THE JOURNAL OF PEDIATRICS
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www.jpeds.com
cooling for encephalopathy (DANCE): a safety and pharmacokinetic trial. Pediatr Res 2015. in press. Ohls RK, Kamath-Rayne BD, Christensen RD, Wiedmeier SE, Rosenberg A, Fuller JA, et al. Cognitive outcomes of preterm infants randomized to darbepoetin, erythropoietin or placebo. Pediatrics 2014;133:1023-30. McAdams RM, McPherson RJ, Mayock DE, Juul SE. Outcomes of extremely low birth weight infants given early high-dose erythropoietin. J Perinatol 2013;33:226-30. Rogers EE, Bonifacio SL, Glass HC, Juul SE, Chang T, Mayock DE, et al. Erythropoietin and hypothermia for hypoxic-ischemic encephalopathy. Pediatr Neurol 2014;51:657-62. Fauchere JC, Koller B, Tschopp A, Dame C, Ruegger CM, Bucher HU, et al. Safety of early high-dose recombinant erythropoietin for neuroprotection in very preterm infants. J Pediatr 2015;167:52-7. Leuchter RH, Gui L, Poncet A, Hagmann C, Lodygensky GA, Martin E, et al. Association between early administration of high-dose erythropoietin in preterm infants and brain MRI abnormality at term-equivalent age. JAMA 2014;312:817-24. Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2006;3:CD004863.
Vol. 167, No. 1 13. Aher S, Ohlsson A. Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2006;3:CD004868. 14. Romagnoli C, Zecca E, Gallini F, Girlando P, Zuppa AA. Do recombinant human erythropoietin and iron supplementation increase the risk of retinopathy of prematurity? Eur J Pediatr 2000;159:627-8. 15. Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2014;4:CD004863. 16. Aher S, Ohlsson A. Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2014;4:CD004868. 17. Costa S, Romagnoli C, Suppa AA, Cota F, Scorrano A, Gallini F, et al. How to administer erythropoietin, intravenous or subcutaneous? Acta Paediatr 2013;102:579-83. 18. Henry E, Christensen RD, Sheffield MJ, Eggert LD, Carroll PD, Minton SD, et al. Why do four NICUs using identical RBC transfusion guidelines have different gestational age-adjusted RBC transfusion rates? J Perinatol 2015;35:132-6. 19. Christensen RD, Carroll PD, Josephson CD. Evidence-based advances in transfusion practice in neonatal intensive care units. Neonatology 2014; 106:245-53.
Developing Indigenous Therapeutic Calcium Supplementation for Treating Nutritional Rickets
N
utritional rickets is a significant global childhood role for calcium deficiency as cause of rickets in these areas. health problem. It has been described in at least 59 Therapeutic vitamin D is traditionally given with calcium countries in the last 20 years1 with prevalence rates supplements for treatment of rickets. Therefore, in these ranging from 10%-70%, being more prevalent in developing areas, vitamin D administration (for presumably VDD countries than in developed nations.2 rickets) would have also corrected any underlying calcium Nutritional rickets, the most common deficiency. This may perhaps be an imporSee related article, p 148 form of rickets, result from either vitamin tant reason for underdetection of calcium D or calcium deficiency.2 Differentiation between these two deficiency rickets globally, though it is reported from forms is subtle and may not be feasible most of the time. certain geographical regions including Ireland, the Vitamin D deficiency (VDD) rickets generally manifests early Netherlands, Belgium, Columbia, developing Asian counduring infancy, whereas rickets attributable to calcium defitries like India, Bangladesh, Mongolia, and certain African ciency often presents at around 3-5 years of life,1 and may countries.1 not manifest with all classic clinical signs seen in cases with Chronic calcium deficiency may result from dietary inadVDD.2 Children in the latter group may have near normal equacy in areas where cereals are major constituent of diet coupled with lack of dairy products.3 Cereal rich diets serum 25 hydroxy vitamin D (S.25OHD) levels but similar 2 radiologic abnormalities as in children with VDD rickets. contain phytates, an inhibitor of calcium absorption, and have been proposed as a cause of decreased calcium VDD was reported as a far more common cause of nutribioavailability.2 Nutritional deficiency of calcium has been tional rickets globally, which paved the way for the recommendations on sunlight exposure and food fortification reported widely. The daily dietary intake of calcium in with vitamin D.3 Subsequent to the thrust on VDD, nutriNigerian children was documented as about 200 mg, which was significantly below the recommended intake of 700 to tional rickets was almost eradicated from many countries 1000 mg for children between 1 and 8 years of age.6 Similar of North America and northern Europe by the 20th century. It was confined to exclusively breastfed African American inintakes have been reported from India7,8 and South Africa.9 fants or in the children of recent immigrants from India, In addition, there could be diverse microbial populations in Pakistan, Bangladesh, North Africa, and the Middle East.4 gut flora of children, commonly seen in children with recurrent intestinal infections, which act differently to Recently, a high prevalence of rickets has been reported sequester calcium away from the sites of absorption, thus in children residing in the areas with ample sunlight exposure with normal S.25OHD levels.5 This suggests a probable S.25OHD VDD
