Cochrane review: Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants

Authors

  • Arne Ohlsson,

    Corresponding author
    1. Departments of Paediatrics, Obstetrics and Gynaecology and Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, M5G 1X5, Canada
    • Departments of Paediatrics, Obstetrics and Gynaecology and Health Policy, Management and Evaluation, University of Toronto, 600 University Avenue, Toronto, Ontario, M5G 1X5, Canada.
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  • Sanjay M Aher

    1. Neonatal Intensive Care Unit, Kilbil Hospital, Nashik, Maharashtra, 42202, India
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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 initiation of EPO in reducing red blood cell (RBC) transfusions in preterm and/or low birth weight infants.

Search strategy

The Cochrane Central Register of Controlled Trials (The Cochrane Library), MEDLINE, EMBASE, CINAHL, abstracts from scientific meetings published in Pediatric Research and reference lists of identified trials and reviews were searched through July 2009.

Selection criteria

Randomised or quasi-randomised controlled trials of early (< 8 days of age) initiation of EPO treatment vs. placebo or no intervention in preterm and/or low birth weight neonates.

Data collection and analysis

Data collection and analysis were accomplished using the methods of the Neonatal Cochrane Review Group.

Main results

Update includes 27 studies that enrolled 2219 preterm infants. Early EPO reduced the risk of the "use of one or more RBC transfusions" [typical RR; 0.80 (95% CI 0.75, 0.86); 16 studies, 1825 infants].

Early EPO led to a significant reduction in the total volume (ml/kg) of blood transfused per infant and in the number of transfusions per infant. Two studies (n = 188) reported a significant reduction in the number of donors to whom the infant was exposed.

There was a significant increase in the risk of stage ≥ 3 retinopathy of prematurity (ROP) in the early EPO group [typical RR; 1.65 (95% CI 1.12, 2.43); 8 studies, 984 infants]. The rates for mortality and other neonatal morbidities were not significantly changed by early EPO treatment nor were neurodevelopmental outcomes at 18 to 22 months in the small number of infants tested to-date.

Authors' conclusions

Early administration of EPO reduces the use of RBC transfusions and the volume of RBCs transfused. These small reductions are of limited clinical importance. Donor exposure is probably not avoided since most studies included infants who had received RBC transfusions prior to trial entry. There was a significant increase in the rate of ROP (stage ≥ 3). Early EPO does not significantly decrease or increase any of the other important adverse outcomes. Ongoing research should deal with the issue of ROP and evaluate the current clinical practice that will limit donor exposure. Due to the limited benefits and the increased risk of ROP, early administration of EPO is not recommended. Evidence is lacking for the possible neuroprotective role of EPO in preterm infants.

Plain Language Summary

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

In newborn infants, the number of red blood cells in the circulation decreases after birth. In infants born before term, this decrease is exaggerated by frequent withdrawal of blood, which may be necessary to monitor the infant's clinical condition. Therefore, infants born before term are likely to require transfusions of red blood cells. Low levels of erythropoietin (EPO), a substance in the blood that stimulates red blood cell production, in preterm infants provide a rationale for the use of EPO to prevent or treat anemia. EPO can be given "early" (before the infant reaches eight days of age) in order to prevent or decrease the use of red blood cell transfusions. More than 2200 infants born before term have been enrolled in 27 studies that used this approach. Early EPO treatment reduces the number of red blood cell transfusions and donor exposures following its use. However, the overall benefit of EPO may not be clinically important, as many of these infants had been exposed to red blood cell transfusions prior to entry into the trials. Treatment with early EPO did not have any important effects on mortality or common complications of preterm birth with the exception that EPO increased the risk for retinopathy of prematurity, a serious complication that may cause blindness in babies born before term. The addition of four new studies enrolling 145 infants did not change the conclusions. Based on our findings, EPO is not recommended for routine use in preterm infants.

Background

Description of the condition

After birth the haemoglobin concentration of newborn infants normally falls to minimal levels of 11 gm/dl in term infants by eight to twelve weeks of age and 7.0 to 10.0 gm/dl in preterm infants by six weeks of age (Stockman 1978). This process is called physiologic anaemia of infancy (Strauss 1986). In very low birth weight (VLBW) infants the hematocrit falls to approximately 24% in infants weighing 1.0 to 1.5 kg and 21% in infants weighing less than 1.0 kg at birth (Stockman 1986). In extremely low birth weight (ELBW) infants, this decline in hematocrit to levels below 7.0 to 10.0 gm/dl is called anaemia of prematurity and is associated with clinical findings such as pallor, poor weight gain, decreased activity, tachypnea, tachycardia and feeding problems that prompt red blood cell transfusions. repeated blood drawing, shortened RBC survival, rapid growth, and attenuated EPO response all contribute to the anaemia of prematurity. 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 of prematurity occur and what the acceptable minimal hematocrit level is in infants requiring supplemental oxygen (Ohls 2002). A rational guide for transfusion therapy for all anemic neonates, whether ventilated or not, is not available (Cohen 1998). Nevertheless, 'top-up' transfusions to treat low haemoglobin or low hematocrit levels are frequently used. As many as 80% of VLBW infants and 95% of ELBW infants receive blood transfusions during their hospitalizations (Widness 1996).

Description of the intervention

The primary goal of EPO therapy is to reduce transfusions. Most transfusions are given during the first three to four weeks of life. The larger or stable preterm infants who respond best to EPO receive few transfusions. ELBW infants, who are sick and have the greatest need for RBC transfusions shortly after birth, have not consistently responded to EPO. This suggests that EPO is a more effective erythropoietic stimulator in more mature neonates. ELBW neonates are more likely to need transfusions even if their erythropoiesis is stimulated by EPO (Kotto-Kome 2004). In addition, ELBW neonates have a smaller blood volume and the relatively larger phlebotomy volumes that are required during hospital stay often necessitate "early" transfusions. In contrast "late" transfusions are more often given because of anaemia of prematurity (Garcia 2002). Most preterm infants who require blood transfusions will receive their first transfusion in the first two weeks of life (Zipursky 2000). Reducing the number of RBC transfusions reduces the risk of transmission of viral infections and may reduce costs. Frequent RBC transfusions may be associated with retinopathy of prematurity (Hesse 1997) and bronchopulmonary dysplasia.

Preterm infants need iron for erythropoiesis. As neonatal blood volume expands with rapid growth, infants produce large amounts of haemoglobin. Several studies have observed a decrease in serum ferritin concentration during EPO treatment, an indication of iron deficiency (Finch 1982). The use of higher, more effective doses of EPO might be expected to increase iron demand and the risk of iron deficiency (Genen 2004). Iron supplementation during erythropoietin treatment has been observed to reduce the risk of the development of iron deficiency (Shannon 1995). The range of iron doses used in EPO treated infants is between 1 mg/kg/day to 10 mg/kg/day (Kotto-Kome 2004).

How the intervention might work

EPO, with the addition of iron, effectively stimulate erythropoiesis. Plasma erythropoietin (EPO) levels in neonates are lower than those of older children and adults. Brown and colleagues reported that between two and thirty days of life the mean EPO concentration was 10 mIU/ml as compared to 15 mIU/ml in concurrently studied adults (Brown 1983). A low plasma EPO level is an important reason that nadir hematocrit values of preterm infants are lower than those of term infants (Stockman 1986; Dallman 1981). Low plasma EPO levels provide a rationale for use of EPO in the prevention or treatment of anaemia of prematurity. Studies in newborn monkeys and sheep have demonstrated that neonates have a large volume of distribution and more rapid elimination of EPO necessitating the use of higher doses than required for adults (Ohls 2000). A recent systematic review of EPO administration in VLBW infants noted a wide range of doses used, from 90 to 1400 IU/kg/week (Kotto-Kome 2004). Side effects following EPO use in adults include hypertension, bone pain, rash and rarely seizures. Only transient neutropenia has been reported in neonates (Ohls 2000).

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 of EPO studies 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).

EPO has recently 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 neuroprotective effect in preterm infants, especially in perinatal asphyxia (Juul 2002, Dame 2001). This aspect of EPO use in neonates has not been systematically reviewed.

It is likely that additional studies of EPO in preterm or LBW infants have been published since the reviews noted above. We performed a series of Cochrane reviews on the use of EPO in preterm infants including: 'Early administration of erythropoietin (EPO) (starting in infants ≤ 7 days of age) vs. placebo/no treatment' (this review), 'Late EPO (starting in infants > 7 days of age) vs. placebo/no treatment' (Aher 2006a) and 'Early vs. late EPO' (as per previous definitions) (Aher 2006b). The cutoff of ≤ 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.

This review concerns the early administration of EPO (starting in infants ≤ 7 days of age). The main rationale for such EPO therapy is to reduce exposure of neonates to red blood cell transfusion and its associated risks. Between 60% and 100% of preterm infants are transfused before three weeks of age (Shannon 1995; Juul 1999; Zipursky 2000) and EPO administered during this period might decrease the need for RBC transfusions (Brown 1990; Kotto-Kome 2004). Several studies have concentrated on the effectiveness of administering EPO beginning in the first week of life in reducing or eliminating these "early" transfusions. We conducted a systematic review to evaluate all available studies where EPO was begun during the first week of life to assess the effect on erythrocyte transfusions.

Objectives

Primary objective:

To assess the effectiveness and safety of early initiation of EPO (initiated before eight days after birth) in reducing red blood cell transfusions in preterm and/or low birth weight infants.

Secondary objectives:

Subgroup analyses were performed within this review for low (≤ 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO and the amount of iron supplementation; none, low (≤ 5 mg/kg/day) and high (> 5 mg/kg/day).

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 of treatment) vs. placebo or no intervention.

Types of outcome measures

Primary outcomes

1. The proportion of infants exposed to one or more red blood cell transfusions.

Secondary outcomes
  • 1The total volume (ml/kg) of blood transfused per infant;
  • 2Number of transfusions per infant;
  • 3Number of donors to whom the infant was exposed;
  • 4Mortality during initial hospital stay (all causes of mortality);
  • 5Retinopathy of prematurity (any stage and stage ≥ 3);
  • 6Proven sepsis (clinical symptoms and signs of sepsis and positive blood culture for bacteria or fungi);
  • 7Necrotizing enterocolitis (NEC) (Bell's stage II or more) or (stage not reported);
  • 8Intraventricular haemorrhage (IVH); all grades (we included in this group results from studies that did not define the grade) and grades III and IV;
  • 9Periventricular leukomalacia (PVL); cystic changes in the periventricular areas (note: for this updated review we included persisting increased echogenicity in this outcome);
  • 10Length of hospital stay (days);
  • 11Bronchopulmonary dysplasia (BPD) (supplementary oxygen at 28 days of age or at 36 weeks postmenstrual age (PMA) with or without compatible X-ray; we included an additional group in which the age at BPD was not stated);
  • 12Sudden infant death after discharge;
  • 13Neutropenia;
  • 14Hypertension (not a pre-specified outcome);
  • 15Long-term outcomes assessed at any age beyond one year of age by a validated cognitive, motor, language, or behavioural/school/social interaction/adaptation test;
  • 16Cerebral palsy;
  • 17Post hoc analysis: Any side effects reported in the trials. (It is not possible to predict every side effect that can occur with a certain intervention. However, it is important that 'new side-effects' are reported).

Search methods for identification of studies

The standard search method of the Cochrane Neonatal Review Group was used.

Electronic searches

The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006) was searched to identify relevant randomised and quasi-randomised controlled trials. MEDLINE was searched for relevant articles published from 1966 to November 2005 using the following MeSH terms or text words: (exp Erythropoietin/OR erythropoietin:.mp. OR rhuepo.mp.) AND (anaemia/OR exp anaemia, neonatal/) AND (blood transfusion/OR blood component transfusion/OR erythrocyte transfusion/) AND (infant, newborn/OR infant, low birth weight/OR infant, very low birth weight/OR infant, premature/OR exp Infant, Premature, Diseases) OR (neonate: OR prematur*: OR newborn:).mp. OR newborn infant [age limit]) AND (clinical trial.pt. OR Randomized Controlled Trials/OR (random: OR rct OR rcts OR blind OR blinded OR placebo:).mp. OR (review.pt. OR review, academic.pt.) AND human. EMBASE from 1980 to November 2005 and CINAHL 1982 to November 2005 were searched 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]. No language restrictions were applied.

For this review update, the same search strategy was applied in July 2009.

Searching other resources

Manual searches of bibliographies and personal files were performed. No language restrictions were applied. Abstracts published from the Pediatric Academic Societies' Meetings and the European Society of Pediatric Research Meetings (published in Pediatric Research) were hand searched from 1980 to April 2005. Clinical trials registries were also searched for ongoing or recently completed trials (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp)

Data collection and analysis

The standard review methods of the Cochrane Neonatal Review Group were used to assess the methodological quality of studies.

Selection of studies

All abstracts and published studies identified as potentially relevant by the literature search were assessed for the inclusion in the review by the two authors. For studies identified as abstracts the primary author was contacted when possible to obtain further information if the full publication was not available.

Data extraction and management

Each author extracted data separately on a data abstraction form. The information was compared and differences were resolved by consensus. One review author (AO) entered data into RevMan and the other (SA) cross checked the printout against his own data abstraction forms and errors were corrected. This update was conducted by one reviewer (AO).

Assessment of risk of bias in included studies

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 were three potential answers to these questions: yes, no, cannot tell.

In addition, the following issues were evaluated and entered into the Risk of Bias Table:

  • 1Sequence generation: Was the allocation sequence adequately generated? 
  • 2Allocation concealment: Was allocation adequately concealed? 
  • 3Blinding of participants, personnel and outcome assessors: Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment? 
  • 4Incomplete outcome data: Were incomplete outcome data adequately addressed? 
  • 5Selective outcome reporting: Are reports of the study free of suggestion of selective outcome reporting? 
  • 6Other sources of bias: Was the study apparently free of other problems that could put it at a high risk of bias?

Measures of treatment effect

Statistical analyses were performed using Review Manager software. Categorical data were analysed using relative risk (RR), risk difference (RD) and the number needed to treat to benefit (NNTB) or number needed to treat to harm (NNTH). Continuous data were analysed using weighted mean difference (WMD). The 95% Confidence interval (CI) was reported on all estimates.

Assessment of heterogeneity

Heterogeneity tests including the I squared (I2) statistic were performed to assess the appropriateness of pooling the data.

Data synthesis

Meta-analysis was performed using Review Manager software (RevMan 5), supplied by the Cochrane Collaboration. For estimates of typical relative risk and risk difference we used the Mantel-Haenszel method. For measured quantities we used the inverse variance method. All meta-analyses were to be done using the fixed effect model.

Subgroup analysis and investigation of heterogeneity

Subgroup analyses were performed within this review for low (≤ 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO and no iron, low (≤ 5 mg/kg/day) and high (> 5 mg/kg/day) doses of supplemental iron by any route (co-intervention). Any amount of iron given i.v. was classified as high dose iron.

Two post-hoc analyses were conducted to try and explain the between study heterogeneity for the primary outcome 'Use of one or more red blood cell transfusions'. In the first post-hoc analysis we divided the studies into two groups 'High quality studies' and 'Studies of uncertain quality'. In the second post-hoc analysis, we analysed the results for the three studies in which most of the neonatal intensive care units enrolling patients used satellite units of red blood cells for transfusion.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies.

Results of the search

Twenty-seven studies enrolling 2219 infants were included. A second publication (Haiden 2006a) of a previously included study was identified (Haiden 2005).The studies were performed in 19 countries (Austria, Belgium, Chile, China, France, Germany (FRG and GDR), Greece, Italy, Iran, Mexico, New Zealand, Poland, Singapore, South Africa, Switzerland, Turkey, the UK, the US). Eleven studies were excluded (see Characteristics of excluded studies).

All studies fulfilled our inclusion criteria of a gestational age < 37 weeks and birth weight < 2500 g. Inclusion of infants in the studies was based on either gestational age or birth weight or a combination. The highest cut-off for birth weight was 1800 g and the highest cut-off for gestational age was 35 weeks (Chang 1998). The lowest cut-off for birthweight was 401 g (Ohls 2001A). Most studies used an upper cut-off for birth weight of 1500 g and a gestational age of 32 - 33 weeks.

EPO was administered subcutaneously (s.c.) or intravenously (i.v.) or in a combination of i.v. followed by s.c. when i.v. access was no longer available. The dose ranged from 70 IU/kg/week (Obladen 1991) to 2100 IU/kg/week (Haiden 2005). The duration of EPO treatment ranged from two weeks (Ohls 1995; Ohls 1997) to nine weeks (Maier 2002) or to discharge from hospital (several studies). The study by Fauchère 2008, was designed to ascertain whether administration of high dose EPO (3000 IU rhEPO/kg body weight) given i.v. 3 to 6, 12 to 18, and 36 to 42 hours after birth would have a neuro-protective effect. In that study no infant was treated at a later time with EPO.

