Home > Health & Research > Health Education Campaigns & Programs > Cochrane Neonatal Review > Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants

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

Skip sharing on social media links
Share this:

Authors

Sanjay M Aher1, Arne Ohlsson2

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & 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. 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.

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 Ontario M5G 1X5
Canada

E-mail: aohlsson@mtsinai.on.ca

Dates

Assessed as Up-to-date: 09 May 2012
Date of Search: 24 March 2012
Next Stage Expected: 24 March 2014
Protocol First Published: Issue 3, 2004
Review First Published: Issue 3, 2006
Last Citation Issue: Issue 10, 2012

What's new

Date / Event Description
06 May 2012
New citation: conclusions not changed

Updated search found no new trials.

No changes to conclusions.

06 May 2012
Updated

This update in May 2012 updates the review "Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants" published in the Cochrane Database of Systematic Reviews, Issue 3, 2006 and with last update in October 2009 (Aher 2006).

History

Date / Event Description
09 September 2009
Updated

This review (2009) updates the existing review "Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants" published in the Cochrane Database of Systematic Reviews, Issue 3, 2006 (Aher 2006).

Updated search found no new trials.

No changes to conclusions.

17 September 2008
Amended

Converted to new review format.

08 May 2006
New citation: conclusions changed

Substantive amendment

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 early versus late initiation of EPO in reducing red blood cell (RBC) transfusions in preterm and/or low birth weight (LBW) infants.

Search methods

The standard search of the Cochrane Neonatal Review Group (CNRG) was performed in 2006 and updated in 2009. Updated search in September 2009 as follows: The Cochrane Library, MEDLINE (search via PubMed), CINAHL and EMBASE were searched from 2005 to September 2009. The searches were repeated in March 2012. The Pediatric Academic Societies' Annual meetings were searched electronically from 2000 to 2012 at Abstracts2ViewTM as were clinical trials registries (ClinicalTrials.gov, Controlled-Trials.com External Web Site Policy, and WHO International Clinical Trials Registry Platform (ICTRP) External Web Site Policy.

Selection criteria

Randomised or quasi-randomised controlled trials enrolling preterm or LBW infants less than eight days of age. Intervention: Early initiation of EPO (initiated at less than eight days of age) versus late initiation of EPO (initiated at eight to 28 days of age).

Data collection and analysis

The standard methods of the CNRG were followed. Weighted treatment effects included typical risk ratio (RR), typical risk difference (RD), number needed to treat to benefit (NNTB), number needed to treat to harm (NNTH) and mean difference (MD), all with 95% confidence intervals (CI). A fixed-effect model was used for meta-analyses and heterogeneity was evaluated using the I-squared (I2) test.

Results

No new trials were identified in March of 2012. Two high quality randomised double-blind controlled studies enrolling 262 infants were identified. A non-significant reduction in the 'Use of one or more RBC transfusions' [two studies 262 infants; typical RR 0.91 (95% CI 0.78 to 1.06); typical RD -0.07 (95% CI -0.18 to 0.04; I2 = 0% for both RR and RD] favouring early EPO was noted. Early EPO administration resulted in a non-significant reduction in the "number of transfusions per infant" compared with late EPO [typical MD - 0.32 (95% CI -0.92 to 0.29)]. There was no significant reduction in total volume of blood transfused per infant or in the number of donors to whom the infant was exposed. Early EPO led to a significant increase in the risk of retinopathy of prematurity (ROP) (all stages) [two studies, 191 infants; typical RR 1.40 (95% CI 1.05 to 1.86); typical RD 0.16 (95% CI 0.03 to 0.29); NNTH 6 (95% CI 3 to 33)]. There was high heterogeneity for this outcome (I2 = 86% for RR and 81% for RD). Both studies (191 infants) reported on ROP stage greater than/or equal to 3. No statistically significant increase in risk was noted [typical RR 1.56 (95% CI 0.71 to 3.41); typical RD 0.05 (-0.04 to 0.14)] There was no heterogeneity for this outcome (0% for both RR and RD). No other important favourable or adverse neonatal outcomes or side effects were reported.

Authors' conclusions

The use of early EPO did not significantly reduce the 'Use of one or more RBC transfusions' or the 'Number of transfusions per infant" compared with late EPO administration. The finding of a statistically significant increased risk of ROP (any grade) and a similar trend for ROP stage greater than/or equal to 3 with early EPO treatment is of great concern.

Plain language summary

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

The number of red blood cells falls after birth in preterm infants due to the natural breakdown of erythrocytes and blood letting. Low levels of erythropoietin (EPO), a substance in the blood that stimulates red blood cell production in preterm infants, provide a rationale for the use of EPO to prevent or treat anaemia. A total of 262 infants born preterm have been enrolled in two studies of early versus late administration of EPO to prevent blood transfusions. There were no demonstrable benefits of early versus late administration of EPO with regards to reduction in the use of red blood cell transfusions, number of transfusions, the amount of red cells transfused or number of donor exposures per infant. However, the use of early EPO compared with late EPO administration increases the risk of retinopathy of prematurity, a serious complication in babies born before term. Currently, there is a lack of evidence that either treatment confers any substantial benefits with regard to any donor blood exposure, as many infants enrolled in both studies were exposed to donor blood prior to study entry, and early EPO increases the risk of retinopathy of prematurity. Neither early nor late administration of EPO is recommended.

[top]

Background

Description of the condition

The haemoglobin concentration 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 haematocrit 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 haematocrit is not "physiologic", as it is associated with clinical findings that prompt red blood cell transfusions. The diagnostic accuracy of different clinical signs and laboratory findings has not been studied. It is still unknown how low haematocrit levels can fall before clinical signs of anaemia of prematurity occur and what is the minimal haematocrit level acceptable in infants requiring supplemental oxygen (Ohls 2002). Nevertheless, "top-up" transfusions to treat low haemoglobin or low haematocrit 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 for older children and adults. Brown and colleagues reported that, between days two and 30 of life, the mean EPO concentration was 10 mLU/mL, as compared to 15 mLU/mL in concurrently studied adults (Brown 1983). A low plasma EPO level is a key reason that nadir haematocrit values of preterm infants are lower than those of term infants (Stockman 1986; Dallman 1981). Low plasma EPO levels provide a rationale for use of EPO in the prevention or treatment of anaemia of prematurity. Studies in newborn monkeys and sheep have demonstrated that neonates have a large volume of distribution and more rapid elimination of EPO, necessitating the use of higher doses than required for adults (Ohls 2000). A 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).

