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

Title

Reviewers

Dates

Contact reviewer

Contribution of reviewers

Internal sources of support

External sources of support

Text of review

Synopsis

Abstract

Background

Objectives

Search strategy

Selection criteria

Data collection & analysis

Main results

Reviewers' conclusions

Background

EPO and 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 mU/ml, as compared to 15 mU/ml in concurrently studied adults (Brown 1983). A low plasma EPO level is a key reason that nadir hematocrit values of preterm infants are lower than those of term infants (Stockman 1986; Dallman 1981). Low plasma EPO levels provide a rationale for use of EPO in the prevention or treatment of anemia of prematurity. Studies in newborn monkeys and sheep have demonstrated that neonates have a large volume of distribution and more rapid elimination of EPO, necessitating the use of higher doses than required for adults (Ohls 2000). A recent systematic review of EPO administration noted a wide range of doses used, from 90 to 1400 IU/kg/week (Kotto-Kome 2004). Side effects reported in adults include hypertension, bone pain, rash and rarely seizures. Only transient neutropenia has been reported in neonates (Ohls 2000).

The primary goal of EPO therapy is to reduce transfusions. Most transfusions are given during the first three to four weeks of life. The larger or stable preterm infants who respond best to EPO receive few transfusions. ELBW infants, who are sick and have the greatest need for RBC transfusions shortly after birth, have not consistently responded to EPO. This suggests that EPO is a more effective erythropoietic stimulator in more mature neonates. ELBW neonates are more likely to need transfusions even if their erythropoiesis is stimulated (Kotto-Kome 2004). In addition, ELBW neonates have a smaller blood volume and the relatively larger phlebotomy volumes that are required during hospital stay often necessitate "early" transfusions. In contrast, "late" transfusions are more often given because of anemia 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.

In preterm infants, iron is needed for erythropoiesis. As neonatal blood volume expands with rapid growth, infants produce large amounts of haemoglobin. Several studies have observed decrease in serum ferritin concentration - [an indication of iron deficiency (Finch 1982)- during erythropoietin treatment]. The use of higher, more effective doses of erythropoietin might be expected to increase iron demand and the risk of iron deficiency (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).

Systematic reviews of the efficacy of EPO in anemia of prematurity have been published (Vamvakas 2001; Garcia 2002; Kotto-Kome 2004). Vamvakas et al concluded that there is extreme variation in the results, and until this variation is better understood, it is too early to recommend EPO as standard treatment for the anemia 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 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, which included reports up to October 2002. We performed a series of Cochrane reviews on the use of EPO in preterm infants including: 'Early postnatal administration of erythropoietin (EPO) (starting in infants ≤ 7 days of age) vs. placebo/no treatment' , 'Late postnatal EPO (starting in infants > 7 days of age) vs. placebo/no treatment' (this protocol) and 'Early vs. late EPO' (as per previous definitions). 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) and will allow us to compare the results between our planned reviews and previously published reviews.

This review concerns late administration of EPO (starting in infants > 7 days of age, but not older than 28 days, after reaching 40 weeks postmenstrual age). The main rationale for such EPO therapy is to avoid exposure of neonates to multiple blood donors and the risks associated with this exposure. It is likely that many sick neonates would have received a transfusion prior to entry into trials enrolling infants > 7 days of age. We did a systematic review to evaluate all available studies where EPO was begun after seven days of life, to assess the effect on the use of one or more red blood cell transfusions in preterm/very low birth weight infants.

Objectives

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

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

SECONDARY OUTCOMES:
1. The total volume (ml/kg) of blood transfused per infant
2. Number of transfusions per infant
3. Number of donors to whom the infant was exposed
4. Mortality during initial hospital stay (all causes of mortality)
5. Retinopathy of prematurity (any stage and stage > 3)
6. Proven sepsis (clinical symptoms and signs of sepsis and positive blood culture for bacteria or fungi)
7. Necrotizing enterocolitis (NEC) (Bell's stage II or more)
8. Intraventricular haemorrhage (IVH); all grades and grades III and IV
9. Periventricular leukomalacia (PVL); cystic changes in the periventricular areas
10. Bronchopulmonary dysplasia (BPD) (supplementary oxygen at 28 days of age or at 36 weeks postmenstrual age and compatible X-ray)
11. Sudden infant death after discharge
12. Long term outcomes assessed at any age beyond one year of age by a validated cognitive, motor, language, or behavioural/school/social interaction/adaptation test
13. Neutropenia
14. Hypertension (as this outcome was frequently reported by the authors this outcome has been added since the protocol was published)
15. Length of hospital stay (days)
16. Any side effects reported in the trials

