Journal of the American College of Nutrition

ISSN: 0731-5724 (Print) 1541-1087 (Online) Journal homepage: http://www.tandfonline.com/loi/uacn20

Mineral requirements of low-birth-weight infants. W W Koo & R C Tsang To cite this article: W W Koo & R C Tsang (1991) Mineral requirements of low-birthweight infants., Journal of the American College of Nutrition, 10:5, 474-486, DOI: 10.1080/07315724.1991.10718174 To link to this article: http://dx.doi.org/10.1080/07315724.1991.10718174

Published online: 02 Sep 2013.

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Mineral Requirements of Low-Birth-Weight Infants Winston W. K. Koo, MBBS, FACN, and Reginald C. Tsang, MD, FACN Departments of Pediatrics and Obstetrics and Gynecology, University of Tennessee, Memphis (W. W. K. K.), and Perinatal Research Institute, Children's Hospital Medical Center, University of Cincinnati Medical Center (R. C. T.)

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Key words: calcium, magnesium, phosphorus, preterm infants, bone mineralization, parenteral nutrition, feeding The minerals calcium (Ca), magnesium (Mg), and phosphorus (P) are essential for tissue structure and function. Recent studies have resulted in a more rational approach to the management of mineral intake in preterm infants receiving parenteral nutrition (PN) and enterai nutrition (EN). For preterm infants requiring PN, the use of PN solutions with a Ca content of 1.25-1.5 mmol/dl (50-60 mg/dl), a P content of 1.29-1.45 mmol/dl (40-45 mg/dl), and an Mg content of 0.2-0.3 mmol/dl (5-7 mg/dl) is supported by studies of mineral homeostasis with serial chemical and calcic-tropic hormone measurements, standard balance studies, and improved radiographie indices of bone mineralization. For infants requiring EN, an intake of approximately 4 mmol (200 mg) of Ca, 3.2 mmol (100 mg) of P, and 0.33 mmol (8 mg) of Mg/kg/day based on an average retention rate of 64% for Ca, 71% for P, and 50% for Mg should be sufficient to meet the requirements of preterm infants in early infancy. This level of intake is supported by data from balance studies using standard and stable isotope techniques, changes in bone mineral content (BMC) measurements, and calciotropic hormone data. Based on the timing of development of fractures and rickets, changes in BMC, and skeletal growth data, the increased Ca and P intake should continue for at least 3 months after birth or until reaching a body weight of about 3.5 kg. In addition, nonnutritional factors may have the potential to increase mineral loss and disturb mineral homeostasis; chronic diuretic therapy increases mineral loss, and aluminum contamination of nutrients theoreti­ cally may compound any skeletal disorder. Thus, attention to the level of mineral intake and factors important in mineral loss and mineral metabolism should optimize mineral retention in small preterm infants. Abbreviations: BMC = bone mineral content, Ca = calcium, EN = enterai nutrition, GFR = glomerular filtration rate, Mg = magnesium, P = phos­ phorus, PN = parenteral nutrition, 250HD = 25-hydroxyvitamin D

INTRODUCTION The minerals calcium (Ca), magnesium (Mg), and phosphorus (P) are essential for tissue structure and function. Their physiology and metabolism are interre­ lated which, in turn, modulate the nutritional require­ ments. Preterm infants, particularly those with birth weight < 1 kg, miss the period of most rapid in utero accretion of these minerals. The intrauterine accretion rates of Ca, Mg, and P are > 2.5 mmol (100 mg), 0.12 mmol (3 mg), and 1.94 mmol (60 mg)/kg/day, respec­ tively, beyond 24 weeks gestation, and reach peaks of approximately 3.3 mmol (130 mg) Ca, 0.13 mmol (3.2 mg) Mg, and 2.39 mmol (74 mg) P/kg/day between 28 and 36 weeks gestation [1-5]. Recommendations for

mineral intake in small preterm infants are usually based on the perceived need to replace the expected gains in body minerals if the infant had remained in utero until term gestation [4,5] and to minimize the risk for development of complications of poor bone mineraliza­ tion, including rickets and fractures [6-8].

PARENTERAL REQUIREMENTS Almost all preterm infants require parenteral nutrition (PN), usually beginning 2-3 days after birth. Duration of PN varies depending on toleration of enterai feeding and presence of other complications such as respiratory dis­ tress and necrotizing enterocolitis.

