Aluminum Exposure From Parenteral Nutrition in Preterm Infants: Bone Health at 15-Year Follow-up Mary S. Fewtrell, Nick J.

Bishop, Caroline J. Edmonds, Elizabeth B. Isaacs and Alan Lucas Pediatrics 2009;124;1372-1379; originally published online Oct 26, 2009; DOI: 10.1542/peds.2009-0783

The online version of this article, along with updated information and services, is located on the World Wide Web at: http://www.pediatrics.org/cgi/content/full/124/5/1372

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright 2009 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

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Aluminum Exposure From Parenteral Nutrition in Preterm Infants: Bone Health at 15-Year Follow-up
WHATS KNOWN ON THIS SUBJECT: Aluminum has neurotoxicity and may impair short-term bone health. We showed reduced neurodevelopmental scores in preterm infants who were previously exposed to aluminum from parenteral nutrition solutions. It is not known whether aluminum exposure has long-term health consequences. WHAT THIS STUDY ADDS: Neonates who are exposed to parenteral aluminum may have reduced lumbar spine and hip bone mass during adolescence, potential risk factors for later osteoporosis and hip fracture. The potential adverse long-term consequences of early aluminum exposure deserve renewed attention.
AUTHORS: Mary S. Fewtrell, MD,a Nick J. Bishop, MD,b Caroline J. Edmonds, PhD,a Elizabeth B. Isaacs, PhD,a and Alan Lucas, MDa
aMedical Research Council Childhood Nutrition Research Centre, University College London Institute of Child Health, London, United Kingdom; and bAcademic Unit of Child Health, Shefeld Childrens NHS Foundation Trust, Shefeld, United Kingdom

KEY WORDS preterm infant, bone health, parenteral nutrition, aluminum ABBREVIATIONS PNparenteral nutrition DXA dual-energy x-ray absorptiometry BMC bone mineral content BA bone area BMD bone mineral density LSlumbar spine WBwhole body BMAD bone mineral apparent density SDSSD score www.pediatrics.org/cgi/doi/10.1542/peds.2009-0783 doi:10.1542/peds.2009-0783 Accepted for publication Jun 9, 2009 Address correspondence to Mary S. Fewtrell, MD, MRC Childhood Nutrition Research Centre, UCL Institute of Child Health, 30 Guilford St, London WC1N 1EH, UK. E-mail: m.fewtrell@ich.ucl.ac. uk PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright 2009 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no nancial relationships relevant to this article to disclose.

abstract
OBJECTIVE: Aluminum has known neurotoxicity and may impair shortterm bone health. In a randomized trial, we showed reduced neurodevelopmental scores in preterm infants who were previously exposed to aluminum from parenteral nutrition solutions. Here, in the same cohort, we test the hypothesis that neonatal aluminum exposure also adversely affects long-term bone health, as indicated by reduced bone mass. METHODS: Bone area (BA) and bone mineral content (BMC) of lumbar spine, hip, and whole body were measured with dual radiograph absorptiometry in 13- to 15-year-olds who were born preterm and randomly assigned standard or aluminum-depleted parenteral nutrition solutions during the neonatal period. RESULTS: Fifty-nine children (32% of survivors) were followed. Those who were randomly assigned to standard parenteral nutrition solution had lower lumbar spine BMC, apparently explained by a concomitant decrease in bone size. In nonrandomized analyses, children who were exposed to neonatal aluminum intakes above the median (55 g/kg) had lower hip BMC (by 7.6% [95% condence interval 0.2113.8]; P 0.02), independent of bone (or body) size. CONCLUSIONS: Neonates who are exposed to parenteral aluminum may have reduced lumbar spine and hip bone mass during adolescence, potential risk factors for later osteoporosis and hip fracture. These ndings need conrmation in larger, more detailed studies. Nevertheless, given our previous nding of adverse developmental outcome in these individuals and the sizeable number of contemporary infants who undergo intensive neonatal care and are still exposed to aluminum via parenteral feeding solutions, the potential adverse longterm consequences of early aluminum exposure now deserve renewed attention. Pediatrics 2009;124:13721379

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Aluminum is the most common metallic element in the earths crust but has no known biological role. It accumulates in the body when protective gastrointestinal mechanisms are bypassed, renal function is impaired, or exposure is high, all of which apply frequently to sick or preterm infants. Recognized clinical manifestations of aluminum toxicity, for instance from older renal dialysis solutions, included progressive dementia, anemia, and bone disease. Parenteral feeding solutions that are used for infants are contaminated with aluminum,1,2 mostly from calcium gluconate solutions stored in glass vials, where complex-forming anions dissolve aluminum from the glass during autoclaving. When fed parenterally, infants retain up to 78% of the aluminum,3 with high serum, urine, and tissue levels.4 Increased aluminum concentrations have been observed postmortem in the brain of a parentally fed preterm infant.5 Given the known toxicity of aluminum and the increasing survival of high-risk neonates who require parenteral nutrition (PN), we explored whether early exposure to intravenous aluminum has adverse long-term effects on health. Assigning infants to high levels of aluminum exposure would have been unethical; however, because standard PN solutions contain signicant aluminum, it was ethical for us to conduct a randomized trial to compare these with corresponding solutions specially sourced for low aluminum content. Our trial, conducted in preterm infants, showed that those who were exposed for 10 days to standard solutions had impaired neurologic development at 18 months postterm.6 Bone health was not assessed at that stage; however, in rats, pigs, dogs, and adult humans, excess aluminum accumulates at the mineralization front and is associated with rePEDIATRICS Volume 124, Number 5, November 2009