Search strategy for identification of studies

Methods of the review

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

The statistical methods included (typical when applicable) relative risk (RR), risk difference (RD), number needed to treat to benefit (NNTB) or number needed to treat to harm (NNTH) for dichotomous outcomes and weighed mean difference (WMD) for continuous outcomes reported with their 95% confidence intervals (CI). A fixed effects model was used for meta-analysis.

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

Subgroup analyses were performed within this review for low (≤ 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO, and in addition within those subgroups for no iron, low (≤ 5 mg/kg/day) and high (> 5 mg/kg/day) doses of supplemental iron (co-intervention).

Description of studies

Excluded studies

One study (Ohls 1991) was excluded as it compared an EPO treated group with a group receiving blood transfusions. Two studies (Messer 1993; Testa 1998) were excluded as they were not randomized controlled trials. Two abstracts (Ahmadpour Kacho 2004; Amin 2004) were excluded as one study from Saudi Arabia lacked information to ascertain whether the study was a randomized controlled trial or not (Amin 2004) and one study conducted in Iran did not provide the age of the infants at the time of enrolment (Ahmadpour Kacho 2004). We were unable to contact the authors for additional information. One study was a dose-finding study of Darepoetin (longer acting and more potent than EPO) (Warwood 2005). Infants were randomized to receive either 1 microgram/kg or 4 microgram/kg of a single dose of darepoetin. There was no untreated control group.

Included studies

Twenty-eight studies were included in this review. They are detailed in the Table of Included Studies and they are briefly discussed below.
The detailed guidelines used for transfusions are outlined in the Additional Table (Table 01 Transfusion guidelines).

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

• Objective: To evaluate the effect of EPO on lipid peroxidation and the activities of erythrocyte antioxidant enzymes in very low birth weight infants.
• Population: Appropriately grown preterm infants with GA < 33 weeks and birthweight < 1,500 g.
• Intervention: The EPO group received high dose of EPO from day 10 of life, totaling 750 IU/kg/week (high dose). Infants in the control group received no placebo. All infants received 3 mg/kg/day (low dose) of elemental iron.
• Outcomes assessed: Use of one or more red blood cell transfusions.

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

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

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

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

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

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

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

• Objective: To investigate the safety and efficacy of EPO for the prevention of anemia of prematurity.
• Population: Infants with GA between 27 and 33 weeks.
• Intervention: The EPO group received low dose EPO (between 50 and 150 IU) twice a week from 7 days of age and the placebo group received 4% albumin from seven days of age until discharge home. All infants received iron (6.25 mg) in the form of ferrous glycine sulphate from four weeks of age (high dose).
• Outcomes assessed: Use of one or more red blood cell transfusions, volume transfused (ml/kg), mortality, hospital stay, SIDS, neutropenia.

• Objective: To stimulate erythrocyte production by the use of EPO and thereby decrease the requirement for red blood cell transfusions.
• Population: Preterm infants with birth weights </= 1300 g, postnatal age > 20 days.
• Intervention: The EPO group received EPO 300 IU/kg body weight, three times a week (900 IU/kg/week; high dose) from 20 days of age for six to eight weeks. The control group did not received any placebo. All infants received oral elemental iron 10 mg/kg/day (high dose).
• Outcomes assessed: Mortality, side effects, hypertension, neutropenia

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

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

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

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

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

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

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

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

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

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

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

• Objective: To determined whether EPO would prevent anemia of prematurity and reduce the need for transfusion in infants with very low birth weight.
• Population: Preterm infants with gestational age < 32 weeks, birth weight of < 1250 g. Postnatal age at the first dose was two to four weeks.
• Intervention: The EPO group received 200 IU/kg s. c. three times weekly (600 IU/kg/week, high dose), for 4 weeks. The control group received an equivalent volume of placebo s. c., three times weekly, for four weeks. All infants received oral supplements of elemental iron (3 mg/kg/day) (low dose) during the study period.
• Outcomes assessed: Use of one or more red blood cell transfusions, number of blood transfusions per infant, NEC, IVH, major adverse events.