Presented in part at the 31st Annual Meeting of the American College of Nutrition, Albuquerque, New Mexico, October 14,1990. Address reprint requests to Winston Koo, M.B.B.S., Newborn Center, 853 Jefferson Avenue, Room 201, Memphis, Tennessee 38163.

Journal of the American College of Nutrition, Vol. 10, No. 5,474-^86 (1991) © 1991 John Wiley & Sons, Inc.

CCC 0731-5724/91/050474-13$04.00

Mineral Requirements ofPreterm Infants Table 1. Factors Influencing the Delivery and Urinary Losses of Calcium (Ca) and Phosphorus (P) in Parenteral Nutrition 1. Ca and P "solubility" in solution increases with: Decreased absolute content of Ca and P Decreased pH of base solution used Mixing P in PN solution before adding Ca 2. Urinary loss of Ca or P increases with: Excessive infusion of Ca, P, fluid, glucose, sodium, amino acids, vitamin D Diuretic therapy

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Modified from [19] with permission.

Ca, Mg, and P needs of preterm infants requiring PN are now better defined with knowledge of the factors that affect the ability to maintain these minerals in PN solu­ tions [9-14] and in vivo data on the metabolic response [8,15,16] and mineral retention [17,18] during PN therapy. Mineral Solubility in PN Solution The maintenance of Ca and P salts in PN solution depends on the type and amount of other nutrients, par­ ticularly the increase in amino acid concentration. In ad­ dition, other factors are important in the maintenance of Ca and P solubility in PN solution (Table 1) [9-14,19]. With attention to details in the preparation of PN solu­ tions, Ca and P can be delivered simultaneously in amounts similar to or greater than those retained by in­ fants fed human milk. Under normal circumstances, the amount of Mg for daily needs is easily maintained in PN solution. PN solutions with a Ca and P content of 15 mM each (60 and 46.5 mg/dl, respectively) and an Mg con­ tent of 3 mM (7.2 mg/dl) in a 2% amino acid solution are stable throughout the delivery system for the usual period of infusion [10]. The recommended amount of Ca and P delivered in PN solutions is described per liter to prevent Ca-P precipitation at high concentrations of Ca and P in PN solution [20,21]. The latter results if there is fluid restriction, and the recommended intake is based on per kg body weight A number of Ca, Mg, and P salts are soluble and may be used in PN, but there appear to be few significant practical advantages over the use of Ca gluconate, Mg sulfate, and a mixture of mono- and dibasic phosphate salts of sodium and potassium [9-14,22-25]. Higher molar concentrations of phosphate can be maintained in solution when Ca gluconate, instead of Ca chloride, is used as the Ca source. This is because the degree of dissociation of Ca gluconate decreases as its concentra­

tion increases; thus, the concentration of Ca available for precipitation when added as the gluconate salt is less than that available when added as the chloride salt [22,23]. Mg sulfate increases sulfate excretion and pos­ sibly increases calciuria during PN therapy [24,25]. In preterm infants who received PN solution with monobasic phosphate salt as the only inorganic phos­ phate, blood pH was lower and urine Ca excretion was higher as the mean P intake was increased from 1.0 to 1.7 mmol (32-54 mg)/kg/day [18]. In contrast to the traditional mode of Ca and P delivery from an amino acid-dextrose solution, there are no data to document the safety and efficacy of the recommended concentrations of Ca, Mg, and P in the total nutrient admixture, a tech­ nique whereby all PN nutrients, including lipid emul­ sion, are mixed and delivered from the same container [26,27].

Determination of Mineral Requirement in Infants Receiving PN Use of PN solution with Ca, P, and Mg contents of 15 mM (60 mg/dl), 15 mM (46.5 mg/dl), and 3 mM (7.2 mg/dl), respectively, can maintain stable biochemical and calciotropic hormone indices of mineral homeostasis. These include normal and stable serum concentra­ tions of Ca, P, parathyroid hormone, calcitonin, 25hydroxyvitamin D (250HD), and 1,25-dihydroxyvitamin D, and renal tubular reabsorption of phosphate [8,15]. Balance studies in clinically stable infants receiving 1.31.5 mmol (52-58 mg) Ca/kg/day and 1.1-1.3 mmol (3440 mg) P/kg/day from PN have demonstrated that the mean fractional retention was 88-91% for Ca and 89— 97% for P [17,18] (Figs. 1 and 2). Fluctuations in the serum concentrations of Mg occur frequently in associa­ tion with changes in the amount of Mg delivered in PN solution [8,15,28] and related to increased gastrointes­ tinal loss without appropriate Mg replacement since

