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Iron Supplementation in Prematurity: How Much is Too Much?
EDITORIALS
Iron Supplementation in Prematurity: How Much is Too Much?
he body must control cellular iron concentrations within a narrow range to prevent deficiency or toxicity. In prematurity, iron deficiency may critically disrupt normal development, including brain development. At the other extreme, iron overload is problematic due to the relatively poor antioxidant capabilities of premature infants. In prematurity, recognizing iron deficiency or excess is also difficult, due to lack of clinically available indices of deficiency or toxicity. Thus, defining the precise therapeutic target for iron administration in premature infants has been a challenge. In this issue of The Journal, Brække et al1 present work that helps to address the question: How much iron is too much? The authors give relatively high-dose oral iron supplements to stable premature infants and evaluate antioxidant status, as well as oxidative stress. In conjunction with iron, the authors also supplemented vitamin E. As has been practiced in Norway for years,2 the authors treat stable premature infants with 18 mg of ferrous fumarate daily, which can deliver as much as 18 mg/kg of elemental iron to very low birth weight infants. This dose, which is not adjusted for weight, is severalfold higher than the American Academy of Pediatrics recommendation of 2 to 4 mg/kg per day elemental for premature infants3 and 3 to 6 mg/kg per day in premature infants treated with erythropoietin (rhEpo).4 Historically, neonatologists in the United States have used caution when supplementing growing premature infants with iron. In the 1970s, vitamin E– deficient oxidative hemolysis occurred in premature infants fed ironfortified formulas with a high unsaturated fatty acid content.5 Although biochemical deficiency may be seen, clinical vitamin E deficiency is rare in premature infants because of the low polyunsaturated fatty acid content relative to vitamin E content of fortified human milk and current premature infant formulas. On the other extreme, recent changes in clinical practice place premature infants in potential jeopardy for insufficient tissue iron. In 1989, premature infants of birth weight less than 1500 g received between 8 and 10 transfusions before hospital discharge, but they currently receive fewer than 2 transfusions.6-8 Erythrocyte transfusions are rich in iron. Advances in perinatal care that improve infant stability, lower phlebotomy losses, and lower hematocrit
T
rhEpo
Editorials
Recombinant erythropoietin
targets for transfusions have decreased mean erythrocyte transfusion numbers.7,8 Currently it is unclear which premature infants are candidates for rhEpo, but treating with rhEpo may increase the risk for tissue iron depletion. In term infants, iron deficiency anemia in early life may have long-term consequences, including neurocognitive disturbances that remain after therapeutic iron replacement.9 Compared with outcomes after the diagnosis of iron deficiency anemia, early iron supplementation of at-risk term infants may improve long-term neurologic outcome.9 Because of improved outcomes in iron-supplemented, at-risk term infants, the positive and negative consequences of early supplements in at-risk premature infants should be further studied. The strength of the current work by Brække et al1 is the thorough interrogation of high-dose iron supplementation using multiple indices of iron status, measures of oxidative stress, and indicators of antioxidant status. The current work complements earlier work in rhEpo-treated premature infants given oral or intravenous iron.10,11 These studies used sensitive and specific indicators of hydroxyl radicals and found no evidence of oxidative stress.10,11 Similar to the current study, Miller et al12 examined iron therapy in the absence of rhEpo