was provided by Clinical Research Center grants from the National Institutes of Health to the University of California, San Francisco (Grant M01-RR-01271), to Yale University (Grant M01-RR-06022), to the University of Iowa (Grant M01-RR-00059), to the University of New Mexico (Grant M01-RR-00997), and to Stanford University (Grant M01-RR-00070). Further support came from National Institutes of Health Grant HD-14426 at Stanford; from Presbyterian/St.Luke’s Community Foundation Grant 9017 to Dr. Brown; from the Children’s Miracle Network Telethon at the University of Iowa; and from the Chief, Navy Bureau of Medicine and Surgery, Washington, D.C., at the Naval Medical Center San Diego (Clinical Investigation Program S-91-083).

Declarations of interest: Marlene Brim and Robert I. Abels are employees of the R.W. Johnson Pharmaceutical Research Institute and own stock in its parent company, Johnson and Johnson, Inc.

Participants

157 preterm infants with GA < 31 weeks with birth weight less than/or equal to 1250 g
Mean (SD) age (days) at study entry; EPO group 22.9 ± 10.1; Placebo group 24.1 ± 9.9

Interventions

Sc injection of rHuEPO (unnamed product) at a dose of 100 IU/kg, or an identical volume of placebo suspension, were given from Monday through Friday (500 IU/kg/week; high dose) for 6 weeks or until the infants were ready to be discharged home. Doses of rHuEPO (or placebo) were adjusted weekly according to changes in body weight
There were 77 infants in the rHuEPO group and 80 infants in the placebo group
Participants received oral iron supplements at study entry to achieve a total enteral intake of 3 mg/kg/day of elemental iron (low dose)
Total iron intake was increased to 6 mg/kg/day when the infants tolerated full caloric feeding enterally
Infants also received 15 IU of supplemental vitamin E and an additional 1 mL/day of an enteral multivitamin preparation

Outcomes

Exposure of a proportion of infants to one or more red blood cell transfusions
Mean number of erythrocyte transfusions per infant
Mortality
Sepsis
NEC
Threshold ROP
Hypertension
SIDS
Side effects

Notes

Infants who had received blood transfusions prior to study entry were included
Guidelines for blood transfusions were developed
This study reports 4 post-discharge infants deaths among 125 infants followed until they were at least 6 months old. Three placebo-treated infants died; 2 of probable SIDS and one from aspiration pneumonia
The only late infant death in an EPO-treated infant occurred at 11 months of age from late NEC.

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computer-generated randomisation was used

Allocation concealment (selection bias) Low risk

The personnel responsible for administrative support, oversight, and monitoring of the study, the study chair and all investigators were masked to treatment group assignments throughout the study

Blinding (performance bias and detection bias) Low risk

A placebo was used

Incomplete outcome data (attrition bias) Low risk

Outcomes reported for all infants randomised

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Whitehall 1999

Methods

Single centre, randomised controlled clinical trial, single-centre study in Australia

Study period: August 1992 to March 1993

Funding sources: None reported

Declarations of interest: None declared

Participants

42 infants with GA less than/or equal to 32 weeks
Postnatal age 14 days
Exclusion criteria: major congenital anomaly, primary haematological disease, hypertension, seizures, failure to obtain consent

Interventions

10 infants with BW less than/or equal to 1000 g and 12 infants with BW > 1000 g received 400 IU/kg of EPO (EPREX, Janssen-Cilag) sc every second day x 10 doses (high dose)
10 infants with BW less than/or equal to 1000 g and 10 infants with BW > 1000 g received no placebo
Both groups received 3 mg/kg/day of iron (low dose) increased to 6 mg/kg/day (high dose) as tolerated

Outcomes

Total volume (mL/kg) of blood transfused
Number of transfusions per infant
Mortality during hospital stay

Notes

Unknown whether infants were included if they had received blood transfusion prior to study entry
Guidelines for blood transfusions were in place

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computer-generated random numbers were used

Allocation concealment (selection bias) Low risk

Sealed coded envelopes were used

Blinding (performance bias and detection bias) High risk

No placebo was used

Incomplete outcome data (attrition bias) Low risk

Outcomes reported for all randomised infants

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Yamada 1999a

Methods

Single-centre, randomised controlled clinical trial, Japan

Study period: Not stated

Funding sources: Not stated

Declarations of interest: Not stated

Participants

55 infants with BW 1000 - 1499 g and GA < 33 weeks and postnatal age < 40 days

Interventions

28 infants received 200 IU/kg of EPO (unnamed product) sc twice a week (400 IU/kg/week, low dose) for 8 weeks and oral iron (3 mg/kg/day). 27 infants in the control group received no treatment or placebo

Outcomes

Exposure of a proportion of infants to one or more red blood cell transfusions
The total volume (mL) of blood transfused per infant
Number of transfusions per infant

Notes

Unknown if infants who had received transfusions prior to enrolment were excluded or not
Conservative red blood cell transfusion guidelines were followed

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

Randomly assigned

Blinding (performance bias and detection bias) High risk

No placebo was used

Incomplete outcome data (attrition bias) Low risk

Outcomes reported for all randomised infants

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Yamada 1999b

Methods

Single-centre, randomised controlled clinical trial, Japan

Study period: Not reported

Funding sources: Not stated

Declarations of interest: Not stated

Participants

27 infants with BW 500 to 999 g and GA < 33 weeks and postnatal age < 40 days

Interventions

15 infants received EPO 200 IU/kg of EPO (unnamed product) sc twice a week (400 IU/kg/week, low dose) sc for 8 weeks and oral iron (3 mg/kg/day). 12 infants in the control group received no treatment or placebo

Outcomes

Exposure of a proportion of infants to one or more red blood cell transfusions
The total volume (mL) of blood transfused per infant
Number of transfusions per infant

Notes

Unknown if infants who had received transfusions prior to enrolment were excluded or not
Conservative red blood cell transfusion guidelines were followed

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

No information provided

Allocation concealment (selection bias) Unclear risk

No information provided; randomly assigned

Blinding (performance bias and detection bias) High risk

No placebo was used

Incomplete outcome data (attrition bias) Low risk

Outcomes for all randomised infants were reported

Selective reporting (reporting bias) Unclear risk

The study was not entered into a trials registry and we cannot tell if there were any deviations from the study protocol