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Mineral Requirements ofPreterm Infants 180 1601 140 100 80-

Retention mg/kg/d

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40 60 80 100 120 140 160 200 220 240

Intake mg/kg/d Fig. 1. Calcium retention with different nutrient sources derived from references in the literature: (O) human milk [66,67,79]; ( · ) human milk with various amounts of Ca and P supplement [68,75,79,82,84,85]; (Δ) low mineral containing infant formula [67,68,84]; (A) high mineral containing infant formula [82,85-87]; (x) parenteral nutrition [17,18]; (horizontal bar) range of intake from human milk at 200 ml/kg/day; (vertical bar) range of in utero accretion.

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20

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Intake mg/kg/d Fig. 2. Phosphorus retention with different nutrient sources derived from references in the literature: (O) human milk [66,67,79]; ( · ) human milk with various amounts of Ca and P supplement [68,75,79,82,84,85]; (Δ) low mineral containing infant formula [67,68,84]; (A) high mineral containing infant formula [82,85-87]; (x) parenteral nutrition [17,18]; (horizontal bar) range of intake from human milk at 200 ml/kg/day; (vertical bar) range of in utero accretion.

gastrointestinal fluid may have an Mg content > 7 mmol/L (16.8 mg/dl) [29]. An Mg content of 0.3 mmol in PN solutions, delivering approximately 0.3-0.4 mmol (7.2-9.6 mg)/kg/day, appears best to maintain stable serum Mg concentrations [8,15,28]. The above bio­

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chemical and hormonal findings are indicative of mini­ mal metabolic stress to the Ca, Mg, and P homeostatic mechanisms [21,30] and are considered desirable goals in the management of low-birth-weight infants. We would recommend introduction of the Ca and P content

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Mineral Requirements of Preterm Infants Table 2. Approach to the Use of High Calcium (Ca) and Phosphorus (P) Content (15 mM each; 60 mg Ca and 46.5 mg P/dl) in Parenteral Nutrition Solution 1. Increase by 10% increments daily from 70% or 80% of the maximum content 2. Adjust Ca and P content if necessary by daily monitoring of serum Ca and P concentration, until 100% of desired content Thereafter, measure serum Ca and P at weekly intervals. Measurement of renal reabsorption of P may be performed at weekly intervals

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Modified from [19] with permission.

of PN solutions at 70% of the desired concentration. Stepwise increase in the Ca and P content over the first 3 days of PN would minimize the risk of biochemical dis­ turbance that may occur with a more rapid introduction of maximum mineral loading [8,15,19,21] (Table 2). PN-related bone disease is well described in adults [31,32] and in infants [6,33]. It is likely to have multifactorial etiology, although substrate deficiency, particularly of Ca and P, is important in the development of nutrition­ al bone disease in infants [6,20]. Metabolic bone disease as indicated by standard biochemical and radiographical findings is reported recently to be less severe when the Ca [0.68 mmol (27.2 mg)/kg/day] and P [0.61 mmol (18.9 mg)/kg/day] delivered in PN solutions were doubled, i.e., 1.36 mmol Ca and 1.22 mmol P/kg/day [16]. These data are further support for higher ranges of Ca and P intake for infants requiring PN. Other factors such as Ca:P ratios, and renal and gastrointestinal losses of minerals are important to con­ sider in achieving optimal mineral retention in infants receiving PN therapy. Normally, infants are tolerant of a wide range of Ca:P ratios, as demonstrated by the ap­ parent tolerance of the infusion of extremes of Ca:P ratios from 4:1 to 1:8 [20]. However, the best combina­ tions that minimized the disturbance to the Ca and P homeostatic mechanism, with best Ca and P retention, are solutions with Ca:P ratios of 1:1-1.3:1 by molar ratio or 1.3:1-1.7:1 by weight [8,15-18]. ACa:P ratio of < 1:1 by weight should not be used because of potential risk for disturbance of Ca and P homeostasis (hyperphosphatemia, hypocalcemia) [34-36]. The kidneys normally represent the main excretory route during PN [8,15-18,34-39], and urinary losses may have a significant impact on mineral balances. For example, in an infant with 60% of serum Ca (2.5 mmol/L) being ultrafiltrable and a glomerular filtration rate (GFR) of 20 ml/min (28.8 L/day), the daily amount of filtered Ca would be 43.2 mmol (864 mg). Thus, a small percent increase in renal loss of Ca could sig­ nificantly alter Ca balance, particularly at the low range of Ca intake [20]. Many factors, including P deficiency,