Many different EPO preparations were used; EPREX 2000, Santa-Farma-Gurel, Istanbul (Arif 2005), Eprex, Cilag, Italy (Carnielli 1998), Cilag A.G., Zug, Switzerland (Soubasi 1993; Soubasi 1995; Soubasi 2000), Eprex 4000, Cilag de Mexico SA de CV (Lima-Rogel 1998), Eprex, Janssen-Cilag, Auckland, New Zealand (Meyer 2003), Eprex, Cilag comp (Khatami 2008), Recormon, Boehringer (Avent 2002; Lauterbach 1995), NeoRecormon, F. Hoffman-La Roche, Basel, Switzerland (Maier 2002), Epoetin beta, Boehringer-Mannheim, GmbH, Germany (Maier 1994; Obladen 1991), Kirin Brewery, Co., Ltd., Japan (Chang 1998), unnamed product (Bierer 2006, Carnielli 1992; He 2008; Ohls 1995; Ohls 1997; Ohls 2001A; Ohls 2001B; Romagnoli 2000; Yeo 2001), Erypo, Janssen-Cilag pharmaceuticals, Vienna, Austria (Haiden 2005; Meister 1997), Eritropoyetina del Laboraorio Andromaco (Salvado 2000) and Epoietin Beta, Roche, Basel, Switzerland (Fauchère 2008).

Previous donor exposure was an exclusion criterion in one study (Arif 2005). Maier et al (Maier 1994) included 28 infants (23%) in the EPO group and 17 (14%) in the control group who had received red blood cell transfusions prior to study entry. Maier et al (Maier 2002) reported that 24 (32%) of the infants in the early EPO group and 22 (31%) in the control group were exposed to donor blood before they entered the study. The authors of the remaining studies reported their specific exclusion criteria but did not list prior transfusion as an exclusion criterion. We assumed that infants who had received prior red blood cell transfusions were included.

Details for the transfusion guidelines are reported in Additional Tables (Table 1 Transfusion guidelines). As noted in the table, transfusion guidelines were based on various Hct and/or Hgb levels. In addition, researchers used many other criteria such as need for assisted ventilation, supplemental oxygen, age of the infant, weight gain, clinical condition, and physiological or biochemical signs thought to be associated with anaemia. In a few studies, we were unable to categorize the different guidelines that could be meaningfully used for secondary analyses.

Table 1. Transfusion guidelines
ReferenceIndications
Arif 2005Infants with Hgb concentrations < 7 g/dl and with a reticulocyte count lower than < 100 000/µL or Hgb concentrations < 8 g/dl having bradycardia, tachypnoea or apnea, or who were not able to gain weight despite adequate calorie intake were chosen as candidates for blood transfusion
Avent 2002Infants received blood transfusions if they met the following criteria: 1. Hgb of 10 g/dl and one of the following: (i) an oxygen requirement greater than 30 %; (ii) less than 1250 g body weight. 2. Hgb < 8 g/dl and one of the following: (i) three or more episodes of apnea (respiration absent for 20 s) or bradycardia (heart rate of < 100 beats/min) in a 24-h period not due to other causes and not responsive to methylxanthine treatment; (ii) fractional inspired oxygen concentrations increasing by > 10 % per week; (iii) tachycardia (> 170 beats/min) or tachypnoea (>70 breaths/min) sustained over a 24-h period associated with acute cardiac decompression.
Bierer 2006Transfusions were administered in accordance with a conservative transfusion protocol as per Ohls (Ohls 2001B)
Carnielli 1992Infants were transfused during the first week of life with packed erythrocytes if the Hct level was < 0.42 or 0.36, depending on whether or not the patient was receiving supplemental oxygen. After the first week of life, indications for transfusions were Hct < 0.36 for oxygen-dependent patients and 0.32 if breathing room air. Anemia was the only indication for giving packed erythrocytes to all infants.
Carnielli 1998Infants received transfusions of packed cells during the first week of life if their peripheral Hct (heel stick) was < 0.42 or 0.36, depending on whether or not the patient was receiving supplemental oxygen. After the first week of life, indications for transfusion were Hct < 0.36 for oxygen dependent patients and 0.32 if in room air. Hct concentrations for red blood cell transfusions for blood obtained from venepuncture or arterial samples were 4% lower than the above mentioned values (0.38 and 0.32 for oxygen dependent and non-oxygen dependent patients in the first week and 0.32 and 0.28 thereafter). All infants received dedicated units of red blood cells.
Chang 1998Not stated whether transfusion guidelines were in place or not.
Fauchère 2008Transfusion guidelines not provided.
Haiden 2005Infants were transfused at Hct < 0.20 a) if asymptomatic with reticulocytes < 100 000/µL Infants were transfused at Hct < 0.30 a) if receiving < 35% supplemental hood oxygen b) if on CPAP or mechanical ventilation with mean air way pressure < 6 cm H2O c) if significant apnea and bradycardia are noted (> 9 episodes in 12 h or 2 episodes in 24 h 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 h e) if weight gain < 10 g/day is observed over 4 days while receiving > 100 kcal/kg/day f) if undergoing surgery Transfuse for Hct < 0.35 a) if receiving > 35% supplemental hood oxygen b) if intubated on CPAP or mechanical ventilation with mean airway pressure > 6-8 cm H2O Do not transfuse: a) to replace blood removed for laboratory tests alone b) for low Hct alone
He 2008Transfusion guidelines not reported in the Englsih abstract of this study. We have requested the full text in Chinese from the authors.
Khatami 2008"Guidelines for red-cell transfusions were based on the relatively strict existing policy in the nursery which was used to administer transfusions during the study period".
Lauterbach 1995Transfusion was given when the Hct level reached 0.28 and if clinical symptoms of tachypnoea, tachycardia, bradycardia were present at a Hct of 0.32.
Lima-Rogel 1998According to criteria published by Klaus and Fanaroff
Maier 1994Infants who were receiving ventilation or who were less than two weeks old and had signs of anaemia were given transfusions if their hematocrit fell below 0.40, their Hgb concentration fell below 14 g/dl (8.7 mmol/liter), or blood samples totaling at least 9 ml/kg had been obtained from them since their previous transfusion. Spontaneously breathing infants, more than two weeks old, whose fraction of inspired oxygen was < 0.40 were given transfusions if they had signs of anemia and their Hct fell below 0.32 and their Hgb concentration below 11 g/dl (6.8 mmol/L); if they had signs of anemia, the corresponding cutoff values were 0.27 and 9 g/dl (5.6 mmol/L).
Maier 2002Infants with artificial 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 assumed by the treating neonatologist, or surgery was planned. Twelve of the 14 centres used satellite pack of the original red cell pack to reduce donor exposure.
Meister 1997Infants more than two weeks old who have been breathing spontaneously and whose fraction of inspired oxygen was less than 0.40 were given transfusions if they had signs of anaemia and their Hct fell below 11 g/dl (6.8 mmol/L); if they had no signs of anaemia, the corresponding cutoff values were 0.27 and 9 g/dl (5.6 mmol/L).
Meyer 2003Indications for transfusions were: Hct of 0.36-0.40 and critically ill with: requirement for oxygen > 45% via CPAP; ventilation (mean airway pressure > 10 cm water); severe sepsis; active bleeding. Hct of 0.31-0.35 and: requirement for oxygen (up to 45%) via CPAP; ventilation (mean airway pressure 7-10 cm water); Hct of 0.21-0.30 and: gain less than 10 g/day averaged over one week; experience either at least 10-12 apneic or bradycardic episodes in 12 hours or two or more such episodes requiring bag and mask ventilation within a 24 hour period, not due to other causes and not responsive to methylxanthine treatment; have a sustained tachycardia (> 170 beats/min) or tachypnoea (> 70/min) per 24 hours and not attributable to other causes; develop cardiac decompensation secondary to a clinically apparent patent ductus arteriosus; positive pressure ventilation on low settings (mean airway pressure < 7 cm water) or nasal CPAP; those requiring surgery Hct 0.20 and reticulocyte count < 100 x 109/l.
Obladen 1991Indications for transfusion of packed red cells: If venous Hct < 0.42, Hgb < 14 g/dl or > 9 ml/kg blood sampled since last transfusion transfuse if infant is ventilated or requires FiO2 > 0.40. If age 1-2 weeks and symptoms of anaemia (apneic spells, distended abdomen, failure to thrive) transfuse if venous Hct is < 0.36, Hgb < 12 g/dl or > 9 ml/kg blood sampled since last transfusion. If age 3-5 weeks and symptoms of anaemia (apneic spells, distended abdomen, failure to thrive) transfuse if venous Hct is < 0.30, Hgb < 10 g/dl or > 9 ml/kg blood sampled since last transfusion. If no symptoms of anaemia transfuse at any age if venous Hct is < 0.27, Hgb < 9 g/dl.
Ohls 1995Transfusions were given during the first three week of life if the hematocrit was < 0.33, and if the infant had one or more symptoms thought to be due strictly to anemia. Symptoms were defined as tachycardia (heart rate > 160 beats/min, calculated as the average of all heart rates recorded by the bedside nurse during the preceding 24-hour period), an increasing oxygen requirement (an increase in fraction of inspired oxygen of > 0.20 during a 24-hour period), "lethargy" as assessed by the primary caregiver, or an increase in the number of episodes of bradycardia requiring stimulation to increase the heart rate from less than 60 beats/min (an increase of such episodes by 3 or more per day. Infants in both groups whose Hct were > 0.33 and yet whose phlebotomy losses exceeded 10 ml/kg body weight received an infusion of 5% albumin, administered in aliquots of not less than 10 ml/kg. Infants were not given transfusions if they were free of symptoms, even if the Hct fell to < 0.33.
Ohls 1997Transfusions were administered in both groups according to standardized transfusion criteria: for infants requiring mechanical ventilation, transfusions were given if the Hct fell below 0.33. For infants not receiving ventilatory support, transfusions were given if the Hct fell below 0.28, and the infant was experiencing symptoms. Symptoms were defined as tachycardia (heart rate > 160 beats/min, calculated as the average of all heart rates recorded by the bedside nurse over the preceding 24-hour period), an increasing oxygen requirement (an increase in fraction of inspired oxygen of > 0.20 over a 24-hour period, or an elevated lactate level (>2.5 mmol/L). In some instances a new donor would be used each day for the newborn intensive care unit (university of Florida), and in other instances a unit would be dedicated to a single infant for the life of the unit (University of New Mexico and University of Utah).
Ohls 2001 AIf Hct </=35/Hgb </=11 g/dl transfuse infants requiring moderate or significant mechanical ventilation (MAP >8 cm H2O and FiO2 >0.4). If Hct </= 30/Hgb </= 10 g/dl transfuse infants requiring minimal respiratory support (any mechanical ventilation or endotracheal/nasal CPAP >6 cm H2O and FiO2 </= 0.4) If Hct </= 25/Hgb </= 8 g/dl transfuse infants not requiring mechanical ventilation but who are on supplemental O2 or CPAP with an FiO2 </= 0.4 and in whom 1 or more of the following is present: 24 h of tachycardia (180 beats/min) or tachypnea (>80 breaths/min) an increased oxygen requirement from the previous 48 h, defined as 4-fold increase in nasal canula flow (i.e., 0.25 L/min to 1 L/min) or an increase in nasal CPAP 20% from the previous 48 h (i.e., 5 cm to 6 cm H2O) weight gain <10 g/kg/day over the previous 4 days while receiving 100 kcal/kg/day an increase in the episodes of apnea and bradycardia (> 9 episodes in a 24-h period or 2 episodes in 24 h requiring bag-mask ventilation) while receiving therapeutic doses of methylxanthines, undergoing surgery If Hct </= 25/Hgb </= 7 g/dl transfuse asymptomatic infants with and an absolute reticulocyte count <100 000 cells/µL
Ohls 2001 BSee Ohls 2001 A
Romagnoli 2000Infants on mechanical ventilation and/or on > 30% of inspired oxygen received packed erythrocytes when their Hct levels dropped to < 0.40. Otherwise the transfusion was performed when the Hct fell to < 0.35 from the 2nd to the 4th week of life and below 0.23 thereafter.
Salvado 2000Preterm infants with Hct < 0.20. Preterm infants with Hct < 0.30 when presenting with frequent apneas, or tachycardia >180 beats/min, or requiring surgery.
Soubasi 1993Neonates, who were well, were transfused if their Hct was < 0.25 combined with signs referable to their anemia, such as poor weight gain, persistent episodes of bradycardia or tachypnoea, and apnea. Neonates with severe respiratory disease (BPD), particularly those requiring oxygen and/or ventilator support, received transfusions to maintain their hematocrit level at > 0.40
Soubasi 1995Infants who were receiving mechanical ventilation or who were less than 2-weeks-old were given transfusion if their Hct fell below 0.40. Spontaneously breathing infants more than 2-weeks-old whose fraction of inspired oxygen was less than 0.35 were given transfusion if they had signs of anaemia and their Hct fell below 0.30; if they had no signs of anaemia, transfusion was given if Hct fell below 0.25. Growing, asymptomatic infants were transfused if Hct fell below 0.20. Signs of anaemia included; tachycardia, (>170 beats/min) or tachypnoea (> 70 per min) sustained over a 24-h period or associated with acute cardiac decompression; recurrent apnoea (respirations absent for 20 s) or bradycardia (heart rate < 100 beats/min) in a 24-h period not due to other causes and not responsive to methylxanthine treatment; an increased in fractional oxygen requirement by 20% or more over a 24-h period; or weight gain of < 10 g/day averaged over a 1-week period while on adequate caloric intake.
Soubasi 2000Neonates were transfused when Hct was < 0.20, if they were asymptomatic, or < 0.30 if they were receiving O2 < 0.35 and/or unexplained breathing disorders combined with signs referable to their anemia, such as poor weight gain, episodes of persistent bradycardia or tachycardia.
Yeo 2001Infants who were receiving mechanical ventilation or who were less than 2-weeks-old were given transfusion if their Hct fell below 0.40. Spontaneously breathing infant more than 2-weeks-old whose fraction of inspired oxygen was less than 0.35 were given transfusion if they had signs of anemia and their Hct fell below 0.30; if they had no signs of anemia, transfusion was given if Hct fell below 0.25. Growing, asymptomatic infants were transfused if Hct fell below 0.20. Signs of anemia included; tachycardia, (>170 beats/min) or tachypnoea (> 70 per min) sustained over a 24-h period or associated with acute cardiac decompression; recurrent apnoea (respirations absent for 20 s) or bradycardia (heart rate < 100 beats/min) in a 24-h period not due to other causes and not responsive to methylxanthine treatment; an increased in fractional oxygen requirement by 20% or more over a 24-h period; or weight gain of < 10 g/day averaged over a 1-week period while on adequate caloric intake.

Transfusion guidelines were reported to be in place in all but two studies (Chang 1998; Fauchère 2008); we are awaiting the information from the trial by He 2008. Lima-Rogel et al. (Lima-Rogel 1998) referred to the 3rd Spanish edition of 'Care of the high-risk neonate' by Klaus and Fanaroff for the guidelines they adhered to (Klaus 1987). We were not able to locate that book but in the 3rd English edition of the book we could not find transfusion guidelines for preterm infants (Klaus 1986).

In the study by Carnielli et al (Carnielli 1998) all infants received dedicated units of red blood cells. In one of the studies by Ohls et al. (Ohls 1997) it is stated that "In some instances a new donor would be used each day for the newborn intensive care unit (University of Florida) and in other instances a unit would be dedicated to a single infant for the life of the unit (University of New Mexico and University of Utah)". These two studies did not report on our primary outcome of 'Use of one or more red blood cell transfusions'. 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 the two studies by Ohls et al (Ohls 2001A; Ohls 2001B) it is noted that "Whenever possible designated donor units that were capable of providing at least four transfusions were assigned to each infant (available in six of the eight participating centres)". In a secondary (post hoc) analysis we combined the results of these three studies.

Iron was administered in all studies but one (Fauchère 2008). We are awaiting the information from the trial by He 2008. In most studies, both the EPO and the control groups received iron but often the dose was lower in the control groups. In three studies (Carnielli 1992; Carnielli 1998; Romagnoli 2000), the infants in the control groups did not receive iron. In one study the use of iron was not stated in the abstract (He 2008).

Eleven studies were excluded (see Characteristics of Excluded Studies Table).

Included studies

For details see the table 'Characteristics of Included Studies Table'.

Arif 2005 was a single centre study performed in Istanbul, Turkey.

  • Objective: To determine whether EPO would prevent anemia of prematurity and reduce the need for transfusion.

  • Population: Preterm infants < 33 weeks GA, birth weight < 1500 g, seven days old, not having had a previous blood transfusion.

  • Intervention: The EPO group received EPO 200 IU/kg s. c. from the seventh day of life and continued twice weekly (low dose) for 6 weeks. Placebo was not given to the control group. Both groups received iron (3 - 5 mg/kg per day orally) (low dose).

  • Outcomes assessed: Use one or more red blood cell transfusions, mortality, NEC, ROP, BPD, neutropenia, side effects.

Avent 2002 was a two centre study performed in South Africa.

  • Objective: To evaluate the effectiveness of early treatment with EPO (both high and low dose) in comparison to conventional treatment with packed red blood cell transfusions in the management of anaemia of prematurity in a country with limited resources.

  • Population: Preterm infants < 7 days of age, in room air or requiring up to 30% oxygen at study entry with birth weight between 900 and 1500 g. Infants were stratified by weight < 1250 g and > 1250 g.

  • Intervention: One group received EPO 400 IU/kg s.c. three times a week (high dose), a second group received EPO 250 IU/kg s.c. three times a week (high dose). All infants received a therapeutic dose of 6 mg/kg (high dose) elemental iron orally every day and it was increased to 8 - 10 mg/kg (high dose iron) if the hypochromic cells became 20 per cent or more of the total cell population.

  • Outcomes assessed: Use of one or more red blood cell transfusions, total volume (ml/kg) of blood transfused per infant, number of blood transfusions per infant, mortality and sepsis.

Bierer 2006(new study) was a single centre study at the University of New Mexico, Albuguerque, New Mexico, USA.

