Secondary objectives:
Subgroup analyses of low (< 500
IU/kg/week) and high (> 500 IU/kg/week) doses of EPO and, within these
subgroups, analyses of the use of low (< 5 mg/kg/day) and high (> 5
mg/kg/day) doses of supplemental iron, in reducing red blood cell transfusions
in these infants.
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 mIU/ml as compared to 15 mIU/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 anaemia of prematurity. Studies in newborn monkeys and sheep have demonstrated that neonates have a large volume of distribution and more rapid elimination of EPO, necessitating the use of higher doses than required for adults (Ohls 2000). A recent systematic review of EPO administration noted a wide range of doses used, from 90 to 1400 IU/kg/week (Kotto-Kome 2004). Side effects reported in adults include hypertension, bone pain, rash and rarely seizures. Only transient neutropenia has been reported in neonates (Ohls 2000).
The primary goal of EPO therapy is to reduce transfusions. Most transfusions are given during the first three to four weeks of life. The larger or stable preterm infants who respond best to EPO receive few transfusions. ELBW infants, who are sick and have the greatest need for RBC transfusions shortly after birth, have not consistently responded to EPO. This suggests that EPO is a more effective erythropoietic stimulator in more mature neonates. ELBW neonates are more likely to need transfusions even if their erythropoiesis is stimulated (Kotto-Kome 2004). In addition, ELBW neonates have a smaller blood volume and the relatively larger phlebotomy volumes that are required during hospital stay often necessitate "early" transfusions. In contrast "late" transfusions are more often given because of anaemia of prematurity (Garcia 2002). Most preterm infants who require blood transfusions will receive their first transfusion in the first two weeks of life (Zipursky 2000). Reducing the number of RBC transfusions reduces the risk of transmission of viral infections and may reduce costs. Frequent RBC transfusions may be associated with retinopathy of prematurity (Hesse 1997) and bronchopulmonary dysplasia.
Preterm infants need iron for erythropoiesis. As neonatal blood volume expands with rapid growth, infants produce large amounts of haemoglobin. Several studies have observed a decrease in serum ferritin concentration (an indication of iron deficiency) (Finch 1982) - during erythropoietin treatment. The use of higher, more effective doses of erythropoietin might be expected to increase iron demand and the risk of iron deficiency (Genen 2004). Iron supplementation during erythropoietin treatment has been observed to reduce the risk of the development of iron deficiency (Shannon 1995). The range of iron doses used in EPO treated infants is between 1 mg/kg/day to 10 mg/kg/day (Kotto-Kome 2004).
The efficacy of EPO in anaemia of prematurity has recently been systematically reviewed (Vamvakas 2001; Garcia 2002; Kotto-Kome 2004). Vamvakas et al concluded that there is extreme variation in the results, and until this variation is better understood, it is too early to recommend EPO as standard treatment for the anaemia of prematurity (Vamvakas 2001). Garcia et al concluded that administering EPO to VLBW neonates can result in a modest reduction in late erythrocyte transfusions and that this effect is dependent on the dose of EPO used (Garcia 2002) . Kotto-Kome et al concluded that if EPO is begun in the first week of life, a moderate reduction can be expected in the proportion of VLBW neonates transfused. The reduction is less significant for early transfusion than for late transfusion (Kotto-Kome 2004).
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 neuro-protective 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' 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) to allow us to compare the results between our reviews and previously published reviews.
This review concerns 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.
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).
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) or (stage not reported)
8. Intraventricular
haemorrhage (IVH); all grades (we included in this group results from studies
that did not define the grade) and grades III and IV
9. Periventricular
leukomalacia (PVL); cystic changes in the periventricular areas
10. Length of
hospital stay (days)
11. Bronchopulmonary dysplasia (BPD) (supplementary
oxygen at 28 days of age or at 36 weeks post menstrual age with or without
compatible X-ray; we included an additional group in which the age at BPD was
not stated)
12. Sudden infant death after discharge
13. Neutropenia
14.
Hypertension (not a pre-specified outcome)
15. 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
16. Post 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)
For studies identified as abstracts, the primary author would be contacted to obtain further information if the full publication was not available. The quality of included trials was evaluated independently by the review authors using the following criteria:
Blinding of randomisation
Blinding of intervention
Blinding of outcome
measure assessment
Completeness of follow up
There are three potential answers to these questions yes, no, cannot tell.
The statistical methods included (typical) 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) reported with 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 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 to try and explain the between study heterogeneity for the primary outcome 'Use of one or more red blood cell transfusions' were conducted. 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 analyzed 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.
Twenty-three studies enrolling 2074 infants were included. The studies were performed in 18 countries (Austria, Belgium, Chile, China, France, Germany (FRG and GDR), Greece, Italy, Mexico, New Zealand, Poland, Singapore, South Africa, Switzerland, Turkey, the UK, the US). Seven 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).
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), 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 (Carnielli 1992;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).
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 01 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, physiological or biochemical signs thought to be associated with anemia. We were unable to categorize the different guidelines in a few groups that could be meaningfully used for secondary analyses.