excessive intakes of intravenous fluid, sodium, Ca, Mg, vitamin D, and amino acids, are reported to increase urine Ca loss (Table 1). Calciuria at > 40% of Ca intake can occur with low P intake in PN in spite of associated low Ca intake [37,38]. The calciuria with P deficiency may be reduced by as much as 75% with an increase in P delivery to > 1 mmol (31 mg)/kg/day [36-38]. Cyclic PN with delivery of PN over shorter periods (10-18 hr/day) results in greater urine Ca loss compared to a continuous infusion of PN [40] or to periods without PN infusion [31,32]. Nonnutritional factors, including all commonly used diuretics (e.g., furosemide, spironolactone, and thiazide) and theophylline, are also reported to increase urine Ca loss and disturbed bone mineralization [41-45]. Increased urine Ca loss may result from an in­ creased filtered load of Ca (with or without extracellular fluid expansion), decreased reabsorption of Ca from parathyroid hormone resistance associated with P deficiency, and increased sulfate, oxalate, or acid load [20,24,31,32,34-38,40-52]. Altered urine excretion of Mg and P also can sig­ nificantly affect mineral balances. For example, in an infant with 70% of serum Mg (0.9 mmol/L) and 90% of serum P (1.6 mmol/L) being ultrafiltrable and with a GFR of 20 ml/min, the daily amount of filtered Mg and P would be 18.4 mmol (444 mg) and 46.6 mmol (723 mg), respectively. Urinary loss of Mg and P also may be increased by similar factors affecting urinary loss of Ca [20,53,54]. However, renal handling of Mg appears to be unaffected by variations in the quantity or type of amino acids infused and appears independent of the Ca and P content in PN solution or the urinary excretion of Ca, P, and sodium [8,15,49]. In infants receiving low P intake, the renal tubular reabsorption of phosphate may ap­ proach 100% [8,15,55]. Normally, an intravenous intake or 0.3-0.4 mmol (710 mg) Mg/kg/day appears to result in the least distur­ bance to Mg metabolism for most infants [8,15,28]. Hypermagnesemia may occur in infants receiving higher Mg intake [8,15], while negative balances for Mg and other nutrients (e.g., sodium, potassium, and zinc) may

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Mineral Requirements ofPreterm Infants result from loss of large volumes of gastrointestinal fluid without appropriate replacement [29,56,57]. Vitamin D metabolism plays a crucial role in Ca and P homeostasis. Its major physiologic functions include an increase in gut absorption of Ca and P and an increase in mobilization of bone Ca and P to the extracellular fluid [58]. Thus, when Ca and P are delivered during PN and the infants are not being fed enterally, the physiologic requirement for vitamin D would be mini­ mal. Recent studies have demonstrated that about 30 IU/kg/day up to a maximum total 400 IU/day of vitamin D delivered in amino acid-dextrose solution [8,15,17,18, 59,60] or 160 IU/kg/day up to a maximum total 400 IU/day in lipid emulsion [61] are adequate to maintain normal vitamin D status for infants requiring PN. The latter is the currently recommended vitamin D intake for infants receiving PN [21]. There are no documented major complications as­ sociated with the currently recommended Ca [1.25-1.5 mmol (50-60 mg)/dl], P [1.29-1.45 mmol (40-45 mg)/dl], and Mg [0.2-0.3 mmol (5-7 mg)/dl] intakes for infants receiving PN [21]. Serial abdominal ultrasound examination showed that "biliary sludge" did not occur with greater frequency in infants receiving this higher Ca-P solution compared to those with lower mineral in­ take. Biliary sludge appeared to resolve upon enterai feeding. In the absence of chronic diuretic therapy, ab­ normal renal ultrasound findings have not been reported at mis Ca and P intake [8,15]. Aluminum, a potential toxin, is present in many intravenous nutrients, par­ ticularly the minerals [62]. However, definitive evidence of aluminum toxicity has not been documented at the currently recommended Ca and P intake. In small preterm infants, even greater concentrations of Ca and P than could be easily maintained in PN solu­ tion may be needed to achieve intrauterine accretion of these minerals. The use of alternate infusion of Ca and P to increase the delivery of these minerals and to avoid Ca-P precipitation in PN solutions has been shown to result in lower Ca and P retention rates (42-63%) [34, 35] compared to the Ca and P retention rates (73-97%) when Ca and P are infused simultaneously [17,18]. In addition, hypercalcemia and hypophosphatemia may occur during high Ca infusion, whereas hyperphosphatemia and hypocalcemia may occur during high P infusion [34]. Furthermore, infusion of P alone results in elevated urinary cyclic adenosine monophosphate, sup­ porting the presence of increased circulating parathyroid hormone [34,36]. Overall, the best means to further in­ crease Ca and P retention appears to be the early intro­ duction of high Ca- and P-containing enterai feeding.