  • Objective: To evaluate the relationship between EPO concentrations and neurodevelopmental outcome in extremely low birth weight infants.

  • Population: Preterm infants who weighed ≥ 400 g but ≤ 1000 g at birth, were < 32 weeks' gestation and who were between 24 and 96 hours of age at the time of study entry.

  • Intervention: The EPO group received 400 IU/kg i.v. or s.c. three times per week (1200 IU/kg/week, high dose). Iron supplementation was according to the study by Ohls 2001B (high dose).

  • Outcomes assessed: Number of red blood cell transfusions per infant, mortality, NEC, BPD at 36 weeks PMA, ROP stage ≥ 3, IVH ≥ 3, mean Psychomotor Developmental Index (PDI) and Mental Development Index (MDI) scores and PDI and MDI scores < 70 at 18 to 22 month's corrected age; cerebral palsy, blindness, hearing loss or any neurodevelopmental impairment at 18 to 22 months corrected age.

Carnielli 1992 was a single centre study performed in Italy.

  • Objective: to determine whether early administration of high dose of rHuEPO and iron to premature infants would be well tolerated and would reduce the need for blood transfusions.

  • Population: Preterm infants with birth weight ≤ 1750 g and a GA ≤ 32 weeks, two days old.

  • Intervention: The EPO group received EPO 400 IU, three times weekly (high dose) i.v. or s. c. and iron 20 mg/kg once a week i.v. (high dose iron) from second day of life until discharge. The control group did not receive either EPO or iron.

  • Outcome assessed: Number and volume of transfusions, number of donor exposure, mortality during hospital stay, neutropenia and hospital stay in days.

Carnielli 1998 was a single centre study performed in Italy.

  • Objective: To determine whether iron supplementation would enhance erythropoiesis in preterm infants treated with EPO.

  • Population: Birth weight ≤ 1750 g and GA ≤ 32 weeks, two days old.

  • Intervention: The EPO + iron group received 400 IU/kg EPO three times a week (high dose) and 20 mg/kg/week of i.v. iron (high dose). The EPO + no iron group received EPO, 400 IU/kg three times a week (high dose) without iron (no iron); infants in the control group received no treatment or placebo.

  • Outcomes assessed: Number of donor exposures, BPD, IVH, sepsis, ROP, days on ventilator, days of oxygen, days in hospital, days to regain birthweight and weight gain from birth to eight weeks.

Chang 1998 was a single centre study performed in China.

  • Objective: To assess the efficacy and the optimum dose of EPO on the anaemia of prematurity.

  • Population: Infants with GA ≤ 35 weeks, birth weight ≤ 1800 g , age one day and no Rh or ABO incompatibility.

  • Intervention: Infants in EPO group one received EPO 150 IU/kg three times a week for six weeks (low dose). Infants in EPO group two received EPO 250 IU/kg three times a week for six weeks (high dose) and infants in the control group (group three) received no EPO treatment. Infants in all three treatment groups received oral iron 20 mg/kg/day (high dose) from day seven after birth.

  • Outcomes assessed: use of one or more red blood cell transfusions, hypertension and side effects.

Fauchère 2008 (new study) was a single centre study performed in Switzerland.

  • Objective: To investigate whether administration of high-dose EPO to very preterm infants shortly after birth and subsequently during the first two days is safe in term of short-term outcomes.

  • Population: Preterm infants with GA 24 0/7 to 31 6/7 weeks.

  • Intervention: Infants in EPO group received 3000 IU rhEpo/kg i.v. 3 to 6, 12 to 18, and 36 to 42 hours after birth. The placebo group received an equal volume of normal saline.

  • Outcomes assessed: Mortality, IVH (all grades and grades III-IV), persisting periventricular echodensity (included in the analysis for PVL), ROP (all stages and stages 3 - 4), sepsis, NEC (stage not reported), BPD (36 weeks PMA), side effects.

Haiden 2005 was a multicentre study performed at neonatal intensive care units of the Department of Pediatrics, University of Vienna, Austria.

  • Objective: The aim of the study was to evaluate the effect of EPO therapy on platelet reactivity and thrombopoiesis in extremely low birth weight infants.

  • Population: Preterm infants with BW ≤ 800 g and GA ≤ 32 weeks, < 8 days old.

  • Intervention: The EPO group received 300 IU/kg/day of EPO i.v. (as long as i.v. access was available), or 700 IU/kg three times per week (2100 IU/kg/week, high dose) and iron dextran 1.5 mg/kg/day i.v. or iron polymerase complex 9 mg/kg/day orally (high dose).

  • Outcomes assessed: Use of one or more red blood cell transfusions, number of donors, mortality, NEC, PVL, IVH (grade I - II), IVH grade III - IV), hospital stay, BPD (age not stated), ROP (stage I - II), ROP (stage III - IV).

He 2008 (new study) was a single centre study performed in the Department of Neonatology, Zhangzhou Municipal Hospital, Zhangzhou, Fujian, China.

  • Objective: The aim of the study was to evaluate the effect of early EPO therapy on neuro-behavioural development in preterm infants.

  • Population: Preterm infants, seven days old.

  • Intervention: The EPO group received 250 IU/kg/day three times weekly i.v. for four weeks (750 IU/kg/week, high dose). The use of iron not stated.

  • Outcomes assessed: Neonatal Behavioral Neurological Assessment at 40 weeks post menstrual age and Gesell Developmental Schedule at six and 12 months after birth.

Khatami 2008 (new study) was a single centre study performed at Ghaem Medical Center in Tehran, Iran

  • Objective: The aim of the study was to evaluate whether EPO therapy would decrease the need for red blood cell transfusions and prevent anaemia of prematurity.

  • Population: Preterm infants with BW > 1000 g but < 1750 g and GA > 28 weeks but < 34 weeks, and were between 48 and 96 hours old at the time of entering the study.

  • Intervention: The EPO group received 500 IU/kg/day of EPO s.c. twice weekly (1000 IU/kg/week, high dose) and iron (ferrous sulfate) 3 mg/kg/day enterally (low dose).

  • Outcomes assessed: Number of red blood cell transfusions per patient, weight gain, hospital stay.

Lauterbach 1995 was a single centre study conducted in Poland.

  • Objective: To evaluate the role of EPO in the treatment of anemia of prematurity.

  • Population: Preterm infants with GA < 35 weeks and birthweight ≤ 1500 g, seven days old.

  • Interventions: Infants in EPO group I received EPO 100 IU/kg twice a week between days 7 and 37 (low dose), and infants in EPO group II received 400 IU/kg twice weekly (high dose) during the same time period. The control group received no treatment or placebo. Both EPO groups and the control group received 10 mg/kg/week of iron i.v. (high dose).

  • Outcomes assessed: Total volume (ml/kg) of blood transfused between days 7 and 37.

Lima-Rogel 1998 was a single centre study performed in Mexico

  • Objective: To determine the efficacy of EPO in very low birth weight newborns less than 72 hours of age.

  • Population: infants with birth weight between 750 and 1500 g, < 72 hours old.

  • Intervention: Infants in the EPO group received EPO 150 IU/kg/d (high dose) during the first 6 weeks and infants in the control group received placebo. Both groups received iron 4 mg/kg/day (low dose).

  • Outcomes assessed: Number of transfusions per group, sepsis, NEC, IVH and BPD.

Maier 1994 was a multicentre trial conducted in 12 centres in 6 European countries (Germany, Switzerland, U. K., Belgium, the Netherlands, France).

  • Objective: To determine whether EPO would prevent anaemia and reduce the need for transfusion in infants with very low birth weights.

  • Population: Infants with birth weights 750 to 1499 g, and three days old.

  • Intervention: The EPO group received 250 IU of EPO/kg i.m. three times per week (750 IU/kg/week, high dose). The treatment continued until day 40 to 42 for total of 17 doses. Infants in the control group did not receive placebo but adhesive tape was placed on both thighs, which remained there until next visit. Oral iron 2 mg/kg/day was started on day 14 in all infants (low dose).

  • Outcomes assessed: Use of one or more red blood cell transfusions, number of transfusions per infant, mortality, ROP, sepsis, NEC, IVH all grades, neutropenia, hypertension, side effects, weight gain and costs.

Maier 2002 was a multicentre trial conducted in 14 centres in four European countries (Germany, Switzerland, France, Belgium).

  • Objective: To investigate whether EPO reduces need the need for transfusion in ELBW infants and to determine the optimal time for treatment

  • Population: Infants with birth weight between 500 and 999 g. three to five days old.

  • Intervention: The EPO group received EPO 250 IU/kg, i.v. or s. c. three time a week (high dose) starting on day three to five of life, for nine weeks. The control group 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 (high dose) at days 24 to 26 of life.

  • Outcomes assessed: Use of one or more red blood cell transfusions, Number of donors the infant was exposed to, number of transfusions per infant, mortality during hospital stay, NEC, IVH, PVL, ROP, BPD, growth, days in oxygen, days in NICU and days in hospital.

Meister 1997 was a single centre trial conducted in Austria.

  • Objective: To evaluate the effect of EPO on circulating hematopoietic progenitor cells in anaemic premature infants.

  • Population: Preterm infants with birth weights of 750 to 1499 g, at an age of five to ten days.

  • Intervention: The EPO group received EPO 300 IU/kg s. c. three times a week (high dose) for four weeks. The control group did not receive the drug or placebo. Oral iron administration was started with a dose of 6 mg/kg/day (high dose) and increased after two weeks to 8 mg/kg/day (high dose). The control group received iron alone.

  • Outcomes assessed: Cumulative volume of blood transfused/kg.

Meyer 2003 was single centre trial conducted in New Zealand.

  • Objective: To comprehensively identify preterm infants likely to require blood transfusion and to investigate the effectiveness of EPO in this high risk subgroup.

  • Population: Preterm infants with gestation < 33 weeks and birth weight < 1700 g, at an age of 48 hours.

  • Intervention: Infants in the treatment group received EPO at 1200 IU/kg/week s. c. in three divided doses until three weeks of age and then the dose was reduced to 600 IU/kg/week until 34 weeks corrected GA or for a minimum of 3 weeks. Infants in the control group received sham treatment. Both group received elemental iron. 21 infants in control group received sham treatment to avoid subcutaneous injection. Iron at a dose of 6 mg /kg/day (high dose) was given to the EPO group once they had attained a postnatal age of two weeks and receiving at least 50% energy intake orally. Those in control group received 2 mg/kg/day iron (low dose) from the same age in a more dilute preparation so that an equivalent volume was given.

  • Outcomes assessed: Use of one or more red blood cell transfusions and number of donors the infant was exposed to.

Obladen 1991 was a multicentre study conducted at five centres in three European countries [Germany (FRG), Germany (GDR), UK].

  • Objective: To investigate whether treatment with EPO reduces the anaemia of prematurity and thus the need for transfusion by one third in preterm infants.

  • Population: Preterm infants with GA 28 - 32 completed weeks, three days old.

  • Intervention: The EPO group received EPO 30 IU/kg (low dose) every third day from fourth to 25 th day of life. The control group did not receive study drug or placebo. Iron treatment 2 mg/kg (low dose) orally was started on day 14 if there was no feeding intolerance

  • Outcomes assessed: Use of one or more red blood cell transfusions, total volume of blood transfused per infant, mortality, chronic lung disease, IVH, NEC, BPD and hypertension.

Ohls 1995 was a single centre trial conducted in the USA.

  • Objective: To determine whether administering EPO to ill VLBW infants, beginning on the first or second day of life, would reduce blood transfusions and be cost-effective.

  • Population: Infants less than 48 hours of age with birth weight 750 and 1500 g and GA > 27 weeks.

  • Intervention: The EPO group received EPO 200 IU/kg/day (high dose) i.v. for 14 consecutive days. The control group received similar volume of 0.9% saline solution in similar fashion as placebo. Infants in both groups received iron, 2 mg/kg/day (low dose) orally when they were taking 70 ml/kg per day enterally, which was increased to 6 mg/kg per day (high dose) when the infants were receiving more than 100 ml/kg per day of feeds.

  • Outcomes assessed: Use of one or more red blood cell transfusions, total volume of blood transfused per infant, number of transfusions per infant, neutropenia, thrombocytopenia, neutrophilia, NEC and IVH.

Ohls 1997 was multicentre trial conducted in the USA.

  • Objective: To evaluate the effect of EPO on the transfusion requirements of preterm infants weighing 750 g or less.

  • Population: Infants with birth weight 750 g or less and 72 hours of age or younger.

  • Intervention: The EPO group received EPO 200 IU/kg/day (high dose) i.v., for 14 consecutive days. The control group received placebo as an equivalent volume of diluent in similar fashion. All infants received 1 mg/kg/day iron dextran in TPN solution during treatment period (high dose)

  • Outcomes assessed: Total volume of blood transfused per infant, number of transfusions per infant, mortality, sepsis, IVH, BPD and ROP.

Ohls 2001A was a multicentre trial conducted in USA.

  • Objective: To evaluate the effects of early EPO therapy on the transfusion requirements of preterm infants below 1000 g.

  • Population: Infants with birth weight 401 to 1000 g, GA < 32 weeks and between 24 and 96 hours of age at the time of study entry.

  • Intervention: The EPO group received 400 IU/kg EPO 3 times weekly (high dose) i.v. or s. c. when i.v. access was not available. The placebo/control group received sham s. c. injections when i.v. access was not available. Treatment was continued until discharge, transfer, death or 35 completed weeks corrected gestational age. EPO treated infants received a weekly i.v. infusion of 5 mg/kg iron dextran (high dose) until they had an enteral intake of 60 ml/kg/day. Placebo/control infants received 1 mg/kg iron dextran (high dose) once a week, administered in a similar manner. Once infants in both groups had enteral intake of 60 mg/kg/day they were given iron at a dose of 3 mg/kg/day (low dose) . The dose was gradually increased to 6 mg/kg/day (high dose) depending on enteral intake.

  • Outcomes assessed: Use of one or more red blood cell transfusions, mean number of erythrocyte transfusions per infant, number of donors to whom the infant was exposed, total volume of blood transfused per infant, late onset sepsis, mortality, chronic lung disease, ROP, severe IVH, NEC >Bell's stage II, BPD, neutropenia and hypertension. In a follow-up study of the 72 EPO treated and 70 placebo control infants surviving to discharge follow-up data at 18 to 22 months' corrected age were collected on 51 EPO -treated infants (71%) and 51 placebo/controls (73%). The outcomes assessed were growth, psychomotor development, rehospitalization and transfusions.

Ohls 2001B was a multicentre trial conducted in the USA.

  • Objective: To evaluate the effects of early EPO therapy on the transfusion requirements of preterm infants below 1250 g.

  • Population: Infants with birth weight between 1001 g to 1250 g, GA < 32 weeks and between 24 and 96 hours of age at the time of study entry.

  • Intervention: The EPO group received 400 IU/kg EPO 3 times weekly (high dose) i.v. or s. c. when i.v. access was not available. The placebo/control group received sham s. c. injections when i.v. access was not available. Treatment was continued until discharge, transfer, death or 35 completed weeks corrected gestational age. EPO treated infants received a weekly i.v. infusion of 5 mg/kg iron dextran (high dose) until they had an enteral intake of 60 ml/kg/day. Placebo/control infants received 1 mg/kg iron dextran (high dose) once a week, administered in a similar manner. Once infants in both groups had enteral intake of 60 mg/kg/day they were given iron at a dose of 3 mg/kg/day (low dose). The dose was gradually increased to 6 mg/kg/day (high dose) depending on enteral intake.

  • Outcomes assessed: Use one or more red blood cell transfusions, mean number of erythrocyte transfusions per infant, number of donors to whom the infant was exposed, total volume of blood transfused per infant, late onset sepsis, mortality, chronic lung disease, ROP, severe IVH, NEC >Bell's stage II, BPD, neutropenia and hypertension.

Romagnoli 2000 was a single centre trial conducted in Italy.

  • Objective: To evaluate whether EPO and iron supplementation increase the risk of retinopathy of prematurity.

  • Population: Infants with gestational age 30 weeks and those with GA 31 - 34 weeks with respiratory distress syndrome, seven days old.

  • Intervention: The EPO group received EPO 300 IU/kg s.c., three times a week (high dose) and Iron 1 mg/kg/day i.v. (high dose). The control group did not receive EPO, placebo or iron.

  • Outcomes assessed: Use of one or more red blood cell transfusions, number of blood transfusions per infant, ROP, NEC, IVH >garde II, BPD at 28 days, and sepsis.

Salvado 2000 was a single centre trial conducted in Chile.

  • Objective: To asses the benefits of early EPO administration to reduce the requirement of blood transfusion in very low birth weight infants.

  • Population: Newborn infants with birth weight under 1500 g. Treatment started before 12 days of age (mean age EPO group 7.75 days, control group 7.96 days).

  • Intervention: The EPO group received EPO 200 IU/kg s.c. three times a week (high dose) during four weeks. The control group received a similar volume of isotonic saline solution in similar fashion. All infants received oral iron at a dose of 3 mg/kg/day (low dose).

  • Outcomes assessed: Number of transfusions per infant, sepsis, IVH and days on ventilator.

Soubasi 1993 was a single centre study conducted in Greece.

  • Objective: To assess whether EPO treatment is safe and reduces the need for transfusion.

  • Population: Infants with GA ≤ 31 weeks, birthweight ≤ 1500 g, age one to seven days, no history of haemolytic disease and clinically stable.

  • Intervention: The EPO group received 150 IU/kg/dose of EPO twice a week (low dose) during 4 weeks. The control group received no placebo. From the 15th day of life iron was started at 3 mg/kg/day (low dose) in all infants.