Other bias Low risk

Appears free of other bias

Footnotes

AGA = appropriate for gestational age
BPD = bronchopulmonary dysplasia
BW = birth weight
EPO = erythropoietin
GA = gestational age
Hb = haemoglobin
Hct = hematocrit
iv = intravenous (or intravenously)
im = intramuscular (or intra muscularly)
IU = units
IVH = intraventricular haemorrhage
NEC = necrotising enterocolitis
NICU = neonatal intensive care unit
PCV = packed cell volume (hematocrit)
PMA = postmenstrual age
PRBC = packed red blood cells
PVL = periventricular leukomalacia
RDS = respiratory distress syndrome
ROP = retinopathy of prematurity
rHuEPO = recombinant human erythropoietin
sc = subcutaneous (or subcutaneously)
SD = standard deviation
SEM = standard error of the mean
SIDS = sudden infant death syndrome
TPN: total parenteral nutrition
VLBW: very low birth weight

Characteristics of excluded studies

Ahmadpour Kacho 2004

Reason for exclusion

Published in abstract form only. Randomised controlled trial of erythropoietin vs no treatment in preterm low birth weight infants. The abstract lacks information on the age of the infants at the time of enrolment.

Amin 2004

Reason for exclusion

Published in abstract form only. The authors state that this was a controlled clinical trial of erythropoietin vs conventional therapy in preterm very low birth weight infants. It is not clear if this was a randomised controlled trial or not.

Badiee 2006

Reason for exclusion

No outcomes of interest.

Bechensteen 1997

Reason for exclusion

Both groups got EPO.

Messer 1993

Reason for exclusion

This is not a randomised controlled trial. Non-randomised controls were used.

Meyer 1996

Reason for exclusion

All infants were treated with EPO.

Mohammadzadeh 2005

Reason for exclusion

Both groups got EPO.

Ohls 1991

Reason for exclusion

This study compared EPO with erythrocyte transfusion and not placebo.

Ohls 2012

Reason for exclusion

This study compared 2 dosing schedules; once a week vs 3 times a week of EPO in infants greater than/or equal to 7 days of age. It appears that this study was published as an abstract in 2008 when a lower number of infants had been enrolled (14 in the abstract vs 20 in the full publication).

Pasha 2008

Reason for exclusion

No outcomes of interest. "No subject from the study group required red blood cell transfusion". The authors do not state if any infant was transfused in the control group.

Pathak 2003

Reason for exclusion

Both groups got EPO.

Testa 1998

Reason for exclusion

The study used historical controls.

Warwood 2005

Reason for exclusion

This study was a dose-finding study of darepoetin (longer-acting and more potent than EPO). Infants were randomised to 2 different doses of darepoetin.

Warwood 2011

Reason for exclusion

No outcomes of interest for this review were presented apart from need for transfusion. One of the study subjects qualified for and received a blood transfusion. However, the authors do not state which group this infant belonged to.

Widness 2006

Reason for exclusion

No outcomes of interest for this review were presented.

Footnotes

EPO: erythropoietin

Characteristics of studies awaiting classification

  • None noted

Characteristics of ongoing studies

  • None noted

Additional tables

1 Transfusion guidelines

Reference

Indications

Akisu 2001

Guidelines for transfusions were not presented

Al-Kharfy 1996

The indications for transfusion were 1) shock, 2) cumulative loss of greater than/or equal to 10% of the blood volume in 72 hours or less when further blood sampling is expected, 3) Hb < 130 g/dL in acutely ill neonates with cardiorespiratory disease, and 4) Hb < 80 to 100 g/L with clinical signs of anaemia. A volume of 15 mL/kg was recommended for each transfusion

Atasay 2002

Criteria for blood transfusion (10 mL/kg packed red cells) were as follows: a Hct < 30% when signs and symptoms attributed to anaemia including persistent tachycardia (180 beats/min for 24 hours), frequent apnoea with bradycardia and daily weight gain < 10 g/kg despite optimal protein and caloric intake (3.5 g/kg, 100 kcal/kg/day). Infants were transfused with a Hct of 35% to 40% if they received more than 40% oxygen or ventilation therapy

Bader 1996

Criteria for blood transfusion (10 mL/kg of red cells) were as follows: a) a Hct < 25%, b) an increased frequency of apnoeic events which required either stimulation or aminophylline therapy, c) changes in heart rate patterns, e.g. an increase in frequency of bradycardia (< 80 beats/min) or tachycardia (> 180 beats/min, d) failure of weight gain of > 10 g/kg/day despite an optimal caloric intake of > 120 kcal/day and e) lethargy without evidence of sepsis

Bechensteen 1993

Indications of blood transfusions were: 1) Hb < 80 g/L or 2) otherwise at the discretion of the clinician caring for the infant according to symptoms and signs

Bierer 2009

Very specific transfusion criteria were in place for infants on mechanical ventilation, for infants who required supplemental oxygen and for infants on room air

Chen 1995

Transfusions were given because of frequent and prolonged apnoeas

Corona 1998

Transfusions were considered based on the clinical condition (pallor, tachycardia, tachypnoea, apnoea with or without bradycardia, poor weight gain, difficulties with sucking) and haematological parameters (Hb < 70 g/L, Hct < 26%, with low reticulocyte counts)

Donato 1996

During the first week of life, infants were given transfusions of packed red blood cells for replacement when blood drawn for analysis was in excess of 8 mL/kg of body weight; fresh whole blood was given if signs attributable to hypovolaemia or anaemia developed. Subsequently, infants with heart rate > 180 beats/min, severe, apnoea/bradycardia or poor weight gain (< 10 g/day in spite of a 100 calories/day intake during 5 consecutive days) were transfused if the Hct was < 25% (or < 30% if oxygen or mechanical ventilation was required); asymptomatic infants were transfused only when a central Hct < 23% was reached

Emmerson 1993

The decision to give a blood transfusion to a study infant was made by the medical staff of the neonatal unit who were blinded to the randomisation. The unit policy at the time of the study was to transfuse a preterm infant who had a Hb < 100 g/L and who had symptoms consistent with those caused by anaemia. The symptoms and signs of anaemia included poor feeding, tachycardia, tachypnoea, apnoea, and pallor. Infants with a Hb < 80 g/L were transfused even if asymptomatic