Serum 25 hydroxy vitamin D Vitamin D deficiency
The authors declare no conflicts of interest. 0022-3476//$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.04.012
12
July 2015 manifesting as calcium deficiency rickets in a subset.10 Calcium deficiency has also been attributed to loss of nutrients in the soil through intensive agriculture or flooding, or toxic effects of industrial environmental contaminants such as arsenic, organophosphates, and lead in these regions.2 The treatment of calcium deficiency is simply calcium supplementation, which may suffice without vitamin D. This would be a more economical and feasible option, especially for developing countries, knowing the higher costs of vitamin D supplements. In this issue of The Journal, Thacher et al have evaluated the therapeutic role of indigenous calcium formulations in management of calcium deficiency rickets.11 In the present study, a total of 96 children were randomized to receive powdered limestone (920 mg elemental Ca) or ground fish (952 mg elemental Ca) daily for 24 weeks. At the end of 24 weeks, the authors found comparable improvement in serum calcium, S.25OHD, radiologic healing, and bone mineral density between both groups, implying similar efficacy of both regimens.11 Calcium has been used successfully for the treatment of nutritional rickets earlier by the same author group. In a comparative trial on 123 Nigerian children, supplementation of calcium with or without vitamin D was found to be superior to vitamin D alone in the treatment of rickets.12 The calcium doses used were 3000 to 1000 mg of elemental calcium per day, administered over 3 to 6 months.12,13 As highlighted by the authors, this mode of calcium dispensing was costly and unaffordable for most Nigerian families.11 There is a plentiful and inexpensive supply of natural calcium sources available like ground fish or limestone in Nigeria. These sources would thus prove to be an inexpensive, sustainable, and culturally acceptable option for calcium supplementation. The cost of ground fish was approximately US$ 1-2 per month, whereas the cost of limestone treatment of 6 months was approximate US$ 0.08, in sharp contrast to the high cost of calcium supplements (US$ 190 for a 6-month course). In a preliminary work conducted by the authors, supplemental calcium intake of 400 mg per day, given as calcium tablets or powdered ground fish (10 g per day), was found to be effective in treating rickets. Incidence of rickets and serum calcium were found to be comparable between the 2 groups over an 18-month follow-up period.14 Hansen et al had reported similar calcium absorption from small Bengali fish compared with a milk meal.15 Limestone was also found to be an effective and inexpensive therapeutic option for rickets when evaluated in a randomized controlled trial on 72 Nigerian children with calcium deficiency rickets. The S.25OHD improved with calcium carbonate used as powdered limestone, independent of baseline S.25OHD levels.16 In the present study, Thacher et al also showed comparable improvement in serum vitamin D with both agents, without additional vitamin D administration.11 As postulated, low calcium intake may increase vitamin D catabolism, thus
EDITORIALS increasing vitamin D requirement to maintain a normal circulating concentration of S.25OHD.4 It also results in high circulating 1,25 di-hydroxy vitamin D levels reflecting compensatory hyperparathyroidism to maximize intestinal calcium absorption at the cost of phosphorus retention, which further impairs bone mineralization.17 Nutritional rehabilitation improved fractional calcium absorption in Nigerian children with rickets, suggesting an inhibitory effect of active rickets on calcium absorption, which improved with a rapid catch-up in bone growth.13,18 However, the present study does have certain drawbacks. The study design lacks randomization. The percentage of children who achieved the primary outcome of a radiographic score of
7.
8.
9.
10.
11.