Transfusion guidelines were reported to be in place in all but one study (Chang 1998). 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 centers 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 centers)". In a secondary (post hoc) analysis we combined the results of these three studies.
Iron was administered in all studies. 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.
Included Studies:
Arif 2005 was a
single centre study performed in Istanbul, Turkey.
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)
Outcome 01.02: Use of one or more red blood cell
transfusions [high dose of EPO (> 500 U/kg/week)]
A
total of 15 studies enrolling 1432 patients testing a high dose of EPO
(Outcome table 01.02) 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 01.02) 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 01.02) 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%)].
Outcome 01.03: Use of one or more red blood cell transfusions [low dose
of EPO (<500 U/kg/week)]
A total of three studies including 192 patients testing
a low dose of EPO (Outcome table 01.03) 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 01.03) 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:
Outcome 01.04: The total volume (ml/kg) of red blood cells
transfused per infant
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 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).
Outcome 01.05: Number of red blood cell transfusions per
infant
The results from 13 studies enrolling 1115 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
-0.27 (95% CI -0.42,-0.12). There was statistically significant heterogeneity
for this outcome (p = 0.002, I2 = 61.5%)
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).
Outcome 01.06: Number of donors to whom the infant was
exposed
Two studies enrolling 188 infants reported on this outcome in means and SDs. The significant typical WMD for 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).
Outcome 01.7: Mortality during initial hospital stay (all causes of
mortality)
A total of 13 studies enrolling 1485 infants
reported on this outcome. Mortality was not significantly altered by the use of
EPO [typical RR; 0.90 (95% CI 0.66, 1.22); typical RD -0.01 (95% CI -0.04,
0.02)]. There was no statistically significant heterogeneity for the outcome (RR
p = 0.96; I2 = 0%; RD p = 0.98; I2 = 0).
Outcome 01.08: Retinopathy of prematurity (any stage or
stage not stated by authors)
A total of 10 studies
enrolling 1425 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) ROP (any stage or stage not stated by
authors) [typical RR; 1.18 (95% CI 0.99, 1.40; p = 0.06); typical RD; 0.04 (95%
CI 0.00, 0.08); p = 0.06)]. There was no statistically significant heterogeneity
for this outcome [RR (p = 0.22; I2 = 24.2%; RD (p = 0.10,
I2 = 39.4%)].
Outcome 01.09: Retinopathy of prematurity (stage
>3)
A total of six
studies enrolling 930 infants reported on severe ROP (stage > 3). EPO
significantly increased retinopathy of prematurity (stage >3),
[typical RR; 1.71 (94% CI 1.15, 2.54; typical RD; 0.05 (95% CI 0.01, 0.09);
NNTH; 20 (95% CI 11, 100 ]. There was no statistically significant heterogeneity
for this outcome for RR (p = 0.82; I2 = 0%), but there was
statistically significant heterogeneity for RD (p = 0.0007; I2 =
76.4%).
Ohls 1997 reported no differences in ROP (stage 3 or greater) rates between groups (data not provided).
Outcome 01.10: Proven sepsis (clinical symptoms and signs of sepsis and
positive blood culture for bacteria or fungi)
Ten studies
including 1162 infants reported on this outcome. EPO did not significantly
change the rates of proven sepsis [typical RR 0.92 (95% CI 0.74, 1.13); typical
RD - 0.02 (95% CI -0.06, 0.03)]. There was no statistically significant
heterogeneity [RD (p = 0.77; I2 = 0%) or RD (p = 0.66; I2
= 0%)].
Outcome 01.11: Necrotizing enterocolitis (NEC) (stage not
reported)
No study stated the stage of NEC reported. We included any
outcome stated as NEC in this analysis.
Ten studies reporting on 1471 infants
were included. EPO did not significantly change the rates of NEC [typical RR;
1.02 (95% CI 0.69, 1.51); typical RD 0.00 (95% CI -0.02, 0.03)]. There was no
statistically significant heterogeneity for this outcome [RR (p = 0.86; I2
= 0%); RD (p = 0.67; I2 = 0%)].
Ohls 1995 reported no
differences in NEC rates between groups (data not provided)
Outcome 01.12: Intraventricular haemorrhage (IVH); all grades
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. A total of 8 studies including 744 infants reported on this outcome. EPO
did not significantly change the rate of IVH (all grades), [typical RR; 0.99
(95% CI 0.70, 1.40); typical RD 0.00 (95% CI -0.05, 0.05)]. There was no
statistically significant heterogeneity for this outcome [RR (p = 0.91;
I2 = 0%); RD (p = 0.87; I2 = 0%)].
Ohls 1995 and Ohls 1997 reported no
differences in IVH rates between groups (data not provided)
Outcome
01.13: Intraventricular haemorrhage (IVH); grades III and IV
A
total of five studies enrolling 801 infants reported on this outcome. EPO did
not significantly change the rate of IVH (grade III and IV), [typical RR; 1.13
(95% CI 0.64, 1.99); typical RD 0.01 (95% CI -0.02, 0.04)]. There was no
statistically significant heterogeneity for this outcome [RR (p = 0.74;
I2 = 0%); RD (p = 0.67; I2 = 0%)].