Giannakopoulou 1998a; Giannakopoulou 1998b

Indications for blood transfusion were a Hb < 80 g/L or otherwise at the discretion of the physician treating the infants according to symptoms and signs

Griffiths 1997

Infants were transfused if they were ventilated and/or oxygen-dependent with a Hb of < 120 g/L, had clinically symptomatic anaemia, or were asymptomatic with a Hb of < 70 g/L. Infants were transfused if they were ventilated and/or oxygen-dependent with a Hb of < 120 g/L, had clinically symptomatic anaemia, or were asymptomatic with a haemoglobin of < 70 g/L

Javier Manchon 1997

Transfusion guidelines were similar in all three centres (details not provided)

Juul 2003

By NICU policy, on admission, infants weighing < 1000 g at birth were assigned 1 unit of packed red blood cells divided into 8 aliquots. These aliquots were used for transfusions during the first month of life. The following transfusion guideline was used for infants of all birth weights: Transfusion is recommended for a Hct < 35% if the infant requires positive pressure with a mean airway pressure > 6 cm water and requires > 35% oxygen. Transfusion is recommended for Hct < 30% if the infant requires oxygen (< 35% FIO2), is receiving continuous positive airway pressure or intubated with mean airway pressure < 6 cm water, if an infant has significant apnoea and bradycardia while receiving methylxanthines (> 9 episodes in 12 hours or 2 episodes in 24 hours requiring mask-and-bag ventilation), if the heart rate is > 180 beats/min or respiratory rate > 80/min and persists for 24 hours, if weight gain < 10 g per day over 4 days despite adequate calories, or in the presence of sepsis. If the Hct is < 20%, no symptoms are necessary for transfusion
Transfusion volumes were standardised as follows: Infants received an initial transfusion of 15 mL/kg over a period of 3 to 4 hours. A follow-up Hct was checked after 4 hours. If the Hct was < 30%, a second aliquot of 10 mL/kg was given

If the Hct was between 30% and 35%, an additional 5 mL/kg was given

Kivivuori 1999

The Hct values were maintained at > 30% by red blood cell transfusions (10 mL/kg per time) in asymptomatic infants. In infants who had symptoms or signs of anaemia, red blood cells were transfused if the Hct value was < 40%. The transfusion policies were the same in all study hospitals

Kumar 1998

The need for erythrocyte transfusion was assessed by the clinicians caring for each infant and the decision to transfuse was made without consulting the study investigators. According to the practice in the NICU, infants received transfusion if a Hct level of < 27% was associated with one of the following signs and symptoms of anaemia: 1) frequent apnoea and bradycardia, defined as > 6 episodes in 12 hours or any episode requiring bag-and-mask ventilation, in an infant with therapeutic serum levels of theophylline; 2) persistent tachycardia, defined as > 180 beats/min for more than 12 hours; 3) poor weight gain (< 10 g/day averaged over a 7-day period) despite adequate caloric intake; and 4) increasing oxygen requirement in infants with chronic lung disease despite optimum diuretic and bronchodilator therapy

Maier 2002

Infants with artificial ventilation or in > 40% of inspired oxygen were not transfused unless Hct dropped to < 40%. Spontaneously breathing infants were not transfused unless Hct dropped to < 35% during the first 2 weeks of life, 30% during the 3rd to 4th weeks, and 0.25 thereafter. Transfusion was allowed when life-threatening anaemia or hypovolaemia was assumed 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

Meyer 1994

The need for blood transfusion was assessed by the attending neonatal physician and decisions were made independently of the investigators. The following guidelines were developed, based on existing literature and nursery practices: a. Hct < 30% and 1) weight gain of < 10 g/day averaged over 1-week period (infant tolerating full oral feeds and receiving adequate calories). 2) Three or more episodes of apnoea (respirations absent for 20 seconds) or bradycardia (heart rate of < 100 beats per minute) in a 24-hour period not due to other causes and not responsive to methylxanthine treatment. 3) Tachycardia (> 170 beats/min) or tachypnoea (> 70 breaths/min) sustained over a 24-hour period or associated with acute cardiac decompression. 4) Requirement for surgery. a. Development of a clinically significant patent ductus arteriosus (i.e. at least three of the following features: heart rate > 160 beats/min, brisk brachial and/or dorsalis pedis pulses, palpable precordial pulsation, systolic murmur, cardiomegaly on chest radiograph). b. Pulmonary disease and fractional inspired oxygen concentrations increasing by > 10% per week. d. Systemic infection (either clinically suspected or proven on blood culture) associated with a sudden decrease in Hct less than/or equal to 22% and/or an absolute reticulocyte count of < 100 000/microlitre

Pollak 2001

Standard NICU transfusion criteria were used (authors refer to Shannon 1995; see below)

Reiter 2005

Conservative transfusion guidelines were in place and followed. Criteria for red blood cell transfusion in the acutely ill infant requiring mechanical ventilation or nasal continuous positive airway pressure included: phlebotomy loss of > 15% of blood volume associated with hypotension, or Hct < 30%. Criteria for red blood cell transfusion in the convalescent infant requiring no more than supplemental oxygen included: Hct < 28% with symptomatic anaemia (tachycardia, poor somatic growth or metabolic acidosis) or Hct < 20%

Rocha 2001

The decision for blood transfusion within the whole study population was made by the assistant doctor of each newborn, and was based on the following criteria: Hct less than/or equal to 20%, inadequate weight gain, 3 or more apnoea or bradycardia episodes within 24 hours, presurgical procedure requirement, disease associated with sudden Hct decline, restoration of the blood collected for lab exams, maintenance of Hct up to 30% associated with minimal ventilatory support requirement, and Hct up to 35% when ventilation requirements are greater. The assistant doctor who recommended blood transfusion did not know to which group the infant belonged

Romagnoli 2000

Infants on mechanical ventilation and/or on more than 30% of inspired oxygen received packed erythrocytes when their Hct levels dropped below 40%. Otherwise the transfusion was performed when the Hct fell below 35% from the 2nd to the 4th week of life and below 23% thereafter

Ronnestad 1995

Transfusions were given on the orders of the attending physician if Hb was < 90 g/L or otherwise as necessary according to signs and symptoms

