Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 140–151 (DOI: 10.1159/000358463)
Calcium, Phosphorus, Magnesium and Vitamin D Requirements of the Preterm Infant Francis B. Mimouni a, b, d · Dror Mandel a, c, d · Ronit Lubetzky b, d · Thibault Senterre e
Departments of a Neonatology, Shaare Zedek Medical Center, Jerusalem, b Pediatrics and c Neonatology, Dana Dwek Children‘s Hospital and Lis Maternity Hospital, Tel Aviv Medical Center, and d Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; e University of Liège, Department of Neonatology, CHU de Liège, CHR de la Citadelle, Liège, Belgium
Reviewed by Magnus Domellöf, Department of Pediatrics, Umea University, Umea, Sweden; Alison Leaf, National Institute for Health Research, University of Southampton, Southhampton, UK
Abstract
Proper mineral and vitamin D nutrition in preterm infants is essential for adequate bone health. Indeed, preterm infants are at risk of developing osteopenia of prematurity for multiple reasons. Among them: (1) low mineral stores at birth due to reduced gestation (80% of minerals are accreted in bone during the third trimester) [1]; (2) difficulties to rapidly establish adequate enteral nutrient supply [1]; (3) inability to provide an amount of minerals similar to that provided by placental transport during a normal pregnancy using parenteral nutrition [1]; (4) use of medications deleterious to the skeleton such as loop diuretics and corticosteroids [1]; (5) contamination of parenteral nutrition solutions with toxins such as aluminum [1]; (6) immobilization in critically ill
Downloaded by: UCLA Biomedical Library 128.97.90.221 - 4/30/2014 12:08:34 PM
Proper mineral and vitamin D nutrition in preterm infants is essential for adequate bone health because preterm infants are at a risk of prematurely developing osteopenia. This chapter focuses on nutritional aspects of the requirements after a brief description of the perinatal physiology of minerals and vitamin D. The rationale for estimation of nutritional mineral requirements of the preterm infant (based upon estimates of the intrauterine skeletal accretion rate of minerals, and upon estimates of the coefficient of intestinal absorption) is first described. Previous expert recommendations are reviewed and compared to the present recommendations. Finally, vitamin D requirements are thoroughly reviewed based upon what is known of the physiology of vitamin D in preterm infants. A suggestion that each extremely preterm infant should be monitored for adequate vitamin © 2014 S. Karger AG, Basel D status is made.
infants [1], and (7) possibly vitamin D deficiency in some subgroups of preterm infants [2–4]. In this chapter, we will only focus on nutritional aspects of the requirements, after a brief description of the perinatal physiology of minerals and vitamin D.
During the third trimester, the human fetus is exposed to a hormonal milieu particularly prone for ideal bone mineralization [5]. Abundant substrate is provided through active transport of calcium (Ca) against a concentration gradient with relative hypercalcemia leading to decreased bone resorption (due to relatively low parathyroid hormone and low 1,25-dihydroxyvitamin D (1,25(OH)2D)), and increased bone mineralization (due to high calcitonin and possibly also to high 24,25(OH)2D) [5]. During the third trimester, the average accretion rates are 100–120 mg/kg/day for Ca and 50–65 mg/kg/day for phosphorus (P) (up to 150 mg/kg/day for Ca and 75 mg/kg/day for P). Similarly, the term fetus accretes about 760 mg of magnesium (Mg) until birth (on average 3–5 mg/day), just over half of it in bone, and a third in muscles and soft tissues [6]. The intracellular concentration of Mg is about ten times that of the extracellular fluid. Intrauterine accretion rates are extremely difficult to match in an extrauterine environment. Given issues of mineral solubility, there is a limit to how much Ca and P can be introduced in parenteral solution [7]. Human milk, the ideal ‘food’ for human term babies, is probably also the ideal nutrition for preterm babies, if it were only for the improved survival and decreased morbidity such as a reduced incidence of necrotizing enterocolitis [8, 9]. However, reduced growth, and inadequate Ca and in particular P intake are inherent to exclusive human milk feeding, and may