  • Outcomes assessed: Use of one or more red blood cell transfusions, number of transfusions per infant, mortality, sepsis, neutropenia, weight gain, hospital stay.

Soubasi 1995 was a single centre study conducted in Greece.

  • Objective: Follow up of VLBW infants after EPO treatment.

  • Population: Infants with GA ≤ 31 weeks, birth weight ≤ 1500 g, age one to seven days, no history of haemolytic disease and clinically stable.

  • Intervention: The EPO 300 group received EPO 150 IU/kg twice weekly (low dose) and the EPO 750 group received EPO 250 IU/kg three times a week (high dose). The control group did not receive any study drug or placebo. All infants received oral elemental iron, 3 mg/kg per day from day 15 of life (low dose)

  • Outcomes assessed: Use of one or more red blood cell transfusions, number of blood transfusions per infant, mortality, follow up to one year of age, weight gain and hospital stay.

Soubasi 2000 was a single centre trial conducted in Greece.

  • Objective: To investigate the effect of EPO on oxygen affinity and adequate oxygen delivery to the tissues of stable preterm infants.

  • Population: Infants with GA ≤ 31 weeks and birth weight ≤ 1300 g with clinical stability at the time of entry. Although the authors do not state the age at entry, we assumed the age to be seven days from a graph (fig 6.) in the publication.

  • Intervention: The EPO group received 200 IU/kg every alternate day (high dose) s.c. The control group did not receive EPO or placebo. The infants received oral iron at a dose of 12 mg/kg/day (high dose) in the EPO group and 4 mg/kg/day (low dose) in the control group.

  • Outcomes assessed: Use of one or more red blood cell transfusions and number of transfusions per infant.

Yeo 2001 was a single centre study conducted in Singapore.

  • Objective: To study efficacy, safety and cost effectiveness of EPO in reducing transfusion needs in VLBW infants.

  • Population: VLBW infants with GA ≤ 33 weeks, age five days.

  • Intervention: The EPO group received EPO 250 IU/kg/dose s.c. three times a week (high dose) from day five to day. Infants in the control group did not receive a placebo. Infants in both groups received elemental iron, 3 mg/kg/day (low dose) orally from day 10 and increased to 6 mg/kg/day (high dose) when full feeds were well tolerated.

  • Outcomes assessed: Use one or more red blood cell transfusions, mean number of erythrocyte transfusions per infant, total volume of blood transfused per infant, mortality, ROP, Sepsis, NEC, BPD, hypertension, BPD, and costs.

Excluded studies

Eleven studies were excluded (see table 'Characteristics of Excluded Studies').

Risk of bias in included studies

The allocation to study groups was interpreted by us as concealed in 15 studies (Bierer 2006; Fauchère 2008; Haiden 2005; Khatami 2008; Maier 1994; Maier 2002; Meyer 2003; Obladen 1991; Ohls 1995; Ohls 1997; Ohls 2001A; Ohls 2001B; Romagnoli 2000; Salvado 2000; Soubasi 1993). Placebo or sham injection were used in 12 studies (Bierer 2006; Fauchère 2008; Lima-Rogel 1998; Maier 1994; Maier 2002; Meyer 2003; Ohls 1995; Ohls 1997; Ohls 2001A; Ohls 2001B; Salvado 2000; Soubasi 1993). Sample sizes were generally small and ranging from 16 (Bierer 2006) to 292 (Arif 2005) infants enrolled. Seven studies enrolled 100 infants or more. No study was reported according to the CONSORT statement (Begg 1996). There was complete follow-up in all studies.

Effects of interventions

PRIMARY OUTCOMES:

ERYTHROPOIETIN VS. PLACEBO OR NO TREATMENT (COMPARISON 1):

Use of one or more red blood cell transfusions [low (≤ 500 IU/kg/week) and high (> 500 IU/kg/week) dose of EPO] (Outcome 1.1):

A total of 16 studies enrolling 1825 infants reported on the use of one or more red blood cell transfusions. Early EPO significantly reduced the proportion of infants who received one or more red blood cell transfusions [typical RR 0.80 (95% CI 0.75, 0.86); typical RD -0.13 (95% CI -0.17,-0.09); NNT 8 (95% CI 6, 11)].There was statistically significant heterogeneity for this outcome [RR (p = 0.004; I2 = 56.7%); RD (p = 0.003; I2 = 56.0%)]. Further analyses were conducted including studies that used a high dose of EPO (> 500 U/kg/week) or a low dose of EPO (≤ 500 U/kg/week)

Use of one or more red blood cell transfusions [high dose of EPO (> 500 U/kg/week)] (Outcome 1.2):

A total of 15 studies enrolling 1432 patients testing a high dose of EPO reported on this outcome. A high dose of EPO significantly reduced the proportion of infants who received one or more red blood cell transfusions [typical RR 0.79 (95% CI 0.74, 0.86); typical RD -0.14 (95% CI -0.18, -0.09); NNT 7 (95% CI 6, 11)]. There was statistically significant heterogeneity for this outcome [RR (p< 0.0010; I2 62.4%); RD (p = 0.0006; I2 62.9%)].

A subgroup analysis for a high dose of EPO in combination with a high dose of iron (Outcome table 1.2) was conducted. A total of 12 studies enrolling 1067 infants reported on this outcome. A high dose of EPO with a high dose of iron significantly reduced the proportion of infants who received one or more red blood cell transfusions [typical RR 0.84 (95% CI 0.77, 0.92); typical RD -0.11 (95% CI -0.16, -0.06); NNT 9 (95% CI 6, 17)]. The test for heterogeneity was statistically significant [RR (p = 0.03; I2 = 50.3%); RD (p = 0.02; I2 = 50.1%)].

A total of three studies enrolling 365 infants testing a high dose of EPO and a low dose of iron (Outcome table 1.2) reported on this outcome. A high dose of EPO and a low dose of iron significantly reduced the proportion of infants, who received one or more red blood cell transfusions [typical RR of 0.66 (95% CI 0.55, 0.80); typical RD -0.23 (95% CI -0.33, -0.14); NNT 4 (95% CI 3, 7)]. There was statistically significant heterogeneity for this outcome [RR (p = 0.02; I2 = 75.2%); RD (p = 0.02; I2 = 74.5%)].

Use of one or more red blood cell transfusions [low dose of EPO (≤500 U/kg/week)] (Outcome 1.3):

A total of three studies including 192 patients testing a low dose of EPO (Outcome table 1.3) reported on this outcome. A low dose of EPO did not demonstrate a significant reduction in the proportion of infants, who received one ore more red blood cell transfusions [typical RR 0.80 (95% CI 0.60, 1.07); typical RD of -0.10 (95% CI -0.22, 0.02). There was statistically significant heterogeneity for this outcome [RR (p = 0.07; I2 = 69.6%); RD (p = 0.10; I2 = 55.8%)].

Subgroup analysis for a low dose of EPO in combination with a high dose of iron (Outcome table 1.3) was conducted. One study enrolling 30 infants reported on this outcome. In this study there were no outcomes in either group and the RR was not estimable and the non-significant RD was 0.00 (95% CI -0.12, 0.12).

Two studies enrolling 162 infants testing the effectiveness of a low dose of EPO in combination with a low dose of iron (Outcome table 01.03) reported on this outcome. A low dose of EPO in combination with a low dose of iron did not significantly reduce the proportion of infants who received one or more red blood cell transfusions [typical RR was 0.80 (95% CI 0.60, 1.07), the typical RD was -0.12 (95% CI -0.26, 0.03). There was statistically significant heterogeneity (p = 0.07; I2 = 69.6%) for RR and borderline statistically significant heterogeneity for RD (p = 0.17; I2 = 48.0%)

Only one study included a group that received no iron (Carnielli 1998); however, this study did not report on the primary outcome of interest 'Use of one or more red blood cell transfusions'.

SECONDARY OUTCOMES:

The total volume (ml/kg) of red blood cells transfused per infant (Outcome 1.4):

A total of six studies enrolling 515 infants reported on the total volume of red blood cells transfused per infant. The significant typical WMD was a reduction of 6 ml/kg of blood transfused (ml/kg) per infant (95% CI -11, - 1). There was statistically significant heterogeneity for this outcome (p = 0.02; I2 = 63.0%). Carnielli et al (Carnielli 1998) reported on the mean (95% CIs) volume of blood (ml/kg) transfused for the three groups; EPO + iron 16.7 (4.9 - 28.6); EPO only 20.1 (6.2 - 34.2) and the control group 44.4 (29.0 - 59.7) (EPO vs. control, p = 0.028; EPO + iron vs. control, p = 0.009) (p-values according to authors).

Lauterbach et al (Lauterbach 1995) reported that infants treated with 800 IU/kg/week required a statistically significantly lower volume (ml/kg) of packed erythrocytes in comparison to untreated infants both between days seven and 37 of life (18.6 ml vs. 46.8 ml) and between day seven of life and the day of discharge (35.8 ml vs. 94.2 ml); (p < 0.04 for both comparisons).

Maier 2002 reported on the mean (SD) volume of blood transfused as ml/kg/day; early EPO group 0.7 (1.2) and control group 1.1 (1.2), (p-value not provided). Meister reported on the median (first and third quartile) volume of blood transfused as ml/kg/day; EPO group 0 (0, 0.47) and the control group 0.86 (0.5, 1.1).

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

The results from 14 studies enrolling 1131 infants reported on the number of red blood cell transfusions per infant. The significant typical WMD for number of red blood cell transfusions per infant was -0.33 (95% CI -0.48,-0.18). There was statistically significant heterogeneity for this outcome (p = 0.00001, I2 = 78%)

Carnielli et al (Carnielli 1998) reported on the mean (95% CIs) number of red blood cell transfusions for the three groups; EPO + iron 1.0 (0.28 - 1.18); EPO only 1.3 (0.54 - 2.06) and the control group 2.9 (1.84 - 3.88), (control vs EPO, p = 0.065) and (control vs. EPO + iron, p = 0.035) (p-values are according to the authors).

Avent et al (Avent 2002) reported the median and range of number of transfusions across three groups; low dose EPO group 0 (0-1), high dose EPO 0 (0-2) and Control group 0 (0-4); p = 0.03 across the three groups. Haiden et al (Haiden 2005) reported on the number of transfusions; EPO group 2 (0-15), control group 4.5 (0-12) (not statistically significant according to the authors).

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

Two studies enrolling 188 infants reported on this outcome in means and SDs. The significant typical WMD for the number of donors to whom the infant was exposed was -0.63 (-1.07, -0.19). There was no statistically significant heterogeneity for this outcome (p = 0.59; I2 = 0%).

Carnielli et al (Carnielli 1992) reported that the number of donor exposures ranged from 0 - 5 in the EPO group and 0 - 6 in the control group (p-value not provided). Haiden et al. (Haiden 2005) reported on this outcome in a similar fashion; EPO group number of donors 1 (0-10), control group 3 (0-5) (not statistically significant according to the authors).

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

A total of 15 studies enrolling 1546 infants reported on this outcome. Mortality was not significantly altered by the use of EPO [typical RR; 0.93 (95% CI 0.69, 1.26); typical RD -0.01 (95% CI -0.04, 0.02)]. There was no statistically significant heterogeneity for the outcome (RR p = 0.95; I2 = 0%; RD p = 0.79; I2 = 0%).

Retinopathy of prematurity (any stage or stage not stated by authors) (Outcome 1.8):

A total of 11 studies enrolling 1464 infants reported on retinopathy of prematurity. We obtained unpublished data from the study by Maier (Maier 2002) on the highest grade of ROP recorded during the study among examined survivors. EPO increased (borderline significance for RD) ROP (any stage or stage not stated by authors) [typical RR; 1.17 (95% CI 0.98, 1.39); typical RD; 0.04 (95% CI -0.00, 0.08); p = 0.07)]. There was no statistically significant heterogeneity for this outcome [RR (p = 0.27; I 2 = 18%; RD (p = 0.12 I2 = 35%)].

Retinopathy of prematurity (stage ≥3) (Outcome 1.9):

A total of eight studies enrolling 984 infants reported on severe ROP (stage ≥ 3). EPO significantly increased retinopathy of prematurity (stage ≥3), [typical RR; 1.65 (94% CI 1.12, 2.43; typical RD; 0.05 (95% CI 0.01, 0.08); NNTH; 20 (95% CI 13, 100 ]. There was no statistically significant heterogeneity for this outcome for RR (p = 0.87; I2 = 0%) but there was statistically significant heterogeneity for RD (p = 0.006; I2 = 65%). Ohls 1997 reported no differences in ROP (stage 3 or greater) rates between groups (data not provided).

Proven sepsis (clinical symptoms and signs of sepsis and positive blood culture for bacteria or fungi) (Outcome 1.10):

Eleven studies including 1207 infants reported on this outcome. EPO did not significantly change the rates of proven sepsis [typical RR 0.91 (95% CI 0.74, 1.12); typical RD - 0.02 (95% CI -0.06, 0.02)]. There was no statistically significant heterogeneity [RD (p = 0.84; I2 = 0%) or RD (p = 0.74; I2 = 0%)].

Necrotizing enterocolitis (NEC) (stage not reported) (Outcome 1.11):

Only one study stated the stage of NEC reported (Bierer 2006). We included any outcome stated as NEC in this analysis. Twelve studies reporting on 1530 infants were included. EPO did not significantly change the rates of NEC [typical RR; 1.09 (95% CI 0.75, 1.59); typical RD 0.01 (95% CI -0.02, 0.03)]. There was no statistically significant heterogeneity for this outcome [RR (p = 0.81; I2 = 0%); RD (p = 0.64; I2 = 0%)]. Ohls 1995 reported no differences in NEC rates between groups (data not provided)

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

Many authors did not state the grade of IVH. We included in this outcome studies in which the grade was not stated and excluded IVH grades III-IV, when they were known. A total of 9 studies including 789 infants reported on this outcome. EPO did not significantly change the rate of IVH (all grades), [typical RR; 0.96 (95% CI 0.69, 1.32); typical RD -0.01 (95% CI -0.06, 0.04)]. There was no statistically significant heterogeneity for this outcome [RR (p = 0.92; I2 = 0%); RD (p = 0.89; I2 = 0%)]. Ohls 1995 and Ohls 1997 reported no differences in IVH rates between groups (data not provided)

Intraventricular haemorrhage (IVH); grades III and IV (Outcome 1.13):

A total of 7 studies enrolling 861 infants reported on this outcome. EPO did not significantly change the rate of IVH (grade III and IV), [typical RR; 1.18 (95% CI 0.69, 2.03); typical RD 0.01 (95% CI -0.02, 0.04)]. There was no statistically significant heterogeneity for this outcome [RR (p = 0.76; I2 = 0%); RD (p = 0.45; I2 = 0%)].

Periventricular leukomalacia (PVL); cystic changes in the periventricular areas (Outcome 1.14):

Two studies enrolling 185 infants reported on PVL. One study( Fauchère 2008) enrolling 45 infants reported on persisting periventricular echogenicity. We included that study in the analyses. EPO did not significantly change the rate of PVL (3 studies enrolling 228 infants), [typical RR was 0.80 (95% CI 0.57, 1.12); typical RD -0.04 (95% CI -0.10, 0.02)]. There was no statistically significant heterogeneity for this outcome for RR (p = 0.69; I2 = 0%), but for RD (p = 0.08; I2 = 61%). The incidence of persisting periventricular echogenicity was very high in the study by Fauchère 2008 with an over all incidence of 79%.

Length of hospital stay (days) (Outcome 1.15):

A total of five studies enrolling 415 infants reported on the length of hospital stay. EPO did not significantly change length of hospital stay [typical WMD; -1.90 (95% CI -4.38, 0.58)]. There was no statistically significant heterogeneity for this outcome (p = 0.69; I2 = 0%).

Avent el al (Avent 2002) reported the median and range (days) for hospital stay across three groups; low dose EPO 32 (5-54), high dose EPO 32 (16-74) and control group 30 (14-46); p = 0.10 across the three groups.

Haiden et al (Haiden 2005) reported on the hospital stay (days, median and range) EPO group 97 (59 - 162) and control group 89 (77 -157) (not statistically significant according to authors).

Maier 2002 reported on the median (quartiles) for hospital stay; early EPO group 87 (73 - 107, control group 87 (69 - 108).

Bronchopulmonary dysplasia (Outcome 1.16):

- Bronchopulmonary dysplasia (BPD) (supplemental oxygen at 28 days of age) (Outcomes table 1.16.1).

Two studies enrolling 330 infants reported on the use of supplemental oxygen at 28 days. EPO did not significantly change the rate of BPD (supplemental oxygen at 28 days of age), [typical RR; 1.27 (95% CI 0.90, 1.80); typical RD; 0.07 (95% CI -0.03, 0.16)]. There was no statistically significant heterogeneity for this outcome for RR (p = 0.12; I2 = 58.2%) but for RD (p = 0.07; I2 = 69.3%). Ohls 1995 and Ohls 1997 reported no differences in BPD rates between groups (data not provided).

- Bronchopulmonary dysplasia (BPD) (supplemental oxygen at age 36 weeks postmenstrual age) (Outcomes table 1.16.2).

Four studies enrolling 450 infants reported on the use of supplemental oxygen at 36 weeks PMA. EPO did not significantly change the rate of BPD (supplementary oxygen at age 36 weeks PMA), [typical RR;0.98 (95% CI 0.77, 1.23); typical RD -0.01 (95% CI -0.09, 0.07). There was no statistically significant heterogeneity for this outcome [RR (p = 0.65; I2 = 0%); RD (p = 0.44; I2 = 0%)].