Outcome 01.14: Periventricular leukomalacia (PVL); cystic changes in the periventricular areas
Two studies enrolling 185 infants reported on PVL. EPO did not significantly change the rate of PVL, [typical RR was 0.92 (95% CI 0.27, 3.10); typical RD 0.00 (95% CI -0.06, 0.05)]. There was no statistically significant heterogeneity for this outcome [RR (p = 0.45; I2 = 0%); RD (p = 0.54; I2 = 0%)].
Outcome 01.15: Length of hospital stay (days)
A total
of four studies enrolling 375 infants reported on the length of hospital stay.
EPO did not significantly change length of hospital stay [typical WMD; 0.77 (95%
CI -4.63, 6.16)]. There was no statistically significant heterogeneity for this
outcome (p = 0.78; 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).
Outcome 01.16: Bronchopulmonary dysplasia
Bronchopulmonary dysplasia (BPD) (supplemental oxygen at 28 days of age) (Outcomes table 01.16).
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 01.16).
Three studies enrolling 435 infants reported on the use of supplemental oxygen at 36 weeks postmenstrual age. EPO did not significantly change the rate of BPD (supplementary oxygen at age 36 weeks postmenstrual age), [typical RR;1.00 (95% CI 0.78, 1.29); typical RD 0.00 (95% CI -0.08, 0.08). There was no statistically significant heterogeneity for this outcome [RR (p = 0.86; I2 = 0%); RD (p = 0.86; I2 = 0%)].
Bronchopulmonary dysplasia (BPD) (age at diagnosis not stated) (Outcomes table 01.16).
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
Outcome 01.17: Neutropenia
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%).
Outcome 01.18: Hypertension
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%).
Outcome 01.19: 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
Mental Developmental Index
(MDI) < 70 at 18-22 month's corrected age (Outcomes table 01.19)
One study reported on this outcome in 90 children following EPO treatment. The RR was 0.88 (95% CI 0.49, 1.57); RD -0.04 (955 CI; -0.24, 0.15). These findings were not statistically significant.
Outcome 01.20: Psychomotor Developmental Index (PDI) < 70 at 18 - 22
months corrected age
One study reported on this outcome in 90
children following EPO treatment. The RR was 2.33 (95% CI 0.98, 5.53); RD 0.18
(95% CI 0.01, 0.35). These findings were not statistically significant.
Outcome 01.21: Cerebral palsy at 18-22 months corrected
age
One study reported on this outcome in 99 children following
EPO treatment. The RR was 1.06 (95% CI 0.46, 2.45); RD 0.01(-0.14, 0.16). These
findings were not statistically significant.
Outcome 01.22 Any neurodevelopmental impairment at 18-22 month's corrected age
One study reported on this outcome in 99 infants following EPO treatment. The RR was 0.97 (95% CI 0.62, 1.51); RD -0.01 (-0.21, 0.18). These findings were not statistically significant.
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, Lauterbach 1995,
Lima-Rogel
1998, Maier
1994, Meister
1997, Ohls 1995).
Outcome 01.23: Use of one or more red blood cell transfusions (secondary analysis - based on perceived study quality)
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 was there any real differences in the degree of heterogeneity when all studies were analyzed together or in two separate groups.
Outcome 01.24: Use of one or more red blood cell transfusions
(secondary analysis - based on NICUs using mostly satellite units of red blood
cells)
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 01).
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 01).
The use of early EPO in preterm infants (n = 2074) has been extensively studied. 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 regards 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) to become more restrictive (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. The authors explained the changing transfusion practices to be 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 any donor exposure was likely not avoided, as many infants had required red blood cell transfusions prior to 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) with the use of early EPO , which reached statistical significance for ROP stage > 3. With so many secondary outcomes included, this could be a chance finding. Only one study had as its primary objective to "Evaluate whether EPO and 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 the first week of life. In an observational study, Rudzinska 2002 from Poland reported an increased risk of ROP following early vs. late treatment with EPO.
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 therapeutic possibility of 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 should be taken seriously. Previous systematic reviews (including 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 also 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). It is therefore 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.
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, could be obtained from patients' charts. 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 benefits identified in this extensive review.
Meanwhile 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.
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.
Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
Arif 2005 | Randomised, 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 |
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 |
142 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) |
Use of one or more red blood cell transfusions, mortality, NEC, ROP (stage not reported), BP | Infants 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 |
B |
Avent 2002 | Randomised, 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 |
93 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 centers in South Africa Study period not stated |
32 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 |
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 Sepsis Hypertension Length of hospital stay |
It is not stated whether infants who had received blood transfusions prior to study entry were included Transfusion guidelines were in place | B |
Carnielli 1992 | Randomised 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 |
22 preterm infants with gestational age <32 weeks and birth weight
<1750 g and age >2 days Single centre Italy Study period not stated |
11 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 |
Number of transfusions Number of donor exposures (range) Mortality Neutropenia Hospital stay in days Side effects |
It is not stated whether infants who had received blood transfusions
prior to study entry were included Transfusion guidelines were in place |
B |
Carnielli 1998 | Randomised 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 |
63 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 |
22 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 |
Mean number of blood transfusions (95% CI) BPD (age not stated) IVH (grade not stated) Sepsis ROP (stage not stated) Days in hospital |
It is not stated whether infants who had received blood transfusions
prior to study entry were included Transfusion guidelines were in place |
B |
Chang 1998 | Randomised 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 |
45 preterm infants with BW </= 1800 g and GA </= 35 weeks, age 1
day Single center, China Study period March 1996 - March 1998 |
15 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 |
Use of one or more red blood cell
transfusions Sepsis Neutropenia Hypertension Side effects |
It 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 |
B |
Haiden 2005 | Randomised 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) |
40 preterm infants with BW < 800 g and GA < 32
weeks. Neonatal intensive care units in Vienna, Austria Study period October 2000 - November 2002 |
The 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 |
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) | 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 It is not stated whether infants who had received blood transfusions prior to study entry were included Transfusion guidelines were in place |
A |
Lauterbach 1995 | Randomized 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 |
19 preterm infants with GA < 35 weeks and birthweight </= 1500
g. Single centre study conducted in Poland |
Infants 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)
|
Total volume (ml/kg) of blood transfused between days 7 and 37 Side effects |
Transfusion guide lines were in place We could not ascertain whether infants who had received blood transfusions prior to study entry were included |
B |
Lima-Rogel 1998 | Double 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 |
40 VLBW infants with birth weight between 750 and 1500 g and gestation
age < 26 weeks Single center, Mexico Study period: 1995 to 1996 |
21 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) |
Number of transfusions per group Sepsis NEC IVH (grade not reported) BPD (age not stated) |
We could not ascertain whether transfusion guide lines were in place and if infants who had received blood transfusions prior to study entry were included | B |
Maier 1994 | Double 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 |
244 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 |
120 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 |
Use 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 |
Infants 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 |
A |
Maier 2002 | Double 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 |
219 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 |
74 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) |
Use 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) |
Sample 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 |
A |
Meister 1997 | Randomised 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) |
30 preterm infants with birth weight of 750 to 1499 g and five to ten
days old Single center, Austria Study period not stated |
15 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. |
Study gives results as cumulative volume of blood transfused per kg with first and third quartiles | It 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 becasue of development of IVH grade IV |
B |
Meyer 2003 | Double 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 |
43 preterm infants < 33 weeks gestation and < 1700 g Single center, Auckland, New Zealand Two year period 1995-1996 |
22 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) |
Use of one or more red blood cell transfusions Number of donors the infant was exposed to Number of transfusions per infant |
It is not stated whether infants who had received blood transfusions
prior to study entry were included Transfusion guidelines were in place |
A |
Obladen 1991 | Randomised 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 |
93 infants with gestational age of 28-32 completed weeks Five centers, Europe April 1989 to February 1990 |
43 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 |
Use 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 |
It is not stated whether infants who had received blood transfusions
prior to study entry were included Transfusion guidelines were in place |
A |
Ohls 1995 | Randomised controlled trial I Blinding of randomizations - yes II Blinding of intervention - yes III Blinding of outcome measurement - yes IV Complete follow-up - yes |
20 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 |
10 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. |
Use 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 |
It is not stated whether infants who had received blood transfusions
prior to study entry were included Transfusion guidelines were in place |
A |
Ohls 1997 | Double 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 |
28 ELBW infants with birth weight 750 g or less and were 72 hours of
age or younger 3 enters, USA Period not stated |
15 infants recieved EPO (unnamed product) 200 IU/kg/day (1400
IU/kg/day, high dose) i.v., for 14 consecutive days 13 infants recieved placebo as an equivalent volume of diluent in similar fashion All infants recieved 1 mg/kg/day iron dextran in TPN solution during treatment period (high dose) All infants recieved vitamin E, 25 IU/day when they tolerated 60 ml/kg/day feeds enterally |
Total volume of blood transfused per infant Number of transfusions per infant Mortality Sepsis IVH BPD ROP Neutropenia |