12.
www.jpeds.com
cooling for encephalopathy (DANCE): a safety and pharmacokinetic trial. Pediatr Res 2015. in press. Ohls RK, Kamath-Rayne BD, Christensen RD, Wiedmeier SE, Rosenberg A, Fuller JA, et al. Cognitive outcomes of preterm infants randomized to darbepoetin, erythropoietin or placebo. Pediatrics 2014;133:1023-30. McAdams RM, McPherson RJ, Mayock DE, Juul SE. Outcomes of extremely low birth weight infants given early high-dose erythropoietin. J Perinatol 2013;33:226-30. Rogers EE, Bonifacio SL, Glass HC, Juul SE, Chang T, Mayock DE, et al. Erythropoietin and hypothermia for hypoxic-ischemic encephalopathy. Pediatr Neurol 2014;51:657-62. Fauchere JC, Koller B, Tschopp A, Dame C, Ruegger CM, Bucher HU, et al. Safety of early high-dose recombinant erythropoietin for neuroprotection in very preterm infants. J Pediatr 2015;167:52-7. Leuchter RH, Gui L, Poncet A, Hagmann C, Lodygensky GA, Martin E, et al. Association between early administration of high-dose erythropoietin in preterm infants and brain MRI abnormality at term-equivalent age. JAMA 2014;312:817-24. Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2006;3:CD004863.
Vol. 167, No. 1 13. Aher S, Ohlsson A. Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2006;3:CD004868. 14. Romagnoli C, Zecca E, Gallini F, Girlando P, Zuppa AA. Do recombinant human erythropoietin and iron supplementation increase the risk of retinopathy of prematurity? Eur J Pediatr 2000;159:627-8. 15. Ohlsson A, Aher SM. Early erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2014;4:CD004863. 16. Aher S, Ohlsson A. Late erythropoietin for preventing red blood cell transfusion in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2014;4:CD004868. 17. Costa S, Romagnoli C, Suppa AA, Cota F, Scorrano A, Gallini F, et al. How to administer erythropoietin, intravenous or subcutaneous? Acta Paediatr 2013;102:579-83. 18. Henry E, Christensen RD, Sheffield MJ, Eggert LD, Carroll PD, Minton SD, et al. Why do four NICUs using identical RBC transfusion guidelines have different gestational age-adjusted RBC transfusion rates? J Perinatol 2015;35:132-6. 19. Christensen RD, Carroll PD, Josephson CD. Evidence-based advances in transfusion practice in neonatal intensive care units. Neonatology 2014; 106:245-53.
Developing Indigenous Therapeutic Calcium Supplementation for Treating Nutritional Rickets
N
utritional rickets is a significant global childhood role for calcium deficiency as cause of rickets in these areas. health problem. It has been described in at least 59 Therapeutic vitamin D is traditionally given with calcium countries in the last 20 years1 with prevalence rates supplements for treatment of rickets. Therefore, in these ranging from 10%-70%, being more prevalent in developing areas, vitamin D administration (for presumably VDD countries than in developed nations.2 rickets) would have also corrected any underlying calcium Nutritional rickets, the most common deficiency. This may perhaps be an imporSee related article, p 148 form of rickets, result from either vitamin tant reason for underdetection of calcium D or calcium deficiency.2 Differentiation between these two deficiency rickets globally, though it is reported from forms is subtle and may not be feasible most of the time. certain geographical regions including Ireland, the Vitamin D deficiency (VDD) rickets generally manifests early Netherlands, Belgium, Columbia, developing Asian counduring infancy, whereas rickets attributable to calcium defitries like India, Bangladesh, Mongolia, and certain African ciency often presents at around 3-5 years of life,1 and may countries.1 not manifest with all classic clinical signs seen in cases with Chronic calcium deficiency may result from dietary inadVDD.2 Children in the latter group may have near normal equacy in areas where cereals are major constituent of diet coupled with lack of dairy products.3 Cereal rich diets serum 25 hydroxy vitamin D (S.25OHD) levels but similar 2 radiologic abnormalities as in children with VDD rickets. contain phytates, an inhibitor of calcium absorption, and have been proposed as a cause of decreased calcium VDD was reported as a far more common cause of nutribioavailability.2 Nutritional deficiency of calcium has been tional rickets globally, which paved the way for the recommendations on sunlight exposure and food fortification reported widely. The daily dietary intake of calcium in with vitamin D.3 Subsequent to the thrust on VDD, nutriNigerian children was documented as about 200 mg, which was significantly below the recommended intake of 700 to tional rickets was almost eradicated from many countries 1000 mg for children between 1 and 8 years of age.6 Similar of North America and northern Europe by the 20th century. It was confined to exclusively breastfed African American inintakes have been reported from India7,8 and South Africa.9 fants or in the children of recent immigrants from India, In addition, there could be diverse microbial populations in Pakistan, Bangladesh, North Africa, and the Middle East.4 gut flora of children, commonly seen in children with recurrent intestinal infections, which act differently to Recently, a high prevalence of rickets has been reported sequester calcium away from the sites of absorption, thus in children residing in the areas with ample sunlight exposure with normal S.25OHD levels.5 This suggests a probable S.25OHD VDD
