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Nutritional needs of premature infants: Current Issues
NUTRITIONAL NEEDS OF PREMATURE INFANTS: CURRENT ISSUES JACQUES RIGO, MD, PHD,
AND JACQUES
SENTERRE, MD, PHD
With the major advances in life-support measures, nutrition has become one the most debated issues in the care of very low birth weight infants. Current nutritional recommendations are based on healthy premature infants and are designed to provide postnatal nutrient retention during the “stable-growing” period equivalent to the intrauterine gain of a normal fetus. However, this reference is still a matter of debate, especially in the field of protein and mineral requirements. Protein requirements recently have been reevaluated, taking into consideration that (1) fetal lean body mass gain and the contribution of protein gain to lean body mass gain appear as more suitable references than does weight gain; (2) an additional protein supply needs to be provided for early catch-up growth, compensating for the cumulative protein deficit developed during the first weeks of life; (3) an increase in the protein-energy ratio is mandatory to improve the lean body mass accretion and to limit fat mass deposition; (4) the fractional nitrogen absorption rate and protein efficiency vary according to the feeding regimens; and (5) recommended dietary protein allowance needs to be adapted for postconceptional age instead of gestational age or birth weight to integrate the dynamic aspect of growth and protein metabolism. Thus recommended intakes for premature infants 26 to 30 weeks postconceptional age are 3.8 to 4.4 g of protein/kg/d with a protein/energy ratio between 3.0 to 3.3 g/100 kcal, according to their relative postnatal growth restrictions and should decrease progressively up to the time of discharge. After birth, there is a dramatic physiological change in bone metabolism resulting from various factors; abrupt reduction in mineral supply, stimulation of parathyroid hormone secretion, change in hormonal environment, and relative reduction in mechanical stimulation. There is a stimulation of the remodeling process, inducing an increase in endosteal bone resorption and a decrease in physical density. In preterm infants, this process of postnatal bone metabolism adaptation modifies the mineral requirements, with the remodeling stimulation itself providing a part of the mineral requirement necessary for postnatal bone turnover. In extrauterine conditions, the care of premature infants should not necessarily aim to achieve intrauterine calcium accretion rates. Considering long-term appropriate mineralization and the fact that calcium retention between 60 to 90 mg/kg/d suppresses the risk of fracture and clinical symptoms of osteopenia, a mineral intake between 100 to 160 mg/kg/d of highly-absorbed calcium and 60 to 75 mg/kg/d of phosphorus could be recommended. (J Pediatr 2006;149:S80-S88)
ver the past decades there has been a dramatic increase in the survival of premature infants, especially very low birth weight (VLBW) infants. With the major advances in life-support measures, nutrition has become one the most debated issues in the care of low birth weight infants; in this regard, several reports have shown the important effect of nutrition during Supported in part by a Bristol-Myers the first period of life on early and late outcome.1-3 Although the general objective of a Squibb/Mead Johnson unrestricted grant nutritional regimen for premature infants is to support life and achieve a growth rate and by a grant from the Léon Frédéricq foundation of the University of Liège. sufficient to fulfill the individual’s genetic potential, there are many controversies on how From the Pediatrics and Neonatal Departto attain this goal. In this article, we discuss the most important features regarding the ments, University of Liège. nutrition of premature, and particularly VLBW infants, outlining the main aspects of Presented as part of a symposium recogprotein and mineral requirements. nizing the 25th anniversary of the Bristol-
O
PROTEIN REQUIREMENT Present Recommendations The recommended nutrient intakes of premature infants are still a matter of debate, arising from the lack of consensus on the short- and long-term objectives for early BMAD BMC BW Ca
S80
Bone mineral apparent density Bone mineral content Body weight Calcium
LBM P VLBW
Lean body mass Phosphorus Very low birth weight
Myers Squibb Freedom to Discover Nutrition Grants Program held June 7-8, 2005 at the University of Cincinnati, Cincinnati, OH. Submitted for publication Apr 14, 2006; accepted Jun 1, 2006. Reprint requests: Jacques Rigo, MD, PhD, Pediatrics and Neonatal Department - University of Liège, CHR Citadelle, Boulevard du 12e de ligne 1, 4000 Liège, Belgium. E-mail: [email protected]. 0022-3476/$ - see front matter Copyright © 2006 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2006.06.057
Table I. The basis of reevaluating protein requirements for premature infants Previous recommendations Fetal reference related to lean body mass and protein gain instead of weight gain Need for the compensation of the initial protein gap and early catch-up growth All protein supplies are not equivalent in terms of net protein use: affected by immaturity, protein quality and technological processes Protein-energy ratio affects protein deposition and relative lean body mass gain Adaptation to postconceptional age Amino Acid (AA) requirements instead of protein requirement need additional evaluations in enteral and parenteral nutrition (optimal AA composition)
nutrition. Current nutritional recommendations from various international committees4-8 are based on healthy premature infants and designed to provide postnatal nutrient retention during the “stable-growing” period equivalent to the intrauterine gain of a normal fetus. They do not take into consideration the relatively long transitional period that induces the cumulative nutritional deficit and the need to obtain an early catch-up growth. In practice, the shorter the gestation of a neonate the more challenging are the influences of immaturity and the accompanying morbidity on nutritional supply during the first weeks of life.9,10 As a result of this cumulative nutritional deficit during early life, most growth parameters remain subnormal by the time the premature infant reaches a corrected age of 40 weeks; this phenomenon worsens in the case of VLBW and extremely low birth weight infants, suggesting that the current nutritional recommendations need to be reevaluated, taking into account this early nutritional gap and the need for early catch-up growth (Table I). The goal in estimating the protein requirements of premature infants is to provide the quantity and the quality of protein needed to obtain a growth similar to that observed in the fetus during the third trimester of intrauterine life and to obtain an early postnatal catch-up growth, keeping in mind, that, the accretion of lean body mass need to be considered more than the absolute weight gain.11 Dietary protein requirement for premature infants can be estimated by 2 different methods. The first, the factorial approach, considers the requirements as the sum of the obligatory losses (eg, urine, feces, skin), plus the amount incorporated into newly formed tissues. The second, the empirical approach, measures biochemical or physiological responses to graded intakes.
Fetal Reference In the factorial approach, compositional analysis of fetal tissues has been a valuable source of data for our understanding of the nutrient needs of the fetus, and by extension, those of the growing premature infant. During fetal life, the growth Nutritional Needs Of Premature Infants: Current Issues
velocity is particularly high, approximating 1.6%/day for body weight and 1.0%/day for body length,8,12-15 whereas body composition changes dramatically. Fetal accretion rates have been obtained from compositional analyses of aborted fetuses or stillborn infants.16 At 22 weeks of gestational age, the fetus is composed almost exclusively of lean body mass (LBM). The protein content accounts for 9% of body weight (BW) or LBM. At term, lean body mass represents about 87% of BW with a protein content of 12% of BW or 14% of the LBM.11 From those data, optimal weight gain, lean body mass gain, and protein accretion can be estimated for premature infants of similar gestational age (Figure 1). Considering that fat mass deposition is always significantly higher postnatally, LBM gain is preferable to weight gain in the evaluation of postnatal growth in premature infants. Similarly, the contribution of protein gain to LBM gain instead of weight gain appears as a more suitable reference. As shown in Figure 1, that value increases from 12% to 18% during the last trimester of gestation. From these data, the protein increment for growth has been estimated at a value closer to 2.5 g/kg/d.11
The Postnatal Cumulative Nutritional Deficit Recent nutritional studies focused on the daily energy and protein supplies in premature infants to evaluate the contribution of poor nutrition as rate limiting on growth status at the time of discharge.9,10,17 These studies suggested that the cumulative nutritional deficit explained close to 50% of the reduction in growth Z-scores before discharge and that protein is the main determinant of growth velocity of extremely premature infants.9,18 Therefore protein requirement needs to be calculated, adding to obligatory losses not only the protein requirement for growth but also that needed for the additional catch-up growth. In a large population of preterm infants receiving a controlled energy intake, the minimal protein supply necessary to obtain a zero nitrogen balance (to cover all nitrogen losses) was evaluated at 0.75 g/kg/d.19 A similar value was estimated to cover the need for catch-up growth.9 Thus the protein requirements in VLBW infants, so calculated, reach at least 4 g/kg/d. However, the recommended dietary protein allowance needs to be adapted for fractional absorption rate and protein efficiency, as well as to the need for individual variations. The Net Protein Utilization In premature infants, several factors may influence efficiency of net nitrogen utilization (retained to intake ratio). Recent data suggest that nitrogen absorption (absorbed to intake) and efficiency (retained to absorbed) is influenced by several factors such as quality of the protein supply, as well as by some technical processes as those required for hydrolysis processing and sterilization.20,21 Nitrogen absorption and utilization recently were reviewed on more than 200 metabolic balances performed during the last years in premature infants fed human milk, S81
Figure 1. Weight gain, Lean body mass gain and protein accretion during last trimester of gestation (on left). Contribution of protein gain to body weight (BW) gain and to lean body mass (LBM) gain during the last trimester of gestation (on the right).11
Table II. Nitrogen balances according to feeding regimen in premature infants22
mg/kg/d
Fortified human milk* (n ⴝ 88)
Powder formulas* (n ⴝ 49)
Liquid formulas* (n ⴝ 58)
Hydrolyzed protein formulas* (n ⴝ 31)
Intake Fecal excretion Absorbed Urinary excretion Retained Absorption % Net protein utilization† (%) Protein efficiency‡ (%)
517 ⫾ 86 90 ⫾ 28 428 ⫾ 76 121 ⫾ 45 307 ⫾ 56 82.7 ⫾ 4.8 59.7 ⫾ 7.7 72.1 ⫾ 7.6
522 ⫾ 70 49 ⫾ 19 474 ⫾ 75 106 ⫾ 36 368 ⫾ 57 90.7 ⫾ 3.3 71.5 ⫾ 6.5 77.7 ⫾ 6.4
506 ⫾ 58 71 ⫾ 28 434 ⫾ 52 98 ⫾ 21 337 ⫾ 46 86.0 ⫾ 5.0 66.6 ⫾ 5.8 77.5 ⫾ 4.4
553 ⫾ 56 87 ⫾ 26 466 ⫾ 51 122 ⫾ 39 343 ⫾ 42 84.3 ⫾ 4.0 62.4 ⫾ 6.5 74.0 ⫾ 6.9
*P ⬍ .05. †Nitrogen retention/nitrogen intake. ‡Nitrogen retention/nitrogen absorption.