Preterm infants need iron 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 EPO treatment. The use of higher, more effective doses of EPO might be expected to be particularly likely to increase iron demand and the risk of iron deficiency (Genen 2004). Iron supplementation during EPO 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).

Why it is important to do this review

The efficacy of EPO in anaemia of prematurity has recently been systematically reviewed (Vamvakas 2001; Garcia 2002; Kotto-Kome 2004). Vamvakas et al concluded that there is extreme variation in the results, and until this variation is better understood, it is too early to recommend EPO as standard treatment for the anaemia of prematurity (Vamvakas 2001). Garcia et al concluded that administering EPO to VLBW neonates can result in a modest reduction in late erythrocyte transfusions and that this effect is dependent on the dose of EPO used (Garcia 2002). Kotto-Kome et al concluded that if EPO is begun in the first week of life, a moderate reduction can be expected in the proportion of VLBW neonates transfused. The reduction is less significant for early transfusion than for late transfusion (Kotto-Kome 2004).

Additional studies of EPO in preterm or LBW infants have been published since the reviews noted above, justifying additional reviews. The cut-off of less than eight days of age for early and greater than/or equal to eight days for late treatment with EPO, although somewhat arbitrary, was chosen based on previously published meta-analyses (Garcia 2002; Kotto-Kome 2004).

This review compares early administration of EPO (starting in infants less than eight days of age) versus late administration of EPO (starting greater than/or equal to eight days). The main rationale for this review was to evaluate whether early treatment with EPO in preterm infants is more effective than late treatment to decrease exposure to RBC transfusion and the total transfusions required. We performed a systematic review to compare all available studies where EPO was begun during first week of life versus EPO started after the first week of life to assess the effect on any and total number of erythrocyte transfusions.

Objectives

Primary objective:

To assess the effectiveness and safety of early (before eight days after birth) versus late (between eight to 28 days after birth) initiation of EPO in reducing the need for red blood cell transfusions in preterm and/or low birth weight infants.

Subgroup analyses:

We planned subgroup analyses within this review for 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 (greater than/or equal to 5 mg/kg/day) doses of supplemental iron administered by any route.

[top]

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 less than eight days of age.

Types of interventions

Early initiation of EPO (initiated before eight days of age, using any dose, route or duration) versus late initiation of EPO (initiated between eight to 28 days of age, using any dose, route or duration).

Types of outcome measures

Primary outcomes
  1. Use of one or more red blood cell (RBC) transfusions.
Secondary outcomes
  1. the total volume (mL/kg or mL/kg/day) of RBCs 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);
  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 severe IVH (grades III and IV);
  9. periventricular leukomalacia (PVL); cystic changes in the periventricular areas;
  10. length of hospital stay;
  11. bronchopulmonary dysplasia (BPD) (supplemental oxygen at 28 days of age or at 36 weeks postmenstrual age and compatible X-ray);
  12. sudden infant death (SID) after discharge;
  13. 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;
  14. neutropenia;
  15. any side effects reported in the trials.

Search methods for identification of studies

Electronic searches

The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2006, Issue 2) was searched to identify relevant randomised and quasi-randomised controlled trials. MEDLINE was searched for relevant articles published from 1966 to November 2005 using the following MeSH terms or text words: (exp Erythropoietin/OR erythropoietin:.mp. OR rhuepo.mp.) AND (anaemia/OR exp anaemia, neonatal/) AND (blood transfusion/OR blood component transfusion/OR erythrocyte transfusion/) AND (infant, newborn/OR infant, low birth weight/OR infant, very low birth weight/OR infant, premature/OR exp Infant, Premature, Diseases) OR (neonate: OR prematur*: OR newborn:).mp. OR newborn infant [age limit]) AND (clinical trial.pt. OR Randomized Controlled Trials/OR (random: OR rct OR rcts OR blind OR blinded OR placebo:).mp. OR (review.pt. OR review, academic.pt.) AND human. EMBASE from 1980 to November 2005 and CINAHL 1982 to November 2005 using the following MeSH terms or text words: (Erythropoietin/OR erythropoietin: OR epo OR epogen OR epoetin: OR (rhuepo).mp. AND (anaemia/OR exp anaemia, neonatal/) AND (blood transfusion/OR exp blood component transfusion/OR erythrocytes/) AND exp Infant, Premature, Diseases/OR infant, newborn/OR infant, low birth weight/OR infant, very low birth weight/OR infant, premature/OR (neonate: OR newborn: OR prematur*:).mp. OR newborn infant [age limit].

In September 2009, we updated the search as follows: The Cochrane Library, MEDLINE (search via PubMed), CINAHL and EMBASE were searched from 2005 to September 2009.

Search terms: erythropoietin OR rhuepo AND anaemia OR anaemia AND blood transfusion OR blood component transfusion OR erythrocyte transfusion. Limits: human, infant and clinical trial. No language restrictions were applied. ClinicalTrials.gov was also searched with no date restriction. Search terms: Erythropoietin OR rhuepo AND infant.

In March 2012, we updated the searches as per above. In addition we searched clinical trials registries (ClinicalTrials.gov, Controlled-Trials.com External Web Site Policy, and WHO International Clinical Trials Registry Platform (ICTRP) External Web Site Policy).

Searching other resources

In addition to the electronic searches, manual searches of bibliographies and personal files were performed. No language restrictions were applied.

Abstracts published from the Pediatric Academic Societies' Meetings and the European Society of Pediatric Research Meetings (published in Pediatric Research) were handsearched from 1980 to April 2006.

