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Three Part Question

In [a preterm infant who is receiving rHuEPO therapy] does [iron supplementation] reduce the requirement for [blood transfusion]? If so, what method of administration and dose reduces it most successfully?

Clinical Scenario

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?

Search Strategy

({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
Medline 1966-2005, Embase 1996-2005, Cinahl 1982-2005. The Cochrane Library Controlled Trials Register. Search done May 2005

Search Outcome

7 articles were found, 6 of which were relevant. The 6 papers are shown in the table. Jadad score was calculated in all of these

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Carnielli et al. 1998 Italy	63 preterm infants with birthweight <= 1750g and gestational age <= 32 weeks were randomized to 3 groups. Group (1) received 400IU rHuEPO/kg 3 times/week and 20mg/kg/week of IV iron Group (2) 400IU 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 3 (Jadad score).The data in this study was difficult to interpret as mean data and logarithms of data were reported
Fujiu et al. 2004 Japan	24 preterm infants with birthweight 750-1499g, postnatal age 14-28 days and Hb<12g/dL were randomized to 2 groups. Group(1) received 200IU rHuEPO/kg twice weekly and 4mg/kg/day oral iron Group (2) 200IU rHuEPO/kg twice weekly	Individual RCT (level 1b)	Number of transfusions	No transfusions given in either group	Quality score 2 (Jadad score).The methods of randomization were not well descibed. The sample size is small, so the significance that can be attached to the findings of the study is uncertain
Kivivuori et al. 1999 Finland	41 preterm infants with birthweight <1500g were randomized to 3 groups. Group(1) received 300IU rHuEPO/kg 3 times/week and 6mg/kg/day of oral iron Group(2) 300IU rHuEPO/kg 3 times/week and 12mg/kg/day of i.m. iron Group (3) 12mg/kg/day of i.m. iron	Multicentre RCT (level 1b)	Number of transfusions	No statistical difference between groups (p=0.2) concludes that oral iron is sufficient	Quality score 2 (Jadad score). Randomisation method was not well described
Meyer et al. 1996 South Africa	42 preterm infants with birthweight<1500g, gestational age<33 weeks and postnatal age 7-30 days were randomized to 2 groups. Group(1) received 600IU rHuEPO/kg 3 times/week and 6mg/kg/week of IV iron Group(2) 600IU rHuEPO/kg 3times/week and 12mg/kg/day of oral iron	Individual RCT (level 1b)	Number of transfusions	No difference between groups - concludes oral iron is sufficient	Quality score 2 (Jadad score). Randomisation method was inadequately described.
Bader et al. 2001 Israel	30 preterm infants with birthweight <1750g, gestational age 34 weeks and postnatal age 3-5 weeks were randomized to 2 groups. Group(1) received 900µg rHuEPO/kg/week and 8mg/kg/day of oral iron Group(2)900µg rHuEPO/kg/week and 16mg/kg/day of oral iron	Multicentre double blinded RCT (level 1b)	Number of transfusions	No significant difference between groups and concludes that oral iron sufficient	Quality score 2 (Jadad score). Randomisation method was not well described.
Nazir et al. 2002 USA	52 preterm infants with gestational age <= 32 weeks and postnatal age>7days were randomized to 3 groups. Group (1) received 1200IU rHuEPO/kg/week and 6mg/kg/day of oral iron Group(2) 1200IU rHuEPO/kg/week and 12mg/kg/day of oral iron	Individual double blinded RCT (level 1b)	Number of transfusions	No difference between the two groups	Quality score 5 (Jadad score)

Comment(s)

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,(Shannon) especially if they are not extremely small or sick.(Soubasi). 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 anaemia (Franz) if given with vitamins, especially vitamin E.(Jansson). 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 one(Pollak) was excluded owing to poor methodological quality. Two studies by Carnielli et al and Fujiu et al compared rHuEpo and oral iron supplementation with rHuEpo alone; however, the interpretation of the data is difficult because Carnielli et al reported their results only as mean values and logarithms, making statistical analysis difficult. Fujiu et al 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 al and Meyer et al 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 al and Nazir et al 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

1. Carnielli VP, Da Riol R, Montini G Iron supplementation enhances response to high doses of recombinant human erythropoietin in preterm infants Archives of Disease in Childhood Fetal and Neonatal Edition 1998; 79: F44-F48
2. Fujiu T, Maruyama K, Koizumi T Oral iron supplementation in preterm infants treated with erythropoietin Pediatrics International 2004; 46 (6): 635-639
3. Kivivuori SM, Virtanen M, Raivio KO et al. Oral iron is sufficient for erythropoietin treatment of very low birth-weight infants European Journal of Pediatrics 1999; 158: 147-151
4. Meyer MP, Haworth C, Meyer JH et al. A comparison of oral and intravenous iron supplementation in preterm infants receiving recombinant erythropoietin Journal of Pediatrics 1996; 129(2): 258-263
5. Bader D, Kugelman A, Maor-Rogin N et al. The Role if High-Dose Oral Iron Supplementation During Erythropoietin Therapy for Anemia of Prematurity Journal of Perinatology 2001; 21: 215-220
6. Nazir S, Peverini RL, Deming DD et al. Comparison of 2 Iron Doses in Infants Receiving Recombinant Human Erythropoeitin Therapy Archives of Pediatrics and Adolescent Medicine 2002; 156: 540-544
7. Jadad AR, Moore RA. Carroll D. et al. Assessing the quality of reports of randomised clinical trials: is blinding necessary? Control Clin Trials 1996;17:1–12.
8. Shannon KM, Keith JF. Mentzer WC. et al. Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birthweight preterm infants. Pediatrics 1995;95:1–8.
9. Soubasi V, Kremenopoulos G, Diamandi E. et al. In which neonates does early recombinant erythropoetin treatment prevent anemia of prematurity? Results of a randomised controlled study. Pediatr Res 1993;34:675–9.
10. Franz AR, Mihatsch WA. Sander S. et al. Prospective randomised trial of early versus late enteral iron supplementation in infants with a birth weight of less than 1301 grams. Pediatrics 2000;106:700–6.
11. Jansson L. Holmberg L. Nilsson B. et al. Vitamin E requirements of preterm infants. Acta Paediatr Scand 1978;67:459–63.
12. 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.