- Bronchopulmonary dysplasia (BPD) (age at diagnosis not stated) (Outcomes table 1.16.3).

A total of five studies enrolling 528 infants reported on this outcome. EPO did not significantly change the rate of BPD (age at diagnosis not stated), [typical RR; 0.98 (95% CI 0.61, 1.56); typical RD 0.00 (95% CI -0.05, 0.05). There was no statistically significant heterogeneity for this outcome [RR (p = 0.74; I2 = 0%); RD (p = 0.67; I2 = 0%)].

Sudden infant death after discharge (no outcomes table)

No study reported on this outcome

Neutropenia (Outcome 1.17):

Nine studies including 982 infants reported on neutropenia. The non-significant typical RR was 0.81 (95% CI 0.53, 1.24); typical RD - 0.01 (95% CI -0.05, 0.02). There was no statistically significant heterogeneity for this outcome; RR (p = 0.61; I2 = 0%); RD (p = 0.35; I2 = 10.3%).

Hypertension (Outcome 1.18):

A total of six studies enrolling 762 infants reported on hypertension. In five studies there were no outcomes in either the treatment or the control groups. Therefore, these five studies did not provide any information to the typical RR estimate. The RR (for one study) was 3.02 (95% CI 0.12, 73.52). All 6 studies are included in the typical RD; - 0.00 (95% CI -0.01, 0.02). There was no statistically significant heterogeneity for this outcome; RR (not applicable); RD (p = 1.00; I2 = 10.3%).

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 (Outcome 1.19):

Mental Developmental Index (MDI) < 70 at 18-22 month's corrected age (Outcomes table 1.19)

Two studies reported on this outcome in 102 children following EPO treatment. The RR was 0.78 (95% CI 0.44, 1.39); RD -0.08 (95% CI; -0.26, 0.10). These findings were not statistically significant.There was no statistically significant heterogeneity for this outcome (RR p = 0.31, I2 = 2%; RD p = 0.26, I2 = 40%).

Psychomotor Developmental Index (PDI) < 70 at 18 - 22 months corrected age (Outcome 1.20):

Two studies reported on this outcome in 102 children following EPO treatment. The RR was 2.00 (95% CI 0.94, 4.25); RD 0.16 (95% CI -0.00, 0.32). These findings were not statistically significant. There was no statistically significant heterogeneity for this outcome (RR p = 0.36, I2 = 0%; RD p = 0.53, I2 = 0%).

Cerebral palsy at 18-22 months corrected age (Outcome 1.21):

Two studies reported on this outcome in 111 children following EPO treatment. The RR was 1.06 (95% CI 0.46, 2.45); RD 0.01(-0.13, 0.15). These findings were not statistically significant. There was no statistically significant heterogeneity for this outcome (RR not applicable; RD p = 0.94, I2 = 0%).

Any neurodevelopmental impairment at 18-22 month's corrected age (Outcome 1.22):

Two studies reported on this outcome in 111 infants following EPO treatment. The RR was 0.90 (95% CI 0.59, 1.36); RD -0.05 (-0.23, 0.14). These findings were not statistically significant. There was no statistically significant heterogeneity for this outcome (RR p = 0.33, i2 = 0%; RD p = 0.27, I2 = 18%).

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

Side effects were specifically reported not to have occurred in the following trials (Carnielli 1992; Chang 1998; Fauchère 2008; Khatami 2008; Lauterbach 1995; Lima-Rogel 1998; Maier 1994; Meister 1997; Ohls 1995).

Use of one or more red blood cell transfusions (secondary analysis - based on perceived study quality) (Outcome 1.23):

In a post hoc analysis to try and explain the between study heterogeneity for the primary outcome we divided the studies into two groups 'High quality studies' and 'Studies of uncertain quality'. There were no substantial differences between either the point estimates for the effect size for the two groups nor were there any real differences in the degree of heterogeneity when all studies were analyzed together or in two separate groups.

Use of one or more red blood cell transfusions (secondary analysis - based on NICUs using mostly satellite units of red blood cells) (Outcome 1.24):

In a second post hoc analysis to try and explain the between study heterogeneity for the primary outcome we analyzed the results for the three studies in which most of the neonatal intensive care units used satellite units of red blood cells for transfusion. A total of three studies enrolling 435 infants reported on this outcome. The use of EPO in combination with dedicated red blood cell transfusion units did not significantly reduce the use of one or more red blood cell transfusions, [typical RR 0.91 (95% CI 0.81, 1.01; typical RD; -0.07 (95% CI -0.15, 0.01). There was no statistically significant heterogeneity for this outcome (RR; p = 0.52, I2 = 0%; RD; p = 0.68, I2 = 0%).

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 Additional figures - Figure 1). A funnel plot for the outcome “Retinopathy of prematurity (stage ≥ 3)” was symmetrical with no indication of possible publication bias, making the result more robust (Figure 2).

Figure 1.

Funnel plot for "Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants".

Figure 2.

Funnel plot of comparison: 1 Erythropoietin vs. placebo or no treatment, outcome: 1.9 Retinopathy of prematurity (stage >/= 3).

Neonatal Behavioral Neurological Assessment at 40 weeks PMA (Outcome 1.25):

One study enrolling 44 infants reported on this outcome. The mean difference of 1.80 (95% CI 1.26, 2.34) favoured the EPO group. This study was written in Chinese and only the abstract was available in English. We have written to the authors to obtain more information.

Blindness at 18 to 22 month's corrected age (Outcome 1.26):

One study following12 infants reported on this outcome. Blindness did not occur in either of the groups.

Hearing loss at 18 to 22 month's corrected age (Outcome 1.27):

One study following 12 infants reported in this outcome. Hearing loss did not occur in either of the groups.

Discussion

Twenty-seven studies conducted in 19 countries met inclusion criteria. Eleven studies were excluded. These studies included a total of 2219 preterm infants and reported on at least one of the outcomes of interests for this systematic review. The study quality varied and information regarding whether the allocation was concealed or not was often missing. We judged the allocation to study groups to be concealed in 15 studies and a placebo or a sham injection was used in 12 studies ensuring blinding of the intervention. No study was reported according to the "Consort statement" (Begg 1996). Sample sizes were relatively small and ranged from 16 to 292 infants enrolled. Long term (18 to 22 months corrected age) outcomes were reported only in two studies (Ohls 2001A; Bierer 2006). In the study by Ohls (Ohls 2001A) the follow up rates were low; 71 % in the EPO group and 73% of the survivors in the control group. The study by Bierer (Bierer 2006) enrolled only 16 infants and 12 were seen at follow-up. 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 Additional figures - Figure 1).This may indicate that smaller studies with "negative" results have not been published.

In only one study (Arif 2005) did the authors specifically state that infants were not eligible to enter the study if they previously had received a red blood cell transfusion. In two studies it was stated that infants were included if they had received prior red blood cell transfusions; the rates varied between 14 and 32% (Maier 1994; Maier 2002). Although often not stated, it is likely that infants who had received blood transfusion prior to study entry were not excluded as this was not mentioned as an exclusion criterion. All studies except one followed guidelines (with tremendous variation between studies) for red blood cell transfusions (see additional table - Table 1).

The use of early EPO in preterm infants (n = 2219) has been extensively studied. This update of our review added 145 infants of which 12 provided long-term follow-up data. This review provides evidence that early administration of EPO significantly reduces the 'Use of one or more blood transfusions' following study entry with a low NNTB of 8 and a narrow 95 % CI of 6 to 11. From our results we cannot make a recommendation with regard to the best combination of high or low dose EPO and high or low dose of iron. We had arbitrarily set a cutoff of ≤5 mg/kg/day of oral intake of iron for low and high dose of iron. When we conducted the review we discovered that several studies started with i.v. administration of iron in variable doses and we considered any i.v. dose of iron as a high dose. Early EPO significantly reduces the total volume (ml/kg) of red blood cells transfused, the number of red blood cell transfusions per infant and the number of donor exposures. For these outcomes the effect sizes were small and of limited clinical importance.

There was statistically significant heterogeneity for the primary outcome as well as for two important secondary outcomes (the 'Total volume of blood transfused per infant' and 'Number of transfusions per infant'). In an attempt to explore the reason for the between study heterogeneity we performed a post-hoc analysis for the primary outcome. We divided the studies into two groups; 'High quality studies' (studies with concealed allocation and the use of a placebo or sham injections) and 'Studies of uncertain quality' (studies in which those criteria could not be ascertained). There were no substantial differences between either the point estimates for the effect size for the two groups nor was there any real differences in the degree of heterogeneity when all studies were analyzed together or in two separate groups by quality. In our late EPO review (Aher 2006a) some of the heterogeneity could be explained by the same exercise. There could be other explanations for the heterogeneity such as differences in dosing regimens for EPO and iron, EPO preparations, blood sampling, indications for transfusion (the rates of transfusions in the control groups varied), use of non-invasive monitoring, general standards of care and baseline characteristics among the infants enrolled. In an additional post-hoc analysis we analyzed the results from three multicenter studies in which most of the centers used satellite packs of red blood cells for multiple transfusions to the same infant. The use of EPO in combination with dedicated red blood cell transfusion units did not significantly reduce the use of one or more red blood cell transfusions. There was no statistically significant heterogeneity for this outcome.

The use of red blood cells from satellite-bag-equipped, dedicated units decreases donor exposure in low birth weight infants (Lee 1995). In a single center report the red blood cell transfusion guidelines for infants with birth weight < 1000 g were changed three times (in 1989, 1991, and 1995) and became more restrictive with each change (Maier 2000). The changes were made in association with the introduction of new EPO trials. Since 1990 the primary red blood cell pack was divided into three to four satellite packs. The median number of transfusions decreased from seven in the first period to two in the third period. Donor exposure decreased from five to one, and the blood volume transfused decreased from 131 to 37 ml/kg. According to the authors, the changing transfusion practices were due to several factors; stricter transfusion guidelines, increased adherence to transfusion guidelines, efforts to reduce sampling loss, and EPO therapy. The authors suggested that "not using transfusions to replace defined blood volume loss had the highest impact on reduced transfusions" (Maier 2000).

The importance of the marked reduction in the primary outcome in this review is limited by the fact that prior donor exposure was probably not avoided as many infants had required red blood cell transfusions before study entry. We assume that in most studies infants who had received blood transfusions were not excluded as most studies reported specific exclusion criteria that did not include prior red blood cell transfusions. It is unlikely that either the statistically significant reduction of < 1 (WMD - 0.63) donors to whom the infant was exposed or the 6 ml/kg per infant (WMD - 6.03) reduction in total volume of blood transfused is of clinical importance.

With the exception of ROP there were no statistically significant reductions/increases in the many secondary neonatal outcomes that we included a priori in this systematic review. There was a strong trend for increased risk of ROP (any stage reported; p = 0.07) with the use of early EPO, whichmore importantly reached statistical significance for ROP stage ≥3 with no between study heterogeneity (Figure 3). There does not seem to be any evidence for possible publication bias for this outcome as the funnel plot (Figure 2) is symmetrical. With so many secondary outcomes included this could be a chance finding. Only one study had as its primary objective to “Evaluate whether EPOand iron supplementation increase the risk of retinopathy of prematurity” (Romagnoli 2000). In that study there was a statistically significantly increased risk of ROP following EPO treatment. The authors speculated that iron supplementation could be a contributing factor. In our early vs. late EPO review (Aher 2006b) we noted an increase in ROP with early EPO treatment but not in the late EPO review (Aher 2006a). It may be that the infant is at greatest risk if EPO is administered early, starting in our first week of life. In an observational study, Rudzinska 2002 reported an increased risk of ROP following early vs. late treatment with EPO.

Figure 3.

Forest plot of comparison: 1 Erythropoietin vs. placebo or no treatment, outcome: 1.9 Retinopathy of prematurity (stage >/= 3).

Manzoni 2005 reported data on 695 neonates with birth weights < 1500 g who were admitted between 1997 and 2004. Threshold ROP occurred in 31.4 percent (54 of 172) of infants < 1000 g who received erythropoietin therapy as compared with 19.6 percent (22 of 112) of those who did not receive erythropoietin (p = 0 .01 in univariate analysis, p = 0.04 in multivariate analysis; p-values according to authors). The authors suggested that erythropoietin is an additional, independent predictor of severe threshold ROP in infants < 1000 g (Manzoni 2005). In a retrospective case control analysis of 85 very low birth weight infants, Shah et al (Shah 2005) found no difference in the rate of ROP between EPO and control infants. However, they noted a significant weak positive correlation between the duration of EPO treatment and development of threshold ROP (Shah 2005). In an analysis of data from a neonatal network in South America, Musante 2006 et al found that treatment with EPO independently increases the risk of ROP and severe ROP. The incidence and severity of ROP may depend on the dose of EPO (Liu 2006). In a murine-normoxia-induced proliferative retinopathy model, Morita 2003 et al implicated EPO as a key factor in the development ROP, especially in the development of neovascularization. The authors suggested a possible therapeutic use for EPO and vascular endothelial growth factor (VEGF) inhibitors in the treatment of ROP (Morita 2003). Watanabe et al (Watanabe 2005) studied vitreous EPO levels in 73 adult patients with proliferative diabetic retinopathy and found that the median level was significantly higher (p < 0.001) than in 71 patients without diabetes. They suggested that EPO is a potent ischemia-induced angiogenic factor that acts independently of VEGF during retinal angiogenesis in proliferative diabetic retinopathy (Watanabe 2005).

These studies support an association between early EPO and ROP. Therefore, our finding of an increased risk of ROP following early administration of EPO is of concern. Previous systematic reviews (which included fewer studies than in our reviews) have not included ROP (or other common neonatal outcomes) as outcome measures (Vamvakas 2001; Garcia 2002; Kotto-Kome 2004). Those reviews noted similar effect sizes for transfusion needs and reported on statistically significant between study heterogeneity.

In the analysis of 'Retinopathy of prematurity (stage ≥ 3)' (outcome table 01.09) four of the five included studies used a combination of high EPO and high iron doses. In two studies the iron dose was higher in the EPO treated group (Ohls 2001A; Ohls 2001B); in one study the control group did not receive iron (Romagnoli 2000); and in one study iron was provided i.v. in the EPO group from the initiation of therapy whereas the control group received oral iron from the 15th day of life. In one (low EPO) study (Maier 1994) both groups received the same amount of iron (2 mg/kg/day). Therefore, It is possible that the higher doses of iron was the cause of or contributed to the higher rates of ROP (stage ≥ 3) in the EPO treated infants in these trials. In one study (Fauchère 2008) a high dose of EPO was used only during the first few days of life and the authors do not state if iron was used.

Administration of EPO could potentially have a neuroprotective effect in preterm infants, especially in infants with perinatal asphyxia (Juul 2002, Dame 2001). This aspect of EPO use in neonates has not been systematically reviewed. Two studies included in this reviewusedEPOas a neuroprotective agent Fauchère 2008;He 2008). The study of Fauchère 2008 uses early EPOwith the goal of neuroprotection in very preterm infants. The primary hypothesis of this pilot study was that “the rate of survivors without brain injury (IVH and PVL) including ROP are not affected by administration of 3 high doses of EPO early after birth”. The percentage of infants who survived without brain injury or ROP was 53% in the EPO group and 60% in the placebo group. However, five infants died in the EPO group vs. none in the placebo group. The RR for mortality was higher in this study when compared to the results of other trials Figure 4.

Figure 4.

Forest plot of comparison: 1 Erythropoietin vs. placebo or no treatment, outcome: 1.7 Mortality during initial hospital stay (all causes of mortality).

In the study by He 2008 the purpose was to evaluate the effect of early EPO therapy on neurobehavioural development in preterm 7 days old infants. This study was written in Chinese and only the abstract in English was understandable to us (we have contacted the authors but have not received an answer). Neonatal Behavioral Neurological Assessment at 40 weeks PMA and Gesell Developmental Schedule at six and 12 months after birth was used to assess the infants. The results favoured the EPO group.

We excluded the study by Zhu 2009 as the population was term infants with moderate to severe hypoxic ischemic encephalopathy and did not meet our inclusion criterion of PMA < 37 weeks. The authors reported that repeated low dose of EPO reduced the risk of disability for infants with moderate hypoxic ischemic encephalopathy but not for those with severe hypoxic ischemic encephalopathy. To date early EPO meta-analyses have not shown a significant reduction in mortality, proven sepsis, NEC, IVH, PVL, BPD or long-term neurodevelopmental outcomes at 18-22 months but have shown a very significant increase in the risk of ROP. Therefore, it is difficult to hypothesize that early treatment with EPO could have a neuroprotective effect in preterm infants. A number of trials investigation the neuroprotective/long-term effects as well as the risk of ROP with early EPO have been registered with ClinicalTrials.gov (Identifiers: NCT 00910234, NCT 00589953, NCT 00413946, NCT 00945789, NCT 00719407, NCT 00808704). We will assess the results of those trials for possible inclusion in future updates of this review.

Any future studies of EPO should include ROP as an outcome measure of importance and data-monitoring/safety committees should be provided with this information on an ongoing basis. We will try to obtain unpublished data from the authors of published studies. It is likely that the outcome of ROP has been recorded in study protocols or, as most studies are of small sample size, the outcome could be obtained from patients' charts. Until more information is available, either from published or ongoing studies regarding ROP, we do not recommend any new trials of early EPO to reduce blood transfusions, especially in view of the limited benefits identified in this extensive review.

