EPO and iron effectively stimulate erythropoiesis. Plasma erythropoietin (EPO) levels in neonates are lower than those for older children and adults. Brown and colleagues reported that, between day two and 30 of life, the mean EPO concentration was 10 mIU/ml, as compared to 15 mIU/ml in concurrently studied adults (Brown 1983). A low plasma erythropoietin (EPO) level is a key reason that nadir hematocrit values of preterm infants are lower than those of term infants (Stockman 1986; Dallman 1981). Low plasma EPO levels provide a rationale for use of EPO in the prevention or treatment of anaemia of prematurity. Studies in newborn monkeys and sheep have demonstrated that neonates have a large volume of distribution and more rapid elimination of EPO, necessitating the use of higher doses than required for adults (Ohls 2000). A recent systematic review of EPO administration noted a wide range of doses used, from 90 to 1400 IU/kg/week (Kotto-Kome 2004). Side effects reported in adults include hypertension, bone pain, rash and rarely seizures. Only transient neutropenia has been reported in neonates (Ohls 2000).
The primary goal of EPO therapy is to reduce transfusions. Most transfusions are given during the first three to four weeks of life. The larger or stable preterm infants, who respond best to EPO, receive few transfusions. ELBW infants, who are sick and have the greatest need for RBC transfusions shortly after birth, have not consistently responded to EPO. This suggests that EPO is a more effective erythropoietic stimulator in more mature neonates. ELBW neonates are more likely to need transfusions even if their erythropoiesis is stimulated (Kotto-Kome 2004). In addition, ELBW neonates have a smaller blood volume and the relatively larger phlebotomy volumes that are required during hospital stay often necessitate "early" transfusions. In contrast "late" transfusions are more often given because of anaemia of prematurity (Garcia 2002). Most preterm infants who require blood transfusions will receive their first transfusion in the first two weeks of life (Zipursky 2000). Reducing the number of RBC transfusions reduces the risk of transmission of viral infections and may reduce costs. Frequent RBC transfusions may be associated with retinopathy of prematurity (Hesse 1997) and bronchopulmonary dysplasia.
Preterm infants need iron for erythropoiesis. As neonatal blood volume expands with rapid growth, infants produce large amounts of haemoglobin. Several studies have observed 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 be particularly likely to increase iron demand and the risk of iron deficiency (Genen 2004). Iron supplementation during erythropoietin treatment has been observed to reduce the risk of the development of iron deficiency (Shannon 1995). The range of iron doses used in EPO treated infants is between 1 mg/kg/day to 10 mg/kg/day (Kotto-Kome 2004).
The efficacy of EPO in anaemia of prematurity has recently been systematically reviewed (Vamvakas 2001; Garcia 2002; Kotto-Kome 2004). Vamvakas et al concluded that there is extreme variation in the results, and until this variation is better understood, it is too early to recommend EPO as standard treatment for the anaemia of prematurity (Vamvakas 2001). Garcia et al concluded that administering EPO to VLBW neonates can result in a modest reduction in late erythrocyte transfusions and that this effect is dependent on the dose of EPO used (Garcia 2002) . Kotto-Kome et al concluded that if EPO is begun in the first week of life, a moderate reduction can be expected in the proportion of VLBW neonates transfused. The reduction is less significant for early transfusion than for late transfusion (Kotto-Kome 2004).
Additional studies of EPO in preterm or LBW infants have been published since the reviews noted above, justifying additional reviews. The cutoff of less than eight days of age for early and > 8 days for late treatment with EPO, although somewhat arbitrary, was chosen based on previously published meta-analyses (Garcia 2002; Kotto-Kome 2004).
This review compares early administration of EPO (starting in infants less than eight days of age) versus late administration of EPO (starting > 8 days). The main rationale for this review was to evaluate whether early treatment with EPO in preterm infants is more effective than late treatment to decrease exposure to red blood cell transfusion and the total transfusions required. We performed a systematic review to compare all available studies where EPO was begun during first week of life vs. EPO started after the first week of life to assess the effect on any and total number of erythrocyte transfusions.