In May 2012 abstracts from the Pediatric Academic Societies' Annual Meetings were searched electronically at Abstracts2ViewTM from 2000 to 2012.

Data collection and analysis

The standard review methods of the Cochrane Neonatal Review Group and the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011) were used.

Selection of studies

For the original review, both review authors assessed all abstracts and published studies identified as potentially relevant by the literature search for inclusion in the review.

Data extraction and management

For the original review, each review author extracted data separately on a data abstraction form. The information was then compared and differences were resolved by consensus. One review author (AO) entered data into RevMan 5.1 (RevMan 2011) and the other (SA) cross checked the printout against his own data abstraction forms and any errors were corrected. We planned that for any studies identified only as abstracts, we would contact the primary author to obtain further information.

Assessment of risk of bias in included studies

For the original review, the quality of included trials was evaluated independently by the review authors, using the following criteria:
Blinding of randomisation; Blinding of intervention; Blinding of outcome measure assessment; Completeness of follow-up. There are three potential answers to these questions yes, no, cannot tell. This information was added to the Characteristics of Included Studies table.

For the update in 2012, the following issues were evaluated and entered into the 'Risk of bias' table.

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

For each included study, we categorised the risk of bias regarding allocation concealment as:

  • 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;
  • Unclear 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 assignment;
  • 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 described 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 (> 10% missing data);
  • Unclear risk - no or unclear information provided.
Reporting bias

For each included study, we described 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 pre-specified outcomes and all expected outcomes of interest to the review have been reported);

High risk - inadequate (where not all the study's pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; 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 described 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 looks at the data with the results made known to the investigators, difference in number of patients 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, independent quality assessments were conducted by two review authors (SA, AO), who were not blinded to authors, institution or journal of publication.

The update in 2012 was conducted by one author (AO).

Measures of treatment effect

Statistical analyses were performed using Review Manager software (RevMan 5.1) (RevMan 2011). Categorical data were analysed using risk ratio (RR), risk difference (RD), number needed to treat to benefit (NNTB) or number needed to harm (NNTH) for dichotomous outcomes and mean difference (MD) for continuous data. The 95% Confidence interval (CI) was reported on all estimates.

Assessment of heterogeneity

We examined heterogeneity between trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I2 statistic (Higgins 2003). We used the following criteria for describing the percentages of heterogeneity; < 25% no heterogeneity, > 25% to 49% low heterogeneity, 50% to 74% moderate heterogeneity and greater than/or equal to 75% high heterogeneity. If we detected statistical heterogeneity, we planned to explore the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) using post hoc subgroup analyses if possible.

Data synthesis

The analysis was performed using RevMan5.1 (RevMan 2011). 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 planned subgroup analyses within this review for 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 (greater than/or equal to 5 mg/kg/day) doses of supplemental iron administered by any route.

[top]

Results

Description of studies

The update in 2012 did not identify any additional studies. Two studies enrolling 268 infants were identified (Donato 2000; Maier 2002). For details of the studies see table Characteristics of Included Studies. One non randomised study was excluded (Rudzinska 2002). For transfusion guidelines see Additional table (Table 1 Transfusion guidelines).

Donato 2000: This was a blinded multicentre randomised placebo-controlled study conducted in seven private hospitals in Buenos Aires, Argentina between July 1996 to October 1997.

  • Objective: To evaluate whether early treatment (day two to three of life) with EPO in preterm infants with birthweight < 1250 g 1) decreases the number of transfusions during the first two weeks of life; and 2) is more effective than late treatment (day 15) to decrease the total transfusion requirement.
  • Population: Infants with a birthweight < 1250 g and a gestational age < 32 weeks. Infants were excluded if they had major congenital malformations, chromosomal anomalies, haemolytic and/or haemorrhagic disease, intrauterine infections, systemic hypertension, and neutropenia (absolute neutrophil count < 1.5x109/L). No infant was excluded based on severity of illness.
  • Intervention: In the early EPO group, infants received EPO 1250 IU/kg/week (high dose) intravenously (iv) from day two to day 14 of life; in the late EPO group, infants received placebo during this time period. Subsequently, all infants received EPO 750 IU/kg/week (high dose) subcutaneously (sc) for six additional weeks. All infants were given oral iron 6 mg/kg/day as ferrous sulphate (high dose), starting as soon as enteral feedings were initiated and continuing during the entire treatment period as well as folic acid.
  • Outcomes assessed: Number of transfusions during the first two weeks of life and the total transfusion requirement per infant. Other outcomes included use of one ore more RBC transfusions, mortality during hospital stay, intraventricular haemorrhage (grade III/IV), weight gain, ROP (during the study period and among infants examined during the first year of life) and sudden infant death syndrome (SIDS).

Maier 2002: This was a blinded multicentre randomised placebo-controlled study conducted in 14 centres in four European countries (Belgium, France, Germany, Switzerland) between May 1998 to June 1999. An early EPO, a late EPO and a control group were studied. The early EPO and late EPO groups were eligible for inclusion in this review.

  • Objective: To investigate whether EPO reduces the need for transfusion in ELBW infants and to determine the optimal time for treatment.
  • Population: Infants with a birthweight between 500 to 999 g were eligible. Infants were excluded prior to randomisation if they had cyanotic heart disease, major congenital malformation requiring surgery, mother had received an investigational drug during pregnancy, gestational age > 30 completed weeks or lack of consent.
  • Intervention: In the early EPO group infants received 750 IU/kg/week of EPO (high dose) from the first week of life for nine weeks. In the late EPO group, infants received the same treatment three weeks later (high dose). Treatment in both groups continued until days 65 to 68 of life. EPO was given iv in both groups as long as the infant had an iv line in place and sc thereafter. The late EPO group (until EPO was given) received sham-injections. Enteral iron 3 mg/kg was given to all infants from days three to five (low dose) and was increased at days 12 to 14 to 6 mg/kg/day (high dose) and to 9 mg/kg/day at days 24 to 26 of life (high dose).
  • Outcomes assessed: The primary outcome was no transfusion and haematocrit levels never below 30%. Other outcomes included use of one ore more RBC transfusions, mean number of transfusions per infant, volume of red cells transfused (ml/kg/day), mortality during hospital stay, NEC, IVH (grade III/IV), PVL, ROP, BPD, length of hospital stay).