treatment and showed stable blood and urine isoprostanes in premature infants given a sliding-scale ferrous sulfate dose that reached as high as 12 mg/kg per day. Neither Brække et al1 nor Miller et al12 evaluated the prooxidant effects of erythrocyte transfusions, a potential oxidative stress. However, Dani et al13 showed that erythrocyte transfusion neither increased oxidative stress nor impaired antioxidant status despite increased non–transferrin-bound iron levels. There are some limitations to the study. The study is small and short term in nature. Because all infants in this study were fed human milk, it is See related article, p 23 unclear whether findings would be repliReprint requests: Dr Pamela J. Kling, Unicated in infants fed versity of Wisconsin and Meriter Hospital, premature formula. Pediatrics/Division of Neonatology 6 CenAlthough ferrous futer, 202 S Park St, Madison, WI 53715. E-mail: [email protected]. marate is not a univerJ Pediatr 2007;151:3-4 sally available product, 0022-3476/$ - see front matter there are some concluCopyright © 2007 Mosby Inc. All rights sions to be gained from reserved. this study. First, iron 10.1016/j.jpeds.2007.03.041 3
dosage that appears excessive to many in neonatology may not be excessive. Second, because developmental implications favor the strategy of prevention compared with treatment of iron deficiency in at-risk infants, this topic is worthy of further scientific interrogation. Pamela J. Kling, MD University of Wisconsin and Meriter Hospital Pediatrics/Division of Neonatology 6 Center Madison, Wisconsin
REFERENCES 1. Brække K, Bechensteen AG, Blomhoff R, Haaland K, Staff AC. Oxidative stress markers and antioxidant status following oral iron supplementation to very low birth weight infants. J Pediatr 2007;151:23-8. 2. Bechensteen AG, Håga P, Halvorsen S, Whitelaw A, Liestøl K, Lindemann R, et al. Erythropoietin, protein, and iron supplementation and the prevention of anaemia of prematurity. Arch Dis Child 1993;69:19-23. 3. AAP. Iron Deficiency. In: American Academy of Pediatrics, editor. Pediatric Nutrition Handbook. 5th ed. Chicago, IL: American Academy of Pediatrics; 2004. p. 299-312.
4. Siddappa AJM, Rao RB, Wobken JD, Leibold EA, Connor JR, Georgieff MK. Developmental changes in the expression of iron regulatory proteins and iron transport proteins in the perinatal rat brain. J Neurosci Res 2002;68:761-75. 5. Williams ML, Shoot RJ, O’Neal PA, Oski FA. Role of dietary iron and fat on vitamin E deficiency anemia of infancy. N Engl J Med 1975;292:887-90. 6. Strauss RG. Transfusion therapy in neonates. Am J Dis Child 1991;145:904-11. 7. Kling PJ, Sullivan TM, Leftwich ME, Roe DJ. Score for neonatal acute physiology predicts erythrocyte transfusions in premature infants. Arch Dis Pediatr Adolesc Med 1997;151:27-31. 8. Widness JA, Seward VJ, Kromer IJ, Burmeister LF, Bell EF, Strauss RG. Changing patterns of red blood cell transfusion in very low birth weight infants. J Pediatr 1996;129:680-7. 9. Lozoff B, Georgieff MK. Iron deficiency and brain development. Sem Pediatr Neurol 2006;13:158-65. 10. Friel JK, Aziz K, Andrews WL, Serfass RE. Iron absorption and oxidant stress during erythropoietin therapy in very low birth weight premature infants: a cohort study. BMC Pediatrics [serial on the internet]. 2005 Aug; 5 (29): [6p]. Available from: http:// www.biomedcentral.com/1471-2431/5/29. 11. Pollak A, Hayde M, Hayn M, Herkner K, Lombard KA, Lubec G, et al. Effect of intravenous iron supplementation on erythropoiesis in erythropoietin-treated premature infants. Pediatrics 2001;107:78-85. 12. Miller SM, McPherson RJ, Juul SE. Iron sulfate supplementation decreases zinc protoporphyrin to heme ratio in premature infants. J Pediatr 2006;148:44-8. 13. Dani C, Martelli E, Bertini G, Pezzati M, Rossetti M, Buonocore G, et al. Effect of blood transfusions on oxidative stress in preterm infants. Arch Dis Child 2004;89:F408-11.