human milk fortifiers, and various premature formulas.11,22 Data are summarized in Table II. Nitrogen absorption rate (absorbed/intake) differs significantly according to feeding regimen. It was higher with whey protein powder formulas for premature infants (90.7%) than with human milk supplemented with fortifiers (82.7%), hydrolyzed protein powder formulas (84.3%), or ready-to-use predominantly liquid whey formulas for premature infants (86.0%) (Table I). These differences result from the nature of the various protein supplies. In human milk, non-nutritional protein content (lactoferrin, secretory immunoglobulin A, lysozyme) or non-protein nitrogen content (amino-oligosaccharides) are less absorbed than the nutritional protein content (whey proteins, caseins) and contribute to a significant part of the fecal excretion. An interesting observation is the relatively lower absorption rate of ready-to-use liquid formulas or hydrolyzed protein formulas for premature infants, where the technical processes seem to impair nitrogen absorption in relation to heat treatment inducing some Maillard reaction products.21 In addition, with hydrolyzed formulas, the preliminary hydrolysis may alter the physiological absorption process in the lumen or at the border of the gastrointestinal tract.20 S82
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The efficiency of protein gain, estimated by the ratio between retained and metabolizable nitrogen (absorbed), differs also according to the feeding regimen (Table II). The highest values were obtained in premature infants fed powder (77.7%) and liquid (77.5%) formulas. The efficiency was significantly lower in those fed hydrolyzed protein formulas (74.0%) and human milk supplemented with fortifiers (72.1%).22 The lower value obtained with fortified human milk may be related to the non-protein nitrogen (mainly urea) that represents 20% to 25% of the total nitrogen content of human milk and between 13.5% and 17% of the total nitrogen content of fortified human milk (Table II).
The Protein/Energy Ratio Protein and energy needs are reciprocally limiting.11 If there is a surfeit of one, it affects the ability of the infant to assimilate the other. If energy intake is insufficient, protein is used as an energy source, and the nitrogen balance becomes less positive. Increasing the caloric intake will spare the protein loss and improve nitrogen retention, but with limited protein intake, the protein retention reaches a plateau, and the The Journal of Pediatrics • November 2006
Body weight gain=4.66 +5.54*protein intake0.65*(protein-energy ratio) ; r=0.78
Fat Mass gain=0.94 +0.058*Energy intake +0.70* protein energy ratio; r=0.95
3.8 Weight gain (g/kg*d)
3.4 3.0 2.6 2.2 1.8 1.6
2.0
2.4
2.8
3.2
3.6
4.0
4.4
25 22.5 20 17.5 15 12.5 10 7.5 5.0
Protein intake (g/kg*d)
Protein energy ratio (g/100 kcal)
Protein energy ratio (g/100 kcal)
4.2
4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 90
100
110
120
130
140
150
FM gain (g/kg*d) 6.0 5.6 5.2 4.8 4.4 4.0 3.6 3.2 2.8 160 2.4
Energy intake (kcal/kg*d)
Figure 2. Main determinants of protein accretion and whole body composition determined in 27 groups of preterm infants (10 fed fortified human milk and 17 fed preterm formula); n ⫽ 300; birth weight: 1364 ⫾ 116 g, gestational age: 30.7 ⫾ 0.9 weeks).11
energy excess is used for only fat deposition. Nevertheless, when protein supply is satisfactorily close to 4 g/kg/d the effect of energy increase on protein retention appears to be minimal. Analysis of various studies in preterm infants fed human milk, human milk fortifiers, and various preterm formulas11 allows evaluation of the main determinant of weight gain, nitrogen retention, and fat mass deposition. From these data, stepwise regression analysis allows evaluation of the major determinants of weight gain, lean body mass gain, fat accretion, and protein retention. Protein intake and protein energy ratio are the main determinants of weight gain. Protein intake is the only determinant of LBM gain, in contrast to fat mass gain, which is positively related to energy intake and negatively to the protein/energy ratio11 (Figure 2). Therefore, to increase the lean body mass accretion and limit fat mass deposition in premature infants, an increase in the protein/ energy ratio is mandatory.
Adaptation to Postnatal Age Fetal growth is related to gestational age. Weight gain decreases progressively during the last month of gestation to reach a value close to 10 g/kg/d, with a sharper decrease in LBM gain and protein retention. Therefore, in agreement with studies on protein metabolism in premature infants of various gestational ages, the revised values need to be adapted to the postconceptional age instead of gestational age or birth weight to integrate the dynamic aspect of growth and protein metabolism in the recommendation. Amino Acid Balance The potential risk of a more aggressive nutritional strategy is to induce metabolic stress resulting from protein overload or unbalanced amino acid supply. Therefore the most recent technologies have to be applied to improve nitrogen bioavailability, by reducing Maillard reactions and providing the most balanced amino acid composition. Nutritional Needs Of Premature Infants: Current Issues
The whey/casein ratio significantly influences the individual amino acid intakes and, consequently, the plasma amino acid concentrations. Plasma threonine is increased and tryptophan relatively decreased in infants fed whey-predominant formula, whereas methionine and aromatic amino acids are increased in those fed casein-predominant formula.23,24 Use of acidic whey removes the glycomacropeptide and reduces the threonine content, and together with increasing the relative percentage of alpha lactalbumin, they allow improvement of the amino acid balance in premature formula.25-27 Hydrolyzed protein formulas with reduced protein antigenicity recently have been proposed for the feeding of premature infants. However, the use of a higher percentage of whey and the technological processes necessary to perform hydrolysis modifies amino acid content and amino acid bioavailability.20,22 With a more appropriate technology, some of these formulas have been corrected for the threonine content and supplemented with histidine and tryptophan.25,28-30
Revised Protein Recommendation for Premature Infants According to these data, as well as the factorial approach, new recommendations for protein and the protein/ energy ratio can be suggested and are presented in Table III in relation to postconceptional age and the need for catch-up growth.11 The recommended intakes for premature infants 26 to 30 weeks postconceptional age represent 3.8 to 4.4 g of protein/kg/d with a protein/energy ratio between 3.0 to 3.3 g/100 kcal according to their relative postnatal growth restriction. These values are in the range of the recent suggestion from an expert panel from the Life Sciences Research Office and the American Society for Nutritional Sciences, who suggest 3.4 to 4.3 g of protein/kg/d with an energy intake of 120 kcal/kg/d and a protein/energy ratio between 2.5 and 3.6 g/100 kcal.8 S83
Table III. Revised recommended protein intake and protein-energy ratio for premature infants according to postconceptional age and the need for catch-up growth16
26-30 weeks PCA: 16-18 g/kg/d LBM 14% protein retention 30-36 weeks PCA: 14-15 g/kg/d LBM 15% protein retention 36-40 weeks PCA: 13 g/kg/d LBM 17% protein retention
Without need of catch-up growth
With need of catch-up growth
3.8-4.2 g/kg/d PER: ⫾3.0 3.4-3.6 g/kg/d PER: ⫾2.8 2.8-3.2 g/kg/d PER: 2.4-2.6
4.4 g/kg/d PER: ⫾3.3 3.6-4.0 g/kg/d PER: ⫾3.0 3.0-3.4 g/kg/d PER: 2.6-2.8
PCA, Postconceptional age; LBM, lean body mass; PER, protein/energy ratio.
CALCIUM AND PHOSPHORUS REQUIREMENTS Ninety-eight percent of the calcium and 80% of the phosphorus in the body are in the skeleton; these elements are also constituents of the intracellular and extracellular spaces. The metabolic homeostasis of calcium and phosphorus, and the mineralization of the skeleton are complex functions that require the intervention of various parameters: an adequate supply of nutrients, the development of the intestinal absorption process and the effect of several hormones, such as parathyroid hormone, vitamin D and calcitonin, as well as optimum renal and skeletal controls.31,32 Bone formation requires protein and energy for collagen matrix synthesis, and an adequate intake of calcium and phosphorus is necessary for correct mineralization.