Subgroup analyses:
We planned subgroup analyses within this review for
low (< 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO,
and low (< 5 mg/kg/day) and high (> 5 mg/kg/day) doses of
supplemental iron administered by any route.
SECONDARY OUTCOMES:
1. The total volume (ml/kg or ml/kg/day) of red blood cells transfused per
infant
2. Number of transfusions per infant
3. Number of donors to whom
the infant was exposed
4. Mortality during initial hospital stay (all
causes)
5. Retinopathy of prematurity (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
severe IVH (grades III and IV)
9. Periventricular leukomalacia (PVL); cystic
changes in the periventricular areas
10. Length of hospital stay
11.
Bronchopulmonary dysplasia (BPD) (supplemental oxygen at 28 days of age or at 36
weeks postmenstrual age and compatible X-ray)
12. Sudden infant death after
discharge
13 Long term outcomes assessed at any age beyond one year of age by
a validated cognitive, motor, language, or behavioural/school/social
interaction/adaptation test
14. Neutropenia
15. Any side effects reported
in the trials
Quality of included trials was evaluated independently by the review authors,
using the following criteria:
Blinding of randomisation
Blinding of
intervention
Blinding of outcome measure assessment
Completeness of follow
up
There are three potential answers to these questions yes, no, cannot tell.
The statistical methods included (typical) relative risk (RR), risk
difference (RD), number needed to treat to benefit (NNTB) or number needed to
harm (NNTH) for dichotomous outcomes and mean difference (MD) or weighed mean
difference (WMD) reported with 95% confidence intervals (CI). A fixed effects
model was used for meta-analysis.
Heterogeneity tests including the
I-squared (I2) statistic were performed to assess the appropriateness
of pooling the data.
Donato 2000: This was a blinded multicenter randomized placebo controlled study conducted in seven private hospitals in Buenos Aires, Argentina between July 1996 to October 1997.
Maier 2002: This
was a blinded multicenter randomized placebo controlled study conducted in 14
centres in four European countries (Belgium, France, Germany, Switzerland)
between May 1998 to June 1999. An early EPO, a late EPO and a control group were
studied. The early EPO and late EPO groups were eligible for inclusion in this
review.
Comparison 01: Early (0-7 days) vs. late (8-28 days) initiation of EPO
Outcome 01.01: Use of one or more red blood cell transfusions
Both studies reporting on 262 infants assessed the use of one or more red
blood cell transfusions. Neither found a significant effect. The meta-analysis
did not find a significant effect [typical RR 0.91 (95% CI 0.78, 1.06); typical
RD -0.07 (95% CI -0.18, 0.04)]. This result was consistent across
studies.
SECONDARY OUTCOMES:
Outcome 01.02: The total volume (ml/kg) of red blood cells transfused per infant
Donato et al (Donato
2000) reported on this outcome in 144 infants. They did not find a
significant effect [MD 30 ml/kg (95% CI -13.4, 13.6)].
We obtained
unpublished data from Maier et al. (Maier 2002). They
reported on the volume of red blood cells transfused in ml/kg/day. They did not
find a significant effect [MD -0.80 ml/kg/day (95% CI -1.88, 0.28)].
Outcome 01.03: Number of red blood cell transfusions per infant
Both studies reporting on 262 infants assessed the number of red blood cell transfusions per infant. Neither found a significant effect. The meta-analysis did not find a significant effect [typical WMD -0.32, 95% CI -0.92, 0.29)]. This result was consistent across studies.
Outcome 01.04: Number of donors to whom the infant was exposed
Maier (Maier 2002) reported on this outcome in 148 infants. They did not find a significant effect [MD -0.20; (95% CI -0.67, 0.27)].
Outcome 01.05: Mortality during initial hospital stay (all causes)
Both studies reporting on 262 infants assessed mortality during
initial hospital stay. Neither found a significant effect. The meta-analysis did
not find a significant effect [typical RR 0.76 (95% CI 0.39, 1.51); RD - 0.03,
(95% CI -0.11, 0.05)]. This result was consistent across studies.