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ENTERAL REQUIREMENTS Enterai nutrition (EN) in preterm infants allows greater delivery of Ca and P than is possible by PN [4,5]. Human milk contains probably sufficient Mg but insuffi­ cient Ca and P to meet the goal of attaining the amounts equivalent to intrauterine accretion rates [1,2,4,5,63-69]. Evidence supporting inadequacy of mineral intake from human milk and standard infant formulas includes biochemical (low serum and urine P, elevated serum and urine Ca, and elevated serum alkaline phosphatase ac­ tivity) [6,55,66-71] and hormonal (elevated serum 1,25dihydroxyvitamin D) [7,72] disturbances, lower bone mineral content (BMC) [72,73], and abnormal X-rays showing fractures and rickets [6,74]. These abnor­ malities are normalized upon Ca and P supplementation [6,66-73,75,76]. Mineral Delivery in Milks The availability in North America of lyophilized human milk powder as supplement to mother's milk is limited and is being used currently on an experimental basis [68,75]. Human milk supplementation with in­ dividual components or a combination of components (vitamin D, Ca, or P) has been reported [6,70,71,77-80]. However, the most frequently used Ca and P supplemen­ tation for human milk-fed infants is cow milk-based powder [81-83] or concentrated liquid formulation of cow milk-based preterm infant formula [84-87]. Currently, most preterm infants are fed cow milkbased preterm infant formulas with high a Ca-P content because of the low rate of sustained human milk feeding for these infants. The sources of Ca salt most frequently used in infant formulas are Ca carbonate, Ca phosphate tribasic, and Ca chloride [84,88]. A loss of 30-40% of Ca and P from sedimentation in the milk, especially during constant infusion over a period of 3-6 hours, has been reported [89-91]. The mineral loss is less with newer formulations and with bolus delivery of feeds [82,86,92]. It had been suggested that differences in bioavailability of minerals in infant formulas may contribute to different mineral retention rates [84]. However, a num­ ber of studies using standard balance techniques [82,8587] and stable isotope studies indicate that currently used mineral preparations in cow milk-based preterm infant formulas [93,94] are well absorbed. It is possible that, as shown in adults, the differences in bioavailability be­ tween well-formulated supplements are small relative to differences in absorptive performance between in­ dividuals [95,96].

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Mineral Requirements of Preterm Infants Determination of Mineral Requirements in

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Enterally Fed Infants The data from balance studies using standard techni­ ques or stable isotope techniques, direct measurement of BMC, and other studies on biochemical, hormonal, and radiographie changes of metabolic bone diseases have provided a reasonable basis for recommendation of mineral intake in preterm infants. Standard balance studies are noninvasive and frequently used as a guide for nutrient requirements in clinically stable growing in­ fants in spite of potential pitfalls [97-99]. Specifically, they do not account for all potential sources of nutrient loss (e.g., dermal loss) and cannot permit an estimate of endogenous fecal nutrient losses unless stable isotope techniques are employed. In addition, balance studies do not take into account adaptive changes associated with preexisting nutritional status and nutrient intake — for example, hypercalciuria in P deficiency state and with the use of human milk feeding in small preterm infants. These factors presumably contributed to the variable retention rate for Ca (31-75%) and Mg (44-81%) reported in the standard balance studies [4,66-68,75,7782,84-88,99,100]. However, P retention rates are consis­ tently about 60% or more and frequently reach 90% in small preterm infants fed low P milks [66-68,75,7782,84-88,99,100]. The use of stable isotope techniques has allowed measurement of true intestinal absorption and endogen­ ous intestinal secretion, particularly of Ca [93,94,101103]. The initial stable isotope studies employed extrinsically labeled Ca isotopes [93,101-103]. There were concerns that the protein-bound fraction of milk Ca [104-106] may not undergo exchange with an extrinsic tracer [107] and that studies with extrinsically labeled isotopes may yield spurious results. However, both the extrinsically and intrinsically labeled isotopes of Ca and Mg yielded similar results in vivo [94] and demonstrated that preterm infants are capable of absorbing these minerals in sufficient amounts to achieve in utero accre­ tion rates [93,94,102]. True Ca absorption from the use of intrinsically and extrinsically labeled isotopes [93,94,102] is usually at least 10% higher than the reported net Ca absorption by standard balance studies [4], although significant individual variabilities in intes­ tinal Ca absorption (21-90%) and retention (14-78%) rates were also noted [93,94,101-103]. Fractional Mg absorption from stable isotope studies averages 88% (range 75-93%) [94] and is also higher than the reported net Mg absorption [4]. Intestinal mineral absorption appears to depend to a large extent on the needs of the infant, and the absorp­ tion and retention rates of Ca, Mg, and P are consistently