Fetal Mineral Accretion During pregnancy there is an active calcium (Ca) transfer from the mother to the fetus. To meet the high demand for mineral requirements of the developing skeleton, the fetus maintains higher blood calcium and phosphorous levels than the ambient maternal levels. This is the result of an active transport of calcium across the placenta by a calcium pump in the basal membrane that maintains a 1:1.4 maternal to fetal calcium gradient. From the carcass analysis of stillbirths and deceased neonates, it has been calculated that during the last trimester of gestation the daily accretion per kilogram of body weight is approximately 120 mg of calcium and 70 mg of phosphorus.16,33 At birth, the whole-body content of a term infant is approximately 30 g of calcium and 16 g of phosphorus. Present Recommendations The current mineral recommendations from various international committees are based on healthy premature infants and designed to provide postnatal accretion during the “stable-growing” period equivalent to the intrauterine gain of a normal fetus. Recently, for premature formulas, a content of 123 to 185 mg/100 kcal of calcium and 80 to 110 mg/100 kcal of phosphorus has been suggested by the Life Sciences Research Office,8 whereas the mineral requirement for VLBW infants has been reviewed by Atkinson and Tsang in 2005.34 S84
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Absorptive Capability of the Gastrointestinal Tract After birth, the use of the gastrointestinal tract to provide all nutrients for growth causes a large reduction in calcium bioavailability. Various factors affect Ca absorption: vitamin D status, solubility of calcium salts, quality and quantity of fat intake. In premature infants, the vitamin D requirements are influenced by the body store at birth, which, in turn, are related to the length of gestation and the maternal store. Numerous mineral balance studies have been performed in premature infants fed human milk or formula (Table IV).32,35 In premature infants fed human milk, calcium absorption ranged from 60% to 70% depending on the calcium intake, whereas calcium retention was related to the phosphorus supply. Supplementation of human milk with phosphorus alone improves calcium retention from 25 to 35 mg/kg/d. When calcium and phosphorus are provided together or as human milk fortifiers, calcium retention reaches 60 mg/kg/d and the recent use of human milk fortifiers containing highly soluble calcium glycerophosphate improves calcium retention up to 90 mg/kg/d (Table IV). In formula-fed infants, calcium absorption usually is less than with human milk, ranging from 35 to 60% of intake. Ca and phosphorus (P) absorption and retention are not related to intakes but rapidly reach a plateau because of a decrease in net absorption. Calcium absorption is related to calcium and fat intakes and various processes used for formula preparation. With ready-to-use liquid formulas, calcium absorption usually is lower than with powder formulas. The high fecal calcium excretion observed in preterm infants fed preterm formulas with high calcium content is not necessarily beneficial as it has been related to impaired fat absorption, increased stool hardness, and prolonged gastrointestinal transit time, all risk factors for necrotizing enterocolitis. Nevertheless, calcium retention close to 90 mg/kg/d presently could be expected in premature infants fed premature formula with a highly soluble calcium content.36 However, those values are still lower compared with the values estimated during the last trimester of gestation (100 to 120 mg/kg/d) and considered as the target mineral accretion for VLBW infants. The Journal of Pediatrics • November 2006
Table IV. Calcium and phosphorous absorption and retention in preterm infants fed human milk without or with human milk fortifier, and preterm formulas HM and HMF
Postnatal age (d) Body weight (g) CGA* (wks) Calcium (mg/kg/d) Intake Stool Absorption Urine Retention Net absorption (%) Phosphorous (mg/kg/d) Intake Stool Absorption Urine Retention Net absorption (%)
Preterm formulas
N ⴝ 36
N ⴝ 22
N ⴝ 23
N ⴝ 31
N ⴝ 37
N ⴝ 27
N ⴝ 20
26.4 ⫾ 9.6 1788 ⫾ 284 34.6 ⫾ 1.6
30.4 ⫾ 1.8 1677 ⫾ 209 34.4 ⫾ 1.1
29.7 ⫾ 8.1 1662 ⫾ 231 34.0 ⫾ 1.3
23.3 ⫾ 12.8 1945 ⫾ 286 34.7 ⫾ 1.6
32.7 ⫾ 15.1 1941 ⫾ 245 35.0 ⫾ 1.8
32.5 ⫾ 10.5 1764 ⫾ 244 33.8 ⫾ 1.6
32.7 ⫾ 8.9 1648 ⫾ 114 33.9 ⫾ 1.3
56.4 ⫾ 9.0 21.0 ⫾ 10.3 35.3 ⫾ 8.8 7.0 ⫾ 6.4 28.3 ⫾ 9.3 63.5 ⫾ 15.2
85.5 ⫾ 7.6 26.2 ⫾ 16.4 59.3 ⫾ 16.4 5.8 ⫾ 4.5 53.4 ⫾ 15.6 69.4 ⫾ 18.8
138.4 ⫾ 27.9 56.3 ⫾ 28.7 82.0 ⫾ 26.6 5.0 ⫾ 4.0 77.1 ⫾ 25.4 59.9 ⫾ 17.3
80.5 ⫾ 6.7 39.7 ⫾ 11.1 40.8 ⫾ 13.8 2.1 ⫾ 1.5 38.8 ⫾ 13.9 50.2 ⫾ 15.1
101.0 ⫾ 8.0 46.8 ⫾ 15.1 54.2 ⫾ 13.0 3.2 ⫾ 2.4 50.9 ⫾ 13.1 53.9 ⫾ 13.1
134.5 ⫾ 7.3 72.6 ⫾ 21.9 61.8 ⫾ 17.8 4.9 ⫾ 3.2 57.0 ⫾ 18.1 46.4 ⫾ 14.6
165.9 ⫾ 9.5 103.2 ⫾ 22.7 62.7 ⫾ 21.9 4.9 ⫾ 3.9 57.8 ⫾ 21.8 37.8 ⫾ 13.0
40.3 ⫾ 12.2 3.0 ⫾ 1.6 37.4 ⫾ 12.6 7.9 ⫾ 8.2 29.4 ⫾ 9.1 91.7 ⫾ 4.8
55.6 ⫾ 15.0 3.7 ⫾ 1.8 51.9 ⫾ 15.8 6.3 ⫾ 9.6 45.5 ⫾ 14.9 92.3 ⫾ 5.0
84.7 ⫾ 7.4 5.5 ⫾ 2.4 79.2 ⫾ 7.7 19.4 ⫾ 8.9 59.8 ⫾ 11.7 93.4 ⫾ 3.2
59.2 ⫾ 6.5 6.6 ⫾ 3.5 52.5 ⫾ 7.3 14.2 ⫾ 5.8 38.4 ⫾ 7.6 88.6 ⫾ 6.1
68.7 ⫾ 7.6 5.4 ⫾ 2.4 63.3 ⫾ 7.1 18.1 ⫾ 7.3 45.2 ⫾ 7.0 92.1 ⫾ 3.2
86.2 ⫾ 11.7 13.1 ⫾ 8.3 73.2 ⫾ 10.6 22.3 ⫾ 11.0 50.9 ⫾ 8.1 85.1 ⫾ 8.9
94.5 ⫾ 6.3 34.4 ⫾ 10.1 60.1 ⫾ 14.4 8.8 ⫾ 10.6 51.3 ⫾ 8.2 63.1 ⫾ 11.5
HM, Human milk; HMF, human milk supplemented with fortifiers. *Gestational age at the time of the balance.
Physiological Postnatal Changes in Bone Metabolism During gestation, the fetus receives through the placenta an ample provision of nutritional supplies; nitrogen, energy, minerals and vitamins, allowing quick body length growth, around 1.2 cm/week, during the last trimester of gestation. The fetus is maintained hypercalcemic in a highcalcitonin and estrogen environment promoting the modeling/remodeling ratio in favor of modeling and thus increasing the endocortical bone. In addition, according to the mechanostat theory of bone development, fetal bone also is driven by the mechanical force applied to the fetal skeleton during the intrauterine resistance training, represented by the regular fetal kicks against the uterine wall.37,38 Consequently, at term, the newborn skeleton has a high physical density (bone mass divided by bone volume) with high cortical thickness and relatively small marrow cavities. Dual x-ray absorptiometry is becoming the most accurate and precise non-invasive technique for assessing bone mineralization in vivo.39-44 Validation of its use in subjects with low body mass has supported its increasing use in preterm and term infants. Normative data for bone mineral content (BMC) and projected bone area in healthy preterm and term infants close to birth were established, in order to get reference “intrauterine” values.39,43 Bone mineral apparent density (BMAD), calculated as BMC/bone area1.5, an estimation of volumetric bone mineral density in g/cm3, increases according to gestational age, confirming that during the last trimester of gestation, there is a disproportionate mineral accretion.40,41 The mineralized to total bone volume ratio increases continuously, leading to a progressive change in volumetric bone mineral density35 (Figure 3). Nutritional Needs Of Premature Infants: Current Issues
Figure 3. Physiological evolution of dual energy x-ray absorption (DEXA) apparent bone mineral density (BMD) during last trimester of gestation (filled squares) and during first year of life in healthy term infants (upper triangles) compared with that observed in premature infants (open squares and lower triangles). Comparison to evolution suggested by mechanostat theory (frame).38 BMAD, Bone mineral apparent density; BMC, bone mineral content; BA, bone area.
By contrast, at birth, there is an abrupt interruption of the nutrient supply from the mother through the placenta and the nutritional support progressively is provided by the gastrointestinal route. As a result, the relative hypercalcemic fetus becomes a relative hypocalcemic newborn inducing a stimulation of the parathyroid hormone secretion. In addition, there is a large reduction in calcium availability for bone mineralization compared to the prenatal situation. The hormonal environment changes postnatally, because the placental S85
supply of estrogen and many other hormones has been cut off. In addition, mechanical stimulation is likely to be lower postnatally. The infant’s movements typically occur without much resistance, thus putting smaller loads on the skeleton.37,38,42 Therefore there is a need for postnatal adaptation of the skeleton. Thus some of the factors implied in the fetal modeling/remodeling ratio disappear, inducing an increase in endosteal bone resorption. The physical density of long bones, such as the femoral diaphysis, decreases by about 30% during the first six months of life. This mostly is due to an increase in marrow cavity size, which is faster than the increase in the cross-sectional area of the bone cortex. In term infants, these postnatal changes classically have been called “physiological osteoporosis of infancy,” but this appears without an increase in bone fragility. This phenomenon is well-illustrated with the evolution of bone mineral apparent density (BMAD, g/cm3). By contrast to that obtained during fetal life, from birth to the first months of life there is a rapid reduction of BMAD, followed by a stabilization up to the end of the first year of life35,45 (Figure 3). For VLBW infants, there is also at birth an abrupt interruption of the nutrient supply from the mother through the placenta and the nutritional support needs to be provided by parenteral and enteral route. From birth to theoretical term, mineral supplies are far from those provided during fetal life, whereas length and skeletal growth remain relatively high. In addition, the postnatal adaptations of the skeletal system to extrauterine conditions also occur in premature infants, with the difference that they occur earlier than in term babies.41 Thus the process of birth interrupts the active fetal bone mineralization and, combined with the reduction in calcium availability, contributes to a reduction in bone physical density. In this situation, there is a sharp postnatal decrease in BMAD during the early postnatal weeks of life up to discharge close to theoretical term35,46 (Figure 3). These postnatal changes classically have been called “preterm osteopenia⬙ but, contrary to that observed in term infants, these changes are a common event in preterm infants and can be accompanied by an increase in bone fragility and fracture risk.
