A preterm baby on the neonatal intensive care unit develops anaemia of prematurity, requiring a blood transfusion. The parents of the baby are Jehovah's Witnesses and do not believe in blood transfusions. They do agree to allow their baby to have recombinant human erythropoietin (rHuEPO) treatment instead. However, the clinical staff are unsure whether giving coexisting iron supplementation with rHuEPO treatment will further reduce the requirement for transfusion, and if so in what dose and form should the iron supplement be given?
Structured clinical question
In a preterm infant who is receiving rHuEPO therapy [patient], does iron supplementation [intervention] reduce the requirement for blood transfusion [outcome]? If so, what method of administration and dose [intervention] reduces it most successfully [outcome]?
Search strategy
Primary sources: Medline was searched for articles published from 1966 to 2005, Embase from 1996 to 2005, Cinahl from 1982 to 2005, and also the Cochrane Library Controlled Trials Register 1900 to 2005. The search was carried out in May 2005 using the keywords {neonate(s) or infant(s) or newborn(s) or preterm(s)} and {erythropoietin or EPO or rHuEPO or recombinant human erythropoietin} and {an(a)emia or iron deficiency or iron or Fe or ferric compounds or ferrous compounds or ferrous sulphate or ferrous sulfate or ferrous fumarate} and {red cell transfusion}) limit to randomized controlled trials.
We found seven articles, six of which were relevant (table 1).1–6 Jadad score was calculated in all of these.7
Table 1 Is supplementary iron useful when preterm infants are treated with erythropoietin?
| First author, year, country | Patient group | Study type (level of evidence) | Outcome | Key results | Study weaknesses |
|---|---|---|---|---|---|
| Carnielli et al,1 1998, Italy | 63 preterm infants with birth weight ⩽1750 g and gestational age ⩽32 weeks were randomised to three groups: group 1 received 400 IU rHuEPO/kg, 3 times/week and 20 mg/kg/week of IV iron; group 2 received 400 IU rHuEPO/kg, 3 times/week; group 3 control | Individual double‐blind RCT (level 1b) | Number of transfusions | Fewer transfusions with those receiving IV iron | Quality score Jadad scale 3; the data in this study were difficult to interpret as mean data and logarithms of data were reported |
| Fujiu et al,2 2004, Japan | 24 preterm infants with birth weight 750–1499 g, postnatal age 14–28 days and Hb <12 g/dl were randomised to two groups: group 1 received 200 IU rHuEPO/kg twice weekly and 4 mg/kg/day oral iron; group 2 received 200 IU rHuEPO/kg twice weekly | Individual RCT (level 1b) | Number of transfusions | No transfusions given in either group | Quality score Jadad scale 2; methods of randomisation were not well described; the sample size was small, so the significance that could be attached to the findings of the study is uncertain |
| Kivivuori et al,3 1999, Finland | 41 preterm infants with birth weight <1500 g were randomised to three groups: group 1 received 300 IU rHuEPO/kg, 3 times/week and 6 mg/kg/day of oral iron; group 2 received 300 IU rHuEPO/kg, 3 times/week and 12 mg/kg/day of IM iron; group 3 received 12 mg/kg/day of IM iron | Multicentre RCT (level 1b) | Number of transfusions | No statistical difference between groups (p = 0.2) | Quality score Jadad scale 2; randomisation method was not well described |
| Meyer et al,4 1996, South Africa | 42 preterm infants with birth weight <1500 g, gestational age<33 weeks and postnatal age 7–30 days were randomised to two groups: group 1 received 600 IU rHuEPO/kg, 3 times/week and 6 mg/kg/week of IV iron; group 2 received 600 IU rHuEPO/kg, 3 times/week and 12 mg/kg/day of oral iron | Individual RCT (level 1b) | Number of transfusions | No difference between groups, concludes that oral iron is sufficient | Quality score Jadad scale 2; randomisation method was inadequately described |
| Bader et al,5 2001, Israel | 30 preterm infants with birth weight <1750 g, gestational age <34 weeks and postnatal age 3–5 weeks were randomised to two groups: group 1 received 900 µg rHuEPO/kg/week and 8 mg/kg/day of oral iron; group 2 received 900 µg rHuEPO/kg/week and 16 mg/kg/day of oral iron | Multicentre double‐blinded RCT (level 1b) | Number of transfusions | No significant difference between groups, concludes that oral iron is sufficient | Quality score Jadad scale 2; randomisation method was not well described |
| Nazir et al,6 2002, USA | 52 preterm infants with gestational age ⩽32 weeks and postnatal age >7 days were randomised to three groups: group 1 received 1200 IU rHuEPO/kg/week and 6 mg/kg/day of oral iron; group 2 received 1200 IU rHuEPO/kg/week and 12 mg/kg/day of oral iron | Individual double‐blinded RCT (level 1b) | Number of transfusions | No difference between the two groups | Quality score Jadad scale 5 |
Hb, haemoglobin; IM, intramuscular; IV, intravenous; rHuEPO, recombinant erythropoietin; RCT, randomised controlled trial.