Samanci 1996

The need for packed erythrocyte transfusions was judged by the attending neonatologist. Guidelines for erythrocyte transfusions were developed as follows: 1) Hct of less than/or equal to 22% and an absolute reticulocyte count of 100 000/microlitre, 2) Hct of less than/or equal to 30% and a) tachycardia (> 180 beats/min) and tachypnoea (> 70 breaths/min) persisting for 24 hours; or b) 3 or more episodes of apnoea or bradycardia in 24 hours, not due to other causes and not responsive to methylxanthine treatment; or c) average weight gain of < 10 g/day over a 1-week period (infant tolerating full oral feed and receiving adequate calories); or d) undergoing surgery. 3) Systemic infection associated with a sudden decrease in Hct

Shannon 1991

Transfusions were ordered by the clinicians caring for each infant without consulting the investigators. Written guidelines for erythrocyte transfusions were developed for the nursery 1 year before the start of the study. A copy of these guidelines was taped to the bed of each study infant. In general, babies who were otherwise well received transfusions only if they had a Hct < 25% and signs referable to their anaemia, such as slowing in rate of growth, persistent severe tachycardia and tachypnoea, or worsening of episodes of apnoea and bradycardia

Shannon 1992

See Shannon 1991 above

Shannon 1995

Transfuse infants at Hct less than/or equal to 20%: a) if asymptomatic with reticulocytes < 100 000/microlitre. Transfuse infants at Hct less than/or equal to 30%: a) if receiving < 35% supplemental hood oxygen, b) if on CPAP or mechanical ventilation with mean airway pressure < 6 cm water, c) if significant apnoea and bradycardia are noted (9 episodes in 12 hours or 2 episodes in 24 hours requiring bag-and-mask ventilation) while receiving therapeutic doses of methylxanthines, d) if heart rate > 180 beats/min or respiratory rate > 80 breaths /min persists for 24 hours, e) if weight gain < 10 g/day is observed over 4 days while receiving greater than/or equal to 100 kcal/kg/day, f) if undergoing surgery. Transfuse for Hct less than/or equal to 35%: a) if receiving > 35% supplemental hood oxygen, b) if intubated on CPAP or mechanical ventilation with mean airway pressure greater than/or equal to 6 - 8 cm water. Do not transfuse: a) to replace blood removed for laboratory tests alone, b) for low Hct alone

Whitehall 1999

Guidelines for red cell transfusions for anaemia of prematurity were based on the existing policy in the nursery, generally adopted by the neonatologists. They were as follows:
I. Transfuse infants at Hb 80 g/L, (a) If reticulocyte count is < 4% and (b) If receiving supplemental oxygen > 30% or (c) If unexplained recurrent apnoeas/bradycardias are noted (> 1 - 2/hour) or (d) If persistent tachycardia (heart rate > 170/min) or tachypnoea (respiratory rate > 60/min) is noted, or (e) If there is failure to gain weight or successive weight loss on weekly recordings for 3 consecutive weeks. In absence of a clear evidence in the literature justifying red cell transfusions at a Hb of 80 g/L in otherwise asymptomatic neonates who are failing to thrive, it was decided that failure to gain weight or successive weight loss on weekly recordings for 3 consecutive weeks was a fair and substantial clinical indicator of the need to transfuse
II. Transfuse infants at Hb 100 g/L, (a) If receiving supplemental oxygen 30% and (b) needing intermittent mandatory ventilation or continuous positive airway pressure by nasal prongs for recurrent (> 1 - 2 per hour), apnoeas/bradycardias with saturations < 90% on the pulse oximeter
III. Transfuse Infants at Hb 120 g/L, (a) If receiving mechanical ventilatory support with mean airway pressure 10 cm of water and supplemental oxygen 30% during the acute phase of illness after birth

Yamada 1999a

Conservative red blood cell transfusion guidelines were followed (details not presented, as we were unable to translate the information)

Yamada 1999b

Conservative red blood cell transfusion guidelines were followed (details not presented, as we were unable to translate the information)

Footnotes

CPAP: continuous positive airways pressure
Hb: haemoglobin
Hct: hematocrit
NICU: neonatal intensive care unit

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References to studies

Included studies

Akisu 2001

Akisu M, Tuzun S, Arslanoglu S, Yalaz M, Kultursay N. Effect of recombinant human erythropoietin administration on lipid peroxidation and antioxidant enzyme(s) activities in preterm infants. Acta Medica Okayama 2001;55(6):357-62.

Al-Kharfy 1996

* Al-Kharfy T, Smyth JA, Wadsworth L, Krystal G, Fitzgerald C, Davis J et al. Erythropoietin therapy in neonates at risk of having bronchopulmonary dysplasia and requiring multiple transfusions. Journal of Pediatrics 1996;129(1):89-96.

Smyth JA, Ainsworth L, Krystal G, Wadsworth L. Effect of erythropoietin therapy on oxygen dependency in premature infants. Pediatric Research 2002;51(3):330 A.

Atasay 2002

Atasay B, Gunlemez A, Akar N, Arsan S. Does early erythropoietin therapy decrease transfusions in anemia of prematurity? Indian Journal of Pediatrics 2002;69(5):389-91.

Bader 1996

Bader D, Blondheim O, Jonas R, Admoni O, Abend-Winge M, Reich D et al. Decreased ferritin levels, despite iron supplementation, during erythropoietin therapy in anaemia of prematurity. Acta Paediatrica 1996;85(4):496-501.

Bechensteen 1993

* Bechensteen AG, Haga P, Halvorsen S, Whitelaw A, Liestol K, Lindemann R et al. Erythropoietin, protein, and iron supplementation and the prevention of anaemia of prematurity. Archieves of Disease in Childhood 1993;69(1 Spec No):19-23.

Bechensteen AG, Halvorsen S, Haga P, Cotes PM, Liestol K. Erythropoietin (Epo), protein and iron supplementation and the prevention of anaemia of prematurity: effects on serum immunoreactive Epo, growth and protein and iron metabolism. Acta Paediatrica 1996;85(4):490-5.

Bechensteen AG, Halvorsen S, Haga P. Erythropoiesis during rapid growth. Role of erythropoietin and nutrition. Annals of the New York Academy of Sciences 1994;718:339-40.

Bechensteen AG, Refsum HE, Halvorsen S, Haga P, Liestol K. Effects of recombinant human erythropoietin on fetal and adult hemoglobin in preterm infants. Pediatric Research 1995;38(5):729-32.