For the present, it is important that neonatal intensive care units develop practice guidelines to limit blood losses and donor exposure in neonates. The use of satellite packs and conservative transfusion guidelines reduces the exposure to multiple donors during the hospital stay. The need for red blood cell transfusions is linked to the loss of blood from sampling for laboratory testing.

To date only a limited number of infants have been followed long-term. From the meta-analyses of two studies (Bierer 2006; Ohls 2001A) there is no indication that early EPO would have a neuroprotective effect and improve neurodevelopmental outcomes at 18-22 months' corrected age. He (He 2008) in a study published in Chinese (only the abstract in English was available to us) reported significantly higher developmental quotients of gross motor, fine motor and language at 12 months after birth in the EPO treated group compared to the control group (p , 0.05).

Overall, early EPO provides very limited clinical benefits. It is associated with an increased risk for ROP stage ≥ 3 and, therefore, its use is not recommended. The addition of 100 infants in this updated review did not statistically significantly change any of the previously reported results.

Authors' conclusions

Implications for practice

Early administration of EPO reduces the use one or more red blood cell transfusions, the volume of red blood cells transfused, and the number of donors and transfusions the infant is exposed to following study entry. Donor exposure is probably not avoidable, as most studies included infants who had received red cell transfusions prior to trial entry. Although statistically significant, the reductions are of limited clinical importance. There was a significant increase in the rate of ROP (stage ≥ 3) with early EPO use. Animal data and observational studies in humans support a possible association between treatment with EPO and the development of ROP. EPO does not significantly reduce or increase any of many other important adverse outcomes including mortality. In view of the limited clinical benefits and the increase in ROP (stage ≥ 3) the administration of early EPO is not recommended.

Implications for research

Future research should focus on strategies to minimize red blood cell donor exposure during the first week of life when the likelihood for the need of red blood cell transfusion is at its peak. Such strategies, which include the use of satellite packs in combination with late EPO treatment may reduce further donor exposure. There is a concern that early EPO exposure increases the risk of ROP, a serious complication of preterm birth. This increased risk could be associated with higher doses of iron used in the early EPO group of the trials. Ongoing studies must include ROP as an outcome measure of importance and data-monitoring/safety committees should be provided with this information on an ongoing basis. We will try to obtain unpublished data regarding ROP from the authors of published studies. Until more information is available either from published studies or ongoing studies regarding ROP, we do not recommend any new trials of early EPO, especially in view of the limited clinical benefits identified in this extensive review. Futher long-term follow-up data are needed.

Acknowledgements

We are thankful to Dr. Rolf Maier, Zentrum für Kinder- und Jugendmedizin, Philipps-Universität, Marburg, Germany and Dr. Gulcan Türker, University of Kocaeli, Kocaeli, Turkey, who provided us with additional information regarding their studies.

We would like to thank Ms. Elizabeth Uleryk, Chief Librarian, The Hospital for Sick Children (SickKids), Toronto, Ontario, Canada, for developing the search strategy for this review.

Dr. Silvio Gonzalez, Departmental Fellow, Division of Neonatology, The Hospital for Sick Children (SickKids), Toronto, Ontario, Canada, helped with the translation of sections of two papers from Spanish to English.

Mrs. Eva Ohlsson, Toronto, Ontario, Canada, helped with the translation of sections of one paper from Polish to English.