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

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

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

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

• Objective: To assess the efficacy of EPO in the treatment of anemia of prematurity
• Population: Infants with birth weight 1000 to 1499 g, gestational age < 33 weeks, hemoglobin < 12 g/dl and oral milk intake > 50 ml/kg/day
• Intervention: The EPO group received EPO (200 IU/kg twice a week, low dose) for 8 weeks and the control group received no study drug or placebo. All infants received 3 mg/kg/day of oral iron (low dose).
• Outcomes assessed: Use of one or more red blood transfusions, total volume of blood transfused (ml/infant), number of transfusions per infant, side effects

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

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

Three studies did not state that guidelines for red blood cell transfusions were in place (Akisu 2001, Chen 1995, Shannon 1991). In only one study was it explicit that infants who had received erythrocyte transfusions prior to study entry were excluded (Samanci 1996). For transfusion guidelines see Additional Table (Table 01 Transfusion guidelines).

Methodological quality of included studies

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

Results

Primary outcome:

Comparison 01: Late initiation of EPO (8-28 days) vs. placebo or no intervention

Outcome 01.01: The use of one or more red blood cell transfusions

A total of 19 studies including 912 infants reported on the use of one or more red blood cell transfusions following the use of either low or high dose of EPO. There was a significant reduction in the use of one or more red blood cell transfusions [typical RR; 0.66 (95% CI 0.59, 0.74); typical RD; -0.21(95% CI -0.26, -0.16); NNTB; 5 (95% CI 4, 6)]. There was statistically significant heterogeneity for this outcome [for RR (p< 0.00001; I² = 74.0%);for RD (p = 0.0006; I² = 58.9%)].

Subgroup analyses

Further analyses were conducted including studies that used a high dose of EPO (> 500 IU/kg/week) or a low dose of EPO (< 500 IU/kg/week).

Outcome 01.02: High dose of EPO

The summary estimates for 13 studies including 682 patients testing a high dose of EPO (Outcome table 01.02) were statistically significant with a typical RR of 0.71 (95% CI 0.62, 0.81), a typical RD of -0.17 (95% CI -0.23, -0.11) and a NNT of 6 (95% CI 4, 9). There was statistically significant heterogeneity for this outcome for RR (p< 0.00001; I² was 74.4%) and for RD (p = 0.001; with I² 62.5%).

A subgroup analysis for high dose of EPO in combination with high dose of iron (Outcome table 01.02) was conducted. Six studies (n = 318) showed a typical RR of 0.74 (95% CI 0.62, 0.88), a typical RD of -0.16 (95% CI -0.24, -0.08) and NNT of 6 (95% CI 4, 13). The test for heterogeneity was statistically significant for RR (p = 0.0003; I² = 78.8%) and for RD (p = 0.0003; I² = 78.3%).

Seven studies of high EPO and low dose of iron (Outcome table 01.02) (n = 364) showed a typical RR of 0.68 (95% CI 0.55, 0.83), a typical RD of -0.18 (95% CI -0.27, -0.09) and NNT of 6 (95% CI 4, 11). There was statistically significant heterogeneity for RR (p = 0.001; I² = 72.6%) but not for RD (p = 0.20; I² = 29.7%).

Outcome 01.03: Low dose of EPO

The summary estimates for seven studies including 239 patients testing a low dose of EPO (Outcome table 01.03) were statistically significant with a typical RR of 0.52 (95% CI 0.41, 0.66), a typical RD of -0.34 (95% CI -0.45, -0.23) and a NNT of 3 (95% CI 2, 4). There was statistically significant heterogeneity for RR (p = 0.01; I² = 63.2%) but not for RD (p = 0.33; I² = 13.7%).