lead to a particular form of rickets of prematurity, with severe hypophosphatemia and hypercalcemia [10]. Thus the need to ‘fortify’ human milk with minerals, which efficiently increases linear growth during the in-hospital period [11], with less convincing effects when fortifiers are used after discharge [12]. An alternative to fortified human milk is the administration of formulas designed to meet or approximate the mineral (and the other nutritional) needs of the preterm infant. Nevertheless, one must not assume that all minerals added to formulas or to human milk fortifiers are necessarily absorbed. Indeed, multiple factors regulate mineral intestinal absorption. These include the vitamin D status of the infant, the concentration of Ca and P and their ratio, the concentration and physical properties of major macronutrients such as protein or lactose, the amount and source of fat, and the production process (heat treatment of liquid formulae may promote a Maillard reaction that may decrease Ca absorption [13]). In addition, other elements may theoretically compete with intestinal Ca absorption, such as sodium, zinc, or iron. Thus, ‘more’ mineral intake is not necessarily translated in more mineral accreted, and a high mineral supply has the potential for more soap formation with dietary fat, more fecal Ca, more fat and energy losses, and more con-
Calcium, Phosphorus, Magnesium and Vitamin D Requirements of the Preterm Infant Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 140–151 (DOI: 10.1159/000358463)
141
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Perinatal Mineral Homeostasis
Table 1. Recommendations on the daily intake of Ca, P, Mg and vitamin D for preterm VLBW infants issued by different bodies and authors Intake recommendation
ESPGAN 1987
ESPGHAN 2010
LSRO, 2002
Atkinson Rigo, 2007 and Tsang, 2005
AAP, 2013
Current authors’ proposal, 2013
Ca, mg/kg/day P, mg/kg/day Mg, mg/kg/day Vitamin D, IU/day
70–140 120–140 150–220 120–200 100–160 150–220 120–200 50–90 60–90 100–130 70–120 60–90 75–140 60–140 4.85–9.7 8–15 6.8–17 mg/100 kcal 7.2–9.6 not provided not provided 8–15 800–1,600 800–1,000 90–225 200–1,000 800–1,000 200–400 400–1,000
stipation [14, 15]. Under certain circumstances, high Ca intakes can result in the formation of precipitates with casein and long-chain fatty acids that may lead to intestinal obstruction [16]. The intestinal absorption of Mg is poorly understood. Approximately 40% of ingested Mg is absorbed from formula, mostly in the proximal gut [17], and Mg absorbed and retained from human milk averages 41% of intake in preterm infants, with a range of 17–66% [18]. This coefficient of absorption in preterm infants is affected by the luminal concentration of Mg and its solubility. Ca and Mg do not compete with each other for intestinal absorption in preterm infants, but high phosphate content in formula may decrease intestinal Mg through formation of insoluble complexes [17].
In term infants, the model followed is usually that of human milk. Human milk is adapted to the needs of the human infant, and formulas are for the most part designed in order to mimic either the composition or the functions of human milk. In contrast, it cannot be assumed that human milk, naturally ‘designed’ to fit the extrauterine needs of the term infant, can be used as the ‘perfect’ model for the preterm infant. Indeed, intrauterine and extrauterine growth rates, nutrient accretion, etc., are not identical. Thus, nutritional mineral requirements of the preterm infant have been traditionally estimated upon two major bases: the first one relates to the intrauterine accretion rate of minerals by the skeleton, and the other one relates to the coefficient of absorption of minerals by the preterm intestine. Subsequently, several sets of recommendations have been published by various experts. There are the 1987 ESPGAN recommendations [19], commented upon and revised in 2010 [20], the Life Science Research Office recommendations (LSRO) [21], the Atkinson and Tsang recommendations [22], and the recommendations by Rigo et al. [23, 24] together with recent AAP recommendations [25] (table 1). These recommendations apply to very low birth weight infants until they reach a postmenstrual age of approximately 40 weeks and a birth weight close to normal term birth weight.
