EPO and iron effectively stimulate erythropoiesis. Plasma erythropoietin (EPO) levels in neonates are lower than those of older children and adults. Brown and colleagues reported that between two and thirty days of life the mean EPO concentration was 10 mU/ml, as compared to 15 mU/ml in concurrently studied adults (Brown 1983). A low plasma EPO level is a key reason that nadir hematocrit values of preterm infants are lower than those of term infants (Stockman 1986; Dallman 1981). Low plasma EPO levels provide a rationale for use of EPO in the prevention or treatment of anemia of prematurity. Studies in newborn monkeys and sheep have demonstrated that neonates have a large volume of distribution and more rapid elimination of EPO, necessitating the use of higher doses than required for adults (Ohls 2000). A recent systematic review of EPO administration noted a wide range of doses used, from 90 to 1400 IU/kg/week (Kotto-Kome 2004). Side effects reported in adults include hypertension, bone pain, rash and rarely seizures. Only transient neutropenia has been reported in neonates (Ohls 2000).
The primary goal of EPO therapy is to reduce transfusions. Most transfusions are given during the first three to four weeks of life. The larger or stable preterm infants who respond best to EPO receive few transfusions. ELBW infants, who are sick and have the greatest need for RBC transfusions shortly after birth, have not consistently responded to EPO. This suggests that EPO is a more effective erythropoietic stimulator in more mature neonates. ELBW neonates are more likely to need transfusions even if their erythropoiesis is stimulated (Kotto-Kome 2004). In addition, ELBW neonates have a smaller blood volume and the relatively larger phlebotomy volumes that are required during hospital stay often necessitate "early" transfusions. In contrast, "late" transfusions are more often given because of anemia of prematurity (Garcia 2002). Most preterm infants who require blood transfusions will receive their first transfusion in the first two weeks of life (Zipursky 2000). Reducing the number of RBC transfusions reduces the risk of transmission of viral infections and may reduce costs. Frequent RBC transfusions may be associated with retinopathy of prematurity (Hesse 1997) and bronchopulmonary dysplasia.
In preterm infants, iron is needed for erythropoiesis. As neonatal blood volume expands with rapid growth, infants produce large amounts of haemoglobin. Several studies have observed decrease in serum ferritin concentration - [an indication of iron deficiency (Finch 1982)- during erythropoietin treatment]. The use of higher, more effective doses of erythropoietin might be expected to increase iron demand and the risk of iron deficiency (Genen 2004). Iron supplementation during erythropoietin treatment has been observed to reduce the risk of the development of iron deficiency (Shannon 1995). The range of iron doses used in EPO treated infants is between 1 mg/kg/day to 10 mg/kg/day (Kotto-Kome 2004).
Systematic reviews of the efficacy of EPO in anemia of prematurity have been published (Vamvakas 2001; Garcia 2002; Kotto-Kome 2004). Vamvakas et al concluded that there is extreme variation in the results, and until this variation is better understood, it is too early to recommend EPO as standard treatment for the anemia of prematurity (Vamvakas 2001). Garcia et al concluded that administering EPO to VLBW neonates can result in a modest reduction in late erythrocyte transfusions and that this effect is dependent on the dose of EPO used (Garcia 2002) . Kotto-Kome et al concluded that if EPO is begun in the first week of life, a moderate reduction can be expected in the proportion of VLBW neonates transfused. The reduction is less significant for early transfusion than for late transfusion (Kotto-Kome 2004).
EPO has been found to have important non-hematopoietic functions in the brain and other organs during development (Juul 2002). Administration of EPO could potentially have a neuroprotective effect in preterm infants, especially in perinatal asphyxia (Juul 2002; Dame 2001). This aspect of EPO use in neonates has not been systematically reviewed.
It is likely that additional studies of EPO in preterm or LBW infants have been published since the reviews noted above, which included reports up to October 2002. We performed a series of Cochrane reviews on the use of EPO in preterm infants including: 'Early postnatal administration of erythropoietin (EPO) (starting in infants ≤ 7 days of age) vs. placebo/no treatment' , 'Late postnatal EPO (starting in infants > 7 days of age) vs. placebo/no treatment' (this protocol) and 'Early vs. late EPO' (as per previous definitions). The cutoff of ≤ 7 days of age for early and > 7 days for late treatment with EPO, although somewhat arbitrary, was chosen based on previously published meta-analyses (Garcia 2002; Kotto-Kome 2004) and will allow us to compare the results between our planned reviews and previously published reviews.
This review concerns late administration of EPO (starting in infants > 7 days of age, but not older than 28 days, after reaching 40 weeks postmenstrual age). The main rationale for such EPO therapy is to avoid exposure of neonates to multiple blood donors and the risks associated with this exposure. It is likely that many sick neonates would have received a transfusion prior to entry into trials enrolling infants > 7 days of age. We did a systematic review to evaluate all available studies where EPO was begun after seven days of life, to assess the effect on the use of one or more red blood cell transfusions in preterm/very low birth weight infants.
Secondary objective:
Subgroup analyses of low (≤ 500 IU/kg/week) and high
(> 500 IU/kg/week) doses of EPO, and low (≤ 5 mg/kg/day) and high (> 5
mg/kg/day) doses of supplemental iron in reducing red blood cell transfusions in
preterm and/or low birth weight infants.
SECONDARY OUTCOMES:
1. The total volume (ml/kg) of blood transfused
per infant
2. Number of transfusions per infant
3. Number of donors to
whom the infant was exposed
4. Mortality during initial hospital stay (all
causes of mortality)
5. Retinopathy of prematurity (any stage and stage
> 3)
6. Proven sepsis (clinical symptoms and signs of sepsis and
positive blood culture for bacteria or fungi)
7. Necrotizing enterocolitis
(NEC) (Bell's stage II or more)
8. Intraventricular haemorrhage (IVH); all
grades and grades III and IV
9. Periventricular leukomalacia (PVL); cystic
changes in the periventricular areas
10. Bronchopulmonary dysplasia (BPD)
(supplementary oxygen at 28 days of age or at 36 weeks postmenstrual age and
compatible X-ray)
11. Sudden infant death after discharge
12. Long term
outcomes assessed at any age beyond one year of age by a validated cognitive,
motor, language, or behavioural/school/social interaction/adaptation test
13. Neutropenia
14. Hypertension (as this outcome was frequently
reported by the authors this outcome has been added since the protocol was
published)
15. Length of hospital stay (days)
16. Any side effects
reported in the trials
For the studies identified as abstract, the primary author was to be contacted to obtain further information. The two studies identified as abstracts did not provide enough information for us to be able to contact the authors (Ahmadpour Kacho 2004; Amin 2004). The quality of included trials was evaluated independently by the review authors, using the following criteria:
Blinding of randomisation
Blinding of intervention
Blinding of outcome
measure assessment
Completeness of follow up
There were three potential answers to these questions yes, no, cannot tell
The statistical methods included (typical when applicable) relative risk (RR), risk difference (RD), number needed to treat to benefit (NNTB) or number needed to treat to harm (NNTH) for dichotomous outcomes and weighed mean difference (WMD) for continuous outcomes reported with their 95% confidence intervals (CI). A fixed effects model was used for meta-analysis.
Heterogeneity tests including the I squared (I2) statistic were performed to assess the appropriateness of pooling the data.
Subgroup analyses were performed within this review for low (≤ 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO, and in addition within those subgroups for no iron, low (≤ 5 mg/kg/day) and high (> 5 mg/kg/day) doses of supplemental iron (co-intervention).
Excluded studies
One study (Ohls
1991) was excluded as it compared an EPO treated group with a group
receiving blood transfusions. Two studies (Messer 1993; Testa 1998) were
excluded as they were not randomized controlled trials. Two abstracts (Ahmadpour Kacho
2004; Amin 2004)
were excluded as one study from Saudi Arabia lacked information to ascertain
whether the study was a randomized controlled trial or not (Amin 2004) and one study
conducted in Iran did not provide the age of the infants at the time of
enrolment (Ahmadpour Kacho
2004). We were unable to contact the authors for additional information. One
study was a dose-finding study of Darepoetin (longer acting and more potent than
EPO) (Warwood
2005). Infants were randomized to receive either 1 microgram/kg or 4
microgram/kg of a single dose of darepoetin. There was no untreated control
group.
Included studies
Twenty-eight studies were included in this review. They are detailed in the
Table of Included Studies and they are briefly discussed below.
The detailed
guidelines used for transfusions are outlined in the Additional Table (Table 01 Transfusion
guidelines).
Akisu 2001 was a
single centre study performed at University of Ege, Ismir Turkey.
Different Erythropoietin preparations were used; Recormon, Boehringer-Mannheim, Germany (Akisu 2001); Eprex [(Provided by Cilag Zug, Switzerland, Ortho Pharmaceutical Canada Ltd., Janssen-Cilag or Guler Pharmaceutical Corp, Istanbul, Turkey) (Al-Kharfy 1996, Atasay 2002, Bader 1996, Bechensteen 1993, Chen 1995, Emmerson 1993, Giannakopoulou 1998a, Giannakopoulou 1998b, Griffiths 1997, Kivivuori 1999, Meyer 1994, Ronnestad 1995, Samanci 1996, Whitehall 1999)]; Amgen (Shannon 1991), Eogen alpha, Amgen, Inc. Thousand Oaks, CA, USA (Reiter 2005); unnamed products (Corona 1998, Javier Manchon 1997, Juul 2003, Kumar 1998, Shannon 1992, Shannon 1995), NeoRecormon, F. Hofman-La Roche, Basel, Switzerland (Maier 2002), Erypo, Janssen-Cilag Pharma, Vienna, Austria (Pollak 2001), and Hemax, Bio Sidus, S. A. (Donato 1996).
Three studies did not state that guidelines for red blood cell transfusions were in place (Akisu 2001, Chen 1995, Shannon 1991). In only one study was it explicit that infants who had received erythrocyte transfusions prior to study entry were excluded (Samanci 1996). For transfusion guidelines see Additional Table (Table 01 Transfusion guidelines).
We performed two "post hoc" secondary analyses for the primary outcome "Use
of one or more red blood cell transfusions". In the first, we compared those
studies that used concealed allocation (a placebo or sham-injection to blind the
intervention) and in which there was blinding of outcome measure assessment to
those studies in which this was not evident from the published report. In the
second post-hoc analysis, we compared the studies that used strict criteria for
red blood cell transfusions to those that used no or less strict criteria.
Primary outcome:
Comparison 01: Late initiation of EPO (8-28 days) vs. placebo or no
intervention
Outcome 01.01: The use of one or more
red blood cell transfusions
A total of 19 studies including 912 infants reported on the use of one or more red blood cell transfusions following the use of either low or high dose of EPO. There was a significant reduction in the use of one or more red blood cell transfusions [typical RR; 0.66 (95% CI 0.59, 0.74); typical RD; -0.21(95% CI -0.26, -0.16); NNTB; 5 (95% CI 4, 6)]. There was statistically significant heterogeneity for this outcome [for RR (p< 0.00001; I2 = 74.0%);for RD (p = 0.0006; I2 = 58.9%)].
Subgroup analyses
Further analyses were conducted including studies that used a high dose of EPO (> 500 IU/kg/week) or a low dose of EPO (< 500 IU/kg/week).
Outcome 01.02: High dose of EPO
The summary estimates for 13 studies including 682 patients testing a high dose of EPO (Outcome table 01.02) were statistically significant with a typical RR of 0.71 (95% CI 0.62, 0.81), a typical RD of -0.17 (95% CI -0.23, -0.11) and a NNT of 6 (95% CI 4, 9). There was statistically significant heterogeneity for this outcome for RR (p< 0.00001; I2 was 74.4%) and for RD (p = 0.001; with I2 62.5%).
A subgroup analysis for high dose of EPO in combination with high dose of iron (Outcome table 01.02) was conducted. Six studies (n = 318) showed a typical RR of 0.74 (95% CI 0.62, 0.88), a typical RD of -0.16 (95% CI -0.24, -0.08) and NNT of 6 (95% CI 4, 13). The test for heterogeneity was statistically significant for RR (p = 0.0003; I2 = 78.8%) and for RD (p = 0.0003; I2 = 78.3%).
Seven studies of high EPO and low dose of iron (Outcome table 01.02) (n = 364) showed a typical RR of 0.68 (95% CI 0.55, 0.83), a typical RD of -0.18 (95% CI -0.27, -0.09) and NNT of 6 (95% CI 4, 11). There was statistically significant heterogeneity for RR (p = 0.001; I2 = 72.6%) but not for RD (p = 0.20; I2 = 29.7%).