Subgroup analysis for low dose of EPO in combination with high dose of iron (Outcome table 01.03) was conducted. Three studies (n = 77) showed a typical RR of 0.50 (95% CI 0.31, 0.79), a typical RD of -0.31 (95% CI -0.49, -0.13) and a NNT of 3 (95% CI 2, 8). There was no statistically significant heterogeneity for this outcome for RR (p = 0.42; I² = 0%) and RD (p = 0.79), I² = 0%.

Four studies (n = 162) evaluated the effectiveness of low dose of EPO in combination with low dose of iron (Outcome table 01.03). The typical RR was 0.53 (95% CI 0.40, 0.70), the typical RD was -0.36 (95% CI -0.49, - 0.22) and the NNT was 3 (95% CI 2, 5). There was statistically significant heterogeneity (p = 0.003; I² = 78.4%) for RR and borderline statistically significant heterogeneity for RD (p = 0.10; I² = 52.8%)

Secondary outcomes:

Outcome 01.04: The total volume (ml/kg) of blood transfused per infant

Four studies including 177 infants reported on the total volume of blood transfused per infant. The typical weighted mean difference between the groups was statistically significant with a WMD of -7 ml/kg (95% CI -12, -3) transfused per infant. The test for heterogeneity was statistically significant (p = 0.0006, I² = 82.6%). Corona et al (Corona 1998) (n = 60) reported on this outcome but provided only the means with no SD. In the two EPO groups combined the mean was 20 ml/kg and in the control group it was 32 ml/kg (p < 0.01, according to the authors).

Outcome 01.05: Number of red blood cell transfusions per infant

The number of red blood cell transfusions per infant was reported in eight studies enrolling 422 patients. The significant typical WMD was -0.78 (95% CI -0.97, -0.59) favouring the EPO group. The test for heterogeneity was not statistically significant (p = 0.16; I² = 32.3%). In the study by Griffiths et al (Griffiths 1997) (n = 42), the median number of blood transfusions was lower for the infants in the EPO group (difference in medians -2, 95% CI -4, 0).

Outcome 01.06: Number of donors to whom the infant was exposed

Only Maier (Maier 2002) reported on donor exposure in 145 enrolled infants. The non-significant MD was -0.40 (95% CI -0.90, 0.10).

Outcome 01.07: Mortality during initial hospital stay (all causes of mortality)

Fourteen studies including 767 infants reported on mortality during initial hospital stay. The non significant typical RR was 0.82 (95% CI 0.49, 1.39) and the typical RD was -0.01 (95% CI -0.05, 0.02). There was no statistically significant heterogeneity for this outcome for either RR (p = 0.47; I² = 0%) or RD (p = 0.88; I² = 0%).

Outcome 01.08: Retinopathy of prematurity (all stages)

Three studies including 331 patients reported on ROP (all stages), with a typical RR 0.79 (95% CI 0.57, 1.10) and a typical RD of -0.05 (95% CI -0.13, 0.02). This outcome was not statistically significantly different between the groups. There was no statistically significant heterogeneity for this outcome for either RR (p = 0.41; I² = 0%) or RD (p = 0.43; I² = 0%).

Outcome 01.09: Retinopathy of prematurity stage > 3)

Two trials enrolling 212 patients reported on severe ROP (stage 3 or greater). The typical RR was 0.83 (95% CI 0.23, 2.98) and the typical RD was -0.01 (95% CI -0.06, 0.05); neither were statistically significant. There was no statistically significant heterogeneity for this outcome for either RR (p = 0.29; I² = 9.3%) or RD (p = 0.36; I² = 0%).

Outcome 01.10: Proven sepsis (Clinical symptoms and signs of sepsis and positive blood culture)

Four studies including 321 infants reported on this outcome. The typical RR was 0.69 (95% CI 0.38, 1.25) and the typical RD was -0.04 (95% CI -0.11, 0.03), both not statistically significant. There was no statistically significant heterogeneity for this outcome for either RR (p = 0.72; I² = 0%) or RD (p = 0.56; I² = 0%).

Outcome 01.11: Necrotizing enterocolitis (NEC) (Bell's stage II or higher)

Five studies including 426 infants reported on NEC. In some studies the stage was not reported but the results are included in the meta-analyses. The typical RR was 0.85 (95% CI 0.40, 1.77) and the typical RD -0.01(95% CI -0.06, 0.04). Both estimates were not statistically significant. There was no statistically significant heterogeneity for this outcome for either RR (p = 0.80; I² = 0%) or RD (p = 0.90; I² = 0%).