Risk of bias in included studies

Neither of the two trials provided information on how the random sequence was generated. Both included studies (Donato 2000; Maier 2002) were randomised double-blind controlled studies with concealed allocation. Donato et al. (Donato 2000) report that infants were assigned to one of the two groups at birth through a central randomisation process. Placebo and EPO were indistinguishable before and after reconstitution. Parents, investigators, and nurses were unaware of each patient's treatment group. Maier et al. (Maier 2002) concealed the allocation by means of numbered sealed envelopes. To assure blinding and to avoid placebo injections, sham injections were given to the late EPO group prior to starting treatment with EPO. In both studies, outcomes were assessed by individuals unaware of treatment assignment. Sample size calculations were performed in both studies. Six infants with significant protocol violations were excluded from the study by Donato et al (Donato 2000). The group assignment was not reported, but it is likely that the excluded infants were equally distributed between the groups as 57 infants remained in each group. In the study by Maier et al (Maier 2002), no infant was withdrawn from the early EPO and late EPO groups. Follow-up was complete for the study by Maier (Maier 2002), but not in the study by Donato (Donato 2000). (See Table Characteristics of Included Studies). Both studies were industry funded (Donato 2000; Maier 2002). We obtained unpublished data from the authors of both studies.

Effects of interventions

Early (zero to seven days) versus late (eight to 28 days) initiation of EPO (Comparison 01):

PRIMARY OUTCOME:
Outcome 1.1: Use of one or more red blood cell transfusions (Figure 1)

Both studies reporting on 262 infants assessed the use of one or more red blood cell transfusions. Neither found a significant effect. The meta-analysis did not find a significant effect [typical risk ratio (RR) 0.91 (95% confidence interval (CI) 0.78 to 1.06); typical risk difference (RD) -0.07 (95% CI -0.18 to 0.04)]. This result was consistent across the two studies.There was no heterogeneity for RR or RD (0%).

SECONDARY OUTCOMES:
Outcome 1.2.1 and 1.2.2: The total volume (mL/kg) of red blood cells transfused per infant

Donato et al (Donato 2000) reported on this outcome in 144 infants. They did not find a significant effect [mean difference (MD) 0.30 mL/kg (95% CI -13.04 to 13.64)].
We obtained unpublished data from Maier et al. (Maier 2002). They reported on the volume of red blood cells transfused in 148 infants in mL/kg/day. They did not find a significant effect [MD -0.80 mL/kg/day (95% CI -1.88 to 0.28)]. Test for heterogeneity not applicable.

Outcome 1.3: Number of red blood cell transfusions per infant

Both studies reporting on 262 infants assessed the number of red blood cell transfusions per infant. Neither found a significant effect. The meta-analysis did not find a significant effect [typical MD -0.32, 95% CI -0.92 to 0.29)]. This result was consistent across studies. There was no heterogeneity for this outcome (0%).

Outcome 1.4: Number of donors to whom the infant was exposed

Maier (Maier 2002) reported on this outcome in 148 infants. They did not find a significant effect [MD -0.20; (95% CI -0.67 to 0.27)]. Test for heterogeneity not applicable.

Outcome 1.5: Mortality during initial hospital stay (all causes)

Both studies reporting on 262 infants assessed mortality during initial hospital stay. Neither found a significant effect. The meta-analysis did not find a significant effect [typical RR 0.76 (95% CI 0.39 to 1.51); RD - 0.03, (95% CI -0.11 to 0.05)]. This result was consistent across studies. There was no heterogeneity for RR or RD (0%).

Outcome 1.6: Retinopathy of prematurity (ROP) (all stages) (Figure 2)

We obtained unpublished data from both lead authors of the studies included in this review for this outcome. Both studies assessed ROP in a total of 191 infants. Donato et al reported on the rate of ROP in infants examined during the first year of life. Maier et al reported on the worst stage of ROP during the study. There was a significant increase in the incidence of ROP (all stages) in the study by Donato et al (Donato 2000), but not in the study by Maier et al (Maier 2002). The meta-analysis found a significant effect [typical RR 1.40 (95% CI 1.05 to 1.86); typical RD 0.16 (95% CI 0.03 to 0.29); number needed to harm (NNTH); 6 (95% CI 3 to 33)].There was high heterogeneity for this outcome (RR P = 0.007; I2 = 86%; RD P = 0.02; I2 = 81%).

Outcome 1.7: Retinopathy of prematurity (stage greater than/or equal to 3)

We obtained unpublished data from both lead authors of the studies included in this review for this outcome. Both studies assessed this outcome in a total of 191 infants. Donato et al reported on the rate of ROP in infants examined during the first year of life. Maier et al reported on the worst stage of ROP during the study. Neither found a significant effect. The meta-analysis did not find a significant effect [typical RR 1.56 (95% CI 0.71 to 3.41); typical RD 0.05 (95% CI -0.04 to 0.14). This result was consistent across studies.There was no heterogeneity for RR or RD (0%).

Proven sepsis (Clinical symptoms and signs of sepsis and positive blood culture) (No outcome table).

No data for this outcome were reported

Outcome 1.8 Necrotising enterocolitis (NEC) (Bell's stage II or more)

Maier (Maier 2002) reported on this outcome in 148 infants. The study did not find a significant effect [RR 1.00 (95% CI 0.37 to 2.71); RD 0.00 (95% CI -0.09 to 0.09)].

Outcome 1.9.1: Intraventricular haemorrhage (IVH); grades III and IV

Both studies (n = 262) reported on the incidence of IVH grade III and IV. Neither found a significant effect. The meta-analysis did not find a significant effect [typical RR 1.33 (95% CI 0.84 to 2.13); typical RD 0.06 (95% CI -0.04 to 0.16)]. There was no heterogeneity for RR or RD (0%). The results were consistent across studies.