It is not stated whether infants who had received blood transfusions
prior to study entry were included Transfusion guidelines were in place |
A |
Ohls 2001A | Double blind, randomized controlled trial I Blinding of randomization - yes II Blinding of intervention - yes III Blinding of outcome measurement - yes IV Complete follow-up - yes |
172 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 |
87 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 |
Use 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 |
It 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%). |
A |
Ohls 2001B | Double blind, randomized controlled trial I Blinding of randomization - yes II Blinding of intervention - yes III Blinding of outcome measurement - yes IV Complete follow-up - yes |
118 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 |
59 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 |
Use 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 |
It 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. |
A |
Romagnoli 2000 | Randomized, double-blind, controlled clinical trial. I. Blinding of randomization- 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 |
230 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 |
115 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 |
Use 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 |
It is not stated whether infants who had received blood transfusions
prior to study entry were included Protocol was used to administer transfusions during study period |
A |
Salvado 2000 | Randomized, double-blind, controlled clinical trial. I. Blinding of randomization- yes II. Blinding of intervention- yes III. Blinding of outcome-measure assessment- yes IV. Complete follow-up- yes |
60 newborn infants under 1500 g birth weight Single centre Chile April 1998 to December 1999 |
29 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) |
Number of transfusions per infant Sepsis IVH |
A | |
Soubasi 1993 | Randomized, double-blind, controlled trial I Blinding of randomization - yes II Blinding of intervention - yes III Blinding of outcome measurement - yes IV Complete follow-up - yes |
44 newborn infants with birth weight under 1500 g, age 1-7
days Single centre trial conducted in Thessaloniki Greece Period not stated |
The 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 | Number of transfusions per infant, sepsis, IVH and days on ventilator. | It is not stated whether infants who had received blood transfusions
prior to study entry were included Transfusion guidelines were in place |
A |
Soubasi 1995 | Randomized 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 |
97 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 |
33 infants recieved rHuEPO (Cilag AG, Zug, Switzerland) 150 IU/kg
twice weekly (300 IU/kg/week, low dose) 28 infants recieved 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 recieve any treatment All infants recieved 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 |
Use 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) |
It is not stated whether infants who had received blood transfusions
prior to study entry were included Transfusion guidelines were in place |
B |
Soubasi 2000 | Randomized, controlled clinical trial. I. Blinding of randomization- can't tell II. Blinding of intervention- no? III. Blinding of outcome-measure assessment- no IV. Completeness follow-up- yes |
36 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 |
18 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. |
Use of one or more red blood cell transfusions Number of transfusions per infant |
This 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 |
B |
Yeo 2001 | Randomized controlled trial I Blinding of randomization - no II Blinding of intervention - no III Blinding of outcome measurement - no IV Complete follow-up - yes |
100 VLBW infants, <33 weeks GA, hematocrit 0.4-0.6 at
birth Single center, Singapore January 1997 to March 2000 |
50 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 |
Exposure 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 |
It is not stated whether infants who had received blood transfusions
prior to study entry were included Transfusion guidelines were in place |
B |
Study | Reason for exclusion |
Amin 2002 | This study is not a randomized controlled trial |
Brown 1999 | This study compares two different dosing regimens for the same total weekly dose of EPO. There was no control/placebo group |
Fearing 2002 | This study does not give the number of infants allocated to treatment and control groups or the age at which the infants were entered |
Krallis 1999 | No outcomes of interest for this review were reported |
Maier 1998 | This randomized controlled trial compared two doses of EPO; 750 IU/kg/week vs. 1500 IU/kg/week without a non-treated control group |
Ohls 1996 | The 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 2005 | This 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. |
Arif B, Ferhan K. Recombinant human erythropoietin therapy in low-birthweight preterm infants: a prospective controlled study. Pediatrics International 2005;47:67-71.
Avent 2002 {published data only}
Avent M, Cory BJ, Galpin J, Ballot DE, Cooper PA, Sherman G, Davies VA. A comparison of high versus low dose recombinant human erythropoietin versus blood transfusion in the managemant of anaemia of prematurity in a developing country. Journal of Tropical Pediatrics 2002;48:227-33.
Carnielli 1992 {published data only}
Carnielli V, Montini G, Da Riol R, Dall'Amico R, Cantarutti F. Effect of high doses of human recombinant erythropoietin on the need for blood transfusions in preterm infants. Journal of Pediatrics 1992;121:98-102.
Carnielli 1998 {published data only}
Carnielli VP, Riol RD, Montini G. Iron supplementation enhances response to high doses of recombinant human erythropoietin in preterm infants. Archieves of Disease in Childhood Fetal Neonatal Edition 1998;79:F44-8.
Chang 1998 {published data only}
Chang L, Liu W, Liao C, Zhao X. Preventive effects of different dosages of recombinant human erythropoietin on anemia of premature infants. Journal of Tongji Medical University 1998;18:239-42.
Haiden 2005 {published data only}
Haiden N, Cardona F, Schwindt J, Berger A, Kuhle S, Homoncik M et al. Changes in thrombopoiesis and platelet reactivity in extremely low birth weight infants undergoing erythropoietin therapy for treatment of anaemia of prematurity. Thrombosis and Haemostasis 2005;93:118-23.
Lauterbach 1995 {published data only}
Lauterbach R, Kachlik P, Pawlik D, Bajorek I. Evaluation of treatment results for anemia of prematurity treated with various doses of human recombinant erythropoietin. Pediatria Polska 1995;70:739-44.
Lima-Rogel 1998 {published data only}
Lima-Roogel V, Torres-Montes A, Griesse SE, Alvarez CV, Hernandez-Sierra F, Mandeville PB, et al. Eficacia del uso precoz de eritropoyetina en recien nacidos pretermino de muy bajo peso, criticamente enfermos: ensayo clinico controlado [Efficacy of early erythropoietin use in critically ill very-low-birth-weight premature newborn infants: controlled clinical trial]. Sangre 1998;43:191-5.