Bierer 2009

Bierer R, Roohi M, Peceny C, Ohls RK. Erythropoietin increases reticulocyte counts and maintains hematocrit in neonates requiring surgery. Journal of Pediatric Surgery 2009;44(8):1540-5.

Chen 1995

Chen JY, Wu TS, Chanlai SP. Recombinant human erythropoietin in the treatment of anemia of prematurity. American Journal of Perinatology 1995;12(5):314-8.

Corona 1998

Corona G, Fulia F, Liotta C, Barberi I. Clinical use of recombinant human erythropoietin (rHuEPO) in the treatment of preterm anaemia [Uso clinico dell'eritropoietina umana ricombinante (rHuEPO) nell'anemia della prematurita]. Rivista Italiana Pediatria 1998;24:442-9.

Donato 1996

Donato H, Rendo P, Vivas R, Schvartzman G, Digregorio J, Vain N. Recombinant human erythropoietin in the treatment of anemia of prematurity: a randomized, double-blind, placebo-controlled trial comparing three different doses. International Journal of Pediatric Hematology/Oncology 1996;3:279-85.

Emmerson 1993

Emmerson AJ, Coles HJ, Stern CM, Pearson TC. Double blind trial of recombinant human erythropoietin in preterm infants. Archives of Disease in Childhood 1993;68(3 Spec No):291-6.

Giannakopoulou 1998a

Giannakopoulou C, Bolonaki I, Stiakaki E, Dimitriou H, Galanaki H, Hatzidaki E et al. Erythropoietin (rHuEPO) administration to premature infants for the treatment of their anemia. Pediatric Hematology and Oncology 1998;15(1):37-43.

Giannakopoulou 1998b

Giannakopoulou C, Bolonaki I, Stiakaki E, Dimitriou H, Galanaki H, Hatzidaki E et al. Erythropoietin (rHuEPO) administration to premature infants for the treatment of their anemia. Pediatric Hematology and Oncology 1998;15(1):37-43.

Griffiths 1997

Griffiths G, Lall R, Chatfield S, Short A, MacKay P, Williamson P et al. Randomised controlled double blind study of the role of recombinant erythropoietin in the prevention of chronic lung disease. Archives of Disease in Childhood. Fetal and Neonatal Edition 1997;76(3):F190-2.

Javier Manchon 1997

Javier Manchon G, Natal Pujol A, Coroleu Lletget W, Zuasnabar Cotro A, Badia Barnusell J, Junca Piera J et al. Randomized multi-centre trial of the administration of erythropoietin in anemia of prematurity [Estudio multicentrico aleatorizado de administracion de eritropoyetina en la anemia de la prematuridad]. Anales Espanoles de Pediatria 1997;46(6):587-92.

Juul 2003

Juul SE. Enterally dosed recombinant human erythropoietin does not stimulate erythropoiesis in neonates. Journal of Pediatrics 2003;143(3):321-6.

Kivivuori 1999

Kivivuori SM, Virtanen M, Raivio KO, Viinikka L, Siimes MA. Oral iron is sufficient for erythropoietin treatment of very low birth-weight infants. European Journal of Pediatrics 1999;158(2):147-51.

Kumar 1998

Kumar P, Shankaran S, Krishnan RG. Recombinant human erythropoietin therapy for treatment of anemia of prematurity in very low birth weight infants: a randomized, double-blind, placebo-controlled trial. Journal of Perinatology 1998;18(3):173-7.

Maier 2002

Published and unpublished data

Maier RF, Obladen M, Muller-Hansen I, Kattner E, Merz U, Arlettaz R et al. Early treatment with erythropoietin beta ameiliorates anemia and reduces transfusion requirements in infants with birth weights below 1000 g. Journal of Pediatrics 2002;141(1):8-15.

Meyer 1994

Meyer MP, Haworth C, McNeill L. Is the use of recombinant human erythropoietin in anemia of prematurity cost-effective? South African Medical Journal 1996;86(3):251-3.

* Meyer MP, Meyer JH, Commerford A, Hann FM, Sive AA, Moller G et al. Recombinant human erythropoietin in the treatment of the anemia of prematurity: results of a double-blind, placebo-controlled study. Pediatrics 1994;93(6 Pt 1):918-23.

Pollak 2001

Kasper DC, Widness JA, Haiden N, Berger A. Hayde M, Pollak A et al. Characterization and differentiation of iron status in anemic very low birth weight infants using a diagnostic nomogram. Neonatology 2009;95(2):164-71.

* Pollak A, Hayde M, Hayn M, Herkner K, Lombard KA, Lubec G et al. Effect of intravenous iron supplementation on erythropoiesis in erythropoietin-treated premature infants. Pediatrics 2001;107(1):78-85.

Reiter 2005

Reiter PD, Rosenberg AA, Valuck R, Novak K. Effect of short-term erythropoietin therapy in anemic premature infants. Journal of Perinatology 2005;25(2):125-9.

Rocha 2001

Rocha VL, Benjamin AC, Procianoy RS. The effect of recombinant human erythropoietin on the treatment of anemia of prematurity. Journal de Pediatria 2001;77(2):75-83.

Romagnoli 2000

Romagnoli C, Zecca E, Gallini F, Girlando P, Zuppa AA. Do recombinant human erythropoitetin and iron supplementation increase the risk of retinopathy of prematurity? European Journal of Pediatrics 2000;159(8):627-8.

Ronnestad 1995

Ronnestad A, Moe PJ, Breivik N. Enhancement of erythropoiesis by erythropoietin, bovine protein and energy fortified mother's milk during anaemia of prematurity. Acta Paediatrica 1995;84(7):809-11.

Samanci 1996

Samanci N, Ovali F, Dagoglu. Effects of recombinant human erythropoietin in infants with very low birth weights. The Journal of International Medical Research 1996;24(2):190-8.

Shannon 1991

Newton NR, Leonard CH, Piecuch RE, Phibbs RH. Neurodevelopmental outcome of prematurely born children treated with recombinant erythropoietin in infancy. Journal of Perinatology 1999;19(6 Pt 1):403-6.

* Shannon KM, Mentzer WC, Abels RI, Freeman P, Newton N, Thompson D et al. Recombinant human erythropoietin in the anemia of prematurity: results of a placebo-controlled pilot study. Journal of Pediatrics 1991;118(6):949-55.