Outcome 01.06: Retinopathy of prematurity (all stages)
We obtained unpublished data from both lead authors of the studies included in this review for this outcome. Both studies assessed retinopathy of prematurity in a total of 191 infants. Donato et al reported on the rate of ROP in infants examined during the first year of life. Maier et al reported on the worst stage of ROP during the study. There was a significant increase in the incidence of ROP (all stages) in the study by Donato et al (Donato 2000), but not in the study by Maier et al (Maier 2002). The meta-analysis found a significant effect [typical RR 1.40 (95% CI 1.05, 1.86); typical RD 0.16 (95% CI 0.03 0.29); NNTH; 6 (95% CI 3, 33)].There was statistically significant heterogeneity for this outcome (RR p = 0.007; I2 = 86%; RD p = 0.02; I2 = 81%).
Outcome 01.07: Retinopathy of prematurity (stage > 3)
We obtained unpublished data from both lead authors of the studies included in this review for this outcome. Both studies assessed this outcome in a total of 191 infants. Donato et al reported on the rate of ROP in infants examined during the first year of life. Maier et al reported on the worst stage of ROP during the study. Neither found a significant effect. The meta-analysis did not find a significant effect [typical RR 1.56 (95% CI 0.71, 3.41); typical RD 0.05 (95% CI -0.04, 0.14). This result was consistent across studies.
Proven sepsis (Clinical symptoms and signs of sepsis and positive blood culture) (No outcome table).
No data for this outcome were reported
Outcome 01.08 Necrotizing enterocolitis (NEC) (Bell's stage II or more)
Maier (Maier
2002) reported on this outcome in 148 infants. The study did not find a
significant effect [RR 1.00 (95% CI 0.37, 2.71); RD 0.00 (95% CI -0.09, 0.09)].
Outcome 01.09: Intraventricular haemorrhage (IVH); all grades and
grades III and IV
Both studies (n = 262) reported on the
incidence of IVH grade III and IV. Neither found a significant effect. The
meta-analysis did not find a significant effect [typical RR 1.33 (95% CI 0.84,
2.13); typical RD 0.06 (95% CI -0.04, 0.16)]. The results were consistent across
studies.
Outcome 01.10: Periventricular leukomalacia (PVL); cystic changes in the periventricular areas
Maier (Maier 2002) reported on PVL in 148 infants. The study did not find a significant effect [RR 0.09 (95% CI 0.01, 1.62); RD -0.07 (95% CI -0.13, -0.01)].
Length of hospital stay (No outcome table)
Maier (Maier 2002) reported on the length of hospital stay. The median (quartiles) number of days in hospital was 87 days (73, 107) in the early EPO group and 90 days (68, 110) in the late group. There was no statistically significant difference (p = 0.94) across three groups including a control group (87 days; 69, 108).
Outcome 01.11: Bronchopulmonary dysplasia (BPD) (supplementary oxygen
at 28 days of age or at 36 weeks postmenstrual age and compatible
X-ray)
Maier (Maier 2002) reported on
the need for oxygen at 36 weeks postmenstrual age in 148 infants. The study did
not find a significant effect [RR 0.90 (95% CI 0.53, 1.54); RD -0.03 (95% -0.17,
0.12).
Outcome 01.12: Sudden infant death after
discharge
Donato (Donato 2000) reported
no deaths in either group after a follow-up period of 9 - 24 months after
discharge.
Long term outcomes assessed at any age beyond one year of age by a
validated cognitive, motor, language, or behavioural/school/social
interaction/adaptation test (No outcome table).
No data for these
outcomes were reported.
Neutropenia (No outcome table)
Donato (Donato 2000) reported that the incidence of neutropenia was similar in the two groups, but did not provide any data. Maier (Maier 2002) reported that neutrophil counts did not differ between groups, but did not provide any data.
Any side effects reported in the trials (No outcome table)
Donato (Donato 2000) stated "No clinical adverse effect attributable to EPO, oral iron, or folic acid administration was observed".