Outcome 01.03: Low dose of EPO
The summary estimates for seven studies including 239 patients testing a low dose of EPO (Outcome table 01.03) were statistically significant with a typical RR of 0.52 (95% CI 0.41, 0.66), a typical RD of -0.34 (95% CI -0.45, -0.23) and a NNT of 3 (95% CI 2, 4). There was statistically significant heterogeneity for RR (p = 0.01; I2 = 63.2%) but not for RD (p = 0.33; I2 = 13.7%).
Subgroup analysis for low dose of EPO in combination with high dose of iron (Outcome table 01.03) was conducted. Three studies (n = 77) showed a typical RR of 0.50 (95% CI 0.31, 0.79), a typical RD of -0.31 (95% CI -0.49, -0.13) and a NNT of 3 (95% CI 2, 8). There was no statistically significant heterogeneity for this outcome for RR (p = 0.42; I2 = 0%) and RD (p = 0.79), I2 = 0%.
Four studies (n = 162) evaluated the effectiveness of low dose of EPO in
combination with low dose of iron (Outcome table 01.03). The typical RR was
0.53 (95% CI 0.40, 0.70), the typical RD was -0.36 (95% CI -0.49, - 0.22) and
the NNT was 3 (95% CI 2, 5). There was statistically significant heterogeneity
(p = 0.003; I2 = 78.4%) for RR and borderline statistically
significant heterogeneity for RD (p = 0.10; I2 =
52.8%)
Secondary outcomes:
Outcome 01.04: The total volume (ml/kg) of blood transfused per infant
Four studies including 177 infants reported on the total
volume of blood transfused per infant. The typical weighted mean difference
between the groups was statistically significant with a WMD of -7 ml/kg (95% CI
-12, -3) transfused per infant. The test for heterogeneity was statistically
significant (p = 0.0006, I2 = 82.6%). Corona et al (Corona 1998) (n = 60)
reported on this outcome but provided only the means with no SD. In the two EPO
groups combined the mean was 20 ml/kg and in the control group it was 32 ml/kg
(p < 0.01, according to the authors).
Outcome 01.05: Number of red blood cell transfusions per infant
The number of red blood cell transfusions per infant was
reported in eight studies enrolling 422 patients. The significant typical WMD
was -0.78 (95% CI -0.97, -0.59) favouring the EPO group. The test for
heterogeneity was not statistically significant (p = 0.16; I2 =
32.3%). In the study by Griffiths et al (Griffiths 1997) (n
= 42), the median number of blood transfusions was lower for the infants in the
EPO group (difference in medians -2, 95% CI -4, 0).
Outcome 01.06: Number of donors to whom the infant was
exposed
Only Maier (Maier 2002) reported on
donor exposure in 145 enrolled infants. The non-significant MD was -0.40 (95% CI
-0.90, 0.10).
Outcome 01.07: Mortality during initial hospital stay (all causes of
mortality)
Fourteen studies including 767 infants reported
on mortality during initial hospital stay. The non significant typical RR was
0.82 (95% CI 0.49, 1.39) and the typical RD was -0.01 (95% CI -0.05, 0.02).
There was no statistically significant heterogeneity for this outcome for either
RR (p = 0.47; I2 = 0%) or RD (p = 0.88; I2 = 0%).
Outcome 01.08: Retinopathy of prematurity (all stages)
Three studies including 331 patients reported on
ROP (all stages), with a typical RR 0.79 (95% CI 0.57, 1.10) and a typical RD of
-0.05 (95% CI -0.13, 0.02). This outcome was not statistically significantly
different between the groups. There was no statistically significant
heterogeneity for this outcome for either RR (p = 0.41; I2 = 0%) or
RD (p = 0.43; I2 = 0%).
Outcome 01.09: Retinopathy of prematurity stage
> 3)
Two trials
enrolling 212 patients reported on severe ROP (stage 3 or greater). The typical
RR was 0.83 (95% CI 0.23, 2.98) and the typical RD was -0.01 (95% CI -0.06,
0.05); neither were statistically significant. There was no statistically
significant heterogeneity for this outcome for either RR (p = 0.29;
I2 = 9.3%) or RD (p = 0.36; I2 = 0%).
Outcome 01.10: Proven sepsis (Clinical symptoms and signs of sepsis and
positive blood culture)
Four studies including 321
infants reported on this outcome. The typical RR was 0.69 (95% CI 0.38, 1.25)
and the typical RD was -0.04 (95% CI -0.11, 0.03), both not statistically
significant. There was no statistically significant heterogeneity for this
outcome for either RR (p = 0.72; I2 = 0%) or RD (p = 0.56;
I2 = 0%).
Outcome 01.11: Necrotizing enterocolitis (NEC) (Bell's stage II or
higher)
Five studies including 426 infants reported on
NEC. In some studies the stage was not reported but the results are included in
the meta-analyses. The typical RR was 0.85 (95% CI 0.40, 1.77) and the typical
RD -0.01(95% CI -0.06, 0.04). Both estimates were not statistically significant.
There was no statistically significant heterogeneity for this outcome for either
RR (p = 0.80; I2 = 0%) or RD (p = 0.90; I2 = 0%).
Outcome 01.12: Intraventricular haemorrhage (IVH); all
grades
Three studies including 224 patients reported on
intraventricular hemorrhage (all grades). In one study there were no outcomes in
either groups and therefore that study is disregarded when RR is used as the
outcome statistic. The non-significant typical RR was 0.83 (95% CI 0.48, 1.45)
and typical RD was -0.03 (95% CI -0.13, 0.07). There was no statistically
significant heterogeneity for either RR (p = 0.82; I2 = 0%) or RD (p
= 0.91; I2 = 0%). (IVH is probably not a relevant outcome in this
review as most haemorrhages occur during the first few days of life and infants
were enrolled later in these studies).
Outcome 01.13: Periventricular leukomalacia (PVL); cystic changes in
the periventricular areas
One study enrolling 145 infants
reported PVL. The non-significant RR was 4.80 (95% CI 0.57, 40.05) and the RD
was 0.05 (95% CI -0.01, 0.12). Test for heterogeneity not applicable.
Outcome 01.14: Bronchopulmonary dysplasia (BPD) (supplemental oxygen at
28 days of age)
One study (n = 55) reported on BPD at 28
days. All infants in both groups had BPD. The RR was not estimable and the RD
was 0.00 (95%CI; -0.07, 0.07).
Outcome 01.15: Bronchopulmonary dysplasia (BPD) (supplemental oxygen at
36 weeks postmenstrual age)
Three studies enrolling 216
patients reported on the use of supplemental oxygen at 36 weeks postmenstrual
age. The typical RR was 0.89 (95% CI 0.59, 1.35) and the typical RD was -0.03
(95% CI-0.15, 0.08); neither were significant. There was borderline significant
heterogeneity for RR (p = 0.10, I2 = 56.3%) and for RD (p = 0.09,
I2 = 59.0%).
Outcome 01.16: Sudden infant death (SIDS) after discharge
Six studies including 363 infants reported on SIDS. The
typical RR was 1.06 (95% CI 0.25, 4.52) and the typical RD was 0.00 (95% CI
-0.03, 0.04). Both statistics were not significant. There was no significant
heterogeneity for either RR (p = 0.38, I2 = 0%) or RD (p = 0.65,
I2 = 0%).
Outcome 01.17: Neutropenia
Six studies enrolling 164 infants reported on neutropenia. The typical RR was
0.28 (95% CI 0.05, 1.54) (in only two studies did the outcome of interest occur)
and the typical RD was -0.04 (-0.11, 0.03); neither was statistically
significant. There was no statistically significant heterogeneity for RR (p =
0.76, I2 = 0%) and for RD (p = 0.69, I2 =
0%).
Outcome 01.18: Hypertension
Eight studies including 363 infants reported on
hypertension. The RR was 1.20 (95% CI 0.46, 3.14) and the RD 0.01 (95% CI -0.04,
0.05); neither were statistically significant. There was no statistically
significant heterogeneity for either RR (p = 0.26, I2 = 21.1%) or RD
(p=1.00, I2 = 0%).
Outcome 01.19: Length of hospital stay (days)
Length of hospital stay was reported in two studies
enrolling 55 infants. There was no significant difference between the groups
with a typical WMD of -0.4 days (95% CI - 13, 12). There was no statistically
significant heterogeneity (p = 0.37, I2 = 0%).
Long term outcomes assessed at any age beyond one year of age by a validated cognitive, motor, language, or behavioural/school/social interaction/adaptation test.
Long term neurodevelopmental outcomes were not reported in any study.
Any side effects reported in the trials
There were no serious side effects reported in any of the trials that specifically reported on adverse events (Bader 1996, Bechensteen 1993, Chen 1995, Corona 1998, Donato 1996, Giannakopoulou 1998a, Giannakopoulou 1998b, Juul 2003, Kivivuori 1999, Kumar 1998, Rocha 2001, Samanci 1996, Shannon 1991, Shannon 1992, Shannon 1995, Yamada 1994 a; Yamada 1994 b).
Secondary (Post hoc) analyses
In an attempt to further explore the heterogeneity observed in the primary outcome and subgroup analyses, we performed a post-hoc analysis comparing the results of studies that we judged as high-quality with those that we identified as of lower quality or could not precisely define their quality because of lack of information. We also compared the results of studies that used strict criteria for red blood cell transfusions to those that used no criteria or less strict criteria.
Outcome 01.20: Use of one or more blood transfusions (secondary
analysis based on quality)
For five high quality studies
enrolling 357 infants, the typical RR was 0.84 (95% CI 0.73, 0.96); the typical
RD was -0.12 (95% CI -0.21, -0.03). For 14 studies of uncertain quality
enrolling 555 infants, the typical RR was 0.48 (95% CI 0.39, 0.59) and the
typical RD was -0.27 (-0.33, -0.20). The summary effect size was larger in the
studies of poor quality. Although a fair degree of heterogeneity remained, there
was less significant heterogeneity for the high-quality studies (p = 0.05;
I2 = 58.4%) compared to the studies of uncertain quality (p <
0.00001; 12 = 82.1%).
Outcome 01.21: Use of one or more blood transfusions (secondary
analysis based on criteria for red blood cell transfusions)
We considered 14 studies enrolling 733 infants to have
used strict (although variable) guidelines for red blood cell transfusions, and
three studies enrolling 97 infants to have used no criteria or less strict
criteria. We excluded two studies for which we were unable to translate the text
regarding possible transfusion guidelines (Yamada 1994 a; Yamada 1994 b).
For the studies using strict red blood cell transfusion guidelines, the typical
RR was 0.71 (95% CI 0.63, 0.80) and the typical RD was -0.18 (95% CI -0.24,
-0.12). For the studies using no criteria or less strict criteria, the typical
RR was 0.25 (95% CI 0.08, 0.77) and the typical RD was -0.21 (95% CI -0.36,
-0,07). There was statistically significant heterogeneity for the studies using
strict criteria, but not for the studies using no criteria or less strict
criteria. The summary effect size was larger for the studies that did not use
strict guidelines for red blood cell transfusions compared to those that did.
This applied to the typical RR but not to the typical RD.
Funnel plot
A funnel plot for the primary outcome 'Use of one or more red blood cell transfusions' was asymmetric, with a relative absence of smaller studies not having a protective effect (see Additional figures - Figure 01).
Enterally dosed EPO
One study (Juul 2003) using enterally dosed EPO found that the intervention did not significantly influence erythropoiesis or iron utilization when given for a 2-week period, nor did it elevate the serum EPO concentration in preterm or term infants. The authors concluded that enterally dosed EPO is not an effective substitute for parenteral administration (Juul 2003).
In only one study (Samanci 1996) did the authors state that infants were not eligible to enter the study if they previously had received a red blood cell transfusion. Most studies followed guidelines for red blood cell transfusions, although these varied between the studies.
The results show that late administration of erythropoietin reduces the "use of one or more blood transfusions" following study entry. These results were quite consistent (overlapping CIs) when including studies that used both low and high doses of EPO in combination with low and high doses of iron. The NNTB to avoid one red blood cell transfusion was low (range 3 - 6, for different combinations of EPO and iron). The clinical importance of this finding is lessened by the fact that any donor exposure was not avoided, as many infants required red blood cell transfusions prior to study entry. Only one study reported on donor exposure, and they noted no significant differences in the mean difference for number of transfusions (Maier 2002). In addition, there were minimal (but statistically significant) reductions in the total volume (ml/kg) of blood transfused per infant (7 ml/kg) and mean number of transfusions (0.8) per infant.