Shannon 1992

Shannon KM, Mentzer WC, Abels RI, Wertz M, Thayer-Moriyama J, Li WY et al. Enhancement of erythropoiesis by recombinant human erythropoietin in low birth weight infants: a pilot study. Journal of Pediatrics 1992;120(4 Pt 1):586-92.

Shannon 1995

Bard H, Widness JA. Effect of recombinant human erythropoietin on the switchover from fetal to adult hemoglobin synthesis in preterm infants. Journal of Pediatrics 1995;127(3):478-80.

Baxter LM, Vreman HJ, Ball B, Stevenson DK. Recombinant human erythropoietin (r-HuEPO) increases total bilirubin production in premature infants. Clinical Pediatrics 1995;34(4):213-6.

Brown MS, Shapiro H. Effect of protein intake on erythropoiesis during erythropoietin treatment of anemia of prematurity. Journal of Pediatrics 1996;128(4):512-7.

* Shannon KM, Keith JF 3rd, Mentzer WC, Ehrenkranz RA, Brown MS, Widness JA et al. Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants. Pediatrics 1995;95(1):1-8.

Widness JA, Lombard KA, Ziegler EE, Serfass RE, Carlson SJ, Johnson KJ et al. Erythrocyte incorporation and absorption of 58Fe in premature infants treated with erythropoietin. Pediatric Research 1997;41(3):416-23.

Whitehall 1999

Whitehall JS, Patole SK, Campbell P. Recombinant human erythropoietin in anemia of prematurity. Indian Pediatrics 1999;36(1):17-27.

Yamada 1999a

Yamada M, Takahashi R, Chiba Y, Ito T, Nakae N. Effects of recombinant human erythropoietin in infants with anemia of prematurity. I. Results in infants with birth weights between 1,000 and 1,499 gm. Acta Neonatologica Japonica 1999;35(4):755-61.

Yamada 1999b

Yamada M, Takahashi R, Chiba Y, Ito T, Nakae N. Effects of recombinant human erythropoietin in infants with anemia of prematurity. II. Results in infants with birth weights between 500 and 999 gm. Acta Neonatologica Japonica 1999;35(4):762-7.

Excluded studies

Ahmadpour Kacho 2004

Ahmadpour Kacho M, Zahed Pasha YA, Esmaili MR, Hajian K, Moradi SH. The effect of human recombinant erythropoietin on prevention of anemia of prematurity. Pediatric Research 2003;54(4):564.

Amin 2004

Amin A, Alzahrani D. Efficacy of erythropoietin in premature infants. Pediatric Research 2003;54(4):557.

Badiee 2006

Badiee Z, Pourmirzaiee MA, Kelishadi R, Naseri F. Recombinant human erythropoietin and blood transfusion in low-birth weight preterm infants under restrictive transfusion guidelines. Saudi Medical Journal 2006;27(6):817-20.

Bechensteen 1997

Bechensteen AG, Hågå P, Halvorsen S, Liestøl K, Lindemann R, Whitelaw A et al. Effect of low and moderate doses of recombinant human erythropoietin on the haematological response in premature infants on high protein and iron intake. European Journal of Pediatrics 1997;156(1):56-61.

Messer 1993

Messer J, Haddad J, Donato L, Astruc D, Matis J. Early treatment of premature infants with recombinant human erythropoietin. Pediatrics 1993;92(4):519-23.

Meyer 1996

Meyer MP, Haworth C, Meyer JH, Commerford A. A comparison of oral and intravenous iron supplementation in preterm infants receiving recombinant erythropoietin. Journal of Pediatrics 1996;129(2):258-63.

Mohammadzadeh 2005

Mohammadzadeh A, Naseri F. Effect of high versus low doses of human recombinant erythropoietin on the anemia of prematurity. Acta Medica Iranica 2005;43(2):95-8.

Ohls 1991

Bierer R, Roohi M, Ohls RK. A randomized, masked study of weekly erythropoietin dosing in neonates. In: Pediatric Academic Societies' Annual Meeting. 2008:E-PAS2008:633749.3.

* Ohls RK, Christensen RD. Recombinant erythropoietin compared with erythrocyte transfusion in the treatment of anemia of prematurity. Journal of Pediatrics 1991;119(5):781-8.

Ohls 2012

Bierer R, Roohi M, Ohls RK. A randomized, masked study of weekly erythropoietin dosing in neonates. In: Pediatric Academic Societies' Annual Meeting. 2008:E-PAS2008:633749.3.

Ohls RK, Roohi M, Peceny HM, Schrader R, Bierer R. A randomized, masked study of weekly erythropoietin dosing in preterm infants. Journal of Pediatrics 2012;160(5):790-5.

Pasha 2008

Pasha YZ, Ahmadpour-Kacho M, Hajiahmadi M, Hosseini MB. Enteral erythropoietin increases plasma erythropoietin level in preterm infants: a randomized controlled trial. Indian Pediatrics 2008;45(1):25-8.

Pathak 2003

Pathak A, Roth P, Piscitelli J, Johnson L. Effects of vitamin E supplementation during erythropoietin treatment of the anemia of prematurity. Archives of Disease in Childhood. Fetal and Neonatal Edition 2003;88(4):F324-8.

Testa 1998

Testa M, Reali A, Copula M, Pinna B, Birocchi F, Pisu C et al. Role of rHuEpo on blood transfusions in preterm infants after the fifteenth day of life. Pediatric Hematology and Oncology 1998;15(5):415-20.

Warwood 2005

Warwood TL, Ohls RK, Wiedmeier SE, Lambert DK, Jones C, Scoffield SH et al. Single-dose darbepoetin administration to anemic preterm neonates. Journal of Perinatology 2005;25(11):725-30.

Warwood 2011

Warwood TL, Lambert DK, Henry E, Christensen RD. Very low birth weight infants qualifying for a 'late' erythrocyte transfusion: does giving darbepoetin along with the transfusion counteract the transfusion's erythropoietic suppression? Journal of Perinatology 2011;31(Suppl 1):S17-21.

Widness 2006

Widness JA, Serfass RE, Haiden N, Nelson SE, Lombard KA, Pollak A. Erythrocyte iron incorporation but not absorption is increased by intravenous iron administration in erythropoietin-treated premature infants. Journal of Nutrition 2006;136(7):1868-73.