Outcome 01.12: Intraventricular haemorrhage (IVH); all grades

Three studies including 224 patients reported on intraventricular hemorrhage (all grades). In one study there were no outcomes in either groups and therefore that study is disregarded when RR is used as the outcome statistic. The non-significant typical RR was 0.83 (95% CI 0.48, 1.45) and typical RD was -0.03 (95% CI -0.13, 0.07). There was no statistically significant heterogeneity for either RR (p = 0.82; I² = 0%) or RD (p = 0.91; I² = 0%). (IVH is probably not a relevant outcome in this review as most haemorrhages occur during the first few days of life and infants were enrolled later in these studies).

Outcome 01.13: Periventricular leukomalacia (PVL); cystic changes in the periventricular areas

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

Outcome 01.14: Bronchopulmonary dysplasia (BPD) (supplemental oxygen at 28 days of age)

One study (n = 55) reported on BPD at 28 days. All infants in both groups had BPD. The RR was not estimable and the RD was 0.00 (95%CI; -0.07, 0.07).

Outcome 01.15: Bronchopulmonary dysplasia (BPD) (supplemental oxygen at 36 weeks postmenstrual age)

Three studies enrolling 216 patients reported on the use of supplemental oxygen at 36 weeks postmenstrual age. The typical RR was 0.89 (95% CI 0.59, 1.35) and the typical RD was -0.03 (95% CI-0.15, 0.08); neither were significant. There was borderline significant heterogeneity for RR (p = 0.10, I² = 56.3%) and for RD (p = 0.09, I² = 59.0%).

Outcome 01.16: Sudden infant death (SIDS) after discharge

Six studies including 363 infants reported on SIDS. The typical RR was 1.06 (95% CI 0.25, 4.52) and the typical RD was 0.00 (95% CI -0.03, 0.04). Both statistics were not significant. There was no significant heterogeneity for either RR (p = 0.38, I² = 0%) or RD (p = 0.65, I² = 0%).

Outcome 01.17: Neutropenia

Six studies enrolling 164 infants reported on neutropenia. The typical RR was 0.28 (95% CI 0.05, 1.54) (in only two studies did the outcome of interest occur) and the typical RD was -0.04 (-0.11, 0.03); neither was statistically significant. There was no statistically significant heterogeneity for RR (p = 0.76, I2 = 0%) and for RD (p = 0.69, I² = 0%).

Outcome 01.18: Hypertension

Eight studies including 363 infants reported on hypertension. The RR was 1.20 (95% CI 0.46, 3.14) and the RD 0.01 (95% CI -0.04, 0.05); neither were statistically significant. There was no statistically significant heterogeneity for either RR (p = 0.26, I² = 21.1%) or RD (p=1.00, I² = 0%).

Outcome 01.19: Length of hospital stay (days)

Length of hospital stay was reported in two studies enrolling 55 infants. There was no significant difference between the groups with a typical WMD of -0.4 days (95% CI - 13, 12). There was no statistically significant heterogeneity (p = 0.37, I² = 0%).

Long term outcomes assessed at any age beyond one year of age by a validated cognitive, motor, language, or behavioural/school/social interaction/adaptation test.

Long term neurodevelopmental outcomes were not reported in any study.

Any side effects reported in the trials

There were no serious side effects reported in any of the trials that specifically reported on adverse events (Bader 1996, Bechensteen 1993, Chen 1995, Corona 1998, Donato 1996, Giannakopoulou 1998a, Giannakopoulou 1998b, Juul 2003, Kivivuori 1999, Kumar 1998, Rocha 2001, Samanci 1996, Shannon 1991, Shannon 1992, Shannon 1995, Yamada 1994 a; Yamada 1994 b).