Outcome 1.10: Periventricular leukomalacia (PVL); cystic changes in the periventricular areas

Maier (Maier 2002) reported on PVL in 148 infants. The study did not find a significant effect for RR [RR 0.09 (95% CI 0.01, 1.62)]; but for RD [RD -0.07 (95% CI -0.13 to -0.01)]; number needed to benefit (NNTB) = 14 (95% CI 8 to 100). Test for heterogeneity not applicable.

Length of hospital stay (No outcome table)

Maier (Maier 2002) reported on the length of hospital stay. The median (quartiles) number of days in hospital was 87 days (73 to 107) in the early EPO group and 90 days (68 to 110) in the late group. There was no statistically significant difference (P = 0.94) across three groups including a control group (87 days; 69 to 108).

Outcome 1.11: Bronchopulmonary dysplasia (BPD) (supplementary oxygen at 28 days of age or at 36 weeks postmenstrual age and compatible X-ray)

Maier (Maier 2002) reported on the need for oxygen at 36 weeks postmenstrual age in 148 infants. The study did not find a significant effect [RR 0.90 (95% CI 0.53 to 1.54); RD -0.03 (95% -0.17 to 0.12). Test for heterogeneity not applicable.

Outcome 1.12: Sudden infant death after discharge

Donato (Donato 2000) reported no deaths in either group after a follow-up period of nine to 24 months after discharge.

Long-term outcomes assessed at any age beyond one year of age by a validated cognitive, motor, language, or behavioural/school/social interaction/adaptation test (No outcome table).

No data for these outcomes were reported.

Neutropenia (No outcome table)

Donato (Donato 2000) reported that the incidence of neutropenia was similar in the two groups, but did not provide any data. Maier (Maier 2002) reported that neutrophil counts did not differ between groups, but did not provide any data.

Any side effects reported in the trials (No outcome table)

Donato (Donato 2000) stated "No clinical adverse effect attributable to EPO, oral iron, or folic acid administration was observed".

Outcome 1.13: Weight gain during the study period (This outcome was not included in the protocol for this review)

In the study by Donato (Donato 2000), the MD for weight gain during the entire study period was 6.0 g (95% CI -137.37 to 149.37) comparing the early EPO group to the late EPO group. In the study by Maier (Maier 2002), the median weight gain was 890 g in the early EPO group and 872 g in the late EPO group during the first nine weeks of life. Quartiles were not provided.

Outcome 1.14: Thrombocytosis (This outcome was not included in the protocol for this review)

Donato (Donato 2000) reported on thrombocytosis (platelet count > 500 x 109/L) in 114 infants. The study did not show a significant effect [RR 1.06 (95% CI 0.61 to 1.84); RD 0.02 (95% CI -0.15 to 0.19)].

In the study by Maier (Maier 2002) the median increase in platelet count during the study was 118 x 109/L in the early EPO group, 155x109/L in the late EPO group and 186 x 109/L in the control group. A P value was not reported.

Subgroup analyses

We planned subgroup analyses within this review for low (< 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO, and low (< 5 mg/kg/day) and high (> 5 mg/kg/day) doses of supplemental iron administered by any route. However, both included studies used high dose of EPO and high dose of iron, and therefore, subgroup analyses were not performed.

Discussion

The main objective of this review was to assess whether early versus late treatment with EPO would reduce the need for one or more red blood cell transfusions. Two high quality placebo-controlled, multicentre trials conducted in Argentina and in four European countries were identified for this review. These two studies included a total of 262 preterm infants with very low/extremely low birth weight, who were enrolled at approximately three days of age. The dose of EPO varied from 750 to 1250 IU/kg/week (high dose). All infants received supplemental iron (high dose). Both studies used well defined, although not identical, criteria for red blood cell transfusions (see Additional table; Table 1 Transfusion guidelines). In the study by Maier et al (Maier 2002), more than 30% of the enrolled infants had received red blood transfusions prior to study entry. In the study by Donato et al (Donato 2000), 14% had received red blood cell transfusions prior to enrolment.

Early treatment with EPO did not significantly reduce the risk for an infant of receiving a red blood cell transfusion compared with late treatment. There was no statistically significant heterogeneity for this or any of the other effectiveness outcomes of interest, justifying the combination of the results from the two studies when possible. There was no significant reduction in the number of transfusions per infant nor in the number of donors to whom the infant was exposed.

The results for other secondary outcomes included in this review reached statistical significance only for periventricular leukomalacia (PVL) and retinopathy of prematurity (ROP). PVL was reported in one study (Maier 2002). There was a statistically significant reduction for risk difference (RD) but not for risk ratio (RR) (there was no case of PVL in the early EPO group). We consider this finding of borderline statistical significance.

A total of 191 infants of 268 infants enrolled were assessed for ROP (all stages, and stage greater than/or equal to 3). The lack of outcome ascertainment in a large number of infants is of concern. There was a statistically significant increased risk of ROP (any stage reported). The typical RR was 1.45 (95% CI 1.08 to 1.95), the typical RD was 0.18 (95% CI 0.05 to 0.31) and the number needed to harm (NNTH) was six (95% CI 3 to 20). There was statistically significant (high) heterogeneity for this outcome. The heterogeneity is likely at least in part due to differences in the rates of ROP and the different times in the life of the infants when ROP was assessed. There were no striking differences in the dose of EPO or iron used in the two studies. The transfusion guidelines were most strict in the study by Donato et al (Donato 2000). It is possible that there were differences in many aspects of care between Argentina and the four countries enrolling infants in Europe. These differences may have contributed to the differences in rates of ROP. The outcome of ROP (stage greater than/or equal to 3) was assessed in the same population as all stages of ROP. The meta-analysis did not find a significant effect [typical RR 1.56 (95% CI 0.71 to 3.41); typical RD 0.05 (95% CI -0.04 to 0.14)]. This result was consistent across studies. There was no heterogeneity for this outcome. The increased risk of ROP is of concern. The results are similar to the Cochrane review of "Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants" (Ohlsson 2006) (updated in 2012). No other important neonatal adverse outcomes or side effects were noted.