142
Mimouni · Mandel · Lubetzky · Senterre Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 140–151 (DOI: 10.1159/000358463)
Downloaded by: UCLA Biomedical Library 128.97.90.221 - 4/30/2014 12:08:34 PM
Enteral Calcium, Phosphorus and Magnesium Requirements
Calcium, Phosphorus, Magnesium and Vitamin D Requirements of the Preterm Infant Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 140–151 (DOI: 10.1159/000358463)
143
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Mineral accretion estimates during pregnancy are essentially all based upon the cornerstones studies of Widdowson et al. [6], who carefully analyzed the body composition of a large number of aborted fetuses at various gestational ages, including the exact mineral composition of their ashes. According to Widdowson’s work, during the last 3 months of gestation the fetal accretion of Ca, P and Mg is about 20 g, 10 g and 700 mg, respectively, which represents accretion rates of approximately 100–120 mg/kg/day for Ca, 50–65 mg/kg/day for P, and 3–5 mg/kg/day for Mg [6]. The assumptions used for intestinal absorption estimates in the above-mentioned recommendations are based upon either older balance studies, or upon studies using stable isotopes of Ca and Mg [26]. Although these studies have allowed improving massively our knowledge on mineral metabolism and balance, they have shown that there is a significant variability of mineral absorption among preterm infants. The coefficient of absorption of Ca ranges grossly between 40 and 70%, that of P between 60 and 95%, and that of Mg approximates 40% [27, 28]. These variations explain most of the differences among the various experts’ recommendations. The lowest estimate of Ca requirements in mg/kg/day is that of ESPGHAN [19] and the highest is by the LSRO [21] and the AAP [25]. Similarly, the lowest estimate of P requirement is by the ESPGHAN [19] and the highest is by AAP [25] (table 1). In view of the fact that most recent data using stable isotopes of Ca are consistent with relatively lower coefficients of absorption of Ca than older data showed, we favor the higher estimates as proposed by Atkinson and Tsang [22]. We suggest that the daily requirements for Ca should be 120–200 mg/kg. The ESPGHAN [20] used an estimate of 90% of coefficient of absorption for P, an optimistic estimate when considering for instance the data of Lapillonne et al. [29] who found coefficients of absorption of 76% in fortified human milk fed preterm infants and 65.3% in those fed a preterm formula. We suggest that the daily requirements of P should cover a wider range than that recommended by ESPGHAN, and be similar to the Atkinson and Tsang proposals (60–140 mg/kg). In human milk, the Ca:P ratio is 2:1 in mass, close to the actual composition of skeletal minerals (2.2: 1) [20]. Thus, it would seem logical that the Ca:P ratio (by weight) be maintained approximately at the level present in human milk, i.e. approximately 2:1. However, it might be more appropriate taking into account P accretion with lean body mass, especially when optimizing preterm infant macronutrient intakes, and a ratio of 1.6:1–1.8:1 has been suggested by Mize et al. [30], based upon careful balance studies. As far as Mg is concerned, it has been calculated that preterm infants fed human milk are provided with an intake of 5.5–7.5 mg/kg/day [22]. ESPGHAN assumed an absorption coefficient of 40%, and calculated a net accretion of 2.2–3 mg/kg/day, i.e. less than the 3–5 mg/kg/day of intrauterine accretion (for a 1-kg baby) [19, 20]. ESPGHAN recommended that infants fed formula be provided with Mg intakes of 8–12 mg/kg/day, because they had a retention rate within the range of intrauterine accretion [31]. Lapillonne et al. [29] found a 37.5% coefficient of absorption for Mg in their balance studies both in fortified human milk-fed preterm infants and in those fed a preterm formula. In contrast, Koo and Tsang [32]
a ssumed that the coefficient of absorption of Mg is 50%, and thus estimated the requirements to be 8 mg/kg/day (0.33 mmol). We consider coefficient of absorption of approximately 40% a more realistic [18, 29] and recommend a daily Mg intake of 8–15 mg/kg, as suggested by ESPGHAN.