Outcome 01.13: Weight gain during the study period (This outcome was
not included in the protocol for this review)
In the study by
Donato (Donato
2000), the MD for weight gain during the entire study period was 6.0 g (95%
CI -137.37, 149.37) comparing the early EPO group to the late EPO group. In the
study by Maier (Maier
2002), the median weight gain was 890 g in the early EPO group and 872 g in
the late EPO group during the first 9 weeks of life. Quartiles were not
provided.
Outcome 01.14: Thrombocytosis (This outcome was not included in the
protocol for this review)
Donato (Donato 2000) reported
on thrombocytosis (platelet count > 500 x 109/L) in 114 infants.
The study did not show a significant effect [RR 1.06 (95% CI 0.61, 1.84); RD
0.02 (95% CI -0.15, 0.19)].
In the study by Maier (Maier 2002) the median increase in platelet count during the study was 118 x 109/L in the early EPO group, 155x109/L in the late EPO group and 186 x 109/L in the control group. A p-value was not reported.
Subgroup analyses
We planned subgroup analyses within this review for low (< 500 IU/kg/week) and high (> 500 IU/kg/week) doses of EPO, and low (< 5 mg/kg/day) and high (> 5 mg/kg/day) doses of supplemental iron administered by any route. However, both included studies used high dose of EPO and high dose of iron, and therefore subgroup analyses were not performed.
Early treatment with EPO did not significantly reduce the risk for an infant of receiving a red blood cell transfusion compared to late treatment. There was no statistically significant heterogeneity for this or any of the other effectiveness outcomes of interest, justifying the combination of the results from the two studies when possible. There was no significant reduction in the number of transfusions per infant nor in the number of donors to whom the infant was exposed.
The results for other secondary outcomes included in this review reached statistical significance only for PVL and ROP. PVL was reported in one study (Maier 2002). There was a statistically significant reduction for RD but not for RR (there was no case of PVL in the early EPO group). We consider this finding of borderline statistical significance.
A total of 191 infants of 268 infants enrolled were assessed for ROP (all stages, and stage > 3). The lack of outcome ascertainment in a large number of infants is of concern. There was a statistically significant increased risk of ROP (any stage reported). The typical RR was 1.45 (95% CI 1.08, 1.95), the typical RD was 0.18 (95% CI 0.05, 0.31) and the NNTH was 6 (95% CI 3 -20). There was statistically significant heterogeneity for this outcome. The heterogeneity is likely at least in part due to differences in the rates of ROP and the different times in the life of the infants when ROP was assessed. There were no striking differences in the dose of EPO or iron used in the two studies. The transfusion guidelines were most strict in the study by Donato et al (Donato 2000). The outcome of ROP (stage > 3) was assessed in the same population as all stages of ROP. The meta-analysis did not find a significant effect [typical RR 1.56 (95% CI 0.71, 3.41); typical RD 0.05 (95% CI -0.04,0.14)]. This result was consistent across studies. The increased risk of ROP is of concern. The results are similar to the Cochrane review of "Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants" (Ohlsson 2006) No other important neonatal adverse outcomes or side effects were noted.
The results of this systematic review should be considered in conjunction with our other two Cochrane reviews that have been conducted "Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants" (Ohlsson 2006) and "Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants" (Aher 2006a). In our review of "Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants" (Ohlsson 2006), we noted an increased risk of ROP. Based on current evidence, an increased risk of developing ROP with early EPO cannot be excluded. For detailed discussion of the potential association with ROP and EPO, please refer to the Cochrane review of "Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants" (Ohlsson 2006).
Other systematic reviews of EPO do not address the issue of early vs. late treatment. The trials included in this review (Donato 2000; Maier 2002) were not included in the meta-analyses by Vamvakas et al (Vamvakas 2001) and Garcia et al (Garcia 2002). Kotto-Kome et al (Kotto-Kome 2004) included both trials in their meta-analysis of the effect of early EPO on early and late erythrocyte transfusions, but did not compare the effectiveness of early vs. late EPO administration. None of these meta-analyses included analyses on the incidence of ROP.