Maier 1994 {published data only}
Maier RF, Obladen M, Scigalla P, Linderkamp O, Duc G, Hieronimi G, et al. The effect of epoetin beta (recombinant human eryhtropoietin) on the need for transfusion in very-low-birth-weight infants. European Multicentre Erythropoietin Study Group. New England Journal of Medicine 1994;330:1173-8.
Maier 2002 {published and unpublished data}
Maier RF, Obladen M, Muller-Hansen I, Kattner E, Merz U, Arlettaz R, et al. Early treatment with erythropoietin beta ameliorates anemia and reduces transfusion requirements in infants with birth weights below 1000 g. Journal of Pediatrics 2002;141:8-15.
Meister 1997 {published data only}
Meister B, Maurer H, Simma B, Kern H, Ulmer H, Hittmair A. The effect of recombinant human erythropoietin on circulating hematopoietic progenitor cells in anemic premature infants. Stem Cells 1997;15:359-63.
Meyer 2003 {published data only}
Meyer MP, Sharma E, Carsons M. Recombinant erythropoietin and blood transfusion in selected infants. Archieves of Disease in Childhood Fetal Neonatal Edition 2003;88:F41-5.
Obladen 1991 {published data only}
Obladen M, Maier R, Segerer H, Grauel EL, Holland BM, Stewart G et al. Efficacy and safety of recombinant human erythropoietin to prevent the anemias of prematurity. European Randomized Multicenter Trial. Contributions to Nephrology 1991;88:314-26.
Ohls 1995 {published data only}
Ohls RK, Osborne KA, Christensen RD. Efficacy and cost analysis of treating very low birth weight infants with erythropoietin during their first two weeks of life: a randomized, placebo-controlled trial. Journal of Pediatrics 1995;126:421-6.
Ohls 1997 {published data only}
Ohls RK, Harcum J, Schibler KR, Christensen RD. The effect of erythropoietin on the transfusion requirements of preterm infants weighing 750 grams or less: a randomized, double blind, placebo-controlled study. Journal of Pediatrics 1997;131:661-5.
Ohls 2001A {published data only}
Ehrenkranz RA, Ohls RK, Das A, Vohr BR. Neurodevelopmental outcome and growth at 18-22 months in extremely low birth weight infants treated with early eryhtropoietin. Pediatric Research 2002;51:291A.
Ohls RK, Ehrenkranz RA, Das A, Dusick AM, Yolton K, Romano E, et al. Neurodevelopmental outcome and growth at 18 to 22 months' corrected age in extremely low birth weight infants treated with early erythropoietin and iron. Pediatrics 2004;114:1287-91.
Ohls RK, Ehrenkranz RA, Lemons JA, Korones SB, Stoll BJ, Stark AR, et al. A multicenter randomized double-masked placebo-controlled trial of early erythropoietin and iron administration to preterm infants. Pediatric Research 1999;45:216 A.
* Ohls RK, Ehrenkranz RA, Wright LL, Lemons JA, Korones SB, Stoll BJ, et al. Effects of early erythropoietin therapy on the transfusion requirements of preterm infants below 1250 grams birth weight: a multicenter, randomized, controlled trial. Pediatrics 2001;108:934-42.
Ohls 2001B {published data only}
Ohls RK, Ehrenkranz RA, Wright LL, Lemons JA, Korones SB, Stoll BJ, et al. Effects of early erythropoietin therapy on the transfusion requirements of preterm infants below 1250 grams birth weight: a multicenter, randomized, controlled trial. Pediatrics 2001;108:934-42.
Romagnoli 2000 {published data only}
Romagnoli C, Zecca E, Gallini F, Girlando P, Zuppa AA. Do recombinant human erythropoietin and iron supplementation increase the risk of retinopathy of prematurity? European Journal of Pediatrics 2000;159:627-8.
Salvado 2000 {published data only}
Salvado A, Ramolfo P, Escobar M, Nunez A, Aguayo I, Standen J, et al. Uso precoz de la eritropoyetina en la prevencion de la anemia del prematuro [Early erythropoietin use for the prevention of anemia in infant premature]. Revista Medica de Chile 2000;128:1313-7.
Soubasi 1993 {published data only}
Soubasi V, Kremenopoulos G, Diamandi E, Tsantali C, Tsakiris D. In which neonates does early recombinant human eryhtropoietin treatment prevent anemia of prematurity? Results of a randomized, controlled study. Pediatric Research 1993;34:675-9.
Soubasi 1995 {published data only}
Soubasi V, Kremenopoulos G, Diamanti E, Tsantali C, Sarafidis K, Tsakiris D. Follow-up of very low birth weight infants after erythropoietin treatment to prevent anemia of prematurity. Journal of Pediatrics 1995;127:291-7.
Soubasi 2000 {published data only}
Soubasi V, Kremenopoulos G, Tsantali C, Savopoulou P, Mussafiris C, Dimitrou M. Use of erythropoietin and its effects on blood lactate and 2,3-diphosphoglycerate in premature neonates. Biology of the Neonate 2000;78:281-7.