For Whom The Bell Tolls . . . .
lthough the concept of “family-centered care” is nearly a half a century old, its impact on changing the “hospital culture” is most apparent over the last two decades.1 Listening to and understanding the parental perspective regarding death follow-up meetings is an implementation of family-centered care values within our hospitals and medical practice. Many books and medical journals have reported the emotions and opinions of parents during the days, months, and years after the death of their child.2-5 One of the recurring themes is the parents’ need for information about their children’s hospital care and death. In addition, parents reflect on the quality of communication (verbal and nonverbal) that existed between the family, physicians, nurses, and staff. How do physicians and hospitals facilitate these well-documented parental needs? Are we providing a service that parents find beneficial? An evaluation of a parent’s perspective regarding death follow-up meetings would be desirable to provide insight into our practice methodology to achieve these family-centered goals. In this issue of The Journal, Meert et al6 report a descriptive survey of the parent’s perspective of the desirability, content, and conditions for physician-parent meeting after the death of their child in the ICU. The parental responses were obtained by telephone interview after initial contact by mail. Parental responses were documented on several important issues, including the parent’s desire to
A
4
Editorials
meet with the physician, timing and location of the meeting, and who would attend the meeting. Limitations of the study are 1) a relatively small sample size, 2) the interviews were conducted within a time span of 4 to 15 months after the child’s death, and 3) parental responses were obtained from only English- and Spanish-speaking participants, thus potentially limiting data concerning cultural variation. Despite these limitations, valuable insights are provided about parents’ perspectives of medical practice after the death of patients, and these insights should encourage us to examine our death follow-up meeting practices. Not surprisingly, 59% of parents See related article, p 50 desired to meet with the child’s intensive Reprint requests: Michael W. Crossman, care physician at some MD, PhD, Division of Neonatology, Cincinpoint. Unfortunately, nati Children’s Hospital Research Foundation, Department of Pediatrics, University only 13% of parents of Cincinnati College of Medicine, 3333 had a scheduled meetBurnet Avenue, ML 7009, Cincinnati, OH ing with any physician 45229. E-mail: Michael.crossman@cchmc. org. to discuss their child’s J Pediatr 2007;151:4-5 death; 82% of the par0022-3476/$ - see front matter ticipants were willing Copyright © 2007 Mosby Inc. All rights to return to the hosreserved. pital for a scheduled 10.1016/j.jpeds.2007.04.038 The Journal of Pediatrics • July 2007
Iron Supplementation in Prematurity: How Much is Too Much?
he body must control cellular iron concentrations within a narrow range to prevent deficiency or toxicity. In prematurity, iron deficiency may critically disrupt normal development, including brain development. At the other extreme, iron overload is problematic due to the relatively poor antioxidant capabilities of premature infants. In prematurity, recognizing iron deficiency or excess is also difficult, due to lack of clinically available indices of deficiency or toxicity. Thus, defining the precise therapeutic target for iron administration in premature infants has been a challenge. In this issue of The Journal, Brække et al1 present work that helps to address the question: How much iron is too much? The authors give relatively high-dose oral iron supplements to stable premature infants and evaluate antioxidant status, as well as oxidative stress. In conjunction with iron, the authors also supplemented vitamin E. As has been practiced in Norway for years,2 the authors treat stable premature infants with 18 mg of ferrous fumarate daily, which can deliver as much as 18 mg/kg of elemental iron to very low birth weight infants. This dose, which is not adjusted for weight, is severalfold higher than the American Academy of Pediatrics recommendation of 2 to 4 mg/kg per day elemental for premature infants3 and 3 to 6 mg/kg per day in premature infants treated with erythropoietin (rhEpo).4 Historically, neonatologists in the United States have