The results of this systematic review should be considered in conjunction with our other two Cochrane reviews (both updated in 2012) that have been conducted "Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants" (Ohlsson 2006) and "Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants" (Aher 2006a). In our review of "Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants" (Ohlsson 2006), we noted an increased risk of ROP. Based on current evidence, an increased risk of developing ROP with early EPO cannot be excluded. For detailed discussion of the potential association with ROP and EPO, please refer to the Cochrane review of "Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants" (Ohlsson 2006) that was updated in 2012.

Other systematic reviews of EPO do not address the issue of early versus late treatment. The trials included in this review (Donato 2000; Maier 2002) were not included in the meta-analyses by Vamvakas et al (Vamvakas 2001) and Garcia et al (Garcia 2002). Kotto-Kome et al (Kotto-Kome 2004) included both trials in their meta-analysis of the effect of early EPO on early and late erythrocyte transfusions, but did not compare the effectiveness of early versus late EPO administration. None of these meta-analyses included analyses on the incidence of ROP.

Early treatment with EPO did not confer any major benefits compared with late EPO treatment. The major obstacle to reduce any donor exposure during the hospital stay is that as many as one third of these infants will require a red blood cell transfusion prior to the initiation of treatment with EPO. In the study by Maier et al (Maier 2002), 12 of the 14 centres used satellite packs of the original red cell pack to reduce donor exposure in both groups. The use of satellite packs and conservative transfusion guidelines reduces the exposure to multiple donors during the hospitalisation for preterm infants.

It is unlikely that long-acting EPO [Aranesp (Darbepopoietin alfa, Amgen)] would confer any benefits with regards to any donor exposure, but could reduce the number of injections the infant would require (Ohls 2004). To date, only a dose finding trial has been published (Warwood 2005). The authors concluded, based on pharmacodynamic and pharmacokinetic findings, that darbepoetin dosing in neonates would require a higher unit dose/kg and a shorter dosing interval than are generally used for anaemic adults (Warwood 2005).

Administration of EPO could potentially have a neuroprotective effect in preterm infants, especially in infants with perinatal asphyxia (Dame 2001; Juul 2002). This aspect of EPO use will be systematically reviewed separately (Yu 2010).

Authors' conclusions

Implications for practice

Currently there is a lack of evidence that early EPO confers any substantial benefits compared with late administration of EPO, particularly with regard to any donor blood exposure, as a large proportion of infants enrolled in both studies were exposed to donor blood prior to study entry. There is a concern of an increased risk of ROP following early administration of EPO, and such treatment is not recommended.

Implications for research

The impact of either early or late administration of EPO on 'any donor exposure' is likely to be minimal, as many infants would have been exposed to donor blood during the first few days of life, when they are most likely to receive a red blood cell transfusion; a time period during which EPO treatment could not possibly prevent donor exposure. Any ongoing study of EPO should carefully monitor the incidence of ROP and data/safety monitoring committees should be informed of its occurrence. Further studies to compare early versus late administration of EPO are not justified. Research should focus on reducing blood letting and the use of satellite packs from the same donor, should red blood cell transfusions be necessary.

Acknowledgements

We would like to thank Ms. Elizabeth Uleryk, Chief Librarian, the Hospital for Sick Children (SickKids, ) Toronto, Ontario, Canada for developing the search strategy. We are thankful to Dr. Hugo Donato, Buenos Aires, Argentina, and to Dr. Rolf Maier, Zentrum für Kinder- und Jugendmedizin, Philipps-Universität, Marburg, Germany, who provided us with unpublished data regarding their studies.

The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.

Contributions of authors

Sanjay Aher (SA) and Arne Ohlsson (AO) contributed equally to all sections of the protocol for this review. The literature search was conducted with the help of an experienced librarian. Both review authors identified potentially eligible studies from the printouts and agreed on which trials to include. Data collection forms were designed and agreed upon by the two review authors. Quality assessments were conducted and data were abstracted by both review authors independently and compared. One review author (AO) entered the data into RevMan 4.2.8 and the other review author (SA) checked for accuracy. One review author (AO) wrote the full review and the other review author (SA) read and made changes. Changes were made by both review authors following feedback from the editors of the review group.

The September 2009 update was conducted centrally by the Cochrane Neonatal Review Group staff (Yolanda Montagne, Roger Soll, Diane Haughton) and approved by AO.

The March 2012 update was performed by one of the authors (AO).

Declarations of interest

  • None noted.

Differences between protocol and review

We added two additional outcomes: weight gain during the study (Analysis 1.13) and thrombocytosis (Analysis 1.14) not described in the protocol as these were reported in the included trials.

Potential conflict of interest

  • None noted.

[top]

Characteristics of studies

Characteristics of Included Studies

Donato 2000

Methods

Randomised placebo controlled study

  1. Blinding of randomisation- yes
  2. Blinding of intervention - yes
  3. Blinding of outcome-measure assessment - yes
  4. Completeness follow-up - no (see notes)
Participants

120 infants with BW < 1250 g and GA < 32 weeks were included
Exclusion criteria were: major congenital malformations, chromosomal anomalies, haemolytic and/or hemorrhagic disease, intrauterine infections, systemic hypertension, neutropenia
(no patient was excluded based on the severity of disease)
Recruitment period July 1996 to October 1997
7 private hospitals in Buenos Aires, Argentina

Interventions

Infants were randomised to two groups: In the early EPO group 57 infants (mean GA 27.7 wk ± SD 2.4; mean BW 916 ± SD 217) received rHuEPO (Hemax, Bio Sidus S.A, Buenos Aires, Argentina) [1250 IU/kg/week iv (high dose)] starting before 72 hours of life and until day 14 of life. In the late EPO group 57 infants (mean GA 27.9 weeks ± SD 2.5; mean BW 972 ± SD 206 received placebo (human seroalbumin) throughout this period. Starting on the third week of life, both groups received rHuEPO 750 IU/kg/week, divided in 3 doses sc during 6 weeks. All infants were given oral iron 6 mg/kg/day as ferrous sulphate (high dose), starting as soon as enteral feedings were initiated and continuing during the entire treatment period