Spontaneous Early Mineral Catch-up Growth Osteopenia, or rickets, of prematurity seems to be a self-resolving disease quite similar to that observed during adolescence after the initial acceleration of growth. BMC improves spontaneously in most infants and rapid catch-up mineralization is observed after discharge in VLBW infants (Figure 3). At 6 months corrected age, spine and total bone mineral density, corrected for anthropometric values, are in the range of normal term newborn infants.35,47,48 Nevertheless, potential long-term consequences on attainment of peak bone mass are not clearly known. Peak bone mass may be reduced at adulthood but is mainly the result of a persistent growth retardation.49 Thus Fewtrell et al50 found that, at 8 to 12 years of age, former preterm infants were shorter, lighter and had lower BMC than control subjects. However, BMC S86
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Table V. The basis of re-evaluating mineral requirements for premature infants Fetal mineral accretion. Present recommendations. Mineral balances showing limited absorptive capability of the gastrointestinal tract. Physiological changes in bone metabolism at birth, with a stimulation of the remodeling process, inducing a spontaneous reduction in bone mineral density (dual energy x-ray absorption [DEXA] and quantitative ultrasound [QUS]). Spontaneous early catch-up of mineralization during the first months of life.
was appropriate for the body size achieved and was not affected by early diet or human milk feeding.50
Revised Calcium and Phosphorus Recommendation for Premature Infants Up to now, Ca and P requirements in preterm infants usually have been based on demands for matching intrauterine bone mineral accretion rates. Therefore high calcium preterm formulas have been used in spite of the low absorption rate. However, the high fecal calcium excretion has been related to impaired fat absorption, increased stool hardness, and prolonged gastrointestinal transit time, all risk factors for necrotizing enterocolitis. Therefore it is necessary to review the actual recommendation of mineral content for preterm formula (Table V) and to promote the use of calcium sources with a higher fractional absorption rate. More recent consideration of bone physiology suggests that the process of postnatal adaptation could modify the requirements, considering that the remodeling stimulation itself provides a part of the mineral requirement necessary for postnatal bone turnover. The mechanisms of postnatal adaptation of the skeleton are not entirely clear, but it is probably of questionable use to require identical mineral supplies and retention in fetus and preterm infants at similar postconceptional age. Thus, because of the difference between intrauterine and extrauterine conditions, the care of premature infants should not necessarily aim to achieve intrauterine calcium accretion rates. Indeed, in the long run, the skeleton of these infants will adapt to the remodeling stimulation and the mechanical requirements, 2 factors that could reduce the nutritional requirement for calcium. In addition to mineral intake, mechanical stimulation of the skeleton during the neonatal stay would be included in the recommendations.51,52 Considering that calcium retention between 60 to 90 mg/kg/d suppresses the risk of fracture and clinical symptoms of osteopenia, it could become the target accretion rate for preterm infants and a mineral intake between 100 to 160 mg/kg/d of highly absorbed calcium and 60 to 75 mg/kg/d of phosphorus could be recommended.
REFERENCES 1. Lucas A. Long-term programming effects of early nutrition—implications for the preterm infant. J Perinatol 2005; 25(Suppl 2):S2-6.
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2. Jackson AA. Nutrients, growth, and the development of programmed metabolic function. Adv Exp Med Biol 2000;478:41-55. 3. Godfrey KM, Barker DJ. Fetal nutrition and adult disease. Am J Clin Nutr 2000;71:1344S-52S. 4. American Academy of Pediatrics Committee on Nutrition. Nutritional needs of low-birthweight infants. Pediatrics 1985;75:976-86. 5. European Society of Paediatric Gastroenterology and Nutrition, Committee on Nutrition of the Preterm Infant. Nutrition and feeding of preterm infants. Oxford, UK: Blackwell Scientific Publications; Acta Paediatr Scand Suppl 1987;336:1-14. 6. Tsang RC, Lucas A, Uauy R, Zlotkin S, Nutritional needs of the preterm infant: scientific basis and practical guidelines. Baltimore, MD: Williams & Wilkins; 1993. p. 301. 7. Canadian Paediatrics Society & Nutrition Committee. Nutrient needs and feeding of premature infants. Can Med Assoc J 1995;152:1765-85. 8. Klein CJ. Nutrient requirements for preterm infant formulas. J Nutr 2002;132:1395S-577S. 9. Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth retardation: an inevitable consequence of current recommendations in preterm infants? Pediatrics 2001;107:270-3. 10. Rigo J, De Curtis M, Pieltain C. Nutritional assessment and body composition of preterm infants. Semin Neonatol 2002;6:383-91. 11. Rigo J. Protein, amino acid and other nitrogen compounds. In: Tsang RC, Uauy R, Koletzko B, Zlotkin SH, editors. Nutrition of the preterm infant: scientific basis and practice. 3rd ed. Cincinnati: Digital Educational Publishing; 2005. p. 45-80. 12. Lubchenco LO, Hansman C, Boyd E. Intrauterine growth in length and head circumference as estimated from live births at gestational ages from 26 to 42 weeks. Pediatrics 1966;47:403-8. 13. Usher R, McLean F. Intrauterine growth of liveborn Caucasian infants at sea level: standard obtained from measurements in 7 dimensions of infants born between 25 and 44 weeks of gestation. J Pediatr 1969;74:901-10. 14. Thomas P, Peabody J, Turnier V, Clark RH. A new look at intrauterine growth and the impact of race, altitude and gender. Pediatrics 2000;106:e21. 15. Alexander GR, Mor JM, Kogan MD, Leland NL, Kieffer E. Pregnancy outcomes of US-born and foreign-born Japanese Americans. Am J Public Health 1996;86:820-4. 16. Sparks JW. Human intrauterine growth and nutrient accretion. Semin Perinatol 1984;8:74-93. 17. Carlson S.J., Ziegler E.E. Nutrient intake and growth of very low birth weight infants. J Perinatol 1998;18:252-8. 18. Olsen IE, Richardson DK, Schmid CH, Ausman LM, Dwyer JT. Intersite differences in weight growth velocity of extremely premature infants. Pediatrics 2002;110:1125-32. 19. Zello GA, Menendez CE, Rafii M, Clarke R, Wykes LJ, Ball RO, et al. Minimum protein intake for the preterm neonate determined by protein and amino acid kinetics. Pediatr Res 2003;53:338-44. 20. Rigo J, Salle BL, Picaud J-C, Putet G, Senterre J. Nutritional evaluation of protein hydrolysate formulas. Eur J Clin Nutr 1995;49:S26-S38. 21. Rudloff S, Lonnerdal B. Solubility and digestibility of milk proteins in infant formula exposed to different heat treatments. J Pediatr Gastroenterol Nutr 1992;15:25-33. 22. Rigo J, Putet G, Picaud JC, Pieltain C, De Curtis M, Salle BL, et al. Nitrogen balance and plasma amino acids in the evaluation of protein sources for extremely low birthweight infants. In: Ziegler EE, Lucas A, Moro GE, editors. Nutrition of the very low birthweight infant. Nestlé Nutrition Workshop Series, Nestec Ltd, Philadelphia, Pennsylvania: Vevey/Lippincott Williams & Wilkins; 1999;43:139-53. 23. Cooke R, Watson D, Werkman S, Conner C. Effects of type of dietary protein on acid-base status, protein nutritional status, plasma levels of amino acids, and nutrient balance in the very low birth weight infant. J Pediatr 1992;121:444-51. 24. Rigo J, Senterre J. Optimal threonine intake for preterm infants fed on oral or parenteral nutrition. JPEN 1980;4:15-7. 25. Rigo J, Boehm G, Georgi G, Jelinek J, Nyambugabo K, Sawatzki G, et al. An infant formula free of glycomacropeptide prevents hyperthreoninemia in formula-fed preterm infants. J Pediatr Gastroenterol Nutr 2001;32:127-30.