Secondary (Post hoc) analyses

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

Outcome 01.20: Use of one or more blood transfusions (secondary analysis based on quality)

For five high quality studies enrolling 357 infants, the typical RR was 0.84 (95% CI 0.73, 0.96); the typical RD was -0.12 (95% CI -0.21, -0.03). For 14 studies of uncertain quality enrolling 555 infants, the typical RR was 0.48 (95% CI 0.39, 0.59) and the typical RD was -0.27 (-0.33, -0.20). The summary effect size was larger in the studies of poor quality. Although a fair degree of heterogeneity remained, there was less significant heterogeneity for the high-quality studies (p = 0.05; I² = 58.4%) compared to the studies of uncertain quality (p < 0.00001; 1² = 82.1%).

Outcome 01.21: Use of one or more blood transfusions (secondary analysis based on criteria for red blood cell transfusions)

We considered 14 studies enrolling 733 infants to have used strict (although variable) guidelines for red blood cell transfusions, and three studies enrolling 97 infants to have used no criteria or less strict criteria. We excluded two studies for which we were unable to translate the text regarding possible transfusion guidelines (Yamada 1994 a; Yamada 1994 b). For the studies using strict red blood cell transfusion guidelines, the typical RR was 0.71 (95% CI 0.63, 0.80) and the typical RD was -0.18 (95% CI -0.24, -0.12). For the studies using no criteria or less strict criteria, the typical RR was 0.25 (95% CI 0.08, 0.77) and the typical RD was -0.21 (95% CI -0.36, -0,07). There was statistically significant heterogeneity for the studies using strict criteria, but not for the studies using no criteria or less strict criteria. The summary effect size was larger for the studies that did not use strict guidelines for red blood cell transfusions compared to those that did. This applied to the typical RR but not to the typical RD.

Funnel plot

A funnel plot for the primary outcome 'Use of one or more red blood cell transfusions' was asymmetric, with a relative absence of smaller studies not having a protective effect (see Additional figures - Figure 01).

Enterally dosed EPO

One study (Juul 2003) using enterally dosed EPO found that the intervention did not significantly influence erythropoiesis or iron utilization when given for a 2-week period, nor did it elevate the serum EPO concentration in preterm or term infants. The authors concluded that enterally dosed EPO is not an effective substitute for parenteral administration (Juul 2003).

Discussion

In only one study (Samanci 1996) did the authors state that infants were not eligible to enter the study if they previously had received a red blood cell transfusion. Most studies followed guidelines for red blood cell transfusions, although these varied between the studies.

The results show that late administration of erythropoietin reduces the "use of one or more blood transfusions" following study entry. These results were quite consistent (overlapping CIs) when including studies that used both low and high doses of EPO in combination with low and high doses of iron. The NNTB to avoid one red blood cell transfusion was low (range 3 - 6, for different combinations of EPO and iron). The clinical importance of this finding is lessened by the fact that any donor exposure was not avoided, as many infants required red blood cell transfusions prior to study entry. Only one study reported on donor exposure, and they noted no significant differences in the mean difference for number of transfusions (Maier 2002). In addition, there were minimal (but statistically significant) reductions in the total volume (ml/kg) of blood transfused per infant (7 ml/kg) and mean number of transfusions (0.8) per infant.

Of concern is the finding of statistically significant heterogeneity for the primary outcome including all combinations of low and high EPO and low and high iron treatment. The heterogeneity remained for individual combinations of EPO and iron. The heterogeneity could possibly be explained by the fact that the studies were conducted in 21 countries, with presumably different care practices. Of note, the control rates for red blood cell transfusions varied markedly between studies. In an attempt to further explore the heterogeneity, we performed secondary analyses (post-hoc analyses) comparing
1) studies that we judged as high quality compared to those that we identified as of lower quality or could not precisely define their quality because of lack of information, and 2) studies that used strict vs. no criteria or less strict guidelines for red blood cell transfusions. Judging the quality of a study depends to a large extent on the information published and obtaining additional information from the authors may change the evaluations. As noted in the Additional table, there was large variation in the guidelines for red blood cell transfusions. The results of these post-hoc analyses should therefore be interpreted with caution.