Commentary
Anaemia in premature infants is a common problem. Although erythropoietin is not used widely in neonatal practice, there is evidence of its efficacy in reducing the need for transfusion in preterm infants,8 especially if they are not extremely small or sick.9 It is regularly used in situations where blood transfusion is unacceptable. Iron supplementation has been a standard in neonatal care for preterm infants for many years and helps to reduce late anaemia10 if given with vitamins, especially vitamin E.11 However, when stimulating erythropoiesis with rHuEpo to reduce the need for transfusion, iron availability becomes critical. Several studies have investigated rHuEpo efficacy in preterm infants and most of them have used supplementary iron in either the oral or parenteral routes.
The literature on the use of rHuEpo and iron mostly consists of studies on dose variation of rHuEpo rather than variation in the iron supplementation. Our search yielded seven studies, but one12 was excluded owing to poor methodological quality. Two studies by Carnielli et al1 and Fujiu et al2 compared rHuEpo and oral iron supplementation with rHuEpo alone; however, the interpretation of the data is difficult because Carnielli et al1 reported their results only as mean values and logarithms, making statistical analysis difficult. Fujiu et al2 found that no infants in either arm of their study required a blood transfusion. Although this may suggest that there was no difference between the groups, the sample size was small, with only 24 infants in total, and the clinical equivalence could not be shown. In addition, the authors state that losses due to phlebotomy in their study were lower than those in other similar studies. This may be relevant, as one of the most common causes of the anaemia of prematurity is iatrogenic blood loss.
Kivivuori et al3 and Meyer et al4 compared rHuEPO treatment and parenteral iron supplementation with rHuEPO treatment and oral iron supplementation. Combined data from the two studies showed that there was no significant difference between the groups for the number of blood transfusions given (odds ratio (OR) 1.65, 95% confidence interval (CI) 0.41 to 6.64). This seems to suggest that oral iron supplementation is at least sufficient. However, one study used intravenous iron supplementation whereas the other used intramuscular iron supplementation. Differences in absorption of these two different routes may be relevant, but no study has been carried out comparing intravenous with intramuscular iron supplementation.
Bader et al5 and Nazir et al6 compared infants receiving rHuEPO treatment and high‐dose oral iron supplementation with those receiving rHuEPO treatment and low‐dose oral iron supplementation. There was no significant difference between the two groups, when combining data for the two studies, regarding the number of blood transfusions (OR 0.46, 95% CI 0.04 to 5.75).
Preterm infants on special‐care baby units frequently become anaemic and require top‐up blood transfusions. Preterm infants often have low iron stores; this becomes more evident if they do not receive transfusions or iron supplementation. Erythropoietin is used occasionally to stimulate red cell production and prevent anaemia, and the increased erythropoiesis that occurs as a result of rHuEPO treatment will deplete iron stores. The studies currently available do not give an adequate answer to the question as to which is the best mode and dose of iron supplementation with rHuEpo treatment. On the basis of the principle of using the lowest effective dose and the least invasive mode of administration, at present, low‐dose oral iron would seem appropriate for supplementation when rHuEpo is used in preterm infants.
Clinical bottom line
Evidence available to strongly support any specific recommendation for iron supplementation with recombinant erythropoietin treatment in premature infants (grade D) is insufficient.
Low‐dose oral iron supplementation is not inferior to other treatment regimens (grade B).
References
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