Of concern is the finding of statistically significant heterogeneity for the
primary outcome including all combinations of low and high EPO and low and high
iron treatment. The heterogeneity remained for individual combinations of EPO
and iron. The heterogeneity could possibly be explained by the fact that the
studies were conducted in 21 countries, with presumably different care
practices. Of note, the control rates for red blood cell transfusions varied
markedly between studies. In an attempt to further explore the heterogeneity, we
performed secondary analyses (post-hoc analyses) comparing
1) studies that
we judged as high quality compared to those that we identified as of lower
quality or could not precisely define their quality because of lack of
information, and 2) studies that used strict vs. no criteria or less strict
guidelines for red blood cell transfusions. Judging the quality of a study
depends to a large extent on the information published and obtaining additional
information from the authors may change the evaluations. As noted in the
Additional table, there was large variation in the guidelines for red blood cell
transfusions. The results of these post-hoc analyses should therefore be
interpreted with caution.
For the primary outcome of "use of one or more blood transfusions" the
typical RR for five high quality studies was 0.84 (95% CI 0.73, 0.96) and the
typical RD was - 0.12 (95% CI ; -0.21, -0.03). For 14 studies of uncertain
quality, the typical RR was 0.48 (95% CI 0.39, 0.59) and the typical RD -0.27
(95% CI -0.33, -0.20). The CIs for these analyses are not overlapping,
indicating that there is statistically significant differences in the effect
sizes between studies that could be ascertained as being of high quality and
studies of uncertain quality. There was an important reduction in heterogeneity
when the high quality studies were analyzed separately. Studies of higher
quality often show lower effect sizes (Schulz 1995).
The typical effect size (RR) for studies that used strict red blood cell
transfusion guidelines was smaller than for studies that used no or less strict
criteria.
There were no statistically significant reductions/increases in the many secondary neonatal outcomes included in this systematic review. No important side effects were identified. In contrast to the findings in our systematic reviews of early EPO and early vs. late EPO administration, we could not substantiate our concerns about a possible increase in the risk of ROP with EPO treatment (Ohlsson 2006, Aher 2006). It should be noted that only 3 studies reporting on 331 infants assessed ROP (all stages) and two studies reporting on 212 infants assessed ROP (stage > 3) [for details please see the early EPO (Ohlsson 2006) and the early vs. late EPO reviews (Aher 2006)].
In the study by Maier et al (Maier 2002), 12 of the 14 centres used satellite packs of the original red cell pack to reduce donor exposure. In spite of this strategy, there was no statistically significant reduction in donor exposure. However, the use of satellite packs and conservative transfusion guidelines may reduce the exposure to multiple donors during the total hospital stay. The need for red blood cell transfusions is linked to the loss of blood from sampling for laboratory testing (Obladen 1988), and may be significantly altered based on unit policies or guidelines.
The need for i.v., i.m. or s. c. injections with EPO/iron treatment in the neonatal period is associated with repeated painful stimuli and could potentially have adverse long term affects.
Direct comparisons regarding the results of this systematic overview and previous reviews are not appropriate as this review includes a much larger sample of studies (Vamvakas 2001; Kotto-Kome 2004; Garcia 2002).
Late (after eight days of age) administration of EPO does statistically significantly reduce the rate of "use of one or more red blood transfusions". It results in minimal reductions in the number of red blood cell transfusions per infant (< 1) and the total amount of red cells transfused per infant (7 ml/kg), but not in any donor exposure. Late administration of EPO is not associated with significant decreases/increases in common neonatal adverse outcomes including mortality and ROP (although the outcome of ROP was reported in few studies). As most infants enrolled in these trials had been exposed to red blood cell transfusions prior to study entry, the goal of avoiding any donor blood exposure is likely not to be achieved by the use of late EPO administration. There is no need for further research to assess the effectiveness of the late use of EPO. Future research should focus on strategies to minimize red blood cell donor exposure (maximum one donor) during the first week of life, when the likelihood of needing red blood cell transfusions is at its peak and when neither early nor late administration of EPO could have an effect on the need for red blood cell transfusions. Such strategies in combination with late EPO treatment may reduce further donor exposure. The small number of infants in which ROP was ascertained in the included studies makes it impossible to draw any conclusions whether late administration of EPO increases or decreases the risk of ROP. We will seek unpublished information on the unreported incidence of ROP from the studies included in this review.
Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
Akisu 2001 | Randomized controlled study I. Blinding of randomization- can't tell II. Blinding of intervention- no III. Blinding of outcome-measure assessment- no IV. Completeness follow-up- yes |
40 AGA preterm infants with GA < 33 weeks and birth weight <
1500 g were enrolled on day 10 of life Single centre, University of Ege, Izmir, Turkey |
Infants assigned to the treatment group (n = 20) received r-HuEPO
(Recormon, Boehringer-Mannheim, Germany) s. c. 3 times per week, totaling
750 IU/kg/week (high dose) 20 infants were assigned to the control group with no placebo given All infants received 3 mg/kg/day (low dose) of elemental iron All infants received poly vitamin supplements, vitamin D and folate |
Exposure of a proportion of infants to one or more red blood cell transfusions | Unknown whether infants who had received blood transfusions prior to
study entry were included or not This study focused on lipid peroxidation and antioxidant enzyme activities in preterm infants Guidelines for transfusion were not stated |
B |
Al-Kharfy 1996 | A double-blind (sham-injection in the placebo group), randomised,
control trial I. Blinding of randomization- yes II. Blinding of intervention yes III. Blinding of outcome measure assessment- yes IV. Completeness follow-up- yes |
55 preterm infants with birth weight < 1250 g, appropriate for
gestational age, post-natal age 10-17 days, hematocrit less than 0.45 and
a greater than 75% probability of having BPD, determined at 10 days of age
by the predictive score of Sinkin et al. were included Infants were randomly assigned, within 250 g birth weight strata and between 10 and 17 days of age Single centre, Canada March 1992 to May 1994 41 infants received the 6-week treatment schedule |
Infants assigned to the treatment group (n= 27) received r-HuEPO
(Eprex, Ortho Pharmaceutical, Canada Ltd), in a dosage of 200 IU/kg body
weight, by s. c. injection, on Monday, Wednesday and Friday for 6 weeks
(600 IU/kg/week; high dose) In control infants (n=28), because of a desire to avoid repeated subcutaneous placebo injections, sham injections were given and an adhesive dressing was applied to the sham injection site. The care of the infant was then handed back to nursery personnel unaware of treatment assignment Vitamin E (25 IU/day) and folic acid (0.05 mg/day) was commenced when enteral feeding reached 50% of total fluid intake Oral ferrous sulfate solution was administered to the treatment group at 6 mg of elemental iron/kg/day (high dose) and the control group received 2 mg of elemental iron/kg/day |
Number of transfusions per infant Mortality Sepsis ROP (stage >/= 3) Hypertension BPD (at 28 days) |
Unclear whether infants who had received blood transfusions prior to
study entry were included or not This study exclusively enrolled those infants, who were predicted to have >75% probability of having BPD and requiring multiple transfusions All enrolled infants were included in the data analyses Sham injections were given in the control group Erythrocyte transfusions were in accordance with the guidelines developed by the Canadian Paediatric Society Fetus and Newborn Committee |
A |
Atasay 2002 | Prospective, randomized, placebo controlled trial I. Blinding of randomisation- can't tell II. Blinding of intervention- can't tell III. Blinding of outcome measure assessment- can't tell IV. Completeness of follow up- can't tell |
27 very low birth weight infants, with birth weight < 1500 g,
gestational age < 32 weeks and postnatal age 7-10 days Single centre, Turkey October 1997 to February 1999 |
14 infants received 600 IU/kg/week (high dose) rHuEPO (Cilag AG
Schafhausen, Switzerland), by s. c. route, at 7-10 days and continued over
7-8 weeks 13 infants were assigned to control group (no EPO or placebo) Infants in the study group were supplemented with oral iron (ferroglycine sulphate) at the dose of 3 mg/kg/day (low dose) |
Exposure of a proportion of infants to one or more red blood cell transfusions | Infants were enrolled at age 7-10 days. We decided to include this
study in the late EPO systematic review, although some infants may have
been < 8 days old at enrolment Unknown if infants who had received blood transfusions prior to study entry were included or not Transfusion guidelines were followed The authors did not provide information on the mean age of the infants at enrolment Strict transfusion criteria were used in this trial |
B |
Bader 1996 | 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 |
29 preterm infants (birth weight < 1750 g, gestational age < 34
weeks and postnatal age of 3-5 weeks, mean postnatal age 34 +/- 14
days) Two centres, Israel January to December 1992 |
15 infants received 300 IU/kg/day of rHuEPO (Eprex, Cilag Int.) s. c.