higher in infants vs adults [4,108]. In small preterm in­ fants the variance in mineral retention rate appears to depend on individual patient variability to a greater ex­ tent than the effect of body weight and postnatal age [100], but the effect of gestational age has not been clearly demonstrated. The major determinant of mineral retention, par­ ticularly for Ca and Mg, is the extent of mineral absorp­ tion. Increasing mineral content of milks results in greater mineral absorption and retention. In small preterm infants the absolute retention for Ca and P is greater with the use of higher mineral content cow milkbased infant formula designed specifically for preterm infants when compared to the use of human milk and standard cow milk formula with lower Ca and P contents (Figs. 1 and 2). However, the net fractional absorption of Mg and P tends to decrease as intake is increased [4,6668,75,77-82,84-88]. Specific nutrients may affect mineral absorption and retention. In preterm infants fed low-mineral-containing milk, Ca absorption and retention may be increased by vitamin D [77] and P [78,79] supplementation, but the effect of dietary lactose remains unconfirmed [87]. With increasing Ca intake to a level > 150 mg/kg/day, frac­ tional phosphate absorption is decreased [66], and there is also a 5-10% increase in fecal fat loss noted in preterm [109] and term [110] infants. Fecal Ca excretion also was correlated with fecal fat excretion [79]. Sup­ plementation of 2 mmol (80 mg) elemental Ca/day as Ca lactate has been reported to decrease the absorption of major fatty acids in human milk and cow milk-based infant formula [111]. There is no apparent effect on over­ all Mg absorption and retention from manipulations in vitamin D, Ca, and P intake. P absorption for preterm infants fed human milk with low P content frequently approaches 90% of intake [66-68,77-80]. Vitamin D supplementation does not appear to affect P absorption or retention in the preterm infant [77]. Infants fed high-mineral-containing formulas de­ signed for small preterm infants appear to have a net retention of Ca, Mg, and P similar to in utero rates [82,85-87] and no significant alteration in net absorption of fat when compared to infants fed human milk with commercial mineral fortifier [82,85]. Ca retention was negatively correlated with fecal fat excretion [85]. Mg intake in the range provided by the currently available preterm infant formulas has not been documented to have an adverse effect on Ca or P retention. Urinary loss of minerals also may affect mineral retention in enterally fed infants. Preterm infants fed milks with low mineral content can develop hypercal­ ciuria to the extent similar to those receiving PN solu­ tions with low Ca and P content [55,70,71]. P sup-

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Retention mg/kg/d o

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Intake mg/kg/d Fig. 3. Magnesium retention with different nutrient sources derived fromreferencesin the literature: (O) human milk [66]; (·) human milk with various amounts of Ca and P supple­ ment [68,75,84]; (Δ) low mineral containing infant formula [66,68,84,116 (two values)]; (▲) high mineral containing infant formula [87]; (horizontal bar) range of intake from human milk at 200 ml/kg/day; (vertical bar) range of in utero accretion.