Outcomes

Use of one or more red blood cell transfusions
Mean number of transfusions per infant
Mortality during hospital stay
Number of transfusions per patient
Volume of transfused blood per patient (mL/kg)
ROP (during initial study period and during the first year of life) (data obtained from the authors)
Weight gain during study period
Neutropenia
SIDS
Adverse effects

Notes

Sample size calculation was performed
Transfusion guidelines were followed
6 infants (group not stated, but likely to be 3 infants in each group, as 57 infants remained in each group) with significant protocol violations were excluded
8 of 57 (14%) of patients in the early EPO group (mean number of transfusions 1.12; range 1 to 2) and 8 of 57 (14%) patients in the late EPO group (mean number of red blood cell transfusions 1.25; range 1 to 3) received red blood cell transfusions prior to study entry
This study received industry support (Bio Sidus S.A. Laboratory)

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

Central randomisation process

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

Completeness of follow-up - no

6 infants (group not stated, but likely to be 3 infants in each group) with significant protocol violations were excluded

Selective reporting (reporting bias) Unclear risk

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

Other bias Low risk

Appears free of other bias

Maier 2002

Methods

Randomised controlled study

  1. Blinding of randomisation - yes
  2. Blinding of intervention - yes
  3. Blinding of outcome-measure assessment - yes
  4. Completeness follow-up- yes
Participants

148 infants with BW 500 - 999 g
Exclusion criteria: cyanotic heart disease, major congenital malformation requiring surgery, administration of investigational drug during pregnancy, gestational age greater than/or equal to 30 completed weeks
Enrolment period May 1998 to June 1999
14 centres in 4 European countries (Belgium, France, Germany, Switzerland)

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, 28) weeks for BW 778 (660, 880) g] received 250 IU/kg of rHEPO on Mondays, Wednesdays and Fridays (NeoRecormon, F. Hofman-La Roche, Basel Switzerland) (750 IU/week, high dose) starting at days 3-5 of life.
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 was given to all infants from days 3 to 5 (low dose) and was increased at days 12 to 14 to 6 mg/kg/day (high dose) and to 9 mg/kg/day at days 24 to 26 of life (high dose), if transferrin saturation was < 30%. At transferrin saturation of 30% to 80%, the iron dose was kept at 6 mg/kg/day. At transferrin saturation > 80%, iron supplementation was interrupted.

Outcomes

Use of one or more red blood cell transfusions
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
24 (32%) of the infants in the early EPO group and 23 (31%) in the late EPO group received 1 to 3 transfusions before they entered the study.
A third group (control group, n =71) was included in this trial. This study (and this group) is included in the Cochrane reviews of early EPO vs. controls and late EPO vs. controls
Industry funded (F. Hoffman-La Roche, Basel Switzerland)

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 of the randomised infants (control group) was excluded from all evaluations because the parents withdrew consent a few hours after randomisation before the start of treatment phase

Selective reporting (reporting bias) Unclear risk

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

Other bias Low risk

Appears free of other bias

Footnotes

BW = birth weight
GA = gestational age
EPO = erythropoietin
g = grams
IU = international units
iv = intravenously
IVH = intraventricular haemorrhage
NEC = necrotising enterocolitis
NICU = neonatal intensive care unit
PVL = periventricular leukomalacia
rHuEPO = recombinant Human Erythropoietin
ROP = retinopathy of prematurity
sc subcutaneously
SD = standard deviation
SIDS = sudden infant death syndrome
vs - versus

Characteristics of excluded studies

Rudzinska 2002

Reason for exclusion

This was a controlled but not randomised study of early vs. late treatment with EPO in preterm infants with birth weights < 1500 g.

Footnotes

EPO = erythropoietin
g = grams
vs = versus

Additional tables

1 Transfusion guidelines

Reference

Indications

Donato 2000

Indications for transfusion followed slightly modified criteria described in a previous study (Shannon 1995).
The transfusion criteria were:

  1. Hct 0.31-0.35; Receiving > 35% supplemental hood oxygen; Intubated on CPAP or mechanical ventilation with mean airway pressure > 6 to 8 cm water
  2. Hct 0.21-0.30; Receiving < 35% supplemental hood oxygen; On CPAP or mechanical ventilation with mean airway pressure < 6 cm water; Significant apnoea and bradycardia (> 9 episodes in 12 hours or 2 episodes in 24 hours requiring bag and mask ventilation) while receiving therapeutic doses of methylxanthines; Heart rate >180 beats/min or respiratory rate > 80 breaths/min persisting for 24 hours; Weight gain < 10 g/day observed over four days while receiving > 100 kcal/kg/day; Undergoing surgery
  3. Hct < 21%; Asymptomatic with reticulocytes < 1%
  4. Transfuse at any Hct value if hypovolaemic shock develops
  5. Do not transfuse: to replace blood removed for laboratory tests; For low Hct alone. Patients were transfused with packed red blood cells at 15 mL/kg, administered in 2 -3 hours.

Maier 2002

Infants on assisted ventilation or > 40% of inspired oxygen were not transfused unless Hct dropped below 0.40. Spontaneously breathing infants were not transfused unless Hct dropped below 0.35 during the first 2 weeks of life, 0.30 during the 3rd to 4th weeks, and 0.25 thereafter. Transfusion was allowed when life threatening anaemia or hypovolaemia was diagnosed by the treating neonatologist, or surgery was planned. Twelve of the 14 centres used satellite packs of the original red cell pack to reduce donor exposure. The amount of packed red cells transfused was not reported.

Footnotes

CPAP = continuous positive airway pressure
Hct = haematocrit

[top]

References to studies

Included studies

Donato 2000

Published and unpublished data

Donato H, Vain N, Rendo P, Vivas N, Prudent L, Larguia M, et al. Effect of early versus late administration of human recombinant erythropoietin on transfusion requirements in premature infants: results of a randomized, placebo-controlled, multicenter trial. Pediatrics 2000;105:1066-72.