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

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Arif 2005
MethodsRandomised, open controlled study. I. Blinding of randomizations- can't tell II. Blinding of intervention- no III. Blinding of outcome measure assessment-no IV. Complete follow-up- yes
Participants 292 preterm infants < 33 weeks GA, birth weight < 1500 g, no blood sampling > 10 ml in the first 7 days after birth, not having previous blood transfusion, no IVH > grade 1, no history of hematological disease, no urinary tract infection or sepsis Single centre study performed in Istanbul, Turkey Study period 1993 to 2002
Interventions142 infants in EPO group received EPO (EPREX 2000, Santa-Farma-Gurel, Istanbul) 200 IU/kg s.c. from the 7th day of life and continued twice weekly (400 IU/kg/week, low dose) for 6 weeks. 150 infants in the control group did not receive a placebo. Both groups received iron (3-5 mg/kg/day orally) (high dose)
OutcomesUse of one or more red blood cell transfusions, mortality, NEC, ROP (stage not reported), BP
NotesInfants who had received red blood cell transfusion prior to study entry were excluded Transfusion guidelines were in place The iron dose varied from 3-5 mg/kg/day but we included this as a high dose in our sub group analyses
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesComputer assisted randomisation scheme
Allocation concealment?UnclearBlinding of randomisation: unclear
Blinding? All outcomesNoBlinding of intervention: no Blinding of outcome measure assessment: no
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes
Free of selective reporting?Yes 
Free of other bias?Yes 
Avent 2002
MethodsRandomised, open controlled study. I. Blinding of randomizations- can't tell II. Blinding of intervention- no III. Blinding of outcome measure assessment-no IV. Complete follow-up- yes
Participants93 infants < 7 days of life, in room air or requiring 30% oxygen at study entry with birth weight between 900 and 1500 g Infants were stratified by weight <1250 g and >1250 g and then randomised to three treatment groups Two centres in South Africa Study period not stated
Interventions32 infants (low dose group) received EPO (Recormon) s.c., 250 IU/kg, three times a week (high dose) 31 infants (high dose group) received EPO (Recormon) s.c., 400 IU/kg three times a week (high dose) 30 infants (control group) received standard care The endpoint of therapy was reached when the infant was discharged from the hospital. All infants received a therapeutic dose of 6 mg/kg (high dose) elemental iron orally every day, it was increased to 8-10 mg/kg (high dose iron) if the hypochromic cells became 20 per cent or more All infants subsequently received blood transfusions if they met the transfusion criteria
OutcomesUse of one or more red blood cell transfusions Total volume (ml/kg) of blood transfused per infant Number of blood transfusions per infant Mortality Sepsis Hypertension Length of hospital stay
NotesIt is not stated whether infants who had received blood transfusions prior to study entry were included Transfusion guidelines were in place
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear
Allocation concealment?UnclearBlinding of randomisation: unclear
Blinding? All outcomesNoBlinding of intervention: no Blinding of outcome measure assessment: no
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes
Free of selective reporting?Yes 
Free of other bias?Yes 
Bierer 2006
MethodsRandomised, placebo controlled study. I. Blinding of randomizations- all caregivers and investigators (except the research nurses) were masked to the treatment assignment II. Blinding of intervention- yes, sham injections were given in the placebo group and when an i.v. was no longer in place an adhesive bandage covered the true and sham injection sites III. Blinding of outcome measure assessment- yes IV. Complete follow-up- yes
ParticipantsPreterm infants who weighed ≥ 400 g but ≤ 1000 g at birth, who were < 32 weeks' gestation and who were between 24 and 96 hours of age at the time of study entry.
InterventionsIntervention: The EPO group received 400 IU/kg i.v. or s.c. 3 times per week (1200 IU/kg/week, high dose) until discharge, transfer, death, or 35 weeks completed weeks' PMA. Iron supplementation was according to the study by Ohls 2001B (high dose) in both groups.
OutcomesNumber of red blood cell transfusions per infant, mortality, NEC, BPD at 36 weeks PMA, ROP stage ≥ 3, IVH ≥ 3, mean Psychomotor Developmental Index (PDI) and Mental Development Index (MDI) scores and PDI and MDI scores < 70 at 18 to 22 month's corrected age; cerebral palsy, blindness, hearing loss or any neurodevelopmental impairment at 18 to 22 months corrected age.
NotesA conservative transfusion protocol was in place Ohls 2001B
Risk of bias
ItemAuthors' judgementDescription
Allocation concealment?YesBlinding of randomizations: yes, all caregivers and investigators (except the research nurses) were masked to the treatment assignment
Blinding? All outcomesYesBlinding of intervention: yes, sham injections were given in the placebo group and when an i.v. was no longer in place an adhesive bandage covered the true and sham injection sites Blinding of outcome measure assessment: yes
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes
Free of selective reporting?YesTwo infants in the placebo/control group died at 3 months and were not included in the follow-up
Free of other bias?Yes 
Carnielli 1992
MethodsRandomised controlled trial I Blinding of randomization - can't tell II Blinding of intervention - no III Blinding of outcome measurement - no IV Complete follow-up - yes
Participants22 preterm infants with gestational age <32 weeks and birth weight <1750 g and age >2 days Single centre Italy Study period not stated
Interventions11 infants in the EPO group received EPO unnamed product), 400 IU, three times weekly, i.v. (400 IU/ml saline solution for 1 to 2 minutes) if i.v. line in place (1200 IU/kg/week, high dose) and then continued s.c., plus iron (dextriferron) 20 mg/kg once a week i.v. (high dose iron) from second day of life until discharge 11 infants in the control group did not receive either EPO or iron
OutcomesNumber of transfusions Number of donor exposures (range) Mortality Neutropenia Hospital stay in days Side effects
NotesIt is not stated whether infants who had received blood transfusions prior to study entry were included Transfusion guidelines were in place
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear
Allocation concealment?UnclearBlinding of randomisation: unclear
Blinding? All outcomesNoBlinding of intervention: no Blinding of outcome measurement: no
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes
Free of selective reporting?Yes 
Free of other bias?Yes 
Carnielli 1998
MethodsRandomised controlled trial I Blinding of randomizations - can't tell II Blinding of intervention - no III Blinding of outcome measurement - no IV Complete follow-up - yes
Participants63 preterm infants with birth weight <1750 g and gestational age <32 weeks, between the second day to 8 weeks of life Single centre, Italy Study period not stated
Interventions22 infants in EPO + iron group received 400 IU EPO (Eprex, Cilag, Italy) per kg three times a week (high dose) + 20 mg/kg/week of i.v. iron (high dose) 20 infants in EPO group received EPO, 400 IU/kg three times a week (high dose) without iron (low dose) 21 infants in the control group received no treatment or placebo Treatment was continued to the eight week of life (or hospital discharge) EPO was administered i.v. if the patient had an i.v. line and then continued s. c. at the same dose All infants were fed the same preterm formula and they received 80 mcg/kg of folic acid and 25 IU/day of vitamin E during the study period. No oral iron supplements were given during the study period
OutcomesMean number of blood transfusions (95% CI) BPD (age not stated) IVH (grade not stated) Sepsis ROP (stage not stated) Days in hospital
NotesIt is not stated whether infants who had received blood transfusions prior to study entry were included Transfusion guidelines were in place
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear
Allocation concealment?UnclearBlinding of randomization: unclear
Blinding? All outcomesNoBlinding of intervention: no Blinding of outcome measurement: no
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes
Free of selective reporting?Yes 
Free of other bias?Yes 
Chang 1998
MethodsRandomised controlled trial I Blinding of randomizations - can't tell II Blinding of intervention - no III Blinding of outcome measurement - no IV Complete follow-up - yes
Participants45 preterm infants with BW ≤ 1800 g and GA ≤ 35 weeks, age 1 day Single center, China Study period March 1996 - March 1998
Interventions15 infants in group 1 received EPO (Kirin Brewery, Co., Ltd., Japan) 150 IU/kg (450 IU/kg/week, low dose), s. c., three times a week for 6 weeks 15 infants in group 2 received EPO 250 IU/kg (750 IU/kg/week, high dose), s. c., three times a week for 6 weeks 15 infants in group 3 did not receive any treatment All infants received oral iron 20 mg (high dose) from day 7 after birth
OutcomesUse of one or more red blood cell transfusions Sepsis Neutropenia Hypertension Side effects
NotesIt is not stated whether infants who had received blood transfusions prior to study entry were included It is not stated whether transfusion guidelines were in place
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear
Allocation concealment?UnclearBlinding of randomization: unclear
Blinding? All outcomesNoBlinding of intervention: no Blinding of outcome measurement: no
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes
Free of selective reporting?Yes 
Free of other bias?Yes 
Fauchère 2008
MethodsRandomised controlled trial I Blinding of randomizations - yes II Blinding of intervention - yes III Blinding of outcome measurement - yes IV Complete follow-up - yes
ParticipantsPreterm infants born between 24 6/7 and 31 6/7 weeks. Single center, Switzerland Study period September 2005 through November 2006.
Interventions30 infants in the EPO group received 3000 IU rhEpo/kg (Epoietin Beta, Roche, Basel Switzerland) i.v. 3 to 6, 12 to 18, and 36 to 42 hours after birth. No infant was treated later with rhEpo for anemia of prematurity. 15 infants in the placebo group received the same volume of 0.9% NaCl (indistinguishable from rhEpo)
OutcomesMortality, IVH (all grades and grades III-IV), Persisting periventricular echodensity, ROP (all stages and stages 3-4), Sepsis, NEC (stage not reported), BPD at 36 weeks PMA
Notes 
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesComputer-based random-number generator
Allocation concealment?YesAssignment was by the hospital pharmacy
Blinding? All outcomesYesStudy drug and the placebo were indistinguishable
Incomplete outcome data addressed? All outcomesYes 
Free of selective reporting?Yes 
Free of other bias?Yes 
Haiden 2005
MethodsRandomised controlled trial I Blinding of randomizations - yes (sealed envelopes) II Blinding of intervention - no III Blinding of outcome measurement - no IV Complete follow-up - yes (see notes)
Participants40 preterm infants with BW < 800 g and GA < 32 weeks. Neonatal intensive care units in Vienna, Austria Study period October 2000 - November 2002
InterventionsThe EPO group (n = 21) received 300 IU/kg/day of EPO (Erypo, Janssen-Cilag Pharma, Vienna, Austria) i.v. (as long as i.v. access was available), or 700 IU/kg 3 times/week (2100 IU/kg/week, high dose) and iron dextran 1.5 mg/kg/day i.v. or iron polymerase complex 9 mg/kg/day orally (high dose) Therapy was given until 40 weeks GA or discharge The control group (n = 19) did not receive i.v. iron. Iron was started orally from the 15 th day of life or when infant tolerated 60 ml/kg of enteral feeding, which ever came first Placebo was not used
OutcomesUse of one or more red blood cell transfusions, number of donors, mortality, NEC, PVL, IVH (grade I - II), IVH grade III - IV), hospital stay, BPD (age not stated), ROP (stage I - II), ROP (stage III - IV)
Notes47 infants were eligible for enrolment in the study. Four infants were excluded because of parental refusal (n = 2) or IVH grade IV (n = 2) Three infants died before randomization The final cohort included 40 infants It is not stated whether infants who had received blood transfusions prior to study entry were included Transfusion guidelines were in place
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear
Allocation concealment?YesBlinding of randomization: yes (sealed envelopes)
Blinding? All outcomesNoBlinding of intervention: no Blinding of outcome measurement: no
Incomplete outcome data addressed? All outcomesUnclearComplete follow-up: 47 infants were eligible for enrolment in the study. Four infants were excluded because of parental refusal (n = 2) or IVH grade IV (n = 2) Three infants died before randomization The final cohort included 40 infants
Free of selective reporting?Yes 
Free of other bias?Yes 
He 2008
MethodsRandomised controlled trial I Blinding of randomizations - can't tell II Blinding of intervention - can't tell III Blinding of outcome measurement - can't tell IV Complete follow-up - can't tell
ParticipantsPopulation: Preterm infants, 7 days old
InterventionsIntervention: The EPO group received 250 IU/kg/day 3 times weekly i.v. for 4 weeks (750 IU/kg/week, high dose). The use of iron is not stated nor is it stated what the control group received.
OutcomesNeonatal Behavioral Neurological Assessment at 40 weeks PMA, and Gesell Developmental Schedule at 6 and 12 months after birth.
NotesThis study has been published as a full report in Chinese. Only the abstract was written in English. We have requested the full paper and if possible an English translation from the first author (2009 08 08).
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear
Allocation concealment?UnclearBlinding of randomizations: unclear
Blinding? All outcomesUnclearBlinding of intervention: unclear Blinding of outcome measurement: unclear
Incomplete outcome data addressed? All outcomesUnclearComplete follow-up: unclear
Free of selective reporting?UnclearAs we have not been able to obtain an English translation of the full article this item cannot be assessed
Free of other bias?UnclearAs we have not been able to obtain an English translation of the full article this item cannot be assessed
Khatami 2008
MethodsRandomised controlled trial I Blinding of randomizations - yes, sealed envelopes II Blinding of intervention - no, a placebo was not used III Blinding of outcome measurement - no IV Complete follow-up - yes
ParticipantsPopulation: Preterm infants with BW > 1000 g but < 1750 g and GA > 28 weeks but < 34 weeks, and were between 48 and 96 hours old at the time of entering the study.
InterventionsThe EPO group received 500 IU/kg/day of EPO s.c. twice weekly (1000 IU/kg/week, high dose) and iron (ferrous sulfate) 3mg/kg/day enterally (low dose). Control infants received iron (ferrous sulfate) 3mg/kg/day enterally (low dose) at second week of life. Parenteral iron was not administered throughout the study.
OutcomesNumber of red blood cell transfusions per patient, weight gain, hospital stay.
Notes"Guidelines for red-cell transfusions were based on the relatively strict existing policy in the nursery which was used to administer transfusions during the study period".
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear
Allocation concealment?YesBlinding of randomization: yes, sealed envelopes
Blinding? All outcomesNoBlinding of intervention: no, a placebo was not used Blinding of outcome measurement: no
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes
Free of selective reporting?Yes18 infants were excluded due to parents' refusal and unavailability.
Free of other bias?Yes 
Lauterbach 1995
MethodsRandomized controlled trial I Blinding of randomization - can't tell II Blinding of intervention - can't tell III Blinding of outcome measurement - yes IV Complete follow-up - yes
Participants19 preterm infants with GA < 35 weeks and birthweight ≤ 1500 g. Single centre study conducted in Poland
InterventionsInfants in EPO group I (n - 6) received EPO (Recormon, Boehringer Mannheim) 100 IU/kg twice a week i.v. (200 IU/kg/week, low dose) between days 7 and 37, and infants in EPO group II (n = 6) received 400 IU/kg twice weekly (800 IU/kg/week, high dose) during the same time period. The control group (n = 7) received no treatment or placebo. Both EPO groups and the control group received 10 mg/kg/week of iron i.v. (high dose)
OutcomesTotal volume (ml/kg) of blood transfused between days 7 and 37 Side effects
NotesTransfusion guide lines were in place We could not ascertain whether infants who had received blood transfusions prior to study entry were included
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear
Allocation concealment?UnclearBlinding of randomization: unclear
Blinding? All outcomesUnclearBlinding of intervention: no Blinding of outcome measurement: no
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes
Free of selective reporting?Yes 
Free of other bias?Yes 
Lima-Rogel 1998
MethodsDouble blind, randomised controlled trial I Blinding of randomizations - can't tell II Blinding of intervention - yes III Blinding of outcome measurement - yes IV Complete follow-up - yes
Participants40 VLBW infants with birth weight between 750 and 1500 g and gestation age < 26 weeks Single center, Mexico Study period: 1995 to 1996
Interventions21 infants in the EPO group recieved EPO (Eprex 4000, Cilag de Mexico SA de CV) 150 units/kg/day (during the first 6 weeks of life), 1050 IU/kg/week (high dose) and 19 infants in the control group recieved placebo Iron 4 mg/kg/day (low dose)
OutcomesNumber of transfusions per group Sepsis NEC IVH (grade not reported) BPD (age not stated)
NotesWe could not ascertain whether transfusion guide lines were in place and if infants who had received blood transfusions prior to study entry were included
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear
Allocation concealment?UnclearBlinding of randomizations: unclear
Blinding? All outcomesYesBlinding of intervention: yes Blinding of outcome measurement: yes
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes
Free of selective reporting?Yes 
Free of other bias?Yes 
Maier 1994
MethodsDouble blind, randomised controlled trial I Blinding of randomizations - yes II Blinding of intervention - yes III Blinding of outcome measurement - yes IV Complete follow-up - no?, see notes
Participants244 infants with birth weight of 750 to 1499 g, 3 infants were excluded after randomization 12 centers in six European countries September 1991 to December 1992
Interventions120 infants in the EPO group received 250 IU of epoetin beta (Boehringer-Mannheim, Germany) per kilogram, injections on Monday, Wednesday and Friday (750 IU/kg/week, high dose). The treatment continued until day 40 to 42, for a total of 17 doses 121 infants in the control group did not receive placebo but adhesive tape was placed on both thighs, which remained there until next visit Oral iron supplementation, 2 mg/kg/day was started on day 14 in all infants (low dose) Vitamin E supplementation was not part of the protocol
OutcomesUse of one or more red blood cell transfusions Number of transfusions per infant Mortality ROP Sepsis NEC IVH all grades IVH grades III-IV Neutropenia Hypertension Side effects
NotesInfants who had received transfusions prior to study entry were included (28 in the EPO group and 17 in the control group) Transfusion guidelines were in place 33 infants were withdrawn in the EPO group and 28 in the control group The results are reported as per intention to treat
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear
Allocation concealment?YesBlinding of randomization: yes
Blinding? All outcomesYesBlinding of intervention: yes Blinding of outcome measurement: yes
Incomplete outcome data addressed? All outcomesNoComplete follow-up: no 33 infants were withdrawn in the EPO group and 28 in the control group The results are reported as per intention to treat
Free of selective reporting?YesThree of the 244 infants who underwent randomization were excluded; all data on two infants were lost, and treatment (EPO) was inadvertently omitted in one infant, whose records were not completed. The remaining 241 infants were evaluated in an intention-to-treat analysis.
Free of other bias?Yes 
Maier 2002
MethodsDouble blind, randomised controlled trial I Blinding of randomizations - yes (sealed envelopes) II Blinding of intervention - yes III Blinding of outcome measurement - yes IV Complete follow-up - yes
Participants219 ELBW infants were randomly assigned to early EPO, a late EPO or control group on day 3 of life 14 enters in 4 European countries May 1998 to June 1999
Interventions74 infants in the early EPO group received EPO (NeoRecor-mon, F. Hoffman-La Roche, Basel, Switzerland) 250 IU/kg, i.v. or s. c., three times a week (750 IU/kg/week, high dose) starting from day 3 of life, for 9 weeks 74 infants in late EPO group received EPO 250 IU/kg i.v. or s. c., three times a week starting from the fourth week of life, for 6 weeks 71 infants in the control group received sham-injections Enteral iron 3 mg/kg was given to all infants from days 3 to 5 and was increased at days 12 to 14 to 6 mg/kg/day and to 9 mg/kg/day at days 24 to 26 of life (high dose)
OutcomesUse of one or more red blood cell transfusions Number of donors the infant was exposed to (median, quartiles) Number of transfusions per infant (mean) Mortality during hospital stay NEC IVH (grade not stated) PVL ROP (stage not stated) BPD (at 36 weeks corrected age) Growth Days in hospital (median, quartiles)
NotesSample size calculation was performed 24 (32%) of the infants in the early EPO group and 22 (31%) in the control group were exposed to donor blood before they entered the study Transfusion guidelines were followed Industry funded (F. Hoffman-La Roche, Basel Switzerland) One infant was excluded from all evaluations because the parents withdrew consent a few hours after randomization before the start of the treatment phase
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear
Allocation concealment?YesBlinding of randomization: yes (sealed envelopes)
Blinding? All outcomesYesBlinding of intervention: yes - When treatment was to be given, a dosing investigator carrying a "black box" containing appropriate equipment visited each infant, gave or simulated administration of the study medication, and placed adhesive strips on both thighs (of EPO recipients and controls) Blinding of outcome measurement: yes
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes; One of the 220 randomized infants (control group) was excluded from all evaluations because the parents withdrew consent a few hours after randomization before the start of treatment phase
Free of selective reporting?Yes 
Free of other bias?Yes 
Meister 1997
MethodsRandomised controlled trial I Blinding of randomizations - can't tell II Blinding of intervention - no III Blinding of outcome measurement - no IV Complete follow-up - yes (see notes)
Participants30 preterm infants with birth weight of 750 to 1499 g and five to ten days old Single center, Austria Study period not stated
Interventions15 infants in the EPO group received eopoetin alpha (Janssen-Cilag pharmaceuticals, Vienna, Austria) 300 IU/kg s. c. 3 times a week for 4 weeks 15 infants in the control group did not receive the drug Oral iron administration was started with a dose of 6 mg/kg/day and increased after two weeks to 8 mg/kg/day. The control group patients received iron alone.
OutcomesStudy gives results as cumulative volume of blood transfused per kg with first and third quartiles
NotesIt is not stated whether infants who had received blood transfusions prior to study entry were included Transfusion guidelines were in place One infant in the control group was withdrawn from the study because of development of IVH grade IV
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesComputerized random numbers generator
Allocation concealment?UnclearBlinding of randomization: unclear
Blinding? All outcomesNoBlinding of intervention: no Blinding of outcome measurement: no
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes One infant in the control group was withdrawn from the study because of development of IVH grade IV
Free of selective reporting?Yes 
Free of other bias?Yes 
Meyer 2003
MethodsDouble blind, randomised controlled trial I Blinding of randomizations - yes II Blinding of intervention - yes III Blinding of outcome measurement - yes IV Complete follow-up - yes
Participants43 preterm infants < 33 weeks gestation and < 1700 g Single center, Auckland, New Zealand Two year period 1995-1996
Interventions22 infants in EPO group received erythropoietin (Eprex; Janssen-Cilag, Auckland, New Zealand) at a dose of 1200 IU/kg/week (high dose) s. c. in three divided doses until the age of 3 weeks when the dose was reduced to 600 IU/kg/week. Treatment continued until 34 weeks completed gestation or for a minimum of three weeks. 21 infants in the control group received sham treatment, to avoid s.c. injection Ferrous gluconate at a dose of 6 mg of elemental iron/kg/day (high dose) was given to the EPO group once they had attained a postnatal age of 2 weeks and receiving at least 50% energy intake orally. Those in the control group received 2 mg/kg/day iron from the same age in a more dilute preparation so that an equivalent volume was given. All infants received a multivitamin preparation and vitamin E (25 IU/day)
OutcomesUse of one or more red blood cell transfusions Number of donors the infant was exposed to Number of transfusions per infant
NotesIt is not stated whether infants who had received blood transfusions prior to study entry were included Transfusion guidelines were in place
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesComputer generated
Allocation concealment?YesBlinding of randomizations: yes
Blinding? All outcomesYesBlinding of intervention: yes - infants randomized to the control group received sham treatment, to avoid subcutaneous placebo injections. Treatment was administered by a designated nurse not involved in clinical management decisions relating to the infants. Blinding of outcome measurement: yes
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes
Free of selective reporting?Yes 
Free of other bias?Yes 
Obladen 1991
MethodsRandomised controlled trial I Blinding of randomizations - yes (sealed envelopes) II Blinding of intervention - no III Blinding of outcome measurement - no IV Complete follow-up - yes
Participants93 infants with gestational age of 28-32 completed weeks Five centers, Europe April 1989 to February 1990
Interventions43 infants in the EPO group received EPO (Boehringer Mannheim GmbH) 30 IU/kg s.c. every 3rd day (70 IU/kg/week, low dose) from the 4th to 25 th day of life 50 control infants did not receive s. c. injections of placebo, but were managed identically Elemental iron treatment was started on day 14 with 2 mg/day orally
OutcomesUse of one or more red blood cell transfusions Total volume of blood transfused per infant Mortality Chronic lung disease ROP ( infants were followed for ROP, but results not reported) IVH NEC BPD Hypertension Renal failure PDA
NotesIt is not stated whether infants who had received blood transfusions prior to study entry were included Transfusion guidelines were in place
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear
Allocation concealment?YesBlinding of randomizations: yes (sealed envelopes)
Blinding? All outcomesNoBlinding of intervention: no Blinding of outcome measurement: no
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes
Free of selective reporting?Yes 
Free of other bias?Yes 
Ohls 1995
MethodsRandomised controlled trial I Blinding of randomizations - yes II Blinding of intervention - yes III Blinding of outcome measurement - yes IV Complete follow-up - yes
Participants20 ill newborn VLBW infants, less than 48 hours of age, weight between 750 and 1500 g at birth and GA >27 weeks Single centre, USA Study period not stated
Interventions10 infants in the EPO group received EPO (unnamed product), 200 IU/kg/day (1400 IU/kg/week, high dose) i.v. for 14 consecutive days 10 infants in the control group received similar volume of 0.9% saline solution in similar fashion as placebo Infants in both groups received iron, 2 mg/kg per day orally, when they were taking 70 ml/kg/day enterally, which was increased to 6 mg/kg per day (high dose) when the infants were receiving more than 100 ml/kg per day of feeds.
OutcomesUse of one or more red blood cell transfusions Total volume of blood transfused per infant Number of transfusions per infant BPD Neutropenia NEC IVH Side effects
NotesIt is not stated whether infants who had received blood transfusions prior to study entry were included Transfusion guidelines were in place
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear
Allocation concealment?YesBlinding of randomisation: yes
Blinding? All outcomesYesBlinding of intervention: yes Blinding of outcome measurement: yes
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes
Free of selective reporting?YesAfter the interim analysis, the study was discontinued because of significant differences between groups in number of transfusions.
Free of other bias?YesThere were no differences in the number of infants with BPD, IVH, or NEC (data not shown)
Ohls 1997
MethodsDouble blind, randomised controlled trial I Blinding of randomizations - yes II Blinding of intervention - yes III Blinding of outcome measurement - yes IV Complete follow-up - yes
Participants28 ELBW infants with birth weight 750 g or less and were 72 hours of age or younger 3 enters, USA Period not stated
Interventions15 infants received EPO (unnamed product) 200 IU/kg/day (1400 IU/kg/day, high dose) i.v., for 14 consecutive days 13 infants received placebo as an equivalent volume of diluent in similar fashion All infants received 1 mg/kg/day iron dextran in TPN solution during treatment period (high dose) All infants received vitamin E, 25 IU/day when they tolerated 60 ml/kg/day feeds enterally
OutcomesTotal volume of blood transfused per infant Number of transfusions per infant Mortality Sepsis IVH BPD ROP Neutropenia
NotesIt is not stated whether infants who had received blood transfusions prior to study entry were included Transfusion guidelines were in place
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear
Allocation concealment?YesBlinding of randomisation: yes
Blinding? All outcomesYesBlinding of intervention: yes Blinding of outcome measurement: yes
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes
Free of selective reporting?YesTwo infants in each group died before the 21-day study period
Free of other bias?Yes 
Ohls 2001A
MethodsDouble blind, randomised controlled trial I Blinding of randomisation - yes II Blinding of intervention - yes III Blinding of outcome measurement - yes IV Complete follow-up - yes
Participants172 infants with birth weight between 401 g to 1000 g, gestational age <32 weeks and between 24 and 96 hours old at the time of study entry and were likely to survive >72 hours Multicenter trial, USA Trial period not stated
Interventions87 infants in the EPO group received 400 U/kg EPO (unnamed product) 3 times weekly (1200 IU/kg/week, high dose) i.v. or s.c. when i.v. access was not available 85 infants in the placebo/control group received sham s.c. injections when i.v. access was not available. An adhesive bandage covered the true and sham injection sites. Treatment was continued until discharge, transfer, death or 35 completed weeks corrected GA Treated infants received a weekly i.v. infusion of 5 mg/kg iron dextran (high dose) until they had an enteral intake of 60 ml/kg/day. Iron dextran was either added to the TPN solution and administered over 24 hours or diluted in 10% dextrose in water or normal saline and administered over 4 to 6 hours. Placebo/control infants received 1 mg/kg iron dextran once a week, administered in a similar manner. Once infants in both groups had enteral intake of 60 mg/kg/day, they were given iron at a dose of 3 mg/kg/day. The dose was gradually increased to 6 mg/kg/day depending on enteral intake. Study infants received enteral vitamin E 15-25 IU/day and enteral folate supplements 25-50 mcg/day were provided according to centre practice
OutcomesUse of one or more red blood cell transfusions Mean number of erythrocyte transfusions per infant Number of donors the infant was exposed to Total volume of blood transfused per infant Late onset sepsis Mortality Chronic lung disease (at 36 weeks corrected GA) ROP Severe IVH (stage >/= 3) NEC BPD Neutropenia Hypertension Hospital stay At follow-up (see notes) Growth, development, rehospitalization, transfusions
NotesIt is not stated whether infants who had received blood transfusions prior to study entry were included Strict protocol was used to administer transfusions during study period. Of the 72 EPO treated and 70 placebo-control infants surviving to discharge follow-up data at 18 to 22 months' corrected age were collected on 51 of 72 EPO -treated infants (71%) and 51 of 70 placebo/controls (73%).
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear
Allocation concealment?YesBlinding of randomisation: yes - All caregivers and investigators (except the research nurses) were masked to the treatment assignment
Blinding? All outcomesYesBlinding of intervention: yes Blinding of outcome measurement: yes
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes
Free of selective reporting?YesAll infants were followed through their hospital stay up to 120 days
Free of other bias?Yes 
Ohls 2001B
MethodsDouble blind, randomised controlled trial I Blinding of randomisation - yes II Blinding of intervention - yes III Blinding of outcome measurement - yes IV Complete follow-up - yes
Participants118 infants with birth weight between 1001 g to 1250 g, gestational age <32 weeks and between 24 and 96 hours old at the time of study entry and were likely to survive >72 hours Multicenter trial, USA Trial period not stated
Interventions59 infants in the EPO group received 400 IU/kg EPO (unnamed product) 3 times weekly (1200 IU/kg/week, high dose) i.v. or s.c. when i.v. access was not available 59 infants in the placebo/control group received sham s.c. injections when i.v. access was not available. An adhesive bandage covered the true and sham injection sites. Treatment was continued until discharge, transfer, death or 35 completed weeks PMA Treated infants received a weekly i.v. infusion of 5 mg/kg iron dextran (high dose) until they had an enteral intake of 60 ml/kg/day. Iron dextran was either added to the TPN solution and administered over 24 hours or diluted in 10% dextrose in water or normal saline and administered over 4 to 6 hours. Placebo/control infants received 1 mg/kg iron dextran once a week, administered in a similar manner. Once infants in both groups had enteral intake of 60 mg/kg/day, they were given iron at a dose of 3 mg/kg/day. The dose was gradually increased to 6 mg/kg/day depending on enteral intake. Study infants received enteral vitamin E 15-25 IU/day and enteral folate supplements 25-50 mcg/day were provided according to centre practice
OutcomesUse of one or more red blood cell transfusions Mean number of erythrocyte transfusions per infant Number of donors the infant was exposed to Total volume of blood transfused per infant Late onset sepsis Mortality Chronic lung disease ROP severe IVH NEC BPD (at 36 weeks corrected GA) Neutropenia Hypertension Length of hospital stay
NotesIt is not stated whether infants who had received blood transfusions prior to study entry were included Strict protocol was used to administer transfusions during study period.
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear
Allocation concealment?YesBlinding of randomisation: yes
Blinding? All outcomesYesBlinding of intervention: yes - All caregivers and investigators (except the research nurses) were masked to the treatment assignment Blinding of outcome measurement: yes
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes
Free of selective reporting?YesAll infants were followed through their hospital stay up to 120 days
Free of other bias?Yes 
Romagnoli 2000
MethodsRandomized, double-blind, controlled clinical trial. I. Blinding of randomisation- yes (sealed envelopes, on the 7th day of life) II. Blinding of intervention- no III. Blinding of outcome-measure assessment- no (ROP was) IV. Complete follow-up- yes
Participants230 infants with gestational age <30 weeks and 31-34 weeks with RDS and requiring mechanical ventilation, 7 days old Single center, Rome 3 year period ending December 1998
Interventions115 infants received EPO (unnamed product) 300 IU/kg s. c., three times a week (900 IU/kg/week, high dose) from the 2nd to the 7th week and iron 1 mg/kg/day i.v. (high dose) 115 infants did not receive EPO, placebo or iron
OutcomesUse of one or more red blood cell transfusions Number of blood transfusions per infant ROP NEC IVH >grade III - IV Chronic lung disease at 28 days Sepsis
NotesIt 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
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesRandom number allocation
Allocation concealment?YesBlinding of randomisation: yes (sealed envelopes, on the 7th day of life)
Blinding? All outcomesNoBlinding of intervention: no Blinding of outcome-measure assessment: no (ROP was)
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes
Free of selective reporting?UnclearThis study was reported in a "Research letter" format allowing only for few details
Free of other bias?UnclearThis study was reported in a "Research letter" format allowing only for few details
Salvado 2000
MethodsRandomized, double-blind, controlled clinical trial. I. Blinding of randomisation- yes II. Blinding of intervention- yes III. Blinding of outcome-measure assessment- yes IV. Complete follow-up- yes
Participants60 newborn infants under 1500 g birth weight Single centre Chile April 1998 to December 1999
Interventions29 infants in the EPO group received r-EPO (eritropoyetina del Laboraorio Andromaco) 200 IU/kg s.c., 3 times a week (600 IU/kg/week, high dose), during 4 weeks 31 infants in the control group received similar volume of isotonic saline solution in similar fashion All infants received oral iron at a dose of 3 mg/kg/day (low dose)
OutcomesNumber of transfusions per infant Sepsis IVH
Notes 
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear
Allocation concealment?YesBlinding of randomisation: yes
Blinding? All outcomesYesBlinding of intervention: yes Blinding of outcome-measure assessment: yes
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes
Free of selective reporting?Yes 
Free of other bias?Yes 
Soubasi 1993
MethodsRandomized, double-blind, controlled trial I Blinding of randomisation - yes II Blinding of intervention - yes III Blinding of outcome measurement - yes IV Complete follow-up - yes
Participants44 newborn infants with birth weight under 1500 g, age 1-7 days Single centre trial conducted in Thessaloniki Greece Period not stated
InterventionsThe EPO group (n = 25) received 150 IU/kg/dose of EPO (Cilag A.G., Zug, Switzerland) twice a week (300 IU/kg/week, low dose) during 4 weeks. The control group (n = 19) received a placebo. From the 15 th day of life iron was started at 3 mg/kg/day (low dose) in all infants
OutcomesNumber of transfusions per infant, sepsis, IVH and days on ventilator.
NotesIt is not stated whether infants who had received blood transfusions prior to study entry were included Transfusion guidelines were in place
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear
Allocation concealment?YesBlinding of randomisation: yes
Blinding? All outcomesYesBlinding of intervention: yes - "doctors in clinical charge were unaware of the treatment or control status of the babies" Blinding of outcome measurement: yes
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes
Free of selective reporting?Yes 
Free of other bias?Yes 
Soubasi 1995
MethodsRandomized controlled trial I Blinding of randomisation - can't tell II Blinding of intervention - no III Blinding of outcome measurement - no IV Complete follow-up - yes
Participants97 VLBW infants with GA 31 weeks or less, birth weight 1500 g or less and age 1 to 7 days Single centre, Greece Period not stated
Interventions33 infants received rHuEPO (Cilag AG, Zug, Switzerland) 150 IU/kg twice weekly (300 IU/kg/week, low dose) 28 infants received rHuEPO 250 U/kg three times per week (750 IU/kg/week, high dose) EPO was administered from the fist week of life for 6 weeks 36 infants (control) did not receive any treatment All infants received oral elemental iron, 3 mg/kg/day from day 15 of life (low dose) 75 infants were followed, after discontinuation of EPO therapy, weekly until discharge and thereafter at 3, 6 and 12 months of age
OutcomesUse of one or more red blood cell transfusions Number of blood transfusions per infant Mortality Follow up to one year of age Hospital stay 75 infants were followed, after discontinuation of EPO therapy, weekly until discharge and thereafter at 3, 6 and 12 months of age (no neurodevelopmental outcomes reported)
NotesIt is not stated whether infants who had received blood transfusions prior to study entry were included Transfusion guidelines were in place
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesRandom-number table
Allocation concealment?UnclearBlinding of randomisation: unclear
Blinding? All outcomesNoBlinding of intervention: no Blinding of outcome measurement: no
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes
Free of selective reporting?Yes 
Free of other bias?Yes 
Soubasi 2000
MethodsRandomized, controlled clinical trial. I. Blinding of randomisation- can't tell II. Blinding of intervention- no? III. Blinding of outcome-measure assessment- no IV. Completeness follow-up- yes
Participants36 very low birth weight infants with gestational age <31 weeks and birth weight <1300 g with clinical stability at the time of entry Single center, Thessaloniki, Greece Study period not stated
Interventions18 infants in the treatment group received rHuEPO (Cilag AG, Zug, Switzerland) 200 IU/kg every alternate day (700 units/kg/week, high dose) s. c. 18 infants in the control group did not receive EPO or placebo Duration of EPO treatment not stated Additionally, infants received oral iron at a dose of 12 mg/kg/day (high dose) in the EPO group and 4 mg/kg/day in the control group Both groups were supplemented with 500 mcg of oral folate every other day, 10 IU of vitamin E every day and multivitamins, when enteral feeding reached 75% of total fluid intake, until discharge.
OutcomesUse of one or more red blood cell transfusions Number of transfusions per infant
NotesThis study does not mention the exact day when treatment was started It is not stated whether infants who had received blood transfusions prior to study entry were included Transfusion guidelines were in place
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?YesRandom-number table
Allocation concealment?UnclearBlinding of randomisation: unclear
Blinding? All outcomesNoBlinding of intervention: no Blinding of outcome-measure assessment: no
Incomplete outcome data addressed? All outcomesYesCompleteness follow-up: yes
Free of selective reporting?Yes 
Free of other bias?Yes 
Yeo 2001
  1. CI = confidence interval