Serum 25 hydroxy vitamin D Vitamin D deficiency
The authors declare no conflicts of interest. 0022-3476//$ - see front matter. Copyright ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2015.04.012
12
July 2015 manifesting as calcium deficiency rickets in a subset.10 Calcium deficiency has also been attributed to loss of nutrients in the soil through intensive agriculture or flooding, or toxic effects of industrial environmental contaminants such as arsenic, organophosphates, and lead in these regions.2 The treatment of calcium deficiency is simply calcium supplementation, which may suffice without vitamin D. This would be a more economical and feasible option, especially for developing countries, knowing the higher costs of vitamin D supplements. In this issue of The Journal, Thacher et al have evaluated the therapeutic role of indigenous calcium formulations in management of calcium deficiency rickets.11 In the present study, a total of 96 children were randomized to receive powdered limestone (920 mg elemental Ca) or ground fish (952 mg elemental Ca) daily for 24 weeks. At the end of 24 weeks, the authors found comparable improvement in serum calcium, S.25OHD, radiologic healing, and bone mineral density between both groups, implying similar efficacy of both regimens.11 Calcium has been used successfully for the treatment of nutritional rickets earlier by the same author group. In a comparative trial on 123 Nigerian children, supplementation of calcium with or without vitamin D was found to be superior to vitamin D alone in the treatment of rickets.12 The calcium doses used were 3000 to 1000 mg of elemental calcium per day, administered over 3 to 6 months.12,13 As highlighted by the authors, this mode of calcium dispensing was costly and unaffordable for most Nigerian families.11 There is a plentiful and inexpensive supply of natural calcium sources available like ground fish or limestone in Nigeria. These sources would thus prove to be an inexpensive, sustainable, and culturally acceptable option for calcium supplementation. The cost of ground fish was approximately US$ 1-2 per month, whereas the cost of limestone treatment of 6 months was approximate US$ 0.08, in sharp contrast to the high cost of calcium supplements (US$ 190 for a 6-month course). In a preliminary work conducted by the authors, supplemental calcium intake of 400 mg per day, given as calcium tablets or powdered ground fish (10 g per day), was found to be effective in treating rickets. Incidence of rickets and serum calcium were found to be comparable between the 2 groups over an 18-month follow-up period.14 Hansen et al had reported similar calcium absorption from small Bengali fish compared with a milk meal.15 Limestone was also found to be an effective and inexpensive therapeutic option for rickets when evaluated in a randomized controlled trial on 72 Nigerian children with calcium deficiency rickets. The S.25OHD improved with calcium carbonate used as powdered limestone, independent of baseline S.25OHD levels.16 In the present study, Thacher et al also showed comparable improvement in serum vitamin D with both agents, without additional vitamin D administration.11 As postulated, low calcium intake may increase vitamin D catabolism, thus
EDITORIALS increasing vitamin D requirement to maintain a normal circulating concentration of S.25OHD.4 It also results in high circulating 1,25 di-hydroxy vitamin D levels reflecting compensatory hyperparathyroidism to maximize intestinal calcium absorption at the cost of phosphorus retention, which further impairs bone mineralization.17 Nutritional rehabilitation improved fractional calcium absorption in Nigerian children with rickets, suggesting an inhibitory effect of active rickets on calcium absorption, which improved with a rapid catch-up in bone growth.13,18 However, the present study does have certain drawbacks. The study design lacks randomization. The percentage of children who achieved the primary outcome of a radiographic score of