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 ameliorates anemia and reduces transfusion requirements in infants with birth weights below 1000 g. Journal of Pediatrics 2002;141:8-15.

Excluded studies

Rudzinska 2002

Rudzinska IM, Kornacka MK, Pawluch R. Treatment with human recombinant erythropoietin and frequency of retinopathy of prematurity [Leczenie preparatami ludzkiej rekombinowanej erytropoetyny a czeztosc retinopatii u noworodkow przedwczesnie urodzonych (Polish)]. Prezglad Lekarski 2002;59 Supplement 1:83-5.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

Aher 2006a

Aher S, Ohlsson A. Late erythropoietin for preventing red blood cell transfusion. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD004868. DOI: 10.1002/14651858.CD004868.pub2.

Brown 1983

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

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;79:228-35.

Finch 1982

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

Garcia 2002

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

Genen 2004

Genen LH, Klenoff H. Iron supplementation for erythropoietin-treated preterm infants. Cochrane Database of Systematic Reviews 2001, Issue 1. Art. No.: CD003061. DOI: 10.1002/14651858.CD003061.pub2.

Hesse 1997

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

Higgins 2003

Higgin JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. British Medical Journal 2003;327:557-60.

Higgins 2011

Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 [Computer program]. Higgins JPT, Green S. The Cochrane Collaboration, 2011.

Juul 2002

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

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;24:24-9.

Ohls 2000

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

Ohls 2002

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

Ohls 2004

Ohls RK, Dai A. Long-acting erythropoietin: clinical studies and potential uses in neonates. Clinics in Perinatology 2004;31:77-89.

Ohlsson 2006

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 2006, Issue 3. Art. No.: CD004863. DOI: 10.1002/14651858.CD004863.pub2.

RevMan 2011

Review Manager (RevMan) Version 5.1 [Computer program]. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011.

Shannon 1995

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 infants. Pediatrics 1995;95:1-8.

Stockman 1978

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

Stockman 1986

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

Strauss 1986

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

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;41:406-15.

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;25:725-30.

Widness 1996

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

Yu 2010

Yu Z, Guo X, Han S, Lu J, Sun Q, Ohlsson A. Erythropoietin for term and later preterm infants with hypoxicischemic encephalopathy (protocol). Cochrane Database of Systematic Reviews 2010, Issue 2. Art. No.: CD008316. DOI: 10.1002/14651858.CD008316.

Zipursky 2000

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

Other published versions of this review

Aher 2004

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 2004, Issue 3. Art. No.: CD004865. DOI: 10.1002/14651858.CD004865.pub2.

Aher 2006

Aher SM, Ohlsson A. Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD004865. DOI: 10.1002/14651858.CD004865.pub2.

Classification pending references

  • None noted.

[top]

Data and analyses

1 Early (0-7 days) versus late (8-28 days) initiation of EPO

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 2 262 Risk Ratio (M-H, Fixed, 95% CI) 0.91 [0.78, 1.06]
1.2 Total volume of red blood cells transfused per infant 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
1.2.1 Total volume of red blood cells transfused (mL/kg) 1 114 Mean Difference (IV, Fixed, 95% CI) 0.30 [-13.04, 13.64]
1.2.2 Total volume of red cells transfused (mL/kg/day) 1 148 Mean Difference (IV, Fixed, 95% CI) -0.80 [-1.88, 0.28]
1.3 Number of red blood cell transfusions per infant 2 262 Mean Difference (IV, Fixed, 95% CI) -0.32 [-0.92, 0.29]
1.4 Number of donors the infant was exposed to 1 148 Mean Difference (IV, Fixed, 95% CI) -0.20 [-0.67, 0.27]
1.5 Mortality during initial hospital stay (all causes) 2 262 Risk Ratio (M-H, Fixed, 95% CI) 0.76 [0.39, 1.51]
1.6 Retinopathy of prematurity (all stages) 2 191 Risk Ratio (M-H, Fixed, 95% CI) 1.40 [1.05, 1.86]
1.7 Retinopathy of prematurity (stage greater than/or equal to 3) 2 191 Risk Ratio (M-H, Fixed, 95% CI) 1.56 [0.71, 3.41]
1.8 NEC 1 148 Risk Ratio (M-H, Fixed, 95% CI) 1.00 [0.37, 2.71]
1.9 IVH 2 262 Risk Ratio (M-H, Fixed, 95% CI) 1.33 [0.84, 2.13]
1.9.1 Grade III/IV 2 262 Risk Ratio (M-H, Fixed, 95% CI) 1.33 [0.84, 2.13]
1.10 PVL 1 148 Risk Ratio (M-H, Fixed, 95% CI) 0.09 [0.01, 1.62]
1.11 BPD (oxygen at 36 weeks) 1 148 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.53, 1.54]
1.12 Sudden infant death after discharge 1 114 Risk Ratio (M-H, Fixed, 95% CI) Not estimable
1.13 Weight gain (grams) during the study period (from entry to exit from study) 1 114 Mean Difference (IV, Fixed, 95% CI) 6.00 [-137.37, 149.37]
1.14 Thrombocytosis (platelet count > 500 x 10 9/L) 1 114 Risk Ratio (M-H, Fixed, 95% CI) 1.06 [0.61, 1.84]

[top]

Figures

Figure 1 (Analysis 1.1)

Refer to figure 1 caption below.

Forest plot of comparison: 1 Early (0-7 days) vs. late (8-28 days) initiation of EPO, outcome: 1.1 Use of one or more red blood cell transfusions (Figure 1 description).

Figure 2 (Analysis 1.6)

Refer to figure 2 caption below.

Forest plot of comparison: 1 Early (0-7 days) vs. late (8-28 days) initiation of EPO, outcome: 1.6 Retinopathy of prematurity (all stages) (Figure 2 description).

[top]

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

This review is published as a Cochrane review in The Cochrane Library, Issue 10, 2012 (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.