used caution when supplementing growing premature infants with iron. In the 1970s, vitamin E– deficient oxidative hemolysis occurred in premature infants fed ironfortified formulas with a high unsaturated fatty acid content.5 Although biochemical deficiency may be seen, clinical vitamin E deficiency is rare in premature infants because of the low polyunsaturated fatty acid content relative to vitamin E content of fortified human milk and current premature infant formulas. On the other extreme, recent changes in clinical practice place premature infants in potential jeopardy for insufficient tissue iron. In 1989, premature infants of birth weight less than 1500 g received between 8 and 10 transfusions before hospital discharge, but they currently receive fewer than 2 transfusions.6-8 Erythrocyte transfusions are rich in iron. Advances in perinatal care that improve infant stability, lower phlebotomy losses, and lower hematocrit
T
rhEpo
Editorials
Recombinant erythropoietin
targets for transfusions have decreased mean erythrocyte transfusion numbers.7,8 Currently it is unclear which premature infants are candidates for rhEpo, but treating with rhEpo may increase the risk for tissue iron depletion. In term infants, iron deficiency anemia in early life may have long-term consequences, including neurocognitive disturbances that remain after therapeutic iron replacement.9 Compared with outcomes after the diagnosis of iron deficiency anemia, early iron supplementation of at-risk term infants may improve long-term neurologic outcome.9 Because of improved outcomes in iron-supplemented, at-risk term infants, the positive and negative consequences of early supplements in at-risk premature infants should be further studied. The strength of the current work by Brække et al1 is the thorough interrogation of high-dose iron supplementation using multiple indices of iron status, measures of oxidative stress, and indicators of antioxidant status. The current work complements earlier work in rhEpo-treated premature infants given oral or intravenous iron.10,11 These studies used sensitive and specific indicators of hydroxyl radicals and found no evidence of oxidative stress.10,11 Similar to the current study, Miller et al12 examined iron therapy in the absence of rhEpo treatment and showed stable blood and urine isoprostanes in premature infants given a sliding-scale ferrous sulfate dose that reached as high as 12 mg/kg per day. Neither Brække et al1 nor Miller et al12 evaluated the prooxidant effects of erythrocyte transfusions, a potential oxidative stress. However, Dani et al13 showed that erythrocyte transfusion neither increased oxidative stress nor impaired antioxidant status despite increased non–transferrin-bound iron levels. There are some limitations to the study. The study is small and short term in nature. Because all infants in this study were fed human milk, it is See related article, p 23 unclear whether findings would be repliReprint requests: Dr Pamela J. Kling, Unicated in infants fed versity of Wisconsin and Meriter Hospital, premature formula. Pediatrics/Division of Neonatology 6 CenAlthough ferrous futer, 202 S Park St, Madison, WI 53715. E-mail: [email protected]. marate is not a univerJ Pediatr 2007;151:3-4 sally available product, 0022-3476/$ - see front matter there are some concluCopyright © 2007 Mosby Inc. All rights sions to be gained from reserved. this study. First, iron 10.1016/j.jpeds.2007.03.041 3
dosage that appears excessive to many in neonatology may not be excessive. Second, because developmental implications favor the strategy of prevention compared with treatment of iron deficiency in at-risk infants, this topic is worthy of further scientific interrogation. Pamela J. Kling, MD University of Wisconsin and Meriter Hospital Pediatrics/Division of Neonatology 6 Center Madison, Wisconsin
REFERENCES 1. Brække K, Bechensteen AG, Blomhoff R, Haaland K, Staff AC. Oxidative stress markers and antioxidant status following oral iron supplementation to very low birth weight infants. J Pediatr 2007;151:23-8. 2. Bechensteen AG, Håga P, Halvorsen S, Whitelaw A, Liestøl K, Lindemann R, et al. Erythropoietin, protein, and iron supplementation and the prevention of anaemia of prematurity. Arch Dis Child 1993;69:19-23. 3. AAP. Iron Deficiency. In: American Academy of Pediatrics, editor. Pediatric Nutrition Handbook. 5th ed. Chicago, IL: American Academy of Pediatrics; 2004. p. 299-312.