For the primary outcome of "use of one or more blood transfusions" the typical RR for five high quality studies was 0.84 (95% CI 0.73, 0.96) and the typical RD was - 0.12 (95% CI ; -0.21, -0.03). For 14 studies of uncertain quality, the typical RR was 0.48 (95% CI 0.39, 0.59) and the typical RD -0.27 (95% CI -0.33, -0.20). The CIs for these analyses are not overlapping, indicating that there is statistically significant differences in the effect sizes between studies that could be ascertained as being of high quality and studies of uncertain quality. There was an important reduction in heterogeneity when the high quality studies were analyzed separately. Studies of higher quality often show lower effect sizes (Schulz 1995).
The typical effect size (RR) for studies that used strict red blood cell transfusion guidelines was smaller than for studies that used no or less strict criteria.

There were no statistically significant reductions/increases in the many secondary neonatal outcomes included in this systematic review. No important side effects were identified. In contrast to the findings in our systematic reviews of early EPO and early vs. late EPO administration, we could not substantiate our concerns about a possible increase in the risk of ROP with EPO treatment (Ohlsson 2006, Aher 2006). It should be noted that only 3 studies reporting on 331 infants assessed ROP (all stages) and two studies reporting on 212 infants assessed ROP (stage > 3) [for details please see the early EPO (Ohlsson 2006) and the early vs. late EPO reviews (Aher 2006)].

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 spite of this strategy, there was no statistically significant reduction in donor exposure. However, the use of satellite packs and conservative transfusion guidelines may reduce the exposure to multiple donors during the total hospital stay. The need for red blood cell transfusions is linked to the loss of blood from sampling for laboratory testing (Obladen 1988), and may be significantly altered based on unit policies or guidelines.

The need for i.v., i.m. or s. c. injections with EPO/iron treatment in the neonatal period is associated with repeated painful stimuli and could potentially have adverse long term affects.

Direct comparisons regarding the results of this systematic overview and previous reviews are not appropriate as this review includes a much larger sample of studies (Vamvakas 2001; Kotto-Kome 2004; Garcia 2002).

Late (after eight days of age) administration of EPO does statistically significantly reduce the rate of "use of one or more red blood transfusions". It results in minimal reductions in the number of red blood cell transfusions per infant (< 1) and the total amount of red cells transfused per infant (7 ml/kg), but not in any donor exposure. Late administration of EPO is not associated with significant decreases/increases in common neonatal adverse outcomes including mortality and ROP (although the outcome of ROP was reported in few studies). As most infants enrolled in these trials had been exposed to red blood cell transfusions prior to study entry, the goal of avoiding any donor blood exposure is likely not to be achieved by the use of late EPO administration. There is no need for further research to assess the effectiveness of the late use of EPO. Future research should focus on strategies to minimize red blood cell donor exposure (maximum one donor) during the first week of life, when the likelihood of needing red blood cell transfusions is at its peak and when neither early nor late administration of EPO could have an effect on the need for red blood cell transfusions. Such strategies in combination with late EPO treatment may reduce further donor exposure. The small number of infants in which ROP was ascertained in the included studies makes it impossible to draw any conclusions whether late administration of EPO increases or decreases the risk of ROP. We will seek unpublished information on the unreported incidence of ROP from the studies included in this review.

Reviewers' conclusions

Implications for practice

Implications for research

Acknowledgements

Potential conflict of interest

Characteristics of included studies

Characteristics of excluded studies

References to studies

References to included studies

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

Al-Kharfy 1996 {published data only}

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

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

Atasay 2002 {published data only}

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

Bader 1996 {published data only}

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

Bechensteen 1993 {published data only}

* Bechensteen AG, Haga P, Halvorsen S, Whitelaw A, Liestol K, Lindemann R, et al. Erythropoietin, protein, and iron supplementation and the prevention of anaemia of prematurity. Archieves of Disease in Childhood 1993;69:19-23.

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

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

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

Chen 1995 {published data only}

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

Corona 1998 {published data only}

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

Donato 1996 {published data only}

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

Emmerson 1993 {published data only}

Emmerson AJ, Coles HJ, Stern CM, Pearson TC. Double blind trial of recombinant human erythopoietin in preterm infants. Archives of Disease in Childhood 1993;68:291-6.

Giannakopoulou 1998a {published data only}

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

Giannakopoulou 1998b {published data only}

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

Griffiths 1997 {published data only}

Griffiths G, Lall R, Chatfield S, MacKay P, Williamson P, Brown J et al. Randomised controlled double blind study of the role of recombinant erythropoietin in the prevention of chronic lung disease. Archives of Disease in Childhood 1997;76:F190-2.