  2. GA = gestational age

  3. g = grams

  4. IU = international units

  5. i.v. = intravenous/intravenously

  6. s.c. = subcutaneous/subcutaneously

  7. TPN = total parentral nutrition

MethodsRandomized controlled trial I Blinding of randomization - no II Blinding of intervention - no III Blinding of outcome measurement - no IV Complete follow-up - yes
Participants100 VLBW infants, <33 weeks GA, hematocrit 0.4-0.6 at birth Single center, Singapore January 1997 to March 2000
Interventions50 infants in the EPO group received EPO (unnamed product) 250 IU/kg/dose s. c. three times a week (750 IU/kg/week, high dose) from day 5 to day 40 50 infants in the control group did not receive any treatment Infants in both groups received elemental iron, 3 mg/kg/day orally from day 10 and increased to 6 mg/kg/day (high dose) when full feeds were well tolerated
OutcomesExposure of a proportion of infants to one or more red blood cell transfusions Mean number of erythrocyte transfusions per infant Total volume of blood transfused per infant Mortality ROP (stage not stated) Sepsis NEC BPD (age not stated) Hypertension
NotesIt is not stated whether infants who had received blood transfusions prior to study entry were included Transfusion guidelines were in place
Risk of bias
ItemAuthors' judgementDescription
Adequate sequence generation?UnclearUnclear
Allocation concealment?UnclearBlinding of randomization: unclear
Blinding? All outcomesNoBlinding of intervention: no Blinding of outcome measurement: no
Incomplete outcome data addressed? All outcomesYesComplete follow-up: yes
Free of selective reporting?Yes 
Free of other bias?Yes 

Characteristics of excluded studies [ordered by study ID]

Amin 2002This study is not a randomized controlled trial
Brown 1999This study compares two different dosing regimens for the same total weekly dose of EPO. There was no control/placebo group
Fearing 2002This study does not give the number of infants allocated to treatment and control groups or the age at which the infants were entered
Haiden 2006aThis study reports the same findings as in the study by Haiden 2005
Haiden 2006bBoth study groups received erythropoietin
Juul 2008Not a randomised controlled trial
Krallis 1999No outcomes of interest for this review were reported
Maier 1998This randomized controlled trial compared two doses of EPO; 750 IU/kg/week vs. 1500 IU/kg/week without a non-treated control group
Ohls 1996The study compared different routes of administration (s. c. EPO vs. adding EPO to the total parenteral nutrition fluid).There was no untreated control group
Turker 2005This study was labeled by the authors as a quasi-randomized (assignment on an alternating basis) trial. The authors reported on uneven numbers in the two groups (42 infants in the EPO group and 51 in the control group). On request the principal author provided the following information. " In the study period 112 premature infants <1500 g were followed in the NICU. Informed consents were obtained from the parents of 97 babies, but only 93 babies completed the study because 3 patients were lost to follow-up after discharge and one baby died of bronchopulmonary dysplasia before completing the 12-week monitoring period. These 4 babies were omitted from the study group (r-Hu EPO+enteral iron). These infants are included in the result section. At the end of the study r-Hu EPO was not available, and 2 more patients had only iron supplementation. Then the study was closed and these 2 babies were also added to the control group. 97 patients (48 EPO group; 3 lost-to follow-up,1 died, -2 r-Hu Epo was unavailable; 49 controls; +2). Based on this information we excluded the study as it was not a quasi randomized trial.
Zhu 2009The population consisted of infants > 37 weeks PMA.

Data and analyses

Download statistical data

Table Comparison 1.. Erythropoietin vs. placebo or no treatment
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Use of one or more red blood cell transfusions (low and high dose of EPO)161825Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.75, 0.86]
2 Use of one or more blood transfusions (high dose of EPO)151432Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.74, 0.86]
2.1 High dose iron121067Risk Ratio (M-H, Fixed, 95% CI)0.84 [0.77, 0.92]
2.2 Low dose iron3365Risk Ratio (M-H, Fixed, 95% CI)0.66 [0.55, 0.80]
3 Use of one or more red blood cell transfusions (low dose EPO)3192Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.60, 1.07]
3.1 High dose iron130Risk Ratio (M-H, Fixed, 95% CI)Not estimable
3.2 Low dose iron2162Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.60, 1.07]
4 Total volume (ml/kg) of blood transfused per infant6515Mean Difference (IV, Fixed, 95% CI)-6.03 [-10.82, -1.24]
5 Number of blood transfusions per infant141131Mean Difference (IV, Fixed, 95% CI)-0.33 [-0.48, -0.18]
6 Number of donors the infant was exposed to2188Mean Difference (IV, Fixed, 95% CI)-0.63 [-1.07, -0.19]
7 Mortality during initial hospital stay (all causes of mortality)151546Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.69, 1.26]
8 Retinopathy of prematurity (any stage reported)111464Risk Ratio (M-H, Fixed, 95% CI)1.17 [0.98, 1.39]
9 Retinopathy of prematurity (stage >/= 3)8984Risk Ratio (M-H, Fixed, 95% CI)1.65 [1.12, 2.43]
10 Proven sepsis111207Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.74, 1.12]
11 Necrotizing enterocolitis (stage not reported)121530Risk Ratio (M-H, Fixed, 95% CI)1.09 [0.75, 1.59]
12 Intraventricular haemorrhage (all grades)9789Risk Ratio (M-H, Fixed, 95% CI)0.96 [0.69, 1.32]
13 Intraventricular haemorrhage (grade III and IV)7861Risk Ratio (M-H, Fixed, 95% CI)1.18 [0.69, 2.03]
14 Periventricular leukomalacia3228Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.57, 1.12]
15 Length of hospital stay (days)5415Mean Difference (IV, Fixed, 95% CI)-1.90 [-4.38, 0.58]
16 Bronchopulmonary dysplasia12 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
16.1 Supplemental oxygen at 28 days of age2330Risk Ratio (M-H, Fixed, 95% CI)1.27 [0.90, 1.80]
16.2 Supplemental oxygen at 36 weeks5495Risk Ratio (M-H, Fixed, 95% CI)0.97 [0.78, 1.21]
16.3 Age at diagnosis not stated5528Risk Ratio (M-H, Fixed, 95% CI)0.98 [0.61, 1.56]
17 Neutropenia9982Risk Ratio (M-H, Fixed, 95% CI)0.81 [0.53, 1.24]
18 Hypertension6762Risk Ratio (M-H, Fixed, 95% CI)3.02 [0.12, 73.52]
19 MDI < 70 at 18 to 22 months' corrected age (in children examined)2102Risk Ratio (M-H, Fixed, 95% CI)0.78 [0.44, 1.39]
20 PDI < 70 at 18 - 22 months' corrected age (in children examined)2102Risk Ratio (M-H, Fixed, 95% CI)2.0 [0.94, 4.25]
21 Cerebral palsy at 18 - 22 months' corrected age (in children examined)2111Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.46, 2.45]
22 Any neurodevelopmental impairment at 18-22 month's corrected age (in children examined)2111Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.59, 1.36]
23 Use of one or more red blood cell transfusions (secondary analysis)161825Risk Ratio (M-H, Fixed, 95% CI)0.80 [0.75, 0.86]
23.1 High quality studies6558Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.75, 0.92]
23.2 Studies of uncertain quality101267Risk Ratio (M-H, Fixed, 95% CI)0.79 [0.72, 0.87]
24 Use of one or more red blood cell transfusions (in NICUs using mostly satellite units of red blood cells)3435Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.81, 1.01]
25 Neonatal Behavioral Neurological Assessment at 40 weeks PMA144Mean Difference (IV, Fixed, 95% CI)1.80 [1.26, 2.34]
26 Blindness at 18 to 22 month's corrected age112Risk Ratio (M-H, Fixed, 95% CI)Not estimable
27 Hearing loss at 18 to 22 month's corrected age112Risk Ratio (M-H, Fixed, 95% CI)Not estimable
Figure Analysis 1.1.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 1 Use of one or more red blood cell transfusions (low and high dose of EPO).

Figure Analysis 1.2.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 2 Use of one or more blood transfusions (high dose of EPO).

Figure Analysis 1.3.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 3 Use of one or more red blood cell transfusions (low dose EPO).

Figure Analysis 1.4.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 4 Total volume (ml/kg) of blood transfused per infant.

Figure Analysis 1.5.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 5 Number of blood transfusions per infant.

Figure Analysis 1.6.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 6 Number of donors the infant was exposed to.

Figure Analysis 1.7.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 7 Mortality during initial hospital stay (all causes of mortality).

Figure Analysis 1.8.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 8 Retinopathy of prematurity (any stage reported).

Figure Analysis 1.9.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 9 Retinopathy of prematurity (stage >/= 3).

Figure Analysis 1.10.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 10 Proven sepsis.

Figure Analysis 1.11.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 11 Necrotizing enterocolitis (stage not reported).

Figure Analysis 1.12.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 12 Intraventricular haemorrhage (all grades).

Figure Analysis 1.13.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 13 Intraventricular haemorrhage (grade III and IV).

Figure Analysis 1.14.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 14 Periventricular leukomalacia.

Figure Analysis 1.15.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 15 Length of hospital stay (days).

Figure Analysis 1.16.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 16 Bronchopulmonary dysplasia.

Figure Analysis 1.17.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 17 Neutropenia.

Figure Analysis 1.18.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 18 Hypertension.

Figure Analysis 1.19.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 19 MDI < 70 at 18 to 22 months' corrected age (in children examined).

Figure Analysis 1.20.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 20 PDI < 70 at 18 - 22 months' corrected age (in children examined).

Figure Analysis 1.21.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 21 Cerebral palsy at 18 - 22 months' corrected age (in children examined).

Figure Analysis 1.22.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 22 Any neurodevelopmental impairment at 18-22 month's corrected age (in children examined).

Figure Analysis 1.23.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 23 Use of one or more red blood cell transfusions (secondary analysis).

Figure Analysis 1.24.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 24 Use of one or more red blood cell transfusions (in NICUs using mostly satellite units of red blood cells).

Figure Analysis 1.25.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 25 Neonatal Behavioral Neurological Assessment at 40 weeks PMA.

Figure Analysis 1.26.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 26 Blindness at 18 to 22 month's corrected age.

Figure Analysis 1.27.

Comparison 1 Erythropoietin vs. placebo or no treatment, Outcome 27 Hearing loss at 18 to 22 month's corrected age.

What's new

History

Protocol first published: Issue 3, 2004

Review first published: Issue 3, 2006

Contributions of authors

Sanjay Aher (SA) 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. 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 5.0 and the other review author (SA) checked for accuracy. One review author (AO) wrote the sections of 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.

July 2009 update of the review was conducted by one author (AO).

Declarations of interest

None.

Sources of support

Internal sources

  • Mount Sinai Hospital, Toronto, Canada.

External sources

  • No sources of support supplied

Ancillary