Studies awaiting classification

  • None noted

Ongoing studies

  • None noted

Other references

Additional references

Aher 2012b

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 2012, Issue 10. Art. No.: CD004865. DOI: 10.1002/14651858.CD004865.pub3.

Brown 1983

Brown MS, Phibbs RH, Gracia JF, Dallman PR. Postnatal changes in erythropoietin levels in untransfused premature infants. Journal of Pediatrics 1983;103(4):612-7.

Cohen 1998

Cohen A, Manno C. Transfusion practices in infants receiving assisted ventilation. Clinics in Perinatology 1998;25(1):97-111.

CONSORT 2012

Altman DG, Moher D, Schultz KF. Improving the reporting of randomised trials: The CONSORT statement and beyond. Statistics in Medicine 2012;31(25):2985-97.

Dallman 1981

Dallman PR. Anemia of prematurity. Annual Review of Medicine 1981;32:143-60.

Dame 2001

Dame C, Juul SE, Christensen RD. The biology of erythropoietin in the central nervous system and its neurotrophic and neuroprotective potential. Biology of the Neonate 2001;79(3-4):228-35.

Finch 1982

Finch CA. Erythropoiesis, erythropoietin and iron. Blood 1982;60:1241-6.

Garcia 2002

Garcia MG, Hutson AD, Chrisensen RD. Effect of recombinant erythropoietin on "late" transfusions in the neonatal intensive care unit: a meta-analysis. Journal of Perinatology 2002;22(2):108-11.

Hesse 1997

Hesse L, Eberl W, Schlaud M, Poets CF. Blood transfusion. Iron load and retinopathy of prematurity. European Journal of Pediatrics 1997;156(6):465-70.

Higgins 2003

Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327(7414):557-60.

Higgins 2011

Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011], The Cochrane Collaboration. Available from www.cochrane-handbook.org.

Juul 2002

Juul S. Erythropoietin in the central nervous system, and its use to prevent hypoxic-ischemic brain damage. Acta Paediatrica Supplement 2002;91(438):36-42.

Kotto-Kome 2004

Kotto-Kome AC, Garcia MG, Calhoun DA, Christensen RD. Effect of beginning recombinant erythropoietin treatment within the first week of life among very-low-birth-weight neonates, on "early" and "late" erythrocyte transfusions: a meta-analysis. Journal of Perinatology 2004;24(1):24-9.

Ohls 2000

Ohls RK. The use of erythropoietin in neonates. Clinics in Perinatology 2000;27(3):681-96.

Ohls 2002

Ohls RK. Erythropoietin treatment in extremely low birth weight infants: blood in versus blood out. Journal of Pediatrics 2002;141(1):3-6.

Ohlsson 2012

Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD004863. DOI: 10.1002/14651858.CD004863.pub3.

RevMan 2012

Review Manager (RevMan) Version 5.1 [Computer program]. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2012.

Schulz 1995

Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias: Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273(5):408-12.

Stockman 1978

Stockman JA 3rd, Oski FA. Physiological anaemia of infancy and the anaemia of prematurity. Clinics in Hematology 1978;7(1):3-18.

Stockman 1986

Stockman JA 3rd. Anemia of prematurity. Current concept in the issue of when to transfuse. Pediatric Clinics of North America 1986;33(1):111-28.

Strauss 1986

Strauss RG. Current issues in neonatal transfusions. Vox Sanguinis 1986;51(1):1-9.

Vamvakas 2001

Vamvakas EC, Strauss RG. Meta-analysis of controlled clinical trials studying the efficacy of rHuEPO in reducing blood transfusions in the anemia of prematurity. Transfusion 2001;41(3):406-15.

Widness 1996

Widness JA, Seward VJ, Kromer IJ, Burmeiser LF, Bell EF, Strauss RG. Changing patterns of red blood cell transfusion in very low birth weight infants. Journal of Pediatrics 1996;129(5):680-7.

Yu 2010

Yu Z, Guo X, Han S, Lu J, Sun Q, Ohlsson A. Erythropoietin for term and late preterm infants with hypoxic ischemic encephalopathy [Protocol]. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD008316. DOI: 10.1002/14651858.CD008316.

Zipursky 2000

Zipursky A. Erythropoietin therapy for premature infants: cost without benefit? Pediatric Research 2000;48(2):136.

Other published versions of this review

Aher 2006b

Aher SM, Ohlsson A. 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.: CD004868. DOI: 10.1002/14651858.CD004868.pub2.

Aher 2012a

Aher SM, Ohlsson A. Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2012, Issue 9. Art. No.: CD004868. DOI: 10.1002/14651858.CD004868.pub3.

Classification pending references

  • None noted

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Data and analyses

1 Late initiation of EPO (8-28 days) vs. placebo or no intervention

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup."