plementation increases Ca and P retention but also in­ creases urine P excretion [78,79,85]. In adults, high in­ take of some nutrients such as protein are reported to increase urine Ca losses, but there is no evidence that increased protein intake to the range 3.3-3.6 g/kg/day in currently available preterm infant formulas would in­ crease urine Ca loss. Chronic diuretic therapy is the major cause of increased urinary loss of minerals and increasedriskof nephrocalcinosis [112,113]. Other drugs such as theophylline also may increase urine loss of minerals [43]. Thus, prudence in the use of all nutrients and drugs is warranted in the management of mineral intake in infants. Other nonnutritional factors such as aluminum toxicity and physical therapy may also con­ tribute to the development of osteopenia, rickets, and fractures [33,74,114]. The effect of Ca:P ratio on mineral retention rates appears to vary, depending on the type of infant feeding and the actual amount of Ca and P delivered in the feeds. In one report [115] of preterm infants fed standard cow milk formula with addition of varying amounts of mineral mixture to result in final Ca:P ratios of 1.4-3.8:1 by weight (1.1-2.9:1 molar ratio) and intakes of Ca from 2.25 to 6.25 mmol (90-250 mg)/kg/day and of P from 2.13 to 4.13 mmol (66-128 mg)/kg/day), the Ca and P combination mat resulted in retention rates closest to in utero values occurred in infants fed formulas with Ca:P ratio of 3.8:1 by weight (2.9:1 molar ratio) at the Ca intake of 250 mg/kg/day. In contrast, Ca:P ratios of high mineral formula and human milk mineral fortifier

480

designed for preterm infants are approximately 1.8-2:1 by weight (1.4-1.6:1 molar ratio) and when delivered at about 3.75-5.75 mmol (150-230 mg) of Ca and 2.454.13 mmol (76-128 mg) of P per kg per day, the Ca and P retention rates are consistently at or above the in utero values [82,85-87]. In small preterm infants within a few weeks after birth, balance studies have shown that in utero accretion rate can be achieved when human milk [74] and infant formulas [82,85-87] are fortified with Ca and P. Preterm infants fed human milk alone at an intake of about 6 mg of Mg/kg/day may have Mg retention approaching in utero accretion values [66]. Those infants fed human milk with Mg intake of 7-8 mg/kg/day, an amount that theoretically can be delivered from about 200 ml of human milk/kg/day [63,64], consistently showed Mg retention rates comparable to in utero accretion values [68,75]. Preterm infants fed cow milk-based formulas can achieve rates of Mg retention comparable to in utero retention rate [66,68,84,85,116] as early as the first 3 days after birth [116] (Fig. 3). Thus, an intake of ap­ proximately 4 mmol (200 mg) Ca, 0.33 mmol (8 mg) Mg, and 3.2 mmol (100 mg) P/kg/day theoretically should achieve retentions of Ca, Mg, and P comparable to the in utero accretion based on the estimated average Ca retention of 64%, Mg retention of 50%, and P reten­ tion of 71% [4,5]. The recommended amount of Ca and P can be provided by the two commercially available preterm infant formulas containing high mineral content. The amount of Mg from preterm infant formulas ranges

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Mineral Requirements ofPreterm Infants 110 ■o ΐϋ

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No Fractures/Rickets n=23 With Fractures/Rickets n«51 x+SE

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12

Fig. 4. Serial bone mineral content (BMC) over first year in very-low-birth-weight (< 1500 g) infants with (broken line) and without (solid line) radiographically documented fractures andrickets:(shaded bar) range of BMC of term infants. Adapted from [124]. "p < 0.05;+p< 0.01.

from 9 to 18 mg/kg/day, which may be several fold greater than that found in human milk [63,64,84,87]. Metabolic bone disease, as indicated by standard biochemical and radiographie findings, is reported to be less severe in preterm infants fed mineral-fortified cow milk-based formulas compared to those fed standard cow milk formula [117]. Infants in the former group received an average intake of about 5.5 mmol (220 mg) Ca and 2.8 mmol (87 mg) P/kg/day and 460 IU of vitamin D/day. The conflicting reports on the success in match­ ing postnatal changes in BMC (as determined by photon absorptiometry) to the in utero rate of increase in BMC [73,76,81,83] may in part be due to possible individual variations in mineral absorption and differences in bioavailability of mineral fortifiers. Studies that reported the achievement of fetal rates of increase in BMC used a total Ca intake of 210-250 mg/kg/day and total P intake of 112-125 mg/kg/day [73,76]. Thus, in selected infants, higher amounts of mineral intake may be needed. How­ ever, there are reports of complications from Ca- and P-containing bezoars due to Ca and P supplementation of human milk at a total intake of about 6.3 mmol (250 mg) Ca and 6.5 mmol (200 mg) P/kg/day [118] or sup­ plementation of infant formula at a total intake of about 5.9 mmol (235 mg) Ca and 3.6 mmol (112 mg) P/kg/day [91]. It also should be pointed out that the major