Early treatment with EPO did not confer any major benefits compared to late EPO treatment. The major obstacle to reduce any donor exposure during the hospital stay is that as many as one third of these infants will require a red blood cell transfusion prior to the initiation of treatment with EPO. In the study by Maier et al (Maier 2002), 12 of the 14 centers used satellite packs of the original red cell pack to reduce donor exposure in both groups. The use of satellite packs and conservative transfusion guidelines reduces the exposure to multiple donors during the hospitalization for preterm infants.
It is unlikely that long-acting EPO [Aranesp (Darbepopoietin alfa, Amgen)] would confer any benefits with regards to any donor exposure, but could reduce the number of injections the infant would require (Ohls 2004). To date, only a dose finding trial has been published (Warwood 2005). The authors concluded based on pharmacodynamic and pharmacokinetic findings that darbepoetin dosing in neonates would require a higher unit dose/kg and a shorter dosing interval than are generally used for anemic adults (Warwood 2005).
Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
Donato 2000 | Randomized placebo controlled study I. Blinding of randomization- yes II. Blinding of intervention - yes III. Blinding of outcome-measure assessment - yes IV. Completeness follow-up - no (see notes) |
120 infants with BW < 1250 g and GA < 32 weeks were
included Exclusion criteria were: major congenital malformations, chromosomal anomalies, haemolytic and/or hemorrhagic disease, intrauterine infections, systemic hypertension, neutropenia (no patient was excluded based on the severity of disease) Recruitment period July 1996 to October 1997 7 private hospitals in Buenos Aires, Argentina |
Infants were randomized to two groups: In the early EPO group 57 infants (mean GA 27.7 wk +/- SD 2.4; mean BW 916 +/- SD 217) received rHuEPO (Hemax, Bio Sidus S.A, Buenos Aires, Argentina) [1250 IU/kg/week i.v. (high dose)] starting before 72 hours of life and until day 14 of life. In the late EPO group 57 infants (mean GA 27.9 weeks +/- SD 2.5; mean BW 972 +/- SD 206 received placebo (human seroalbumin) throughout this period. Starting on the third week of life, both groups received rHuEPO 750 IU/kg/week, divided in 3 doses s. c. during 6 weeks. All infants were given oral iron 6mg/kg/day as ferrous sulfate (high dose), starting as soon as enteral feedings were initiated and continuing during the entire treatment period | Use of one or more red blood cell transfusions Mean number of transfusions per infant Mortality during hospital stay Number of transfusions per patient Volume of transfused blood per patient (ml/kg) ROP (during initial study period and during the first year of life) (data obtained from the authors) Weight gain during study period Neutropenia SIDS Adverse effects |
Sample size calculation was performed Transfusion guidelines were followed 6 infants (group not stated) with significant protocol violations were excluded 8 of 57 (14%) of patients in the early EPO group (mean number of transfusions 1.12; range 1-2) and 8 of 57 (14%) patients in the late EPO group (mean number of red blood cell transfusions 1.25; range 1-3) received red blood cell transfusions prior to study entry This study received industry support (Bio Sidus S.A. Laboratory) |
A |
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 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 of rHEPO on Mondays,
Wednesdays and Fridays (NeoRecormon, F. Hofman-La Roche, Basel
Switzerland) (750 IU/week, high dose) starting at days 3-5 of life. In the late EPO group 74 infants received the same treatment 3 weeks later Treatment in both groups continued until days 65 to 68 of life. rHEPO was given 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 3mg/kg was given to all infants from days 3 to 5 (low dose) and was increased at days 12 to 14 to 6 mg/kg/day (high dose) and to 9mg/kg/day at days 24 to 26 of life (high dose), if transferrin saturation was < 30%. At transferrin saturation of 30 to 80%, the iron dose was kept at 6 mg/kg/day. At transferrin saturation > 80%, iron supplementation was interrupted. |
Use of one or more red blood cell transfusions Mortality during hospital stay NEC IVH PVL ROP Days in oxygen Days in NICU Days in hospital |
Sample size calculation was performed Transfusion guidelines were followed 24 (32%) of the infants in the early EPO group and 23 (31%) in the late EPO group received 1 to 3 transfusions before they entered the study. A third group (control group, n =71) was included in this trial. This study (and this group) is included in the Cochrane reviews of early EPO vs. controls and late EPO vs. controls Industry funded (F. Hoffman-La Roche, Basel Switzerland) |
A |
Study | Reason for exclusion |
Rudzinska 2002 | This was a controlled but not randomized study of early vs. late treatment with EPO in preterm infants with birth weights < 1500 g. |
Donato H, Vain N, Rendo P, Vivas N, Prudent L, Larguia M, et al. Effect of early versus late administration of human recombinant erythropoietin on transfusion requirements in premature infants: results of a randomized, placebo-controlled, multicenter trial. Pediatrics 2000;105:1066-72.