Vitamin D Requirements
The issue of vitamin D requirements in preterm infants is complex. Requirements may be theoretically affected by the availability of substrates such as Ca, P, Mg and vitamin D itself. In addition, it is unclear whether all the elements of adequate vitamin D metabolism (including production, absorption, action and degradation) are mature in preterm infants. Thus, circulating values of vitamin D and its metabolites at concentrations that appear to be adequate in term infants may not be adequate in preterm infants.
Vitamin D Production in Skin To our knowledge, no studies have been published evaluating vitamin D production in the skin production in preterm infants exposed to UVB. Preterm infants are generally not exposed to UVB during their stay in the NICU. They also are not likely to not be routinely exposed to UVB after discharge. Indeed, the American Academy of Pediatrics (AAP) recommends to use sunblock in infants >6 months of age (in order to protect them from skin cancer), and to avoid exposure to direct sunlight in infants 100 nmol/l [43]. Importantly, in these infants, urinary Ca/creatinine ratios were not reliable indicators of excessive vitamin D intake [43]. Liver 25-Hydroxylation Although the 25-hydroxylation process has not been directly investigated, many studies have shown adequate 25(OH)D increases after administration of vitamin D in preterm infants [34, 39, 40, 44, 45] which support the concept that both absorption and 25-hydroxylation of vitamin D are adequate.
Action of 1,25(OH2)D Ravid et al. [48] have suggested that in vitro 1,25(OH2)D effect on lymphocytes is blunted as compared to adults. However, in their study there were no differences between lymphocytes obtained from term and those obtained from preterm infants. In an in vivo study, 90 preterm infants
Calcium, Phosphorus, Magnesium and Vitamin D Requirements of the Preterm Infant Francis B. Mimouni a, b, d · Dror Mandel a, c, d · Ronit Lubetzky b, d · Thibault Senterre e
Departments of a Neonatology, Shaare Zedek Medical Center, Jerusalem, b Pediatrics and c Neonatology, Dana Dwek Children‘s Hospital and Lis Maternity Hospital, Tel Aviv Medical Center, and d Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; e University of Liège, Department of Neonatology, CHU de Liège, CHR de la Citadelle, Liège, Belgium
Reviewed by Magnus Domellöf, Department of Pediatrics, Umea University, Umea, Sweden; Alison Leaf, National Institute for Health Research, University of Southampton, Southhampton, UK
Abstract
Proper mineral and vitamin D nutrition in preterm infants is essential for adequate bone health. Indeed, preterm infants are at risk of developing osteopenia of prematurity for multiple reasons. Among them: (1) low mineral stores at birth due to reduced gestation (80% of minerals are accreted in bone during the third trimester) [1]; (2) difficulties to rapidly establish adequate enteral nutrient supply [1]; (3) inability to provide an amount of minerals similar to that provided by placental transport during a normal pregnancy using parenteral nutrition [1]; (4) use of medications deleterious to the skeleton such as loop diuretics and corticosteroids [1]; (5) contamination of parenteral nutrition solutions with toxins such as aluminum [1]; (6) immobilization in critically ill
Downloaded by: UCLA Biomedical Library 128.97.90.221 - 4/30/2014 12:08:34 PM
Proper mineral and vitamin D nutrition in preterm infants is essential for adequate bone health because preterm infants are at a risk of prematurely developing osteopenia. This chapter focuses on nutritional aspects of the requirements after a brief description of the perinatal physiology of minerals and vitamin D. The rationale for estimation of nutritional mineral requirements of the preterm infant (based upon estimates of the intrauterine skeletal accretion rate of minerals, and upon estimates of the coefficient of intestinal absorption) is first described. Previous expert recommendations are reviewed and compared to the present recommendations. Finally, vitamin D requirements are thoroughly reviewed based upon what is known of the physiology of vitamin D in preterm infants. A suggestion that each extremely preterm infant should be monitored for adequate vitamin © 2014 S. Karger AG, Basel D status is made.