4. Siddappa AJM, Rao RB, Wobken JD, Leibold EA, Connor JR, Georgieff MK. Developmental changes in the expression of iron regulatory proteins and iron transport proteins in the perinatal rat brain. J Neurosci Res 2002;68:761-75. 5. Williams ML, Shoot RJ, O’Neal PA, Oski FA. Role of dietary iron and fat on vitamin E deficiency anemia of infancy. N Engl J Med 1975;292:887-90. 6. Strauss RG. Transfusion therapy in neonates. Am J Dis Child 1991;145:904-11. 7. Kling PJ, Sullivan TM, Leftwich ME, Roe DJ. Score for neonatal acute physiology predicts erythrocyte transfusions in premature infants. Arch Dis Pediatr Adolesc Med 1997;151:27-31. 8. Widness JA, Seward VJ, Kromer IJ, Burmeister LF, Bell EF, Strauss RG. Changing patterns of red blood cell transfusion in very low birth weight infants. J Pediatr 1996;129:680-7. 9. Lozoff B, Georgieff MK. Iron deficiency and brain development. Sem Pediatr Neurol 2006;13:158-65. 10. Friel JK, Aziz K, Andrews WL, Serfass RE. Iron absorption and oxidant stress during erythropoietin therapy in very low birth weight premature infants: a cohort study. BMC Pediatrics [serial on the internet]. 2005 Aug; 5 (29): [6p]. Available from: http:// www.biomedcentral.com/1471-2431/5/29. 11. Pollak A, Hayde M, Hayn M, Herkner K, Lombard KA, Lubec G, et al. Effect of intravenous iron supplementation on erythropoiesis in erythropoietin-treated premature infants. Pediatrics 2001;107:78-85. 12. Miller SM, McPherson RJ, Juul SE. Iron sulfate supplementation decreases zinc protoporphyrin to heme ratio in premature infants. J Pediatr 2006;148:44-8. 13. Dani C, Martelli E, Bertini G, Pezzati M, Rossetti M, Buonocore G, et al. Effect of blood transfusions on oxidative stress in preterm infants. Arch Dis Child 2004;89:F408-11.
For Whom The Bell Tolls . . . .
lthough the concept of “family-centered care” is nearly a half a century old, its impact on changing the “hospital culture” is most apparent over the last two decades.1 Listening to and understanding the parental perspective regarding death follow-up meetings is an implementation of family-centered care values within our hospitals and medical practice. Many books and medical journals have reported the emotions and opinions of parents during the days, months, and years after the death of their child.2-5 One of the recurring themes is the parents’ need for information about their children’s hospital care and death. In addition, parents reflect on the quality of communication (verbal and nonverbal) that existed between the family, physicians, nurses, and staff. How do physicians and hospitals facilitate these well-documented parental needs? Are we providing a service that parents find beneficial? An evaluation of a parent’s perspective regarding death follow-up meetings would be desirable to provide insight into our practice methodology to achieve these family-centered goals. In this issue of The Journal, Meert et al6 report a descriptive survey of the parent’s perspective of the desirability, content, and conditions for physician-parent meeting after the death of their child in the ICU. The parental responses were obtained by telephone interview after initial contact by mail. Parental responses were documented on several important issues, including the parent’s desire to
A
4
Editorials
meet with the physician, timing and location of the meeting, and who would attend the meeting. Limitations of the study are 1) a relatively small sample size, 2) the interviews were conducted within a time span of 4 to 15 months after the child’s death, and 3) parental responses were obtained from only English- and Spanish-speaking participants, thus potentially limiting data concerning cultural variation. Despite these limitations, valuable insights are provided about parents’ perspectives of medical practice after the death of patients, and these insights should encourage us to examine our death follow-up meeting practices. Not surprisingly, 59% of parents See related article, p 50 desired to meet with the child’s intensive Reprint requests: Michael W. Crossman, care physician at some MD, PhD, Division of Neonatology, Cincinpoint. Unfortunately, nati Children’s Hospital Research Foundation, Department of Pediatrics, University only 13% of parents of Cincinnati College of Medicine, 3333 had a scheduled meetBurnet Avenue, ML 7009, Cincinnati, OH ing with any physician 45229. E-mail: Michael.crossman@cchmc. org. to discuss their child’s J Pediatr 2007;151:4-5 death; 82% of the par0022-3476/$ - see front matter ticipants were willing Copyright © 2007 Mosby Inc. All rights to return to the hosreserved. pital for a scheduled 10.1016/j.jpeds.2007.04.038 The Journal of Pediatrics • July 2007