to lateral aspect of right arm 3 times a week (900 IU/kg/week; high dose),
for a total duration of 4 weeks 14 infants received no placebo or other intervention All infants received enteral vitamin E (25 IU/day), vitamin A and D (400 and 1500 IU/day) and folic acid Two weeks into the study elemental iron supplementation was begun in both groups at a dose of 6 mg/kg/day (high dose) |
Exposure of a proportion of infants to one or more red blood cell
transfusions SIDS Side effects |
Unclear whether infants who had received blood transfusions prior to
study entry were included or not Criteria for blood transfusion were in place |
B |
Bechensteen 1993 | Randomized, open, controlled study. I. Blinding of randomization- yes II. Blinding of intervention- no III. Blinding of outcome measure assessment- can't tell IV. completeness of follow-up- yes |
29 preterm infants (birth weight 900-1400 g, AGA) at 3 weeks of
age 4 participating centres, Norway Period not stated |
14 infants received rHuEPO (Eprex, Cilag), 100 IU/kg three times a
week (300 IU/kg/week; low dose) s. c. from 3 to 7 weeks of age 15 infants received neither EPO nor placebo Oral iron 18 mg/day (high dose) regardless of weight, was commenced at the start of the study (3 weeks). If serum iron concentration fell below 16 micromol/L, the dose was increased to 36 mg/day |
Exposure of a proportion of infants to one or more red blood cell
transfusions Mortality Hypertension Neutropenia Side effects |
Infants receiving blood transfusions < 96 hours before start of
study were excluded Indications for blood transfusions were 1) Hb < 80 g/L or 2) at the discretion of the clinician caring for the infant according to symptoms and signs This study concentrates more on different hematological parameters rather than the need for RBC transfusions |
A |
Chen 1995 | Randomized, controlled clinical trial. I. Blinding of randomization- can't tell II. Blinding of intervention- no III. Complete follow-up- yes IV. Blinding of outcome-measurement- no |
67 preterm infants (birth weight </= 1750 g and gestational age
</= 33 weeks Mean age at entry group A 22.3 +/- 6.6 days; group C 22.3 +/- 6.6. days Single center, Taiwan, Republic of China June 1992 to May 1994. |
26 infants (group A) received rHuEPO (Eprex, Cilag Zug, Switzerland)
150 mg/kg i.v. twice a week (300 IU/kg/week; low dose) for 4 weeks 25 infants (group B) received packed washed erythrocyte transfusion, 10 to 15 ml/kg, during a 2 to 4 hour period when their haemoglobin levels were less than 10 g/dl with signs and symptoms attributed to anemia or who had a haemoglobin level less than 8 g/dl even if asymptomatic. 16 infants (group C) did not received receive rHuEPO or erythrocyte transfusions (3 infants excluded from total 19, as they received erythrocyte transfusion later because of frequent episodes of apnea) All infants received oral elemental iron 3 mg/kg/day (low dose) and vitamin E 5 mg/kg/d |
Mortality Side effects |
Unknown whether infants who had received blood transfusions prior to
study entry were included or not Strict guidelines for transfusions were not in place (transfusions were given based on frequent episodes of apnea) Groups A and C were compared based on intention to treat in this systematic review |
B |
Corona 1998 | Randomized, controlled clinical trial. I. Blinding of randomization- can't tell II. Blinding of intervention- no III. Complete follow-up- yes IV. Blinding of outcome-measurement- no |
60 preterm infants (birth weight < 1500 g and < 33 weeks GA)
Postnatal age (days) group A 10.1 +/- 2; group B 9.5 +/- 3; Group C 9.8 +/- 2 Single centre Italy |
20 infants (group A) received rHuEPO (unnamed product) 150 IU/kg/week
s. c. (low dose) 22 infants (group B) received 300 IU/kg/week s. c. 18 infants (group C) received no treatment All groups received oral iron 4 mg/kg/day |
Exposure of a proportion of infants to one or more red blood cell
transfusions Total volume (ml/kg) of blood transfused per infant (no SD provided) Side effects |
Unknown whether infants who had received blood transfusions prior to
study entry were included or not Infants were included after the first week of life the mean (SD) postnatal age was 10.1 (2) days in group A; 9.5 (3) in group B and 9.8 (2) in group 7 Some infants my have been < 8 days old, but we included this study in the Late EPO review as most infants were >/= 8 days Transfusion guidelines were in place |
B |
Donato 1996 | Prospective, randomized, placebo controlled trial I. Blinding of randomisation- can't tell II. Blinding of intervention- yes III. Blinding of outcome measure assessment- yes IV. Completeness of follow up- yes |
32 preterm infants with gestational age < 34 weeks and birth weight
< 1500 g Age at enrolment was 21 to 35 days of life Mean postnatal age at enrolment (days) group A. 27.0 +/- 3.2; Group B 27.6 +/- 3.6; Group C 29.7 +/- 5.8; Group D 32.1 +/- 7.7 Single centre, Argentina July 1991 to June 1993 |
32 preterm infants were randomly assigned to receive: 1. Group A (n=9) placebo (human seroalbumin) s. c. 2. Group B (n=8) rHuEPO (HEMAX, Bio Sidus, S.A.) at dose of 50 IU/kg s. c.(150 IU/kg/week; low dose) 3. Group C (n=8) rHuEPO at dose of 100 IU/kg s. c. (300 IU/kg/week; low dose) or 4. Group D (n=7) rHuEPO at dose of 250 IU/kg s. c. (750 IU/kg/week; high dose), s. c. 3 days per week during 8 consecutive weeks All patients were given oral iron 6 mg/kg/day (high dose) and folic acid (2 mg/day) supplements, starting on day 15 of age and continuing during whole treatment period |
Exposure of a proportion of infants to one or more red blood cell
transfusions. Average number of transfusions per infant during
treatment Mortality Mean Length of hospitalization time Side effects Hypertension SIDS |
Transfusion criteria were followed in this study | B |
Emmerson 1993 | Randomized, double blind, placebo controlled trial I. Blinding of randomisation- yes II. Blinding of intervention- yes III. Blinding of outcome measure assessment- yes IV. Completeness of follow up- yes |
24 infants with GA between 27 and 33 weeks Postnatal age > 7 days Mean (SE) age (days) at fist dose; EPO group 9 (0.4); Placebo group 8 (0.6) One infant in the EPO group was withdrawn at 14 days of age to enable transfer to another hospital for maternal reasons One centre in the UK |
16 infants were randomly assigned to receive r-HuEpo s. c. (Eprex, Cilag, Ltd). The first 9 infants received 50 IU/Kg of EPO, the next 9 infants received 100 IU/kg and the final six infants received 150 IU/kg of r-HuEpo or placebo (4% albumin) twice a week s. c. after 7 days of age twice weekly s. c. 300 IU/kg/week (low dose) into the buttock commencing after 7 days of age and administered until the infant was discharged home. All infants received iron (6.25 mg) in the form of ferrous glycine sulphate from four weeks of age (high dose). | Exposure of a proportion of infants to one or more red blood cell transfusions, volume transfused (ml/kg), mortality, hospital stay, SIDS, neutropenia | Transfusion guidelines were followed Unknown if infants who had received transfusions prior to study entry were included or not One infant in the EPO group was withdrawn at 14 days of age to enable transfer to another hospital for maternal reasons and was not included in the analyses |
A |
Giannakopoulou 1998a | Randomised controlled trial Blinding of randomization- can't tell II Blinding of intervention- no III. Complete follow-up- yes IV. Blinding of outcome measures- no |
36 preterm infants with birth weights 1000-1300 g, 32 preterm infants with birth weight < 1000 g postnatal age >20 days divided into 4 groups group 1 and 3 were controls and group 2 and 4 were treatment groups one infant in group 2 died and one infant from group 1 was excluded because of severe infection Single centre, Greece Period not stated |
24 infants received rHuEPO (Eprex, Cilag, Schafhausen, Switzerland)
from day 20 of life s. c. at a dose of 300 IU/kg body weight, three times
a week (900 IU/kg/week; high dose) for 6-8 weeks (n=24) 24 control infants did not received any treatment. All received oral elemental iron 10 mg/kg/day (high dose), folic acid 1 mg/day and vitamin E 15 mg/day |
Mortality Hypertension Neutropenia Side effects |
Unknown whether infants who had received blood transfusions prior to
study entry were included or not Guidelines for blood transfusions were in place Under G-1998a we report on the 32 infants weighing < 1000 g |
B |
Giannakopoulou 1998b | See above | See above | See above | See above | Under G-1998b we report on the 36 infants weighing 1000-1300 g | B |
Griffiths 1997 | A multicenter, randomized, placebo controlled, double blind
study. I. Blinding of randomization- yes II. Blinding of intervention yes III. Blinding of outcome measure assessment- yes IV. Complete follow-up- yes (see notes) |
43 preterm infants with gestational age < 32 weeks and/or birth
weight < 1500 g, requirement for mechanical ventilation and/or
supplemental oxygen 4 NICUs in Yorkshire, the UK Study period June 1993-1994 |
21 infants received R-HuEpo (Eprex; Cilag UK) EPO 480 IU/kg/week (low
dose) s. c. and 21 infants received placebo (4% human albumin) s.
c. The first injection was given on the day of randomization, and then twice weekly until the infant either (a) reached 40 weeks postmenstrual age, (b) was transferred to another hospital (not in the study), (c) did not require any mechanical ventilation/oxygen for a period of more than a week, (d) had local adverse reactions/complications related to the trial solution, or (e) had PCV > 60%. All infants received oral iron (3.0 ml/kg/day) (low dose) from four week after birth. |
Mortality, BPD (at 36 weeks post conceptual age), SIDS Median number of blood transfusions |
Infants who received blood transfusions prior to study entry were not
excluded Transfusion guidelines were in place One infant who received treatment was ineligible and was subsequently withdrawn and excluded from the analysis |
A |
Javier Manchon 1997 | A multicenter, randomized, controlled study I. Blinding of randomization- can't tell II. Blinding of intervention- no III. Blinding of outcome measure assessment- no IV .complete follow-up - yes |
Population: Preterm infants < 34 weeks GA, who at 28 days after
birth had hemoglobin levels < 10.5 g/dL Three centres in Barcelona, Spain |
15 infants received 200 IU EPO/kg s. c. (unnamed product) three days a
week for 4 weeks (600 IU/kg/week; high dose) and ferrous sulphate 4
mg/kg/day (low dose) 13 control infants did not receive placebo, EPO or iron |
Exposure of a proportion of infants to one or more red blood cell transfusions between 30 and 60 days of age | Infants were included if they had received blood transfusions prior to
randomization Transfusion guidelines were similar in all three centres (details not provided) |
B |
Juul 2003 | A prospective, blinded, placebo-controlled study. I. Blinding of randomization- can't tell II. Blinding of intervention yes III. Blinding of outcome measure assessment- yes IV. Complete follow-up- yes |
32 preterm infants with birth weight between 700 to 1500 g and
receiving at least 30 ml/kg per day of enteral feeding The mean (SD) GA (weeks) at birth was 27.8 +/- 1.8 in the EPO group and 28.8 +/- 2.1 in the placebo group Mean (SD) postnatal age at study entry was 31.6 +/- 2.0 in the EPO group and 31.9 +/- 1.6 in the placebo group Single centre, USA Period not stated |
15 infants received rEpo 1000 IU/kg per day divided into 2 daily
feedings (7000 IU/kg/week; high dose), for 14 days. 17 infants received placebo (D5W) for 14 days. All subjects received supplemental iron [iron dextran, 1.0 mg/kg/day administered in the hyperalimentation solution, or enteral ferrous sulfate 6 mg/kg per day (high dose)] |
Phlebotomy loss (ml) and PRBC transfusion volume (ml) Evidence of feeding intolerance and other adverse effects |
This is the only study which used oral EPO The results of this study are not included in the meta-analyses |
B |
Kivivuori 1999 | An open randomized study I. Blinding of randomization- can't tell II. Blinding of intervention no III. Blinding of outcome measure assessment- no IV. Complete follow-up- no |
45 very low birthweight infants (4 excluded - see notes) 41 infants included Birthweight ranged from 625 - 1470 g The infants were randomized to three groups One group (n - 14) received rHuEPO and oral iron (mean gestational age 30.1 +/- 0.7 weeks), one group (n = 14) received rHuEPO and i.m. iron ( mean gestational age 28.8 +/- 0.5 weeks), one group (n = 13) received no rHuEPO and i.m. iron (mean gestational age 29.1 +/- 0.6 weeks) Infants who were weaned from the respirator by 2 weeks of age were eligable Four centres; 3 in Helsinki and one in Espoo, Finland |
14 infants received rHuEPO (Cilag A.G., Schafhausen, Switzerland) 300
IU/kg s.c.3 times/week, 900 IU/kg/week (high dose) s. c. and oral iron 6
mg/kg/day (high dose) 14 infants received 900 IU/kg/week of rhuEPO and weekly i.m. iron 12 mg/kg (high dose) 13 infants received i.m. iron 12 mg/kg/week but no rHuEPO |
Exposure of a proportion of infants to one or more red blood cell
transfusions Side effects |
Unknown whether infants who had received blood transfusion prior to
study entry were included or not 4 infants were excluded after randomization; one weighed > 1500 g, one had intestinal "opstipation", one had highly elevated serum transferrin saturation (96%), one accidentally received a high dose of parenteral iron (43 mg/kg) We include the infants in the i.m. iron group in the high dose iron analyses The transfusion policies (not stated) were the same in all hospitals |
B |
Kumar 1998 | Randomised, double blind, placebo- controlled trial I. Blinding of randomization- can't tell II. Blinding of intervention- yes III. Blinding of outcome measure assessment- yes IV .complete follow-up- can't tell |
30 infants (gestational age < 32 weeks, birth weight < 1250 g
with anaemia of prematurity Mean (SD) postnatal age (days) at entry was 40.3 (20.4) in the EPO group and 36.5 (16.6) in the placebo group) Single Centre, USA Period not stated |
300 IU/kg/dose of rHuEPO (unnamed product) s. c. injection twice a
week (600 IU/kg/week; high dose) for 6 weeks (n=15) Identical volume of placebo suspension (normal saline) (n=15) Infants received elemental iron 6 mg/kg/d (high dose) |
Exposure of a proportion of infants to one or more red blood cell
transfusions Number of erythrocyte transfusions (per infant) Entry to discharge duration (days) Side effects |
Infants who had received transfusions prior to randomization were
included Transfusion guidelines were followed |
B |
Maier 2002 | Randomized controlled study I. Blinding of randomization- yes II. Blinding of intervention- yes III. Blinding of outcome-measure assessment- yes IV. Completeness follow-up- yes |
148 infants with BW 500 - 999 g Exclusion criteria: cyanotic heart disease, major congenital malformation requiring surgery, administration of investigational drug during pregnancy, gestational age >/= 30 completed weeks The early EPO group started treatment at 3-5 days of age and the late EPO group 3 weeks later (at 24 to 26 days of age) Enrolment period May 1998 to June 1999 14 centres in 4 European countries (Belgium, France, Germany, Switzerland) |
Infants were randomized to 3 groups (see notes for the control group).