infants [1], and (7) possibly vitamin D deficiency in some subgroups of preterm infants [2–4]. In this chapter, we will only focus on nutritional aspects of the requirements, after a brief description of the perinatal physiology of minerals and vitamin D.
During the third trimester, the human fetus is exposed to a hormonal milieu particularly prone for ideal bone mineralization [5]. Abundant substrate is provided through active transport of calcium (Ca) against a concentration gradient with relative hypercalcemia leading to decreased bone resorption (due to relatively low parathyroid hormone and low 1,25-dihydroxyvitamin D (1,25(OH)2D)), and increased bone mineralization (due to high calcitonin and possibly also to high 24,25(OH)2D) [5]. During the third trimester, the average accretion rates are 100–120 mg/kg/day for Ca and 50–65 mg/kg/day for phosphorus (P) (up to 150 mg/kg/day for Ca and 75 mg/kg/day for P). Similarly, the term fetus accretes about 760 mg of magnesium (Mg) until birth (on average 3–5 mg/day), just over half of it in bone, and a third in muscles and soft tissues [6]. The intracellular concentration of Mg is about ten times that of the extracellular fluid. Intrauterine accretion rates are extremely difficult to match in an extrauterine environment. Given issues of mineral solubility, there is a limit to how much Ca and P can be introduced in parenteral solution [7]. Human milk, the ideal ‘food’ for human term babies, is probably also the ideal nutrition for preterm babies, if it were only for the improved survival and decreased morbidity such as a reduced incidence of necrotizing enterocolitis [8, 9]. However, reduced growth, and inadequate Ca and in particular P intake are inherent to exclusive human milk feeding, and may lead to a particular form of rickets of prematurity, with severe hypophosphatemia and hypercalcemia [10]. Thus the need to ‘fortify’ human milk with minerals, which efficiently increases linear growth during the in-hospital period [11], with less convincing effects when fortifiers are used after discharge [12]. An alternative to fortified human milk is the administration of formulas designed to meet or approximate the mineral (and the other nutritional) needs of the preterm infant. Nevertheless, one must not assume that all minerals added to formulas or to human milk fortifiers are necessarily absorbed. Indeed, multiple factors regulate mineral intestinal absorption. These include the vitamin D status of the infant, the concentration of Ca and P and their ratio, the concentration and physical properties of major macronutrients such as protein or lactose, the amount and source of fat, and the production process (heat treatment of liquid formulae may promote a Maillard reaction that may decrease Ca absorption [13]). In addition, other elements may theoretically compete with intestinal Ca absorption, such as sodium, zinc, or iron. Thus, ‘more’ mineral intake is not necessarily translated in more mineral accreted, and a high mineral supply has the potential for more soap formation with dietary fat, more fecal Ca, more fat and energy losses, and more con-
Calcium, Phosphorus, Magnesium and Vitamin D Requirements of the Preterm Infant Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 140–151 (DOI: 10.1159/000358463)
141
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Perinatal Mineral Homeostasis
Table 1. Recommendations on the daily intake of Ca, P, Mg and vitamin D for preterm VLBW infants issued by different bodies and authors Intake recommendation
ESPGAN 1987
ESPGHAN 2010
LSRO, 2002
Atkinson Rigo, 2007 and Tsang, 2005
AAP, 2013
Current authors’ proposal, 2013
Ca, mg/kg/day P, mg/kg/day Mg, mg/kg/day Vitamin D, IU/day
70–140 120–140 150–220 120–200 100–160 150–220 120–200 50–90 60–90 100–130 70–120 60–90 75–140 60–140 4.85–9.7 8–15 6.8–17 mg/100 kcal 7.2–9.6 not provided not provided 8–15 800–1,600 800–1,000 90–225 200–1,000 800–1,000 200–400 400–1,000
stipation [14, 15]. Under certain circumstances, high Ca intakes can result in the formation of precipitates with casein and long-chain fatty acids that may lead to intestinal obstruction [16]. The intestinal absorption of Mg is poorly understood. Approximately 40% of ingested Mg is absorbed from formula, mostly in the proximal gut [17], and Mg absorbed and retained from human milk averages 41% of intake in preterm infants, with a range of 17–66% [18]. This coefficient of absorption in preterm infants is affected by the luminal concentration of Mg and its solubility. Ca and Mg do not compete with each other for intestinal absorption in preterm infants, but high phosphate content in formula may decrease intestinal Mg through formation of insoluble complexes [17].