Nutritional Needs Of Premature Infants: Current Issues
26. Heine WE, Klein PD, Reeds PJ. The importance of alpha-lactoalbumin in infant nutrition. J Nutr 1991;121:277-83. 27. Heine W, Radke M, Wutzke KD, Peters E, Kundt G. Alpha-lactalbumin-enriched low-protein infant formulas: a comparison to breast milk feeding. Acta Paediatr 1996;85:1024-8. 28. Picaud JC, Rigo J, Normand S, Lapillonne A, Reygrobellet B, Claris O, et al. Nutritional efficacy of preterm formula with a partially hydrolyzed protein source: a randomized pilot study. J Pediatr Gastroenterol Nutr 2001;32:555-61. 29. Lajoie N, Gauthier SF, Pouliot Y. Improved storage stability of model infant formula by whey peptides fractions. J Agric Food Chem 2001;49:1999-2007. 30. Mihatsh WA, Pohlandt F, Protein hydrolysate formula maintains homeostasis of plasma amino acids in preterm infants. J Pediatr Gastroenterol Nutr 1999;29:406-10. 31. Lobaugh B. Blood calcium and phosphorus regulation. In: Anderson JJB, Garner SC, editors. Calcium and phosphorus in health and disease. Boca Raton: CRC Press; 1996. p. 27-43. 32. Rigo J, De Curtis M, Pieltain C, Picaud JC, Salle BL, Senterre J. Bone mineral metabolism in the micropremie. Clin Perinatol 2000;27:147-70. 33. Widdowson EM. Importance of nutrition in development, with special reference to feeding low-birth-weight infants. In: Sauls HS, Benson JD, editors. Nutritional goals for low-birth-weight infants. Proceedings of the Second Ross Clinical Research Conference, Oct. 2-3, 1980. Columbus, OH: Ross Laboratories; 1982. p. 4-11. 34. Atkinson S, Tsang RC. Calcium and phosphorus. In: Tsang RC, Uauy R, Koletzko B, Zlotkin SH, editors. Nutrition of the preterm infant: scientific basis and practice. 2nd ed. Cincinnati: Digital Educational Publishing; 2005. p. 245-75. 35. Rigo J, De Curtis M. Disorders of calcium, phosphorus and magnesium metabolism. In: Martin RJ, Fanaroff AA, Walsh MC, editors. Neonatalperinatal medicine: diseases of the fetus and infant. 8th ed. Philadelphia: Elsevier; 2006. p. 1492-1523. 36. Carnielli VP, Luijendijk IH, van Goudoever JB, Sulkers EJ, Boerlage AA, Degenhart HJ, et al. Feeding premature newborn infants palmitic acid in amounts and stereoisomeric position similar to that of human milk: effects on fat and mineral balance. Am J Clin Nutr 1995;61:1037-42. 37. Rauch F, Schoenau E. The developing bone: slave or master of its cells and molecules? Pediatr Res 2001;50:309-14. 38. Rauch F, Schoenau E. Skeletal development in premature infants: a review of bone physiology beyond nutritional aspects. Arch Dis Child Fetal Neonatal Ed 2002;86:F82-5. 39. Rigo J, Nyamugabo K, Picaud JC, Gerard P, Pieltain C, De Curtis M. Reference values of body composition obtained by dual energy X-ray absorptiometry in preterm and term neonates. J Pediatr Gastroenterol Nutr 1998;27:184-90. 40. Rigo J, De Curtis M, Nyamugabo K, Pieltain C, Gérard P, Senterre J. Premature bone. In: Bonjour JP, Tsang RC, editors. Nutrition and bone development. Nestlé Nutrition Workshop Series. Vol. 41. Philadelphia: Vevey/Lippincott-Raven; 1999. p. 83-97. 41. Rigo J, De Curtis M, Pieltain C, Picaud JC, Salle BL, Senterre J. Bone mineral metabolism in the micropremie. Clin Perinatol 2000;27:147-70. 42. Miller ME. The bone disease of preterm birth: a biomechanical perspective. Pediatr Res 2003;53:10-5. 43. Koo WW, Walters J, Bush AJ, Chesney RW, Carlson SE. Dual-energy X-ray absorptiometry studies of bone mineral status in newborn infants. J Bone Miner Res 1996;11:997-1002. 44. Koo WW, Walters JC, Hockman EM. Body composition in human infants at birth and postnatally. J Nutr 2000;130:2188-94. 45. De Curtis M, Pieltain C, Studzinski F, Moureau V, Gerard P, Rigo J. Evaluation of weight gain during the first 2 months of life in breast- and formula-fed term infants using dual X-ray absorptiometry. Eur J Pediatr 2001;160:319-20. 46. Pieltain C, De Curtis M, Gerard P, Rigo J. Weight gain composition in preterm infants with dual energy X-ray absorptiometry. Pediatr Res 2001;49:120-4.
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47. Avila-Diaz M, Flores-Huerta S, Martinez-Muniz I, Amato D. Increments in whole body bone mineral content associated with weight and length in pre-term and full-term infants during the first 6 months of life. Arch Med Res 2001;32:288-92. 48. Salle BL, Senterre J, Putet G. Calcium, phosphorus, magnesium and vitamin D requirements in premature infants. In: Salle BL, Swyer PR, editors. Nutrition of the low birthweight infant. Nestlé Nutrition Workshop Series. Vol. 32. Nestec Ltd. New-York: Vevey/Raven Press; 1993. p. 125-34. 49. Zamora SA, Belli DC, Rizzoli R, Slosman DO, Bonjour JP. Lower
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femoral neck bone mineral density in prepubertal former preterm girls. Bone 2001;29:424-7. 50. Fewtrell MS, Cole TJ, Bishop NJ, Lucas A. Neonatal factors predicting childhood height in preterm infants: evidence for a persisting effect of early metabolic bone disease? J Pediatr 2000;137:668-73. 51. Aly H, Moustafa MF, Hassanein SM, Massaro AN, Amer HA, Patel K. Physical activity combined with massage improves bone mineralization in premature infants: a randomized trial. J Perinatol 2004;24:305-9. 52. Eliakim A, Nemet D, Friedland O, Dolfin T, Regev RH. Spontaneous activity in premature infants affects bone strength. J Perinatol 2002;22:650-2.
The Journal of Pediatrics • November 2006
AND JACQUES
SENTERRE, MD, PHD
With the major advances in life-support measures, nutrition has become one the most debated issues in the care of very low birth weight infants. Current nutritional recommendations are based on healthy premature infants and are designed to provide postnatal nutrient retention during the “stable-growing” period equivalent to the intrauterine gain of a normal fetus. However, this reference is still a matter of debate, especially in the field of protein and mineral requirements. Protein requirements recently have been reevaluated, taking into consideration that (1) fetal lean body mass gain and the contribution of protein gain to lean body mass gain appear as more suitable references than does weight gain; (2) an additional protein supply needs to be provided for early catch-up growth, compensating for the cumulative protein deficit developed during the first weeks of life; (3) an increase in the protein-energy ratio is mandatory to improve the lean body mass accretion and to limit fat mass deposition; (4) the fractional nitrogen absorption rate and protein efficiency vary according to the feeding regimens; and (5) recommended dietary protein allowance needs to be adapted for postconceptional age instead of gestational age or birth weight to integrate the dynamic aspect of growth and protein metabolism. Thus recommended intakes for premature infants 26 to 30 weeks postconceptional age are 3.8 to 4.4 g of protein/kg/d with a protein/energy ratio between 3.0 to 3.3 g/100 kcal, according to their relative postnatal growth restrictions and should decrease progressively up to the time of discharge. After birth, there is a dramatic physiological change in bone metabolism resulting from various factors; abrupt reduction in mineral supply, stimulation of parathyroid hormone secretion, change in hormonal environment, and relative reduction in mechanical stimulation. There is a stimulation of the remodeling process, inducing an increase in endosteal bone resorption and a decrease in physical density. In preterm infants, this process of postnatal bone metabolism adaptation modifies the mineral requirements, with the remodeling stimulation itself providing a part of the mineral requirement necessary for postnatal bone turnover. In extrauterine conditions, the care of premature infants should not necessarily aim to achieve intrauterine calcium accretion rates. Considering long-term appropriate mineralization and the fact that calcium retention between 60 to 90 mg/kg/d suppresses the risk of fracture and clinical symptoms of osteopenia, a mineral intake between 100 to 160 mg/kg/d of highly-absorbed calcium and 60 to 75 mg/kg/d of phosphorus could be recommended. (J Pediatr 2006;149:S80-S88)
ver the past decades there has been a dramatic increase in the survival of premature infants, especially very low birth weight (VLBW) infants. With the major advances in life-support measures, nutrition has become one the most debated issues in the care of low birth weight infants; in this regard, several reports have shown the important effect of nutrition during Supported in part by a Bristol-Myers the first period of life on early and late outcome.1-3 Although the general objective of a Squibb/Mead Johnson unrestricted grant nutritional regimen for premature infants is to support life and achieve a growth rate and by a grant from the Léon Frédéricq foundation of the University of Liège. sufficient to fulfill the individual’s genetic potential, there are many controversies on how From the Pediatrics and Neonatal Departto attain this goal. In this article, we discuss the most important features regarding the ments, University of Liège. nutrition of premature, and particularly VLBW infants, outlining the main aspects of Presented as part of a symposium recogprotein and mineral requirements. nizing the 25th anniversary of the Bristol-
O
PROTEIN REQUIREMENT Present Recommendations The recommended nutrient intakes of premature infants are still a matter of debate, arising from the lack of consensus on the short- and long-term objectives for early BMAD BMC BW Ca
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Bone mineral apparent density Bone mineral content Body weight Calcium
LBM P VLBW
Lean body mass Phosphorus Very low birth weight
Myers Squibb Freedom to Discover Nutrition Grants Program held June 7-8, 2005 at the University of Cincinnati, Cincinnati, OH. Submitted for publication Apr 14, 2006; accepted Jun 1, 2006. Reprint requests: Jacques Rigo, MD, PhD, Pediatrics and Neonatal Department - University of Liège, CHR Citadelle, Boulevard du 12e de ligne 1, 4000 Liège, Belgium. E-mail: [email protected]. 0022-3476/$ - see front matter Copyright © 2006 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2006.06.057
Table I. The basis of reevaluating protein requirements for premature infants Previous recommendations Fetal reference related to lean body mass and protein gain instead of weight gain Need for the compensation of the initial protein gap and early catch-up growth All protein supplies are not equivalent in terms of net protein use: affected by immaturity, protein quality and technological processes Protein-energy ratio affects protein deposition and relative lean body mass gain Adaptation to postconceptional age Amino Acid (AA) requirements instead of protein requirement need additional evaluations in enteral and parenteral nutrition (optimal AA composition)
nutrition. Current nutritional recommendations from various international committees4-8 are based on healthy premature infants and designed to provide postnatal nutrient retention during the “stable-growing” period equivalent to the intrauterine gain of a normal fetus. They do not take into consideration the relatively long transitional period that induces the cumulative nutritional deficit and the need to obtain an early catch-up growth. In practice, the shorter the gestation of a neonate the more challenging are the influences of immaturity and the accompanying morbidity on nutritional supply during the first weeks of life.9,10 As a result of this cumulative nutritional deficit during early life, most growth parameters remain subnormal by the time the premature infant reaches a corrected age of 40 weeks; this phenomenon worsens in the case of VLBW and extremely low birth weight infants, suggesting that the current nutritional recommendations need to be reevaluated, taking into account this early nutritional gap and the need for early catch-up growth (Table I). The goal in estimating the protein requirements of premature infants is to provide the quantity and the quality of protein needed to obtain a growth similar to that observed in the fetus during the third trimester of intrauterine life and to obtain an early postnatal catch-up growth, keeping in mind, that, the accretion of lean body mass need to be considered more than the absolute weight gain.11 Dietary protein requirement for premature infants can be estimated by 2 different methods. The first, the factorial approach, considers the requirements as the sum of the obligatory losses (eg, urine, feces, skin), plus the amount incorporated into newly formed tissues. The second, the empirical approach, measures biochemical or physiological responses to graded intakes.