In the early EPO group 74 infants [median and quartiles for GA; 26 (25,
28) weeks for BW 778 (660, 880) g] received 250 IU/kg i.v. or s. c. of
rHEPO on Mondays, Wednesdays and Fridays (NeoRecormon, F. Hofman-La Roche,
Basel Switzerland) (750 IU/week i.v. or s. c., high dose) starting at days
3-5 of life. In the late EPO group 74 infants received the same treatment 3 weeks later Treatment in both groups continued until days 65 to 68 of life. rHEPO was given i.v. in both groups as long as the infant had an i.v. line in place and s.c thereafter. The late EPO group received sham-injections until EPO was given. Enteral iron 3 mg/kg/day was given to all infants from days 3 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) |
Exposure of a proportion of infants to one or more red blood cell
transfusions Donor exposure Mortality during hospital stay NEC IVH PVL ROP Days in oxygen Days in NICU Days in hospital |
Sample size calculation was performed Transfusion guidelines were followed Industry funded (F. Hoffman-La Roche, Basel Switzerland) 24 (32%) of the infants in the early EPO group and 23 (31%) in the late EPO group received 1 to 3 transfusions before they entered the study. A third group (control group, n =71) was included in this trial. One infant in the control group was excluded from all evaluations because the parents withdrew consent a few hours after randomization before the start of the treatment phase. |
A |
Meyer 1994 | Randomized, double blind, Placebo-controlled study. I. Blinding of randomization- can't tell II. Blinding of intervention- yes III. Blinding of outcome measure assessment-yes IV. complete follow-up- yes |
80 preterm infants (< 32 weeks gestational age, birth weight <
1500 g, postnatal age 2 to 8 weeks. Single centre, South Africa Period not stated |
40 infants received rHuEPO (Eprex) s. c. 3 times a week at a dose of
200 IU/kg/dose (600 IU/kg/week, high dose). The volume was increased by
the equivalent of 50 IU/kg per dose if the hematocrit declined by 6%
during any 2-week period during the trial, but was withheld if the
hematocrit was > 45%. 40 infants received an identical volume of placebo Infants received 3 mg/kg/day of iron (low dose) |
Exposure of a proportion of infants to one or more red blood cell
transfusions Sepsis NEC SIDS |
Previous blood transfusion was not an exclusion
criterion Transfusion guidelines were followed |
B |
Pollak 2001 | Randomized, unmasked, controlled study. I. Blinding of randomization- yes II. Blinding of intervention - no III. Blinding of outcome measure assessment-no IV. complete follow-up- no (see notes) |
38 preterm infants with GA < 31 weeks and weight < 1300 g at
birth. Single centre study conducted in Vienna, Austria. Study period August 1995 to May 1997 9 infants were disqualified (see 'Notes') |
The 21 day study consisted of a 3-day run-in baseline period during
which 9 mg/kg/day of iron poly maltose complex (IPC; Ferrum Hausmann
Syrup, Vifor International, St Gallen, Switzerland) supplementation was
administered to all participants in all groups. This was followed by an
18-day treatment period during which participants received: 1) the same
oral iron supplementation dose alone (oral iron group, n = 9); 2) 300
IU/kg/day (> 600 IU/kg/week; high dose) of r-HuEPO (Erypo,
Janssen-Cilag Pharma, Vienna, Austria) as an i.v. bolus infusion
administered at 3-day intervals along with the same oral iron supplement
as the oral iron group (EPO + oral iron group, n = 10); or 3) 2 mg of i.v.
iron sucrose/kg/day (Venofer, Vifor International) diluted in 0.9% of
sodium chloride to a final concentration of 2 mg/mL and infused daily over
2 hours (i.v. iron + EPO group, n = 10). To maintain comparability of iron
intake among the 3 groups, this last group also received EPO and oral iron
in an identical manner as the EPO + oral iron group. |
Mortality, sepsis, BPD at 36 weeks, sepsis, ROP (stage not
provided) Hospital stay |
Infants who had received red blood cell transfusions 3 days before
study entry or during the study Transfusion guide lines were in place Of the 38 study participants who began the study, 9 were disqualified during the treatment period (3 infants with sepsis or sepsis like episodes, 2 with NEC, 2 who received blood transfusions, and 2 for a protocol violation) |
A |
Reiter 2005 | Randomized, controlled study. I. Blinding of randomization- can't tell II. Blinding of intervention- no III. Blinding of outcome measure assessment-no IV. complete follow-up- yes (see notes) |
60 preterm infants with GA at birth < 32 week, Hct </= 28%, <
48 weeks conceptual age or 5 months chronological age Single centre the US Study period not stated |
30 infants received EPO (Eogen alpha, Amgen Inc., Thousand Oaks, CA) at 300 IU/kg per day s. c. for 10 days (2100 IU/kg/week; high dose) and oral elemental iron at 6 mg/kg/day (high dose). The control group (n = 30) received only supplemental iron in the same dose | Exposure of a proportion of infants to one or more red blood cell
transfusions Volume of red blood cells transfused (ml/kg) |
It is uncertain whether there was concealed allocation to the two
study groups (A clinical research nurse assigned infants to a study group
using a random number table) Three infants were withdrawn from the initial data analysis 1 from the EPO group and 2 from the control group because post treatment laboratory variables were not obtained Transfusion guidelines were in place and followed |
B |
Rocha 2001 | Randomized, controlled study I. Blinding of randomization- can't tell II. Blinding of intervention- no III. Blinding of outcome measure assessment-no IV. Complete follow-up- no (see notes) |
45 preterm infants with GA </= 33 weeks, BW </= 1550 g,
postnatal age 10-35 days Single centre study in Brazil Study period March 1995 to December 1996 |
In group 1) 15 patients received daily doses of 100 IU/kg of EPO s.c
(unnamed product) (700 IU/kg/week - high dose); in group 2) 15 patients
received 350 IU/kg of EPO s. c. twice weekly (700 IU/kg/week - high dose);
in group 3) 15 patients did not receive EPO Groups 1 and 2 were given iron (ferrous sulphate) 3 mg/kg/day enterally and was increased to 6 mg/kg/day in the second week of treatment In Group 3 iron supplementation was initiated around the 30 th day of life |
Short term side effects Mean number of blood transfusions per patient, but no SD provided Excessive blood transfusions defined as two or more blood transfusions per patient (This was not an outcome identified in our protocol) |
Although stated as a randomized controlled trial in the abstract this
is uncertain as in the text the authors write:"...each of the patients was
systematically placed into on of the three existing groups...". Three
infants (one from group 2 and two from group 3) were not included due to
intercurrent diseases (2 cases of severe sepsis and one case of
necrotizing enterocolitis). The authors do not state in which groups the
specific diseases occurred. The name of the manufacturer of EPO was not provided "Data collection was interrupted after a sample size calculation revealed that the number of patients studied so far would have to be at least doubled in order to obtain a statistical difference between the two groups of preterm infants who used EPO in different posology" The authors were satisfied when a statistical difference regarding excessive blood transfusions was found between the two treated groups and the control group" It is unknown whether infants who had received blood transfusions prior to study entry were included or not Transfusion guidelines were followed |
B |
Ronnestad 1995 | Randomised, double-blind, placebo-controlled trial. I Blinding of randomization- can't tell II. Blinding of intervention-yes III. Blinding of outcome measure assessment- yes lV. Complete follow-up- yes |
24 preterm infants, < 32 weeks, between 14 and 22 days of
age Single Centre, Norway Period not stated |
24 preterm infants were randomly assigned, to receive s. c. either
rHuEPO (Eprex, Cilag) (n=12) 150 IU/kg 3 times per week (450 IU/kg/week;
low dose) or placebo (n=12). Treatment was started between day 14 and 22
and continued for 6 weeks or alternatively until haemoglobin concentration
exceeded 13.0 g/100 ml after 4 weeks of treatment. All infants were fed their own mother's milk 150-180 ml/kg/day, supplemented with a bovine milk protein and electrolyte fortifier. Additionally, they received vitamin E 25 mg/kg/day, a multivitamin formula (Multibionata) 0.5 ml/day and folic acid 100 mcg/day Iron supplementation 4 mg/kg/day (low dose) as ferrous fumarase was started at study entry |
Neutropenia | B | |
Samanci 1996 | 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 |
24 preterm infants with gestational age </= 32 weeks, birth weight
of </= 1250 g and postnatal age at the first dose was 2-4
weeks. Single centre, University of Istanbul, Turkey September 1993 to March 1994 |
12 infants received r-HuEPO (Cilag AG, Switzerland, provided by Guler
Pharmaceutical Corp, Istanbul, Turkey) at a dose of 200 IU/kg, s. c.,
three times weekly (600 IU/kg/week, high dose), for 4 weeks. 12 infants received an equivalent volume of placebo subcutaneously, three times weekly, for 4 weeks All infants received oral supplements of elemental iron (3 mg/kg/day) (low dose) and vitamin E, 25 IU/day, during the study period |
Exposure of a proportion of infants to one or more red blood cell
transfusions Number of blood transfusions per infant IVH Side effects |
Infants who received erythrocyte transfusions before study entry were
excluded Guidelines for erythrocyte transfusions were developed and followed |
A |
Shannon 1991 | Multi-centre, randomized, double-blind, controlled clinical
trial. I. Blinding of randomization- can't tell II. Blinding of intervention- yes III. Blinding of outcome-measure assessment- yes IV. Complete follow-up- yes |
20 preterm infants, including 2 pairs of twins Patients were stratified at entry into two groups- a) "large" (birth weight 901 to 1250 g) and b) "small" (birth weight </= 900 g) 10 small and 10 large babies were entered into the trial Within these two subgroups 5 infants each were randomly assigned to receive either r-HuEPO or placebo Postnatal age 10-35 days 3 centres, USA Study period not stated |
10 infants received i.v. injections of r-HuEPO (Amgen) at a dose of
100 IU/kg, twice each week (200 IU/kg/week; low dose) for 6 weeks. 10 infants received i.v. injections of identical volume of placebo twice each week for 6 weeks. All infants received 3 mg/kg/day of oral iron (low dose) and continued at the discretion of the attending physician. All infants received supplemental vitamin E (5 IU/day). |
Exposure of a proportion of infants to one or more red blood cell
transfusions Mortality NEC Hypertension Neutropenia Side effects |
Unknown whether infants who had received transfusions prior to
randomization were included or not Infants with more complicated courses had large amounts of blood removed for laboratory tests Transfusions were administered at the discretion of the attending physician |
B |
Shannon 1992 | A double-blind, randomised, pilot study I. Blinding of randomization- yes II. Blinding of intervention yes III. Blinding of outcome measure assessment- yes IV. Completeness follow-up- yes |
8 preterm infants with gestational age < 33 weeks and birth weight
<1250 g Postnatal age (range) 8-28 days Single centre, USA October to December 1991 |
4 infants received s.c injections of r-HuEPO (unnamed product) at a
dose of 100 IU/kg, 5 times a week (500 IU/kg/week; high dose) 4 infants received identical volume of placebo suspension, 5 times a week. Oral iron was started in all infants at 3 mg/kg/day (low dose), divided in 3 doses and given between feedings The iron dose was increased to 6 mg/kg/day for infants who were tolerating full caloric feedings Infants also received 1 ml/day of multivitamins and vitamin E (15 IU per day |
Exposure of a proportion of infants to one or more red blood cell
transfusions Major adverse events |
This was a pilot study Unclear if infants were included if they had received transfusions prior to randomization Guidelines for red blood cell transfusions were in place |
A |
Shannon 1995 | Multi-centre, randomized, double-blind, controlled clinical
trial. I. Blinding of randomization- yes II. Blinding of intervention- yes IV. Blinding of outcome-measure assessment- yes IV. Complete follow-up- yes |
157 preterm infants with GA <31 weeks with birth weight of 1250 or
less Mean (SD) age (days) at study entry; EPO group 22.9+/- 10.1; Placebo group 24.1 +/- 9.9 Multi centre study, eleven centres, USA October 1991 to October 1993 |
S.c injection of rHuEPO at a dose of 100 IU/kg, or an identical volume
of placebo suspension, were given from Monday through Friday (500