In term infants, the model followed is usually that of human milk. Human milk is adapted to the needs of the human infant, and formulas are for the most part designed in order to mimic either the composition or the functions of human milk. In contrast, it cannot be assumed that human milk, naturally ‘designed’ to fit the extrauterine needs of the term infant, can be used as the ‘perfect’ model for the preterm infant. Indeed, intrauterine and extrauterine growth rates, nutrient accretion, etc., are not identical. Thus, nutritional mineral requirements of the preterm infant have been traditionally estimated upon two major bases: the first one relates to the intrauterine accretion rate of minerals by the skeleton, and the other one relates to the coefficient of absorption of minerals by the preterm intestine. Subsequently, several sets of recommendations have been published by various experts. There are the 1987 ESPGAN recommendations [19], commented upon and revised in 2010 [20], the Life Science Research Office recommendations (LSRO) [21], the Atkinson and Tsang recommendations [22], and the recommendations by Rigo et al. [23, 24] together with recent AAP recommendations [25] (table 1). These recommendations apply to very low birth weight infants until they reach a postmenstrual age of approximately 40 weeks and a birth weight close to normal term birth weight.
142
Mimouni · Mandel · Lubetzky · Senterre Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 140–151 (DOI: 10.1159/000358463)
Downloaded by: UCLA Biomedical Library 128.97.90.221 - 4/30/2014 12:08:34 PM
Enteral Calcium, Phosphorus and Magnesium Requirements
Calcium, Phosphorus, Magnesium and Vitamin D Requirements of the Preterm Infant Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp 140–151 (DOI: 10.1159/000358463)
143
Downloaded by: UCLA Biomedical Library 128.97.90.221 - 4/30/2014 12:08:34 PM
Mineral accretion estimates during pregnancy are essentially all based upon the cornerstones studies of Widdowson et al. [6], who carefully analyzed the body composition of a large number of aborted fetuses at various gestational ages, including the exact mineral composition of their ashes. According to Widdowson’s work, during the last 3 months of gestation the fetal accretion of Ca, P and Mg is about 20 g, 10 g and 700 mg, respectively, which represents accretion rates of approximately 100–120 mg/kg/day for Ca, 50–65 mg/kg/day for P, and 3–5 mg/kg/day for Mg [6]. The assumptions used for intestinal absorption estimates in the above-mentioned recommendations are based upon either older balance studies, or upon studies using stable isotopes of Ca and Mg [26]. Although these studies have allowed improving massively our knowledge on mineral metabolism and balance, they have shown that there is a significant variability of mineral absorption among preterm infants. The coefficient of absorption of Ca ranges grossly between 40 and 70%, that of P between 60 and 95%, and that of Mg approximates 40% [27, 28]. These variations explain most of the differences among the various experts’ recommendations. The lowest estimate of Ca requirements in mg/kg/day is that of ESPGHAN [19] and the highest is by the LSRO [21] and the AAP [25]. Similarly, the lowest estimate of P requirement is by the ESPGHAN [19] and the highest is by AAP [25] (table 1). In view of the fact that most recent data using stable isotopes of Ca are consistent with relatively lower coefficients of absorption of Ca than older data showed, we favor the higher estimates as proposed by Atkinson and Tsang [22]. We suggest that the daily requirements for Ca should be 120–200 mg/kg. The ESPGHAN [20] used an estimate of 90% of coefficient of absorption for P, an