Yeo 2001 {published data only}
Yeo CL, Choo S and Ho LY. Effect of recombinant human erythropoietin on transfusion needs in preterm infants. Journal of Paediatrics and Child Health 2001;37:352-8.
Amin AA, Alzahrani DM. Efficacy of erythropoietin in premature infants. Saudi Medical Journal 2002;23:287-90.
Brown 1999 {published data only}
Brown MS, Keith III JF. Comparison between two and five doses a week of recombinant erythropoietin for anemia of prematurity: a randomized trial. Pediatrics 1999;104:210-15.
Fearing 2002 {published data only}
Fearing MK, Eades B, Martinez B, Wood N, Accardo L, Browning CA, Gill WL. Cost effective use of recombinant erythropoietin (HuEPO) in very low birth weight (VLBW) infants for improved clinical outcomes. Pediatric Research 2002;51:310A.
Krallis 1999 {published data only}
Krallis N, Cholevas V, Mavridis A, Georgiou I, Bourantas K, Andronikou S. Effect of recombinant human erythropoietin in preterm infants. European Journal of Haematology 1999;63:71-6.
Maier 1998 {published data only}
Maier RF, Obladen M, Kattner E, Natzschka J, Messer J, Regazzoni BM et al. High- versus low-dose erythropoietin in extremenly low birth weight infants. Journal of Pediatrics 1998;132:866-70.
Ohls 1996 {published data only}
Ohls RK, Veerman MW, Christensen RD. Pharmacokinetics and effectiveness of recombinant erythropoietin administered to preterm infants by continuous infusion in total parenteral nutrition solution. Journal of Pediatrics 1996;128:518-23.
Turker 2005 {published data only}
Turker G, Sarper N, Gokalp S, Usluer H. The effect of early recombinant erythropoietin and enteral iron supplementation on blood transfusion in preterm infants. American Journal of Perinatology 2005;22:449-55.
Ohls RK, Hartenburger CH, Holmes G, Kerbleski JF. The vascular effects of erythropoietin in preterm infants. Pediatric Res 2000;47:421A.
* indicates the primary reference for the study
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Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I et al. Improving the quality of reporting of randomized controlled trials. The CONSORT statement. JAMA 1996;276:637-9.
Brown MS, Phibbs RH, Garcia JF, Dallman PR. Postnatal changes in erythropoietin levels in untransfused premature infants. Journal of Pediatrics 1983;103:612-7.
Brown MS, Berman ER, Luckey D. Prediction of the need for transfusion during anemia of prematurity. Journal of Pediatrics 1990;116:773-8.
Cohen A, Manno C. Transfusion practices in infants receiving assisted ventilation. Clinics in Perinatology 1998;25:97-111.
Dallman PR. Anemia of prematurity. Annual Review of Medicine 1981;32:143-60.
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Finch CA. Erythropoiesis, erythropoietin and iron. Blood 1982;60:1241-6.
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Juul S. Erythropoietin in the central nervous system, and its use to prevent hypoxic-ischemic brain damage. Acta Paediatrica Supplement 2002;91:36-42.
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Comparison or outcome | Studies | Participants | Statistical method | Effect size |
---|---|---|---|---|
01 Erythropoietin vs. placebo or no treatment | ||||
01 Use of one or more red blood cell transfusions (low and high dose of EPO) | 16 | 1825 | RR (fixed), 95% CI | 0.80 [0.75, 0.86] |
02 Use of one or more blood transfusions (high dose of EPO) | 15 | 1432 | RR (fixed), 95% CI | 0.79 [0.74, 0.86] |
03 Use of one or more red blood cell transfusions (low dose EPO) | 3 | 192 | RR (fixed), 95% CI | 0.80 [0.60, 1.07] |
04 Total volume (ml/kg) of blood transfused per infant | 6 | 515 | WMD (fixed), 95% CI | -6.03 [-10.82, -1.24] |
05 Number of blood transfusions per infant | 13 | 1115 | WMD (fixed), 95% CI | -0.27 [-0.42, -0.12] |
06 Number of donors the infant was exposed to | 2 | 188 | WMD (fixed), 95% CI | -0.63 [-1.07, -0.19] |
07 Mortality during initial hospital stay (all causes of mortality) | 13 | 1485 | RR (fixed), 95% CI | 0.90 [0.66, 1.22] |
08 Retinopathy of prematurity (any stage reported) | 10 | 1425 | RR (fixed), 95% CI | 1.18 [0.99, 1.40] |
09 Retinopathy of prematurity (stage >/= 3) | 6 | 930 | RR (fixed), 95% CI | 1.71 [1.15, 2.54] |
10 Proven sepsis | 10 | 1162 | RR (fixed), 95% CI | 0.92 [0.74, 1.13] |
11 Necrotizing enterocolitis (stage not reported) | 10 | 1471 | RR (fixed), 95% CI | 1.02 [0.69, 1.51] |
12 Intraventricular hemorrhage (all grades) | 8 | 744 | RR (fixed), 95% CI | 0.99 [0.70, 1.40] |
13 Intraventricular hemorrhage (grade III and IV) | 5 | 801 | RR (fixed), 95% CI | 1.13 [0.64, 1.99] |
14 Periventricular leukomalacia | 2 | 185 | RR (fixed), 95% CI | 0.92 [0.27, 3.10] |
15 Length of hospital stay (days) | 4 | 375 | WMD (fixed), 95% CI | 0.77 [-4.63, 6.16] |
16 Bronchopulmonary dysplasia | RR (fixed), 95% CI | Subtotals only | ||
17 Neutropenia | 9 | 982 | RR (fixed), 95% CI | 0.81 [0.53, 1.24] |
18 Hypertension | 6 | 762 | RR (fixed), 95% CI | 3.02 [0.12, 73.52] |