IU/kg/week; high dose) for 6 weeks or until the infants were ready to be
discharged home. Doses of rHuEPO (or placebo) were adjusted weekly
according to changes in body weight There were 77 infants in the rHuEPO group and 80 infants in the placebo group Patients received oral iron supplements at study entry to achieve a total enteral intake of 3 mg/kg/day of elemental iron (low dose) Total iron intake was increased to 6 mg/kg/day when the infants tolerated full caloric feeding enterally Infants also received 15 IU of supplemental vitamin E and an additional 1 ml/day of an enteral multivitamin preparation |
Exposure of a proportion of infants to one or more red blood cell
transfusions Mean number of erythrocyte transfusions per infant Mortality Sepsis NEC ROP Hypertension SIDS Side effects |
Infants who had received blood transfusions prior to study entry were
included Guidelines for blood transfusions were developed This study reports four post-discharge infants deaths among 125 infants followed until they were at least 6 months old. Three placebo treated infants died; 2 of probable SIDS and one from aspiration pneumonia The only late infant death in an EPO treated infant occurred at 11 month of age from late NEC. |
A |
Whitehall 1999 | Single centre, randomized controlled clinical trial I. Blinding of randomization- can't tell II. Blinding of intervention- no IV. Blinding of outcome-measure assessment- no IV. Complete follow-up- yes |
42 infants with GA </= 32 weeks Postnatal age 14 days Exclusion criteria: major congenital anomaly, primary hematological disease, hypertension, seizures, failure to obtain consent Single centre study in Australia Study period August 1992 to March 1993 |
10 infants with BW </= 1000 g and 12 infants with BW > 1000 g
received 400 IU/kg of EPO (EPREX, Janssen-Cilag) s. c. every second day x
10 doses (high dose) 10 infants with BW </= 1000 g and 10 infants with BW > 1000 g received no placebo Both groups received 3 mg/kg/day of iron (low dose) increased to 6 mg/kg/day (high dose) as tolerated |
Total volume (ml/kg) of blood transfused Number of transfusions per infant Mortality during hospital stay |
Unknown whether infants were included if they had received blood
transfusion prior to study entry Guidelines for blood transfusions were in place |
B |
Yamada 1994 a | Single centre, randomized controlled clinical trial I. Blinding of randomization- can't tell II. Blinding of intervention- no IV. Blinding of come-measure assessment- no IV. Complete follow-up- yes |
55 infants with BW 1000 to 1499 g and GA < 33 weeks and postnatal
age < 40 days Single centre Japan |
28 infants received 200 IU/kg of EPO s. c. twice a week (400 IU/kg/week, low dose) for 8 weeks and oral iron (3 mg/kg/day). 27 infants in the control group received no treatment or placebo | Exposure of a proportion of infants to one or more red blood cell
transfusions The total volume (ml) of blood transfused per infant Number of transfusions per infant |
Unknown if infants who had received transfusions prior to enrolment
were excluded or not Conservative red blood cell transfusion guidelines were followed |
B |
Yamada 1994 b | Single centre, randomized controlled clinical trial I. Blinding of randomization- can't tell II. Blinding of intervention- no IV. Blinding of outcome-measure assessment- no IV. Complete follow-up- yes |
27 infants with BW 500 to 999 g and GA < 33 weeks and postnatal age
< 40 days Single centre Japan |
15 infants received EPO 200 IU/kg of EPO s. c. twice a week (400 IU/kg/week, low dose) s. c. for 8 weeks and oral iron (3 mg/kg/day). 12 infants in the control group received no treatment or placebo | Exposure of a proportion of infants to one or more red blood cell
transfusions The total volume (ml) of blood transfused per infant Number of transfusions per infant |
Unknown if infants who had received transfusions prior to enrolment
were excluded or not Conservative red blood cell transfusion guidelines were followed |
B |
Study | Reason for exclusion |
Ahmadpour Kacho 2004 | Published in abstract form only. Randomized controlled trial of erythropoietin vs. no treatment in preterm low birth weight infants. The abstract lacks information on the age of the infants at the time of enrolment. |
Amin 2004 | Published in abstract form only. The authors state that this was a controlled clinical trial of erythropoietin vs. conventional therapy in preterm very low birth weight infants. It is not clear if this was a randomized controlled trial or not. |
Messer 1993 | This is not a randomized controlled trial. Non-randomized controls were used. |
Ohls 1991 | This study compared erythropoietin with erythrocyte transfusion and not placebo. |
Testa 1998 | The study used historical controls. |
Warwood 2005 | This study was a dose-finding study of Darepoetin (longer acting and more potent than EPO). Infants were randomized to two different doses of Darepoetin. |
Akisu M, Tuzun S, Arslanoglu S, Yalaz M, Kultursay N. Effect of recombinant human erythropoietin administration on lipid preoxidation and antioxidant enzyme(s) activities in preterm infants. Acta Medica Okayama 2001;55:357-62.
Al-Kharfy 1996 {published data only}
* Al-Kharfy T, Smyth JA, Wadsworth L, Krystal G, Fitzgerald C, Davis J, et al. Erythropoietin therapy in neonates at risk of having bronchopulmonary dysplasia and requiring multiple transfusions. Journal of Pediatrics 1996;129:89-96.
Smyth JA, Ainsworth L, Krystal G, Wadsworth L. Effect of erythropoietin therapy on oxygen dependancy in premature infants. Pediatric Research 2002;51:330 A.
Atasay 2002 {published data only}
Atasay B, Gunlemez A, Akar N, Arsan S. Does early erythropoietin therapy decrease transfusions in anemia of prematurity. Indian Journal of Pediatrics 2002;69:389-91.
Bader 1996 {published data only}
Bader D, Blondheim O, Jonas R, Admoni O, Abend-Winge M, Reich D et al. Decreased ferritin levels, despite iron supplementation, during erythropoietin therapy in anaemia of prematurity. Acta Paediatrica 1996;85:496-501.
Bechensteen 1993 {published data only}
* Bechensteen AG, Haga P, Halvorsen S, Whitelaw A, Liestol K, Lindemann R, et al. Erythropoietin, protein, and iron supplementation and the prevention of anaemia of prematurity. Archieves of Disease in Childhood 1993;69:19-23.
Bechensteen AG, Halvorsen S, Haga P, Cotes PM, Liestol K. Erythropoietin (Epo), protein and iron supplementation and the prevention of anaemia of prematurity: effects on serum immunoreactive Epo, growth and protein and iron metabolism. Acta Paediatrica 1996;85:490-5.
Bechensteen AG, Halvorsen S, Haga P. Erythropoiesis during rapid growth. Role of erythropoietin and nutrition. Annals of the New York Academy of Sciences 1994;718:339-40.
Bechensteen AG, Refsum HE, Halvorsen S, Haga P, Liestol K. Effects of recombinant human erythropoietin on fetal and adult hemoglobin in preterm infants. Pediatric Research 1995;38:729-32.
Chen 1995 {published data only}
Chen JY, Wu TS, Chanlai SP. Recombinant human erythropoietin in the treatment of anemia of prematurity. American Journal of Perinatology 1995;12:314-8.
Corona 1998 {published data only}
Corona G, Fulia F, Liotta C, Barberi I. Uso clinico dell'eritropoietina umana ricombinante (rHuEPO) nell'anemia della prematurita [Clinical use of recombinant human erythropoietin (rHuEPO) in the treatment of preterm anaemia]. Rivista Italiana Pediatrica 1998;24:442-9.
Donato 1996 {published data only}
Donato H, Rendo P, Vivas R, Schvartzman G, Digregorio J, Vain N. Recombinant human erythropoietin in the treatment of anemia of prematurity: a randomized, double-blind, placebo-controlled trial comparing three different doses. International Journal of Pediatric Hematology/Oncology 1996;3:279-85.
Emmerson 1993 {published data only}
Emmerson AJ, Coles HJ, Stern CM, Pearson TC. Double blind trial of recombinant human erythopoietin in preterm infants. Archives of Disease in Childhood 1993;68:291-6.
Giannakopoulou 1998a {published data only}
Giannakopoulou C, Bolonaki I, Stiakaki E, Dimitriou H, Galanaki H, Hatzidaki E et al. Erythropoietin (rHuEPO) administration to premature infants for the treatment of their anemia. Pediatric Hematology Oncology 1998;15:37-43.
Giannakopoulou 1998b {published data only}
Giannakopoulou C, Bolonaki I, Stiakaki E, Dimitriou H, Galanaki H, Hatzidaki E et al. Erythropoietin (rHuEPO) administration to premature infants for the treatment of their anemia. Pediatric Hematology Oncology 1998;15:37-43.
Griffiths 1997 {published data only}
Griffiths G, Lall R, Chatfield S, MacKay P, Williamson P, Brown J et al. Randomised controlled double blind study of the role of recombinant erythropoietin in the prevention of chronic lung disease. Archives of Disease in Childhood 1997;76:F190-2.
Javier Manchon 1997 {published data only}
Javier Manchon G, Natal Pujol A, Coroleu Lletget W, Zuasnabar Cotro A, Badia Barnusell J, Junca Piera J et al. Estudio multicentrico aleatorizado de administracion de eritropoyetina en la anemia de la prematuridad [Randomized multi-centre trial of the administration of erythropoietin in anemia of prematurity]. Anales espanoles de pediatria 1997;46:587-92.
Juul 2003 {published data only}
Juul SE. Enterally dosed recombinant human erythropoietin does not stimulate erythropoiesis in neonates. Journal of Pediatrics 2003;143:321-6.
Kivivuori 1999 {published data only}
Kivivuori SM, Virtanen M, Raivio KO, Viinikka L, Siimes MA. Oral iron is sufficient for erythropoietin treatment of very low birth-weight infants. European Journal of Pediatrics 1999;158:147-51.
Kumar 1998 {published data only}
Kumar P, Shankaran S, Krishnan RG. Recombinant human erythropoietin therapy for treatment of anemia of prematurity in very low birth weight infants: a randomized, double-blind, placebo-controlled trial. Journal of Perinatology 1998;18:173-7.
Maier 2002 {published and unpublished data}
Maier RF, Obladen M, Muller-Hansen I, Kattner E, Merz U, Arlettacz R et al. Early treatment with erythropoietin beta ameiliorates anemia and reduces transfusion requirements in infants with birth weights below 1000 g. Journal of Pediatrics 2002;141:8-15.
Meyer 1994 {published data only}
Meyer MP, Haworth C, McNeill L. Is the use of recombinant human erythropoietin in anemia of prematurity cost-effective? South African Medical Journal 1996;86:251-3.
* Meyer MP, Meyer JH, Commerford A, Hann FM, Sive AA, Moller G, et al. Recombinant human erythropoietin in the treatment of the anemia of prematurity: results of a double-blind, placebo-controlled study. Pediatrics 1994;93:918-23.
Pollak 2001 {published data only}
Pollak A, Hayde M, Hayn M et al. Effect of intravenous iron supplementation on erythropoiesis in erythropoietin-treated premature infants. Pediatrics 2001;107:78-85.
Reiter 2005 {published data only}
Reiter PD, Rosenberg AA, Valuck R, Novak K. Effect of short-term erythropoietin therapy in anemic premature infants. Journal of Perinatology 2005;25:125-9.
Rocha 2001 {published data only}
Rocha VLL, Benjamin AC, Procianoy RS. The effect of recombinant human erythropoietin on the treatment of anemia of prematurity. Journal de Pediatria 2001;77:75-83.
Ronnestad 1995 {published data only}
Ronnestad A, Moe PJ, Breivik N. Enhancement of erythropoiesis by erythropoietin, bovine protein and energy fortified mother's milk during anaemia of prematurity. Acta Paediatrica 1995;84:809-11.
Samanci 1996 {published data only}
Samanci N, Ovali F, Dagoglu. Effects of recombinant human erythropoietin in infants with very low birth weights. The Journal of International Medical Research 1996;24:190-8.
Shannon 1991 {published data only}
Newton NR, Leonard CH, Piecuch RE, Phibbs RH. Neurodevelopmental outcome of prematurely born children treated with recombinant erythropoietin in infancy. Journal of Perinatology 1999;19:403-6.
* Shannon KM, Mentzer WC, Abels RI, Freeman P, Newton N, Thompson D, et al. Recombinant human erythropoietin in the anemia of prematurity: results of a placebo-controlled pilot study. Journal of Pediatrics 1991;118:949-55.
Shannon 1992 {published data only}
Shannon KM, Mentzer WC, Abels RI, Wertz M, Thayer-Moriyama J, Li WY, et al. Enhancement of erythropoiesis by recombinant human erythropoietin in low birth weight infants: a pilot study. Journal of Pediatrics 1992;120:586-92.
Shannon 1995 {published data only}
Bard H, Widness JA. Effect of recombinant human erythropoietin on the switchover from fetal to adult hemoglobin synthesis in preterm infants. Journal of Pediatrics 1995;127:478-80.
Baxter LM, Vreman HJ, Ball B, Stevenson DK. Recombinant human erythropoietin (r-HuEPO) increases total bilirubin production in premature infants. Clin Pediatr 1995;34:213-6.
Brown MS, Shapiro H. Effect of protein intake on erythropoiesis during erythropoietin treatment of anemia of prematurity. Journal of Pediatrics 1996;128:512-7.