problems of Ca and P deficiency in preterm infants with bone demineralization and rickets occur predominantly in infants who are severely ill with multiple clinical complications [74]. In such infants thee are also practical difficulties in the ingestion of intakes to match in­ trauterine mineral accretion rates. Duration of Ca and P supplementation is inversely related to the gestational age or birth weight of the in­ fant. Some report that 6-8 weeks of increased mineral supplementation may be insufficient to prevent rickets and fractures in extremely small preterm infants with birth weights < 800 g [74,119]. However, the occurrence of rickets and fractures is greatest at 2-4 months and is rare after 6 months [74,120,121]; several studies have documented that by 6-9 months after birth, the BMC of small preterm infants is within the range of BMC for infants bom at term (Fig. 4), and it continues to increase throughout infancy and childhood in association with in­ crease in skeletal size, i.e., height and weight are sig­ nificant covariants of BMC [122-127]. Thus, there is no physiologic rationale for the Ca and P intake to achieve the maximum in utero accretion rate beyond the body weights comparable to infants at term gestation. For the reference preterm infant with birth weight of 1 kg, the increased Ca and P intake should continue for at least 3 months or until reaching a body weight of about 3.5 kg.

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Mineral Requirements ofPreterm Infants Thereafter, a daily intake equal to the current recom­ mended dietary allowance for term infants [128] of ap­ proximately 60 mg Ca and 50 mg P/kg up to a total daily intake of 600 mg Ca and 500 mg P at 1 year appears to be appropriate. With enterai supplementation of 400 IU [129,130] or 750 IU [131] vitamin D/day, low serum 250HD con­ centrations are reported in small preterm infants fed human milk [129,131] or standard (low mineral) infant formulas [129,130]. The metabolism of vitamin D may be affected by availability of substrates, including vitamin D, Ca, and P [132-134]. Thus, prolonged feed­ ing of low mineral milks and the low vitamin D reserves of small preterm infants theoretically could lead to low serum 250HD concentrations and a diagnosis of vitamin D deficiency. However, daily supplementation of 400 IU of vitamin D appears to be sufficient for small preterm infants receiving PN or EN while receiving the recom­ mended amounts of Ca and P [7,60,135,136]. Further­ more, increased daily vitamin D supplementation to 2000 IU/day in preterm infants does not decrease the development of radiographie osteopenia and rickets when compared to a daily vitamin D supplement of 400 IU [135]. The use of soy formula, in spite of its high Ca and P content, is associated with high frequency of fractures and rickets in small preterm infants [120]. Its use in term infants is reported to result in lower BMC as measured by photon absorptiometry when compared to infants fed cow milk-based formula [137] or human milk [138]. The phytate in soy formula is thought to be responsible for binding to P and reducing absorption [110,139]. How­ ever, newer formulation of soy formula with lower protein content and improved mineral suspension ap­ pears to result in appropriate mineral retention [110] and normal BMC [140,141]. Nevertheless, until more data are available on soy formula, its use for more than a few days in small preterm infants is inappropriate [142]. There is no single parameter that predicts the ade­ quacy of mineral status in small preterm infants. How­ ever, serial biochemical and radiological monitoring of skeletal development, including biweekly serum Ca, P, and alkaline phosphatase and bimonthly X-ray of forearms, can be useful in "screening" for rickets and fractures. Additional measurements, including serial serum concentrations of osteocalcin and calciotropic hormones and bone densitometry, may help to assess the adequacy of mineral status [6,20]. In conclusion, recent studies have resulted in a more rational approach to the management of mineral intake in preterm infants receiving PN and EN. Attention to detail in the delivery of the Ca and P supplementation and in other nutritional and nonnutritional factors that

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affect mineral losses should maximize mineral retention and minimize the development of osteopenia, rickets, and fractures.

ACKNOWLEDGMENTS Supported by grants from the Medical Research Council, Canada (MA-10685), NIH HD 11725, and NIH PERC HD 20748.

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revisionacceptedFebruary 1991.

VOL. 10, NO. 5

Mineral requirements of low-birth-weight infants.

The minerals calcium (Ca), magnesium (Mg), and phosphorus (P) are essential for tissue structure and function. Recent studies have resulted in a more ...
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