Fetal Reference In the factorial approach, compositional analysis of fetal tissues has been a valuable source of data for our understanding of the nutrient needs of the fetus, and by extension, those of the growing premature infant. During fetal life, the growth Nutritional Needs Of Premature Infants: Current Issues
velocity is particularly high, approximating 1.6%/day for body weight and 1.0%/day for body length,8,12-15 whereas body composition changes dramatically. Fetal accretion rates have been obtained from compositional analyses of aborted fetuses or stillborn infants.16 At 22 weeks of gestational age, the fetus is composed almost exclusively of lean body mass (LBM). The protein content accounts for 9% of body weight (BW) or LBM. At term, lean body mass represents about 87% of BW with a protein content of 12% of BW or 14% of the LBM.11 From those data, optimal weight gain, lean body mass gain, and protein accretion can be estimated for premature infants of similar gestational age (Figure 1). Considering that fat mass deposition is always significantly higher postnatally, LBM gain is preferable to weight gain in the evaluation of postnatal growth in premature infants. Similarly, the contribution of protein gain to LBM gain instead of weight gain appears as a more suitable reference. As shown in Figure 1, that value increases from 12% to 18% during the last trimester of gestation. From these data, the protein increment for growth has been estimated at a value closer to 2.5 g/kg/d.11
The Postnatal Cumulative Nutritional Deficit Recent nutritional studies focused on the daily energy and protein supplies in premature infants to evaluate the contribution of poor nutrition as rate limiting on growth status at the time of discharge.9,10,17 These studies suggested that the cumulative nutritional deficit explained close to 50% of the reduction in growth Z-scores before discharge and that protein is the main determinant of growth velocity of extremely premature infants.9,18 Therefore protein requirement needs to be calculated, adding to obligatory losses not only the protein requirement for growth but also that needed for the additional catch-up growth. In a large population of preterm infants receiving a controlled energy intake, the minimal protein supply necessary to obtain a zero nitrogen balance (to cover all nitrogen losses) was evaluated at 0.75 g/kg/d.19 A similar value was estimated to cover the need for catch-up growth.9 Thus the protein requirements in VLBW infants, so calculated, reach at least 4 g/kg/d. However, the recommended dietary protein allowance needs to be adapted for fractional absorption rate and protein efficiency, as well as to the need for individual variations. The Net Protein Utilization In premature infants, several factors may influence efficiency of net nitrogen utilization (retained to intake ratio). Recent data suggest that nitrogen absorption (absorbed to intake) and efficiency (retained to absorbed) is influenced by several factors such as quality of the protein supply, as well as by some technical processes as those required for hydrolysis processing and sterilization.20,21 Nitrogen absorption and utilization recently were reviewed on more than 200 metabolic balances performed during the last years in premature infants fed human milk, S81
Figure 1. Weight gain, Lean body mass gain and protein accretion during last trimester of gestation (on left). Contribution of protein gain to body weight (BW) gain and to lean body mass (LBM) gain during the last trimester of gestation (on the right).11
Table II. Nitrogen balances according to feeding regimen in premature infants22
mg/kg/d
Fortified human milk* (n ⴝ 88)
Powder formulas* (n ⴝ 49)
Liquid formulas* (n ⴝ 58)
Hydrolyzed protein formulas* (n ⴝ 31)
Intake Fecal excretion Absorbed Urinary excretion Retained Absorption % Net protein utilization† (%) Protein efficiency‡ (%)
517 ⫾ 86 90 ⫾ 28 428 ⫾ 76 121 ⫾ 45 307 ⫾ 56 82.7 ⫾ 4.8 59.7 ⫾ 7.7 72.1 ⫾ 7.6
522 ⫾ 70 49 ⫾ 19 474 ⫾ 75 106 ⫾ 36 368 ⫾ 57 90.7 ⫾ 3.3 71.5 ⫾ 6.5 77.7 ⫾ 6.4
506 ⫾ 58 71 ⫾ 28 434 ⫾ 52 98 ⫾ 21 337 ⫾ 46 86.0 ⫾ 5.0 66.6 ⫾ 5.8 77.5 ⫾ 4.4
553 ⫾ 56 87 ⫾ 26 466 ⫾ 51 122 ⫾ 39 343 ⫾ 42 84.3 ⫾ 4.0 62.4 ⫾ 6.5 74.0 ⫾ 6.9
*P ⬍ .05. †Nitrogen retention/nitrogen intake. ‡Nitrogen retention/nitrogen absorption.
human milk fortifiers, and various premature formulas.11,22 Data are summarized in Table II. Nitrogen absorption rate (absorbed/intake) differs significantly according to feeding regimen. It was higher with whey protein powder formulas for premature infants (90.7%) than with human milk supplemented with fortifiers (82.7%), hydrolyzed protein powder formulas (84.3%), or ready-to-use predominantly liquid whey formulas for premature infants (86.0%) (Table I). These differences result from the nature of the various protein supplies. In human milk, non-nutritional protein content (lactoferrin, secretory immunoglobulin A, lysozyme) or non-protein nitrogen content (amino-oligosaccharides) are less absorbed than the nutritional protein content (whey proteins, caseins) and contribute to a significant part of the fecal excretion. An interesting observation is the relatively lower absorption rate of ready-to-use liquid formulas or hydrolyzed protein formulas for premature infants, where the technical processes seem to impair nitrogen absorption in relation to heat treatment inducing some Maillard reaction products.21 In addition, with hydrolyzed formulas, the preliminary hydrolysis may alter the physiological absorption process in the lumen or at the border of the gastrointestinal tract.20 S82
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The efficiency of protein gain, estimated by the ratio between retained and metabolizable nitrogen (absorbed), differs also according to the feeding regimen (Table II). The highest values were obtained in premature infants fed powder (77.7%) and liquid (77.5%) formulas. The efficiency was significantly lower in those fed hydrolyzed protein formulas (74.0%) and human milk supplemented with fortifiers (72.1%).22 The lower value obtained with fortified human milk may be related to the non-protein nitrogen (mainly urea) that represents 20% to 25% of the total nitrogen content of human milk and between 13.5% and 17% of the total nitrogen content of fortified human milk (Table II).
The Protein/Energy Ratio Protein and energy needs are reciprocally limiting.11 If there is a surfeit of one, it affects the ability of the infant to assimilate the other. If energy intake is insufficient, protein is used as an energy source, and the nitrogen balance becomes less positive. Increasing the caloric intake will spare the protein loss and improve nitrogen retention, but with limited protein intake, the protein retention reaches a plateau, and the The Journal of Pediatrics • November 2006
Body weight gain=4.66 +5.54*protein intake0.65*(protein-energy ratio) ; r=0.78
Fat Mass gain=0.94 +0.058*Energy intake +0.70* protein energy ratio; r=0.95
3.8 Weight gain (g/kg*d)
3.4 3.0 2.6 2.2 1.8 1.6
2.0
2.4
2.8
3.2
3.6
4.0
4.4
25 22.5 20 17.5 15 12.5 10 7.5 5.0
Protein intake (g/kg*d)
Protein energy ratio (g/100 kcal)
Protein energy ratio (g/100 kcal)
4.2
4.0 3.8 3.6 3.4 3.2 3.0 2.8 2.6 2.4 2.2 2.0 1.8 90
100
110
120
130
140
150
FM gain (g/kg*d) 6.0 5.6 5.2 4.8 4.4 4.0 3.6 3.2 2.8 160 2.4
Energy intake (kcal/kg*d)
Figure 2. Main determinants of protein accretion and whole body composition determined in 27 groups of preterm infants (10 fed fortified human milk and 17 fed preterm formula); n ⫽ 300; birth weight: 1364 ⫾ 116 g, gestational age: 30.7 ⫾ 0.9 weeks).11
energy excess is used for only fat deposition. Nevertheless, when protein supply is satisfactorily close to 4 g/kg/d the effect of energy increase on protein retention appears to be minimal. Analysis of various studies in preterm infants fed human milk, human milk fortifiers, and various preterm formulas11 allows evaluation of the main determinant of weight gain, nitrogen retention, and fat mass deposition. From these data, stepwise regression analysis allows evaluation of the major determinants of weight gain, lean body mass gain, fat accretion, and protein retention. Protein intake and protein energy ratio are the main determinants of weight gain. Protein intake is the only determinant of LBM gain, in contrast to fat mass gain, which is positively related to energy intake and negatively to the protein/energy ratio11 (Figure 2). Therefore, to increase the lean body mass accretion and limit fat mass deposition in premature infants, an increase in the protein/ energy ratio is mandatory.