* Shannon KM, Keith JF 3rd, Mentzer WC, Ehrenkranz RA, Brown MS, Widness JA, et al. Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants. Pediatrics 1995;95:1-8.
Widness JA, Lombard KA, Ziegler EE, Serfass RE, Carlson SJ, Johnson KJ, Miller JE. Erythrocyte incorportion and absorption of 58Fe in premature infants treated with erythropoietin. Pediatric Research 1997;41:416-23.
Whitehall 1999 {published data only}
Whitehall JS, Patole SK, Campbell P. Recombinant human erythropoietin in anemia of prematurity. Indian Pediatrics 1999;36:17-27.
Yamada 1994 a {published data only}
Yamada M, Takahashi R, Chiba Y, Ito T, Nakae S. Effects of recombinant human erythropoietin in infants with anemia of prematurity. I. Results in infants with birth weights between 1,000 and 1,499 gm. Acta Neonatologica Japonica 1994;35:755-61.
Yamada 1994 b {published data only}
Yamada M, Takahashi R, Chiba Y, Ito T, Nakae S. Effects of recombinant human erythropoietin in infants with anemia of prematurity. II. Results in infants with birth weights between 500 and 999 gm. Acta Neonatologica Japonica 1994;35:762-7.
Ahmadpour Kacho M, Zahedpasha Y, Esmaili MR, Hajian K, Moradi S. The effect of human recombinant erythropoietin on prevention of anemia of prematurity. Pediatric Research 2003;54:564.
Amin 2004 {published data only}
Amin A, Alzahrani D. Efficacy of erythropoietin in premature infants. Pediatric Research 2003;54:557.
Messer 1993 {published data only}
Messer J, Haddad J, Donato L, Astruc D, Matis J. Early treatment of premature infnats with recombinant human erythropoietin. Pediatrics 1993;92:519-23.
Ohls 1991 {published data only}
Ohls RK, Christensen RD. Recombinant erythropoietin compared with erythrocyte transfusion in the treatment of anemia of prematurity. Journal of Pediatrics 1991;119:781-8.
Testa 1998 {published data only}
Testa M, Reali A, Copula M, Pinna B, Birocchi F, Pisu C, Chiappe F et al. Role of rHuEpo on blood transfusions in preterm infants after the fifteenth day of life. Pediatric Hematology Oncology 1998;15:415-20.
Warwood 2005 {published data only}
Warwood TL, Ohls RK, Wiedmeier SE, Lambert DK, Jones C, Scoffield SH et al. Single-dose darbepoetin administration to anemic preterm neonates. Journal of Perinatology 2005;25:725-30.
* indicates the primary reference for the study
Aher SM, Ohlsson A. Early versus late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. In: The Cochrane Database of Systematic Reviews, Issue 3, 2006.
Brown MS, Phibbs RH, Gracia JF, Dallman PR. Postnatal changes in erythropoietin levels in untransfused premature infants. Journal of Pediatrics 1983;103:612-7.
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.
Dame C, Juul SE, Christensen RD. The biology of eythropoietin in the central nervous system and its neurotrophic and neuroprotective potential. Biology of the Neonate 2001;79:228-35.
Fetus and Newborn Committee, Canadian Paediatric Society. Guidelines for transfusion of erythrocytes to neonates and premature infants. Canadian Medical Association Journal 1992;147:1781-92.
Finch CA. Erythropoiesis, erythropoietin and iron. Blood 1982;60:1241-6.
Garcia MG, Hutson AD, Chrisensen RD. Effect of recombinant erythropoietin on "late" transfusions in the neonatal intensive care unit: a meta-analysis. Journal of Perinatology 2002;22:108-11.
Genen LH, Klenoff H. Iron supplementation for erythropoietin-treated preterm infants (Protocol). In: The Cochrane Database of Systematic Reviews, Issue 1, 2001.
Hesse L, Eberl W, Schlaud M, Poets CF. Blood transfusion. Iron load and retinopathy of prematurity. European Journal of Pediatrics 1997;156:465-70.
Juul S. Erythropoietin in the central nervous system, and its use to prevent hypoxic-ischemic brain damage. Acta Paediatrica Supplement 2002;91:36-42.
Kling PJ, Winzerling JJ. Iron status and the treatment of the anemia of prematurity. Clinics in Perinatology 2002;29:283-94.
Kotto-Kome AC, Garcia MG, Calhoun DA, Christensen RD. Effect of beginning recombinant erythropoietin treatment within the first week of life among very-low-birth-weight neonates, on "early" and "late" erythrocyte transfusions: a meta-analysis. Journal of Perinatology 2004;24:24-9.
Obladen M, Sachsenweger M, Stahnke M. Blood sampling in very low birth weight infants receiving different levels of intensive care. European Journal of Pediatrics 1988;147:399-404.
Ohls RK. The use of erythropoietin in neonates. Clinics in Perinatology 2000;27:681-96.
Ohls RK. Erythropoietin treatment in extremely low birth weight infants: blood in versus blood out. Journal of Pediatrics 2002;141:3-6.
Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusions in preterm and/or low birth weight infants. In: The Cochrane Database of Systematic Reviews, Issue 3, 2006.
Rudzinska IM, Kornacka MK, Pawluch R. Leczenie preparatami ludzkiej rekombinowanje erytropoetyny a czestosc retionpatii u noworodkow przedwczesnie urodzonych [Treatment with human recombinant erythropoietin and frequency of retinopathy of prematurity]. Przeglad Lekarski 2002;59 Supplement 1:83-5.
Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence of bias: Dimensions of methodological quality associated with estimates of treatment effects in controlled trials. JAMA 1995;273:408-12.
Shannon KM, Naylor GS, Torkildson JC, et al. Circulating erythroid progenitors in the anemia of prematurity. New England Journal of Medicine 1987;317:728-33.
Stockman JA 3rd, Oski FA. Physiological anaemia of infancy and the anaemia of prematurity. Clinics in Hematology 1978;7:3-18.
Stockman JA 3rd. Anemia of prematurity. Current concept in the issue of when to transfuse. Pediatric Clinics of North America 1986;33:111-28.
Strauss RG. Current issues in neonatal transfusions. Vox Sanguinis 1986;51:1-9.
Vamvakas EC, Strauss RG. Meta-analysis of controlled clinical trials studying the efficacy of rHuEPO in reducing blood transfusions in the anemia of prematurity. Transfusion 2001;41:406-15.
Widness JA, Sawyer ST, Schmidt RL, Chestnut DH. Lack of maternal to fetal trasfer of 125I-labelled erythropoietin in sheep. Journal of Developmental Physiology 1991;15:139-45.
Widness JA, Seward VJ, Kromer IJ, Burmeiser LF, Bell EF, Strauss RG. Changing patterns of red blood cell transfusion in very low birth weight infants. Journal of Pediatrics 1996;129:680-7.
Zanjani ED, Ascensao JL, McGlave PB, Banisadre M, Ash RC. Studies in the liver to kidney switch of erythropoietin production. Journal of Clinical Investigation 1981;67:1183-8.
Zipursky A. Erythropoietin therapy for premature infants: Cost without benefit? Pediatric Research 2000;48:136.
Comparison or outcome | Studies | Participants | Statistical method | Effect size |
---|---|---|---|---|
01 Late initiation of EPO (8-28 days) vs. placebo or no intervention | ||||
01 Use of one or more red blood cell transfusions (low and high dose of EPO) | 19 | 912 | RR (fixed), 95% CI | 0.66 [0.59, 0.74] |
02 Use of one or more red blood cell transfusions (high dose of EPO) | 13 | 682 | RR (fixed), 95% CI | 0.71 [0.62, 0.81] |
03 Use of one or more red blood cell transfusions (low dose of EPO) | 7 | 239 | RR (fixed), 95% CI | 0.52 [0.41, 0.66] |
04 Total volume (ml/kg) of red blood cells transfused per infant | 4 | 177 | WMD (fixed), 95% CI | -7.29 [-11.86, -2.72] |
05 Number of red blood cell transfusions per infant | 9 | 567 | WMD (fixed), 95% CI | -0.78 [-0.97, -0.59] |
06 Number of donors the infant was exposed to | 1 | 145 | WMD (fixed), 95% CI | -0.40 [-0.90, 0.10] |
07 Mortality during initial hospital stay (all causes) | 14 | 767 | RR (fixed), 95% CI | 0.82 [0.49, 1.39] |
08 Retinopathy of prematurity (all stages) | 3 | 331 | RR (fixed), 95% CI | 0.79 [0.57, 1.10] |
09 Retinopathy of prematurity (stage >/= 3) | 2 | 212 | RR (fixed), 95% CI | 0.83 [0.23, 2.98] |
10 Proven sepsis | 4 | 321 | RR (fixed), 95% CI | 0.69 [0.38, 1.25] |
11 Necrotising Enterocolitis Bell's stage 2 or higher | 5 | 426 | RR (fixed), 95% CI | 0.85 [0.40, 1.77] |
12 Intraventricular hemorrhage all grades (or grade not specified) | 3 | 224 | RR (fixed), 95% CI | 0.83 [0.48, 1.45] |
13 Periventricular leukomalacia | 1 | 145 | RR (fixed), 95% CI | 4.80 [0.57, 40.05] |
14 Bronchopulmonary dysplasia (supplementary oxygen at 28 days) | 1 | 55 | RR (fixed), 95% CI | Not estimable |
15 Bronchopulmonary dysplasia (supplementary oxygen at 36 weeks postmenstrual age | 3 | 216 | RR (fixed), 95% CI | 0.89 [0.59, 1.35] |
16 SIDS | 6 | 363 | RR (fixed), 95% CI | 1.06 [0.25, 4.52] |
17 Neutropenia | 6 | 164 | RR (fixed), 95% CI | 0.28 [0.05, 1.54] |
18 Hypertension | 8 | 363 | RR (fixed), 95% CI | 1.20 [0.46, 3.14] |
19 Length of hospital stay (days) | 2 | 55 | WMD (fixed), 95% CI | -0.35 [-12.83, 12.13] |
20 Use of one or more red blood cell transfusions (secondary analysis based on study quality) | 19 | 912 | RR (fixed), 95% CI | 0.66 [0.59, 0.74] |
21 Use of one or more red blood cell transfusions (secondary analysis based on RBC transfusion guidelilnes) | 17 | 830 | RR (fixed), 95% CI | 0.68 [0.60, 0.77] |
01.01 Use of one or more red blood cell transfusions (low and high dose of EPO)
01.02 Use of one or more red blood cell transfusions (high dose of EPO)
01.02.01 High dose iron
01.02.02 Low dose iron
01.03 Use of one or more red blood cell transfusions (low dose of EPO)
01.03.01 High dose of iron
01.03.02 Low dose of iron
01.04 Total volume (ml/kg) of red blood cells transfused per infant
01.05 Number of red blood cell transfusions per infant
01.06 Number of donors the infant was exposed to
01.07 Mortality during initial hospital stay (all causes)
01.08 Retinopathy of prematurity (all stages)
01.09 Retinopathy of prematurity (stage >/= 3)
01.11 Necrotising Enterocolitis Bell's stage 2 or higher
01.12 Intraventricular hemorrhage all grades (or grade not specified)
01.13 Periventricular leukomalacia
01.14 Bronchopulmonary dysplasia (supplementary oxygen at 28 days)
01.15 Bronchopulmonary dysplasia (supplementary oxygen at 36 weeks postmenstrual age
01.19 Length of hospital stay (days)
01.20 Use of one or more red blood cell transfusions (secondary analysis based on study quality)
01.20.01 HIgh quality studies
01.20.02 Studies of uncertain quality
01.21.01 Strict RBC transfusion guidelines
01.21.02 No or less strict RBC guidelines
Reference | Indications |
Akisu 2001 | Guidelines for transfusions were not presented. |
Al-Karfy 1996 | The indications for transfusion were 1) shock, 2) cumulative loss of >/= 10% of the blood volume in 72 hours or less when further blood sampling is expected, 3) Hb < 130 g/L in acutely ill neonates with cardiorespiratory disease, and 4) Hb < 80 to 100 g/L with clinical signs of anemia. A volume of 15 ml/kg was recommended for each transfusion. |
Atasay 2002 | Criteria for blood transfusion (10 ml/kg packed red cells) were as follows: a Hct < 30% when signs and symptoms attributed to anemia including persistent tachycardia (180 beats/min for 24 hours), frequent apnea with bradycardia and daily weight gain < 10 g/kg despite optimal protein and caloric intake (3.5 g/kg, 100 kcal/kg/day). Infants were transfused with a Hct of 35-40% if they received more than 40% oxygen or ventilation therapy. |
Bader 1996 | Criteria for blood transfusion (10 ml/kg of red cells) were a) a Hct < 25%, b) an increased frequency of apneic events which required either stimulation or aminophylline therapy, c) changes in heart rate patterns, e.g. an increase in frequency of bradycardia (< 80 beats/min) or tachycardia (> 180 beats/min, d) failure of weight gain of > 10 g/kg/day despite an optimal caloric intake of > 120 kcal/day and e) lethargy without evidence of sepsis. |
Bechensteen 1993 | Indications of blood transfusions were: 1) Hb < 80 g/L or 2) otherwise at the discretion of the clinician caring for the infant according to symptoms and signs. |
Chen 1995 | Transfusions were given because of frequent and prolonged apneas. |
Corona 1998 | Transfusions were considered based on the clinical condition (pallor, tachycardia, tachypnoea, apnea with or without bradycardia, poor weight gain, difficulties with sucking) and hematological parameters (Hb < 7 g/L, Hct < 26%, with low reticulocyte counts). |
Donato 1996 | During the first week of life, patients were given transfusions of packed red blood cells for replacement when blood drawn for analysis was in access of 8 ml/kg of body weight; fresh whole blood was given if signs attributable to hypovolaemia or anemia developed. Subsequently, patients with heart rate > 180 beats/min, severe, apnea/bradycardia or poor weight gain (< 10 g/day in spite of a 100 calories/day intake during 5 consecutive days) were transfused if the Hct was < 25% (or < 30% if oxygen or mechanical ventilation was required; asymptomatic infants were transfused only when a central Hct < 23% was reached. |
Emmerson 1993 | The decision to give a blood transfusion to a study infant was made by the medical staff of the neonatal unit who were blinded to the randomisation. The unit policy at the time of the study was to transfuse a preterm infant who had a Hb < 100 g/L and who had symptoms consistent with those caused by anaemia. The symptoms and signs of anaemia included poor feeding, tachycardia, tachypnoea, apnea, and pallor. Infants with a Hb < 80 g/L were transfused even if asymptomatic. |
Giannakopoulou 1998 a & b | Indications for blood transfusion were a Hb < 80 g/L or otherwise at the discretion of the physician treating the infants according to symptoms and signs. |
Griffiths 1997 | Infants were transfused if they were ventilated and/or oxygen dependent with a Hb of < 120 g/L, had clinically symptomatic anaemia, or were asymptomatic with a Hb of < 70 g/L. Infants were transfused if they were ventilated and/or oxygen dependent with a Hb of < 120 g/L, had clinically symptomatic anaemia, or were asymptomatic with a haemoglobin of < 70 g/L. |
Javier Manchon 1997 | Transfusion guidelines were similar in all three centres (details not provided). |
Juul 2003 | By NICU policy, on admission, infants weighing < 1000 g at birth
were assigned 1 unit of packed red blood cells divided into 8 aliquots.