optimistic estimate when considering for instance the data of Lapillonne et al. [29] who found coefficients of absorption of 76% in fortified human milk fed preterm infants and 65.3% in those fed a preterm formula. We suggest that the daily requirements of P should cover a wider range than that recommended by ESPGHAN, and be similar to the Atkinson and Tsang proposals (60–140 mg/kg). In human milk, the Ca:P ratio is 2:1 in mass, close to the actual composition of skeletal minerals (2.2: 1) [20]. Thus, it would seem logical that the Ca:P ratio (by weight) be maintained approximately at the level present in human milk, i.e. approximately 2:1. However, it might be more appropriate taking into account P accretion with lean body mass, especially when optimizing preterm infant macronutrient intakes, and a ratio of 1.6:1–1.8:1 has been suggested by Mize et al. [30], based upon careful balance studies. As far as Mg is concerned, it has been calculated that preterm infants fed human milk are provided with an intake of 5.5–7.5 mg/kg/day [22]. ESPGHAN assumed an absorption coefficient of 40%, and calculated a net accretion of 2.2–3 mg/kg/day, i.e. less than the 3–5 mg/kg/day of intrauterine accretion (for a 1-kg baby) [19, 20]. ESPGHAN recommended that infants fed formula be provided with Mg intakes of 8–12 mg/kg/day, because they had a retention rate within the range of intrauterine accretion [31]. Lapillonne et al. [29] found a 37.5% coefficient of absorption for Mg in their balance studies both in fortified human milk-fed preterm infants and in those fed a preterm formula. In contrast, Koo and Tsang [32]
a ssumed that the coefficient of absorption of Mg is 50%, and thus estimated the requirements to be 8 mg/kg/day (0.33 mmol). We consider coefficient of absorption of approximately 40% a more realistic [18, 29] and recommend a daily Mg intake of 8–15 mg/kg, as suggested by ESPGHAN.
Vitamin D Requirements
The issue of vitamin D requirements in preterm infants is complex. Requirements may be theoretically affected by the availability of substrates such as Ca, P, Mg and vitamin D itself. In addition, it is unclear whether all the elements of adequate vitamin D metabolism (including production, absorption, action and degradation) are mature in preterm infants. Thus, circulating values of vitamin D and its metabolites at concentrations that appear to be adequate in term infants may not be adequate in preterm infants.
Vitamin D Production in Skin To our knowledge, no studies have been published evaluating vitamin D production in the skin production in preterm infants exposed to UVB. Preterm infants are generally not exposed to UVB during their stay in the NICU. They also are not likely to not be routinely exposed to UVB after discharge. Indeed, the American Academy of Pediatrics (AAP) recommends to use sunblock in infants >6 months of age (in order to protect them from skin cancer), and to avoid exposure to direct sunlight in infants 100 nmol/l [43]. Importantly, in these infants, urinary Ca/creatinine ratios were not reliable indicators of excessive vitamin D intake [43]. Liver 25-Hydroxylation Although the 25-hydroxylation process has not been directly investigated, many studies have shown adequate 25(OH)D increases after administration of vitamin D in preterm infants [34, 39, 40, 44, 45] which support the concept that both absorption and 25-hydroxylation of vitamin D are adequate.
Action of 1,25(OH2)D Ravid et al. [48] have suggested that in vitro 1,25(OH2)D effect on lymphocytes is blunted as compared to adults. However, in their study there were no differences between lymphocytes obtained from term and those obtained from preterm infants. In an in vivo study, 90 preterm infants