Adaptation to Postnatal Age Fetal growth is related to gestational age. Weight gain decreases progressively during the last month of gestation to reach a value close to 10 g/kg/d, with a sharper decrease in LBM gain and protein retention. Therefore, in agreement with studies on protein metabolism in premature infants of various gestational ages, the revised values need to be adapted to the postconceptional age instead of gestational age or birth weight to integrate the dynamic aspect of growth and protein metabolism in the recommendation. Amino Acid Balance The potential risk of a more aggressive nutritional strategy is to induce metabolic stress resulting from protein overload or unbalanced amino acid supply. Therefore the most recent technologies have to be applied to improve nitrogen bioavailability, by reducing Maillard reactions and providing the most balanced amino acid composition. Nutritional Needs Of Premature Infants: Current Issues
The whey/casein ratio significantly influences the individual amino acid intakes and, consequently, the plasma amino acid concentrations. Plasma threonine is increased and tryptophan relatively decreased in infants fed whey-predominant formula, whereas methionine and aromatic amino acids are increased in those fed casein-predominant formula.23,24 Use of acidic whey removes the glycomacropeptide and reduces the threonine content, and together with increasing the relative percentage of alpha lactalbumin, they allow improvement of the amino acid balance in premature formula.25-27 Hydrolyzed protein formulas with reduced protein antigenicity recently have been proposed for the feeding of premature infants. However, the use of a higher percentage of whey and the technological processes necessary to perform hydrolysis modifies amino acid content and amino acid bioavailability.20,22 With a more appropriate technology, some of these formulas have been corrected for the threonine content and supplemented with histidine and tryptophan.25,28-30
Revised Protein Recommendation for Premature Infants According to these data, as well as the factorial approach, new recommendations for protein and the protein/ energy ratio can be suggested and are presented in Table III in relation to postconceptional age and the need for catch-up growth.11 The recommended intakes for premature infants 26 to 30 weeks postconceptional age represent 3.8 to 4.4 g of protein/kg/d with a protein/energy ratio between 3.0 to 3.3 g/100 kcal according to their relative postnatal growth restriction. These values are in the range of the recent suggestion from an expert panel from the Life Sciences Research Office and the American Society for Nutritional Sciences, who suggest 3.4 to 4.3 g of protein/kg/d with an energy intake of 120 kcal/kg/d and a protein/energy ratio between 2.5 and 3.6 g/100 kcal.8 S83
Table III. Revised recommended protein intake and protein-energy ratio for premature infants according to postconceptional age and the need for catch-up growth16
26-30 weeks PCA: 16-18 g/kg/d LBM 14% protein retention 30-36 weeks PCA: 14-15 g/kg/d LBM 15% protein retention 36-40 weeks PCA: 13 g/kg/d LBM 17% protein retention
Without need of catch-up growth
With need of catch-up growth
3.8-4.2 g/kg/d PER: ⫾3.0 3.4-3.6 g/kg/d PER: ⫾2.8 2.8-3.2 g/kg/d PER: 2.4-2.6
4.4 g/kg/d PER: ⫾3.3 3.6-4.0 g/kg/d PER: ⫾3.0 3.0-3.4 g/kg/d PER: 2.6-2.8
PCA, Postconceptional age; LBM, lean body mass; PER, protein/energy ratio.
CALCIUM AND PHOSPHORUS REQUIREMENTS Ninety-eight percent of the calcium and 80% of the phosphorus in the body are in the skeleton; these elements are also constituents of the intracellular and extracellular spaces. The metabolic homeostasis of calcium and phosphorus, and the mineralization of the skeleton are complex functions that require the intervention of various parameters: an adequate supply of nutrients, the development of the intestinal absorption process and the effect of several hormones, such as parathyroid hormone, vitamin D and calcitonin, as well as optimum renal and skeletal controls.31,32 Bone formation requires protein and energy for collagen matrix synthesis, and an adequate intake of calcium and phosphorus is necessary for correct mineralization.
Fetal Mineral Accretion During pregnancy there is an active calcium (Ca) transfer from the mother to the fetus. To meet the high demand for mineral requirements of the developing skeleton, the fetus maintains higher blood calcium and phosphorous levels than the ambient maternal levels. This is the result of an active transport of calcium across the placenta by a calcium pump in the basal membrane that maintains a 1:1.4 maternal to fetal calcium gradient. From the carcass analysis of stillbirths and deceased neonates, it has been calculated that during the last trimester of gestation the daily accretion per kilogram of body weight is approximately 120 mg of calcium and 70 mg of phosphorus.16,33 At birth, the whole-body content of a term infant is approximately 30 g of calcium and 16 g of phosphorus. Present Recommendations The current mineral recommendations from various international committees are based on healthy premature infants and designed to provide postnatal accretion during the “stable-growing” period equivalent to the intrauterine gain of a normal fetus. Recently, for premature formulas, a content of 123 to 185 mg/100 kcal of calcium and 80 to 110 mg/100 kcal of phosphorus has been suggested by the Life Sciences Research Office,8 whereas the mineral requirement for VLBW infants has been reviewed by Atkinson and Tsang in 2005.34 S84
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Absorptive Capability of the Gastrointestinal Tract After birth, the use of the gastrointestinal tract to provide all nutrients for growth causes a large reduction in calcium bioavailability. Various factors affect Ca absorption: vitamin D status, solubility of calcium salts, quality and quantity of fat intake. In premature infants, the vitamin D requirements are influenced by the body store at birth, which, in turn, are related to the length of gestation and the maternal store. Numerous mineral balance studies have been performed in premature infants fed human milk or formula (Table IV).32,35 In premature infants fed human milk, calcium absorption ranged from 60% to 70% depending on the calcium intake, whereas calcium retention was related to the phosphorus supply. Supplementation of human milk with phosphorus alone improves calcium retention from 25 to 35 mg/kg/d. When calcium and phosphorus are provided together or as human milk fortifiers, calcium retention reaches 60 mg/kg/d and the recent use of human milk fortifiers containing highly soluble calcium glycerophosphate improves calcium retention up to 90 mg/kg/d (Table IV). In formula-fed infants, calcium absorption usually is less than with human milk, ranging from 35 to 60% of intake. Ca and phosphorus (P) absorption and retention are not related to intakes but rapidly reach a plateau because of a decrease in net absorption. Calcium absorption is related to calcium and fat intakes and various processes used for formula preparation. With ready-to-use liquid formulas, calcium absorption usually is lower than with powder formulas. The high fecal calcium excretion observed in preterm infants fed preterm formulas with high calcium content is not necessarily beneficial as it has been related to impaired fat absorption, increased stool hardness, and prolonged gastrointestinal transit time, all risk factors for necrotizing enterocolitis. Nevertheless, calcium retention close to 90 mg/kg/d presently could be expected in premature infants fed premature formula with a highly soluble calcium content.36 However, those values are still lower compared with the values estimated during the last trimester of gestation (100 to 120 mg/kg/d) and considered as the target mineral accretion for VLBW infants. The Journal of Pediatrics • November 2006
Table IV. Calcium and phosphorous absorption and retention in preterm infants fed human milk without or with human milk fortifier, and preterm formulas HM and HMF
Postnatal age (d) Body weight (g) CGA* (wks) Calcium (mg/kg/d) Intake Stool Absorption Urine Retention Net absorption (%) Phosphorous (mg/kg/d) Intake Stool Absorption Urine Retention Net absorption (%)
Preterm formulas
N ⴝ 36
N ⴝ 22
N ⴝ 23
N ⴝ 31
N ⴝ 37
N ⴝ 27
N ⴝ 20
26.4 ⫾ 9.6 1788 ⫾ 284 34.6 ⫾ 1.6
30.4 ⫾ 1.8 1677 ⫾ 209 34.4 ⫾ 1.1
29.7 ⫾ 8.1 1662 ⫾ 231 34.0 ⫾ 1.3
23.3 ⫾ 12.8 1945 ⫾ 286 34.7 ⫾ 1.6
32.7 ⫾ 15.1 1941 ⫾ 245 35.0 ⫾ 1.8
32.5 ⫾ 10.5 1764 ⫾ 244 33.8 ⫾ 1.6
32.7 ⫾ 8.9 1648 ⫾ 114 33.9 ⫾ 1.3
56.4 ⫾ 9.0 21.0 ⫾ 10.3 35.3 ⫾ 8.8 7.0 ⫾ 6.4 28.3 ⫾ 9.3 63.5 ⫾ 15.2
85.5 ⫾ 7.6 26.2 ⫾ 16.4 59.3 ⫾ 16.4 5.8 ⫾ 4.5 53.4 ⫾ 15.6 69.4 ⫾ 18.8
138.4 ⫾ 27.9 56.3 ⫾ 28.7 82.0 ⫾ 26.6 5.0 ⫾ 4.0 77.1 ⫾ 25.4 59.9 ⫾ 17.3
80.5 ⫾ 6.7 39.7 ⫾ 11.1 40.8 ⫾ 13.8 2.1 ⫾ 1.5 38.8 ⫾ 13.9 50.2 ⫾ 15.1
101.0 ⫾ 8.0 46.8 ⫾ 15.1 54.2 ⫾ 13.0 3.2 ⫾ 2.4 50.9 ⫾ 13.1 53.9 ⫾ 13.1
134.5 ⫾ 7.3 72.6 ⫾ 21.9 61.8 ⫾ 17.8 4.9 ⫾ 3.2 57.0 ⫾ 18.1 46.4 ⫾ 14.6
165.9 ⫾ 9.5 103.2 ⫾ 22.7 62.7 ⫾ 21.9 4.9 ⫾ 3.9 57.8 ⫾ 21.8 37.8 ⫾ 13.0
40.3 ⫾ 12.2 3.0 ⫾ 1.6 37.4 ⫾ 12.6 7.9 ⫾ 8.2 29.4 ⫾ 9.1 91.7 ⫾ 4.8
55.6 ⫾ 15.0 3.7 ⫾ 1.8 51.9 ⫾ 15.8 6.3 ⫾ 9.6 45.5 ⫾ 14.9 92.3 ⫾ 5.0
84.7 ⫾ 7.4 5.5 ⫾ 2.4 79.2 ⫾ 7.7 19.4 ⫾ 8.9 59.8 ⫾ 11.7 93.4 ⫾ 3.2
59.2 ⫾ 6.5 6.6 ⫾ 3.5 52.5 ⫾ 7.3 14.2 ⫾ 5.8 38.4 ⫾ 7.6 88.6 ⫾ 6.1
68.7 ⫾ 7.6 5.4 ⫾ 2.4 63.3 ⫾ 7.1 18.1 ⫾ 7.3 45.2 ⫾ 7.0 92.1 ⫾ 3.2
86.2 ⫾ 11.7 13.1 ⫾ 8.3 73.2 ⫾ 10.6 22.3 ⫾ 11.0 50.9 ⫾ 8.1 85.1 ⫾ 8.9
94.5 ⫾ 6.3 34.4 ⫾ 10.1 60.1 ⫾ 14.4 8.8 ⫾ 10.6 51.3 ⫾ 8.2 63.1 ⫾ 11.5
HM, Human milk; HMF, human milk supplemented with fortifiers. *Gestational age at the time of the balance.