These aliquots were used for transfusions during the first month of life.
The following transfusion guideline was used for infants of all
birth weights: Transfusion is recommended for a Hct < 35% if the infant requires positive pressure with a mean airway pressure > 6 cm water and requires > 35% oxygen. Transfusion is recommended for Hct < 30% if the infant requires oxygen (< 35% FIO2), is receiving continuous positive airway pressure or intubated with mean airway pressure < 6 cm water, if an infant has significant apnea and bradycardia while receiving methylxanthines (> 9 episodes in 12 hours or 2 episodes in 24 hours requiring mask-and-bag ventilation), if the heart rate is >180 beats/min or respiratory rate >80/min and persists for 24 hours, if weight gain < 10 g per day over 4 days despite adequate calories, or in the presence of sepsis. If the HCT is < 20%, no symptoms are necessary for transfusion. Transfusion volumes were standardized as follows: Infants received an initial transfusion of 15 mL/kg over a period of 3 to 4 hours. A follow-up HCT was checked after 4 hours. If the HCT was < 30%, a second aliquot of 10 mL/kg was given. If the HCT was between 30% and 35%, an additional 5 mL/kg was given. |
Kivivuori 1999 | The Hct values were maintained at > 30% by red blood cell
transfusions (10 ml/kg per time) in symptomless infants. In infants who
had symptoms or signs of anaemia, red blood cells were transfused if the
haematocrit value was < 40%. The transfusion policies were the same in
all study hospitals. |
Kumar 1998 | The need for erythrocyte transfusion was assessed by the clinicians caring for each infant and the decision to transfuse was made without consulting the study investigators. According to the practice in the neonatal intensive care unit, infants received transfusion if a Hct level of < 27% was associated with one of the following signs and symptoms of anemia: 1) frequent apnea and bradycardia, defined as > 6 episodes in 12 hours or any episode requiring bag and mask ventilation, in an infant with therapeutic serum levels of theophylline; 2) persistent tachycardia, defined as > 180 beats/min for more than 12 hours; 3) poor weight gain (< 10 g/day averaged over a 7-day period) despite adequate caloric intake; and 4) increasing oxygen requirement in infants with chronic lung disease despite optimum diuretic and bronchodilator therapy. |
Maier 2002 | Infants with artificial ventilation or in > 40% of inspired oxygen
were not transfused unless Hct dropped to < 40%. Spontaneously
breathing infants were not transfused unless Hct dropped to < 35%
during the first 2 weeks of life, 30% during the 3rd to 4th weeks, and
0.25 thereafter. Transfusion was allowed when life threatening anemia or
hypovolaemia was assumed by the treating neonatologist, or surgery was
planned. Twelve of the 14 centers used satellite packs of the original red
cell pack to reduce donor exposure. |
Meyer 1994 | The need for blood transfusion was assessed by the attending neonatal physician and decisions were made independently of the investigators. The following guidelines were developed, based on existing literature and nursery practices: a. Hct < 30% and 1) Weight gain of < 10 g/day averaged over 1-week period (infant tolerating full oral feeds and receiving adequate calories). 2) Three or more episodes of apnea (respirations absent for 20 seconds) or bradycardia (heart rate of < 100 beats per minute) in a 24 hour period not due to other causes and not responsive to methylxanthine treatment. 3) Tachycardia (> 170 beats/min) or tachypnoea (> 70 breaths/min) sustained over a 24 hour period or associated with acute cardiac decompression. 4) Requirement for surgery. a. Development of a clinically significant patent ductus arteriosus (i.e. at least three of the following features: heart rate > 160 beats/min, brisk brachial and/or dorsalis pedis pulses, palpable precordial pulsation, systolic murmur, cardiomegaly on chest radiograph). b. Pulmonary disease and fractional inspired oxygen concentrations increasing by > 10% per week. d. Systemic infection (either clinically suspected or proven on blood culture) associated with a sudden decrease in Hct. </= 22 % or and an absolute reticulocyte count of < 100 000/microlitre. |
Pollak 2001 | Standard NICU transfusion criteria were used (authors refer to Shannon 1995; see below). |
Reiter 2005 | Conservative transfusion guidelines were in place and followed. Criteria for RBC transfusion in the acutely ill infant requiring mechanical ventilation or nasal continuous positive airway pressure included: phlebotomy loss of > 15% of blood volume associated with hypotension, or Hct < 30%. Criteria for red blood cell transfusion in the convalescent infant requiring no more than supplemental oxygen included: Hct < 28% with symptomatic anemia (tachycardia, poor somatic growth or metabolic acidosis) or Hct < 20%. |
Rocha 2001 | The decision for blood transfusion within the whole study population was made by the assistant doctor of each newborn, and was based on the following criteria: Hct </= 20%, inadequate weight gain, three or more apnea or bradycardia episodes within 24 hours, presurgical procedure requirement, disease associated with sudden Hct decline, restoration of the blood collected for lab exams, maintenance of Hct up to 30% associated with minimal ventilatory support requirement, and Hct up to 35% when ventilation requirements are greater. The assistant doctor who recommended blood transfusion did not know to which group the patient belonged. |
Ronnestad 1995 | Transfusions were given on the orders of the attending physician if Hb was < 90 g/L or otherwise as necessary according to signs and symptoms. |
Samanci 1996 | The need for packed erythrocyte transfusions was judged by the attending neonatologist. Guidelines for erythrocyte transfusions were developed as follows: 1) Hct of </= 22% and an absolute reticulocyte count of 100 000/microlitre, 2) Hct of </= 30% and a) tachycardia (> 180 beats/min) and tachypnoea (> 70 breaths/min) persisting for 24 hours; or b) three or more episodes of apnea or bradycardia in 24 hours, not due to other causes and not responsive to methylxanthine treatment; or c) average weight gain of < 10 g/day over a 1-week period (infant tolerating full oral feed and receiving adequate calories); or d) undergoing surgery. 3) Systemic infection associated with a sudden decrease in Hct. |
Shannon 1991 | Transfusions were ordered by the clinicians caring for each infant without consulting the investigators. Written guidelines for erythrocyte transfusions were developed for the nursery 1 year before the start of the study. A copy of these guidelines was taped to the bed of each study infant. In general, babies who were otherwise well received transfusions only if they had a Hct < 25% and signs referable to their anemia, such as slowing in rate of growth, persistent severe tachycardia and tachypnoea, or worsening of episodes of apnea and bradycardia. |
Shannon 1992 | See Shannon 1991 above. |
Shannon 1995 | Transfuse infants at Hct </= 20%: a) if asymptomatic with reticulocytes < 100 000/microlitre. Transfuse infants at Hct </= 30%: a) if receiving < 35% supplemental hood oxygen, b) if on CPAP or mechanical ventilation with mean airway pressure < 6 cm water, c) if significant apnea and bradycardia are noted (9 episodes in 12 hours or 2 episodes in 24 hours requiring bag and mask ventilation) while receiving therapeutic doses of methylxanthines, d) if heart rate > 180 beats/min or respiratory rate > 80 breaths /min persists for 24 hours, e) if weight gain < 10 g/day is observed over 4 days while receiving >/= 100 kcal/kg/day, f) if undergoing surgery. Transfuse for Hct </= 35%: a) if receiving > 35% supplemental hood oxygen, b) if intubated on CPAP or mechanical ventilation with mean airway pressure >/= 6-8 cm water. Do not transfuse: a) to replace blood removed for laboratory tests alone, b) for low Hct alone. |
Whitehall 1999 | Guidelines for red-cell transfusions for anemia of prematurity were
based on the existing policy in the nursery, generally adopted by the
neonatologists. They were as follows: I. Transfuse infants at Hb = 80 g/L, (a) If reticulocyte count is < 4% and (b) If receiving supplemental oxygen > 30% or (c) If unexplained recurrent apneas/bradycardias are noted (> 1-2/hour) or (d) If persistent tachycardia (heart rate > 170/min) or tachypnoea (respiratory rate >60/min) is noted or (e) If there is failure to gain weight or successive weight loss on weekly recordings for 3 consecutive weeks. In absence of a clear evidence in the literature justifying red cell transfusions at a Hb of =80 g/L in otherwise asymptomatic neonates who are failing to thrive, it was decided that failure to gain weight or successive weight loss on weekly recordings for 3 consecutive weeks was a fair and substantial clinical indicator of the need to transfuse. II. Transfuse infants at Hb =100 g/L, (a) If receiving supplemental oxygen = 30% and (b) needing intermittent mandatory ventilation or continuous positive airway pressure by nasal prongs for recurrent (> 1-2 per hour), apneas/bradycardias with saturations <90% on the pulse oximeter. III. Transfuse Infants at Hb = 120 g/L, (a) If receiving mechanical ventilatory support with mean airway pressure = 10 cm of water and supplemental oxygen = 30% during the acute phase of illness after birth. |
Yamada 1994 a | Conservative red blood cell transfusion guidelines were followed (details not presented, as we were unable to translate the information). |
Yamada 1994 b | Conservative red blood cell transfusion guidelines were followed (details not presented, as we were unable to translate the information). |
This review is published as a Cochrane review in The
Cochrane Library, Issue 3, 2006 (see http://www.thecochranelibrary.com for
information). Cochrane reviews are regularly updated as new evidence
emerges and in response to feedback. The Cochrane Library should be
consulted for the most recent version of this review. |