Maier 2002 {published and unpublished data}
Maier RF, Obladen M, Muller-Hansen I, Kattner E, Merz U, Arlettaz R, et al. Early treatment with erythropoietin beta ameliorates anemia and reduces transfusion requirements in infants with birth weights below 1000 g. Journal of Pediatrics 2002;141:8-15.
Rudzinska IM, Kornacka MK, Pawluch R. Leczenie preparatami ludzkiej rekombinowanej erytropoetyny a czeztosc retinopatii u noworodkow przedwczesnie urodzonych (Polish) [Treatment with human recombinant erythropoietin and frequency of retinopathy of prematurity]. Prezglad Lekarski 2002;59 Supplement 1:83-5.
* indicates the primary reference for the study
Aher S, Ohlsson A. Late erythropoietin for preventing red blood cell transfusion. In: The Cochrane Database of Systematic Reviews, Issue 3, 2006.
Brown MS, Phibbs RH, Garcia JF, Dallman PR. Postnatal changes in erythropoietin levels in untransfused premature infants. Journal of Pediatrics 1983;103:612-7.
Dallman PR. Anemia of prematurity. Annual Review of Medicine 1981;32:143-60.
Dame C, Juul SE, Christensen RD. The biology of eryhtropoietin in the central nervous system and its neutrophic and neuroprotective potential. Biology of the Neonate 2001;79:228-35.
Finch CA. Erythropoiesis, erythropoietin and iron. Blood 1982;60:1241-6.
Garcia MG, Hutson AD, Christensen RD. Effect of recombinant erythropoietin on "late" transfusions in the neonatal intensive care unit: a meta-analysis. Journal of Perinatology 2002;22:108-11.
Genen 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.
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.
Ohls RK, Dai A. Long-acting erythropoietin: cllinical studies and potential uses in neonates. Clinics in Perinatology 2004;31:77-89.
Ohlsson A, Aher SM. Early 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.
Shannon KM, Keith JF 3rd, Mentzer WC, Ehrenkranz RA, Brown MS, Widness JA et al. Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight infants. Pediatrics 1995;95:1-8.
Stockman 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.
Warwood TL, Ohls RK, Wiedmeier SE, Lambert DK, Jones C, Scoffield SH et al.. Single-dose darbepoetin administration to anemic preterm neonates. Journal of Perinatology 2005;25:725-30.
Widness JA, Sawyer RL, Schmidt RL, Chestnut DH. Lack of maternal to fetal transfer of 125I-labelled erythropoietin in sheep. Journal of Developmental Physiology 1991;15:139-45.
Widness JA, Seward VJ, Kromer IJ, Burmeiser LF, Bell EF. Changing patterns of red blood cell transfusion in very low birth weight infants. Journal of Pediatrics 1996;129:680-7.