Javier Manchon 1997 {published data only}

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

Juul 2003 {published data only}

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

Kivivuori 1999 {published data only}

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

Kumar 1998 {published data only}

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

Maier 2002 {published and unpublished data}

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

Meyer 1994 {published data only}

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

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

Pollak 2001 {published data only}

Pollak A, Hayde M, Hayn M et al. Effect of intravenous iron supplementation on erythropoiesis in erythropoietin-treated premature infants. Pediatrics 2001;107:78-85.

Reiter 2005 {published data only}

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

Rocha 2001 {published data only}

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

Ronnestad 1995 {published data only}

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

Samanci 1996 {published data only}

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

Shannon 1991 {published data only}

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

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

Shannon 1992 {published data only}

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

Shannon 1995 {published data only}

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

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

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

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

Widness JA, Lombard KA, Ziegler EE, Serfass RE, Carlson SJ, Johnson KJ, Miller JE. Erythrocyte incorportion and absorption of 58Fe in premature infants treated with erythropoietin. Pediatric Research 1997;41:416-23.

Whitehall 1999 {published data only}

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

Yamada 1994 a {published data only}

Yamada M, Takahashi R, Chiba Y, Ito T, Nakae S. Effects of recombinant human erythropoietin in infants with anemia of prematurity. I. Results in infants with birth weights between 1,000 and 1,499 gm. Acta Neonatologica Japonica 1994;35:755-61.

Yamada 1994 b {published data only}

Yamada M, Takahashi R, Chiba Y, Ito T, Nakae S. Effects of recombinant human erythropoietin in infants with anemia of prematurity. II. Results in infants with birth weights between 500 and 999 gm. Acta Neonatologica Japonica 1994;35:762-7.

References to excluded studies

Ahmadpour Kacho M, Zahedpasha Y, Esmaili MR, Hajian K, Moradi S. The effect of human recombinant erythropoietin on prevention of anemia of prematurity. Pediatric Research 2003;54:564.

Amin 2004 {published data only}

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

Messer 1993 {published data only}

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

Ohls 1991 {published data only}

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

Testa 1998 {published data only}

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

Warwood 2005 {published data only}

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

* indicates the primary reference for the study

Other references

Additional references

Aher SM, Ohlsson A. Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. In: The Cochrane Database of Systematic Reviews, Issue 3, 2006.

Brown 1983

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Comparisons and data

01.01 Use of one or more red blood cell transfusions (low and high dose of EPO)

01.02 Use of one or more red blood cell transfusions (high dose of EPO)

01.02.01 High dose iron

01.02.02 Low dose iron

01.03 Use of one or more red blood cell transfusions (low dose of EPO)

01.03.01 High dose of iron

01.03.02 Low dose of iron

01.04 Total volume (ml/kg) of red blood cells transfused per infant

01.05 Number of red blood cell transfusions per infant

01.06 Number of donors the infant was exposed to

01.07 Mortality during initial hospital stay (all causes)

01.08 Retinopathy of prematurity (all stages)

01.09 Retinopathy of prematurity (stage >/= 3)

01.10 Proven sepsis

01.11 Necrotising Enterocolitis Bell's stage 2 or higher

01.12 Intraventricular hemorrhage all grades (or grade not specified)

01.13 Periventricular leukomalacia

01.14 Bronchopulmonary dysplasia (supplementary oxygen at 28 days)

01.15 Bronchopulmonary dysplasia (supplementary oxygen at 36 weeks postmenstrual age

01.16 SIDS

01.17 Neutropenia

01.18 Hypertension

01.19 Length of hospital stay (days)

01.20 Use of one or more red blood cell transfusions (secondary analysis based on study quality)

01.20.01 HIgh quality studies

01.20.02 Studies of uncertain quality

01.21 Use of one or more red blood cell transfusions (secondary analysis based on RBC transfusion guidelilnes)

01.21.01 Strict RBC transfusion guidelines

01.21.02 No or less strict RBC guidelines

Additional tables

01 Transfusion guidelines

Additional figures

Figure 01

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

Contact details for co-reviewers