Physiological Postnatal Changes in Bone Metabolism During gestation, the fetus receives through the placenta an ample provision of nutritional supplies; nitrogen, energy, minerals and vitamins, allowing quick body length growth, around 1.2 cm/week, during the last trimester of gestation. The fetus is maintained hypercalcemic in a highcalcitonin and estrogen environment promoting the modeling/remodeling ratio in favor of modeling and thus increasing the endocortical bone. In addition, according to the mechanostat theory of bone development, fetal bone also is driven by the mechanical force applied to the fetal skeleton during the intrauterine resistance training, represented by the regular fetal kicks against the uterine wall.37,38 Consequently, at term, the newborn skeleton has a high physical density (bone mass divided by bone volume) with high cortical thickness and relatively small marrow cavities. Dual x-ray absorptiometry is becoming the most accurate and precise non-invasive technique for assessing bone mineralization in vivo.39-44 Validation of its use in subjects with low body mass has supported its increasing use in preterm and term infants. Normative data for bone mineral content (BMC) and projected bone area in healthy preterm and term infants close to birth were established, in order to get reference “intrauterine” values.39,43 Bone mineral apparent density (BMAD), calculated as BMC/bone area1.5, an estimation of volumetric bone mineral density in g/cm3, increases according to gestational age, confirming that during the last trimester of gestation, there is a disproportionate mineral accretion.40,41 The mineralized to total bone volume ratio increases continuously, leading to a progressive change in volumetric bone mineral density35 (Figure 3). Nutritional Needs Of Premature Infants: Current Issues
Figure 3. Physiological evolution of dual energy x-ray absorption (DEXA) apparent bone mineral density (BMD) during last trimester of gestation (filled squares) and during first year of life in healthy term infants (upper triangles) compared with that observed in premature infants (open squares and lower triangles). Comparison to evolution suggested by mechanostat theory (frame).38 BMAD, Bone mineral apparent density; BMC, bone mineral content; BA, bone area.
By contrast, at birth, there is an abrupt interruption of the nutrient supply from the mother through the placenta and the nutritional support progressively is provided by the gastrointestinal route. As a result, the relative hypercalcemic fetus becomes a relative hypocalcemic newborn inducing a stimulation of the parathyroid hormone secretion. In addition, there is a large reduction in calcium availability for bone mineralization compared to the prenatal situation. The hormonal environment changes postnatally, because the placental S85
supply of estrogen and many other hormones has been cut off. In addition, mechanical stimulation is likely to be lower postnatally. The infant’s movements typically occur without much resistance, thus putting smaller loads on the skeleton.37,38,42 Therefore there is a need for postnatal adaptation of the skeleton. Thus some of the factors implied in the fetal modeling/remodeling ratio disappear, inducing an increase in endosteal bone resorption. The physical density of long bones, such as the femoral diaphysis, decreases by about 30% during the first six months of life. This mostly is due to an increase in marrow cavity size, which is faster than the increase in the cross-sectional area of the bone cortex. In term infants, these postnatal changes classically have been called “physiological osteoporosis of infancy,” but this appears without an increase in bone fragility. This phenomenon is well-illustrated with the evolution of bone mineral apparent density (BMAD, g/cm3). By contrast to that obtained during fetal life, from birth to the first months of life there is a rapid reduction of BMAD, followed by a stabilization up to the end of the first year of life35,45 (Figure 3). For VLBW infants, there is also at birth an abrupt interruption of the nutrient supply from the mother through the placenta and the nutritional support needs to be provided by parenteral and enteral route. From birth to theoretical term, mineral supplies are far from those provided during fetal life, whereas length and skeletal growth remain relatively high. In addition, the postnatal adaptations of the skeletal system to extrauterine conditions also occur in premature infants, with the difference that they occur earlier than in term babies.41 Thus the process of birth interrupts the active fetal bone mineralization and, combined with the reduction in calcium availability, contributes to a reduction in bone physical density. In this situation, there is a sharp postnatal decrease in BMAD during the early postnatal weeks of life up to discharge close to theoretical term35,46 (Figure 3). These postnatal changes classically have been called “preterm osteopenia⬙ but, contrary to that observed in term infants, these changes are a common event in preterm infants and can be accompanied by an increase in bone fragility and fracture risk.
Spontaneous Early Mineral Catch-up Growth Osteopenia, or rickets, of prematurity seems to be a self-resolving disease quite similar to that observed during adolescence after the initial acceleration of growth. BMC improves spontaneously in most infants and rapid catch-up mineralization is observed after discharge in VLBW infants (Figure 3). At 6 months corrected age, spine and total bone mineral density, corrected for anthropometric values, are in the range of normal term newborn infants.35,47,48 Nevertheless, potential long-term consequences on attainment of peak bone mass are not clearly known. Peak bone mass may be reduced at adulthood but is mainly the result of a persistent growth retardation.49 Thus Fewtrell et al50 found that, at 8 to 12 years of age, former preterm infants were shorter, lighter and had lower BMC than control subjects. However, BMC S86
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Table V. The basis of re-evaluating mineral requirements for premature infants Fetal mineral accretion. Present recommendations. Mineral balances showing limited absorptive capability of the gastrointestinal tract. Physiological changes in bone metabolism at birth, with a stimulation of the remodeling process, inducing a spontaneous reduction in bone mineral density (dual energy x-ray absorption [DEXA] and quantitative ultrasound [QUS]). Spontaneous early catch-up of mineralization during the first months of life.
was appropriate for the body size achieved and was not affected by early diet or human milk feeding.50
Revised Calcium and Phosphorus Recommendation for Premature Infants Up to now, Ca and P requirements in preterm infants usually have been based on demands for matching intrauterine bone mineral accretion rates. Therefore high calcium preterm formulas have been used in spite of the low absorption rate. However, the high fecal calcium excretion has been related to impaired fat absorption, increased stool hardness, and prolonged gastrointestinal transit time, all risk factors for necrotizing enterocolitis. Therefore it is necessary to review the actual recommendation of mineral content for preterm formula (Table V) and to promote the use of calcium sources with a higher fractional absorption rate. More recent consideration of bone physiology suggests that the process of postnatal adaptation could modify the requirements, considering that the remodeling stimulation itself provides a part of the mineral requirement necessary for postnatal bone turnover. The mechanisms of postnatal adaptation of the skeleton are not entirely clear, but it is probably of questionable use to require identical mineral supplies and retention in fetus and preterm infants at similar postconceptional age. Thus, because of the difference between intrauterine and extrauterine conditions, the care of premature infants should not necessarily aim to achieve intrauterine calcium accretion rates. Indeed, in the long run, the skeleton of these infants will adapt to the remodeling stimulation and the mechanical requirements, 2 factors that could reduce the nutritional requirement for calcium. In addition to mineral intake, mechanical stimulation of the skeleton during the neonatal stay would be included in the recommendations.51,52 Considering that calcium retention between 60 to 90 mg/kg/d suppresses the risk of fracture and clinical symptoms of osteopenia, it could become the target accretion rate for preterm infants and a mineral intake between 100 to 160 mg/kg/d of highly absorbed calcium and 60 to 75 mg/kg/d of phosphorus could be recommended.
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femoral neck bone mineral density in prepubertal former preterm girls. Bone 2001;29:424-7. 50. Fewtrell MS, Cole TJ, Bishop NJ, Lucas A. Neonatal factors predicting childhood height in preterm infants: evidence for a persisting effect of early metabolic bone disease? J Pediatr 2000;137:668-73. 51. Aly H, Moustafa MF, Hassanein SM, Massaro AN, Amer HA, Patel K. Physical activity combined with massage improves bone mineralization in premature infants: a randomized trial. J Perinatol 2004;24:305-9. 52. Eliakim A, Nemet D, Friedland O, Dolfin T, Regev RH. Spontaneous activity in premature infants affects bone strength. J Perinatol 2002;22:650-2.
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