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Use of one or more red blood cell transfusions (low and high dose of EPO) 20 1142 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.64, 0.79]
1.2 Use of one or more red blood cell transfusions (high dose of EPO) 14 912 Risk Ratio (M-H, Fixed, 95% CI) 0.76 [0.68, 0.86]
  1.2.1 High dose iron 6 318 Risk Ratio (M-H, Fixed, 95% CI) 0.74 [0.62, 0.88]
  1.2.2 Low dose iron 8 594 Risk Ratio (M-H, Fixed, 95% CI) 0.78 [0.67, 0.91]
1.3 Use of one or more red blood cell transfusions (low dose of EPO) 7 239 Risk Ratio (M-H, Fixed, 95% CI) 0.53 [0.42, 0.67]
  1.3.1 High dose of iron 3 77 Risk Ratio (M-H, Fixed, 95% CI) 0.50 [0.31, 0.79]
  1.3.2 Low dose of iron 4 162 Risk Ratio (M-H, Fixed, 95% CI) 0.54 [0.41, 0.71]
1.4 Total volume (mL/kg) of red blood cells transfused per infant 5 197 Mean Difference (IV, Fixed, 95% CI) -1.61 [-5.78, 2.57]
1.5 Number of red blood cell transfusions per infant 11 817 Mean Difference (IV, Fixed, 95% CI) -0.22 [-0.38, -0.06]
1.6 Number of donors the infant was exposed to 2 165 Mean Difference (IV, Fixed, 95% CI) 0.45 [0.20, 0.69]
1.7 Mortality during initial hospital stay (all causes) 14 767 Risk Ratio (M-H, Fixed, 95% CI) 0.82 [0.49, 1.39]
1.8 Retinopathy of prematurity (all stages or stage not reported) 3 404 Risk Ratio (M-H, Fixed, 95% CI) 1.27 [0.99, 1.64]
1.9 Retinopathy of prematurity (stage greater than/or equal to 3) 3 442 Risk Ratio (M-H, Fixed, 95% CI) 1.73 [0.92, 3.24]
1.10 Proven sepsis 5 551 Risk Ratio (M-H, Fixed, 95% CI) 0.75 [0.52, 1.09]
1.11 Necrotising Enterocolitis greater than/or equal to Bell's stage 2 6 656 Risk Ratio (M-H, Fixed, 95% CI) 0.88 [0.46, 1.69]
1.12 Intraventricular haemorrhage all grades (or grade not specified) 4 454 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.53, 1.42]
1.13 Periventricular leukomalacia 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.14 Bronchopulmonary dysplasia (supplementary oxygen at 28 days) 2 285 Risk Ratio (M-H, Fixed, 95% CI) 1.25 [1.00, 1.55]
1.15 Bronchopulmonary dysplasia (supplementary oxygen at 36 weeks postmenstrual age) 3 216 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.59, 1.35]
1.16 SIDS 6 363 Risk Ratio (M-H, Fixed, 95% CI) 1.06 [0.25, 4.52]
1.17 Neutropenia 6 164 Risk Ratio (M-H, Fixed, 95% CI) 0.28 [0.05, 1.54]
1.18 Hypertension 8 363 Risk Ratio (M-H, Fixed, 95% CI) 1.20 [0.46, 3.14]
1.19 Length of hospital stay (days) 2 55 Mean Difference (IV, Fixed, 95% CI) -0.35 [-12.83, 12.13]
1.20 Use of one or more red blood cell transfusions (secondary analysis based on study quality) 20 1142 Risk Ratio (M-H, Fixed, 95% CI) 0.71 [0.64, 0.79]
  1.20.1 HIgh quality studies 5 357 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.73, 0.96]
  1.20.2 Studies of uncertain quality 15 785 Risk Ratio (M-H, Fixed, 95% CI) 0.63 [0.54, 0.73]
1.21 Use of one or more red blood cell transfusions (secondary analysis based on RBC transfusion guidelines) 18 1060 Risk Ratio (M-H, Fixed, 95% CI) 0.74 [0.66, 0.82]
  1.21.1 Strict RBC transfusion guidelines 15 963 Risk Ratio (M-H, Fixed, 95% CI) 0.76 [0.68, 0.85]
  1.21.2 No or less strict RBC guidelines 3 97 Risk Ratio (M-H, Fixed, 95% CI) 0.25 [0.08, 0.77]

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Figures

Figure 1 (Analysis 1.1)

Refer to figure 1 caption below.

Forest plot of comparison: 1 Late initiation of EPO (8 - 28 days) vs placebo or no intervention, outcome: 1.1 Use of one or more red blood cell transfusions (low and high dose of EPO) (Figure 1 description).

Figure 2 (Analysis 1.6)

Refer to figure 2 caption below.

Forest plot of comparison: 1 Late initiation of EPO (8 - 28 days) vs placebo or no intervention, outcome: 1.6 Number of donors the infant was exposed to (Figure 2 description).

Figure 3 (Analysis 1.8)

Refer to figure 3 caption below.Forest plot of comparison: 1 Late initiation of EPO (8 - 28 days) vs placebo or no intervention, outcome: 1.8 Retinopathy of prematurity (all stages or stage not reported) (Figure 3 description).

Figure 4 (Analysis 1.9)

Refer to figure 4 caption below.

Forest plot of comparison: 1 Late initiation of EPO (8 - 28 days) vs placebo or no intervention, outcome: 1.9 Retinopathy of prematurity (stage greater than/or equal to 3) (Figure 4 description).

Figure 5 (Analysis 1.1)

Refer to figure 5 caption below.

Funnel plot of comparison: 1 Late initiation of EPO (8 - 28 days) vs placebo or no intervention, outcome: 1.1 Use of one or more red blood cell transfusions (low and high dose of EPO) (Figure 5 description).

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Sources of support

Internal sources

  • Mount Sinai Hospital, Toronto, Canada

External sources

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA
  • Editorial support of the Cochrane Neonatal Review Group has been funded 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. HHSN275201100016C

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Feedback

1 Feedback from Dr. R. Ohls, 27 March 2013

Summary

Our inclusion of the study by Dr. Romagnoli and co-workers (Romagnoli 2000) in the Early EPO review was questioned by Dr. Robin Ohls, who suggested the study should be included in the Late EPO review. We contacted Dr. Romagnoli and he informed us that the mean (± SD) age of the infants when EPO treatment was started was 10 ± 1 days. We therefore moved the study to this Late EPO review.

Reply

As expected, when the study by Romagnoli 2000 (n = 230) was added the results of the meta-analyses changed. The outcome of BPD (defined as need for supplemental oxygen at 28 days of life) is now of borderline statistical significance with an increased risk in the EPO group. Becasue of the very high heterogeneity (I² = 97%) the results should be interpreted with caution.

Our decision to divide the EPO studies into early and late based on initiating EPO treatment at the cut-off of less than/or equal to 7 days of age for early and > 7 days for late treatment with EPO, although somewhat arbitrary, was chosen based on previously published meta-analyses (Garcia 2002; Kotto-Kome 2004) to allow us to compare the results between our reviews and previously published reviews.

In this update there is a trend towards a non-significant increased risk of retinopathy (ROP) of prematurity.

The concern for an increased risk of ROP is real and because of the arbitrary cut-off age for early vs late EPO treatment we decided post hoc to perform a secondary analysis including all studies that reported on ROP stage greater than/or equal to 3 regardless of the age at initiation of EPO treatment. This analysis is included in the updated Early EPO review and shows an increased risk of ROP greater than/or equal to 3 when all studies of EPO regardless of age at initiation of the treatment were included in the analysis.

Contributors

Dr. R. Ohls


This review is published as a Cochrane review in The Cochrane Library, Issue 4, 2014 (see http://www.thecochranelibrary.com External Web Site Policy 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.