19 MDI < 70 at 18 to 22 months' correceted age (in children examined) | 1 | 90 | RR (fixed), 95% CI | 0.88 [0.49, 1.57] |
20 PDI < 70 at 18 - 22 months' corrected age (in children examined) | 1 | 90 | RR (fixed), 95% CI | 2.33 [0.98, 5.53] |
21 Cerebral palsy at 18 - 22 months' corrected age (in children examined) | 1 | 99 | RR (fixed), 95% CI | 1.06 [0.46, 2.45] |
22 Any neurodevelopmental impairment at 18-22 month's corrected age (in children examined) | 1 | 99 | RR (fixed), 95% CI | 0.97 [0.62, 1.51] |
23 Use of one or more red blood cell transfusions (secondary analysis) | 16 | 1825 | RR (fixed), 95% CI | 0.80 [0.75, 0.86] |
24 Use of one or more red blood cell transfusions (in NICUs using mostly sattelite units of red blood cells) | 3 | 435 | RR (fixed), 95% CI | 0.91 [0.81, 1.01] |
01.01 Use of one or more red blood cell transfusions (low and high dose of EPO)
01.02 Use of one or more blood 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 EPO)
01.03.01 High dose iron
01.03.02 Low dose iron
01.04 Total volume (ml/kg) of blood transfused per infant
01.05 Number of blood transfusions per infant
01.06 Number of donors the infant was exposed to
01.07 Mortality during initial hospital stay (all causes of mortality)
01.08 Retinopathy of prematurity (any stage reported)
01.09 Retinopathy of prematurity (stage >/= 3)
01.11 Necrotizing enterocolitis (stage not reported)
01.12 Intraventricular hemorrhage (all grades)
01.13 Intraventricular hemorrhage (grade III and IV)
01.14 Periventricular leukomalacia
01.15 Length of hospital stay (days)
01.16 Bronchopulmonary dysplasia
01.16.01 Supplemental oxygen at 28 days of age
01.16.02 Supplemental oxygen at 36 weeks
01.16.03 Age at diagnosis not stated
01.19 MDI < 70 at 18 to 22 months' correceted age (in children examined)
01.20 PDI < 70 at 18 - 22 months' corrected age (in children examined)
01.21 Cerebral palsy at 18 - 22 months' corrected age (in children examined)
01.22 Any neurodevelopmental impairment at 18-22 month's corrected age (in children examined)
01.23 Use of one or more red blood cell transfusions (secondary analysis)
01.23.01 High quality studies
01.23.02 Studies of uncertain quality
Reference | Indications |
Arif 2005 | Infants 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 2002 | Infants 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. |
Carnielli 1992 | Infants 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 1998 | Infants 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 1998 | Not stated whether transfusion guidelines were in place or not.
|
Haiden 2005 | Infants 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 |
Lauterbach 1995 | Transfusion was given when the Hct level reached 0.28 and if clinical
symptoms of tachypnea, tachycardia, bradycardia were present at a Hct of
0.32. |
Lima-Rogel 1998 | According to criteria published by Klaus and Fanaroff |
Maier 1994 | Infants who were receiving ventilation or who were less than two weeks
old and had signs of anemia 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 2002 | Infants 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 anemia or hypovolemia was assumed by the treating neonatologist, or surgery was planned. Twelve of the 14 centers used satellite pack of the original red cell pack to reduce donor exposure. |
Meister 1997 | Infants 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 anemia and their Hct fell below 11 g/dl
(6.8 mmol/L); if they had no signs of anemia, the corresponding cutoff
values were 0.27 and 9 g/dl (5.6 mmol/L). |
Meyer 2003 | Indications 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 1991 | Indications 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 anemia (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 anemia (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 anemia transfuse at any age if venous Hct is < 0.27, Hgb < 9 g/dl. |
Ohls 1995 | Transfusions 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 1997 | Transfusions 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 A | If 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 B | See Ohls 2001 A |
Romagnoli 2000 | Infants 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 2000 | Preterm 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 1993 | Neonates, 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 1995 | Infants 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 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 apnea (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 2000 | Neonates 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 2001 | Infants 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 apnea (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. |
This review is published as a Cochrane review in The
Cochrane Library, Issue 3, 2006 (see http://www.thecochranelibrary.com for
information). Cochrane reviws are regularly updated as new evidence
emerges and in response to feedback. The Cochrane Library should be
consulted for the most recent version of this
review. |