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Comparison or outcome | Studies | Participants | Statistical method | Effect size |
---|---|---|---|---|
01 Early (0-7 days) vs. late (8-28 days) initiation of EPO | ||||
01 Use of one or more red blood cell transfusions | 2 | 262 | RR (fixed), 95% CI | 0.91 [0.78, 1.06] |
02 Total volume of red blood cells transfused per infant | WMD (fixed), 95% CI | Subtotals only | ||
03 Number of red blood cell transfusions per infant | 2 | 262 | WMD (fixed), 95% CI | -0.32 [-0.92, 0.29] |
04 Number of donors the infant was exposed to | 1 | 148 | WMD (fixed), 95% CI | -0.20 [-0.67, 0.27] |
05 Mortality during initial hospital stay (all causes) | 2 | 262 | RR (fixed), 95% CI | 0.76 [0.39, 1.51] |
06 Retinopathy of prematurity (all stages) | 2 | 191 | RR (fixed), 95% CI | 1.40 [1.05, 1.86] |
07 Retinopathy of prematurity (stage >/= 3) | 2 | 191 | RR (fixed), 95% CI | 1.56 [0.71, 3.41] |
08 NEC | 1 | 148 | RR (fixed), 95% CI | 1.00 [0.37, 2.71] |
09 IVH | 2 | 262 | RR (fixed), 95% CI | 1.33 [0.84, 2.13] |
10 PVL | 1 | 148 | RR (fixed), 95% CI | 0.09 [0.01, 1.62] |
11 BPD (oxygen at 36 weeks) | 1 | 148 | RR (fixed), 95% CI | 0.90 [0.53, 1.54] |
12 Sudden infant death after discharge | 1 | 114 | RR (fixed), 95% CI | Not estimable |
13 Weight gain (grams) during the study period (from entry to exit from study) | 1 | 114 | WMD (fixed), 95% CI | 6.00 [-137.37, 149.37] |
14 Thrombocytosis (platelet count > 500 x 10 to the 9th /L) | 1 | 114 | RR (fixed), 95% CI | 1.06 [0.61, 1.84] |
01.01 Use of one or more red blood cell transfusions
01.02 Total volume of red blood cells transfused per infant
01.02.01 Total volume of red blood cells transfused (ml/kg)
01.02.02 Total volume of red cells transfused (ml/kg/day)
01.03 Number of red blood cell transfusions per infant
01.04 Number of donors the infant was exposed to
01.05 Mortality during initial hospital stay (all causes)
01.06 Retinopathy of prematurity (all stages)
01.07 Retinopathy of prematurity (stage >/= 3)
01.09.01 Grade III/IV
01.11 BPD (oxygen at 36 weeks)
01.12 Sudden infant death after discharge
01.13 Weight gain (grams) during the study period (from entry to exit from study)
01.14 Thrombocytosis (platelet count > 500 x 10 to the 9th /L)
Reference | Indications |
Donato 2000 | Indications for transfusion followed slightly modified criteria described in a previous study (Shannon 1995). The transfusion criteria were: A) Hct 0.31-0.35; Receiving >35% supplemental hood oxygen; Intubated on CPAP or mechanical ventilation with mean airway pressure >6-8 cm water B) Hct 0.21-0.30; Receiving <35% supplemental hood oxygen; On CPAP or mechanical ventilation with mean airway pressure <6 cm water; Significant apnea and bradycardia (>9 episodes in 12 hours or 2 episodes in 24 hours requiring bag and mask ventilation) while receiving therapeutic doses of methylxanthines; Heart rate >180 beats/min or respiratory rate >80 breaths/min persisting for 24 hours; Weight gain <10 g/day observed over 4 days while receiving >100 kcal/kg/day; Undergoing surgery C) Hct <21%; Asymptomatic with reticulocytes <1% D) Transfuse at any hematocrit value if hypovolemic shock develops E) Do not transfuse: to replace blood removed for laboratory tests; For low Hct alone. Patients were transfused with packed red blood cells at 15 ml/kg, administered in 2-3 hours. |
Maier 2002 | Infants on assisted ventilation or > 40% of inspired oxygen were
not transfused unless Hct dropped below 0.40. Spontaneously breathing
infants were not transfused unless Hct dropped below 0.35 during the first
2 weeks of life, 0.30 during the 3rd to 4th weeks, and 0.25 thereafter.
Transfusion was allowed when life threatening anaemia or hypovolaemia was
diagnosed by the treating neonatologist, or surgery was planned. Twelve of
the 14 centres used satellite packs of the original red cell pack to
reduce donor exposure. The amount of packed red cells transfused was not
reported. |
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 the
review. |