TABLE 1 Composition and Aluminum Content of the Standard and Aluminum-Depleted Intravenous
Feeding Solutions
Component Standard Aluminum Volume (mL) Vamin infanta Intralipid 20% Vitalipida Solivitoa Neotrace Potassium acid phosphate Polyfusor phosphatea Calcium gluconate Calcium chloride Dextrose, sodium, potassium Total aluminum intake at 180 mL/kg per day 50.0 15.0 1.0 1.0 1.6 1.3 8.0 102 Aluminum Content ( ) Solution Low Aluminum Volume (mL) Aluminum Content ( )

1.5 0.1 0.3 0.1 1.2 2.8 38.8 0.1 45 g/kg per d

50.0 1.5 15.0 0.1 1.0 0.3 1.0 0.1 1.6 1.2 14.4 0.3 2.1 0.5 102 0.1 4.0 to 4.5 g/kg per d

Vamin infant contained essential amino acids without added electrolytes; 6.5 g protein/100 mL. Intralipid 20% was a fat emulsion that contained 20 g/dL fatty acids. Vitalipid contained fat-soluble vitamins, and Solivito contained water-soluble vitamins. Neotrace was an in-house preparation that contained copper and zinc only. Vamin infant, Intralipid 20%, Vitalipid, and Solivito were manufactured by Kabi Vitrum. a Not available in the United States.

duced bone formation.7 Adults with uremia and those who are on total parenteral nutrition have low bone formation, with patchy osteomalacia.7 Sedman et al8 found that bone aluminum concentrations were 10 times higher in preterm infants who were fed parenterally for 3 weeks than in control subjects. None of these studies tested whether early aluminum exposure might inuence long-term bone health and, notably, result in reduced bone mass, believed to be a key predictor of osteoporosis and fracture risk. In this study, therefore, we used our trial to test experimentally the hypothesis that neonatal exposure to aluminum in standard PN solutions results in reduced bone mass during adolescence.

METHODS
Study subjects were adolescents who were previously randomly assigned to aluminum-depleted versus standard PN solutions during the neonatal period. Details are given elsewhere6 but summarized here. Randomized Trial A total of 227 preterm infants (gestation 34 weeks, birth weight 1850 g)

were recruited from NICUs in Cambridge and Norwich, United Kingdom, between May 1988 and January 1991. Infants were eligible for the study when there was a clinical decision to initiate intravenous feeding. Infants were randomly assigned according to a multiple random permuted-block method to receive either standard (S) or aluminum-depleted (AD) PN solution. Investigators and staff were blind to the assignments. The study was approved by the research ethics committee, and parental consent was obtained. PN was introduced (typically on postnatal day 2 or 3) and stopped at the discretion of NICU medical staff. The composition of the 2 solutions (Table 1) was identical except that the AD solution contained less aluminum and more chloride, reecting use of calcium chloride rather than calcium gluconate. Using a mixed sodium-potassium phosphate solution instead of potassium acid phosphate further reduced aluminum and minimized the increase in chloride. Data were collected on the neonatal course of each infant, including detailed records of intravenous uids
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and PN, enteral feeds, and clinical events. The aluminum content of the PN solutions was measured by graphite-furnace atomic-absorption spectrometry (see Bishop et al6 for details). Total aluminum exposure from PN, expressed as g/kg, was calculated for each infant from the daily volume of PN solution. Follow-up Study Subjects were invited for follow-up at ages 13 to 15 years to examine longterm effects of the intervention on (1) bone health and (2) cognitive and neurologic outcomes (to be reported separately). Children with neurologic impairment or a previous Bailey score of 85 were excluded. The study was approved by the Great Ormond Street Hospital Research Ethics Committee. Written informed consent was obtained from a parent and written assent from the child. Weight was measured by using digital scales and height by using a portable stadiometer. A food frequency questionnaire quantied current calcium intake (Calquest9); a simple questionnaire determined hours of weight-bearing activity per week, and parents rated the childs activity level compared with his or her peers (rated 15: 1 much less active; 5 much more active). A general medical and fracture history was taken, including previous and current medications. Bone Densitometry Dual-energy radiograph absorptiometry (DXA; Lunar Prodigy, GE, Waukesha, WI) was used to measure bone mineral content (BMC), bone area (BA) and bone mineral density (BMD) at the lumbar spine (LS; L2L4), hips, and whole body (WB). Children wore light indoor clothing after removing metal objects. Total radiation exposure was below daily background levels ( 7 Sv/d in the United Kingdom). As recommended by the International
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TABLE 2 Study Plan

Infants Randomly Assigned Groups Standard Aluminum Total enrolled Died in neonatal period Lost to follow-up by 18 mo Seen at 18 mo Eligible for 15-y follow-up Seen for follow-up Declined or failed to attend No reply to invitation Untraceable Not eligible for 15-y follow-up Previous Bayley score 85 or neurocognitive impairment, or no Bayley performed Received no TPN
TPN indicates total parenteral nutrition.

Low Aluminum 115 13 7 92 92 33 10 24 25 10 8 2

112 14 8 90 85 26 12 24 23 13 10 3

Society for Clinical Densitometry,10 we used total body less head values for WB scans. Statistics Groups were compared using t test or 2 test. Some variables were transformed to ensure normal distribution. The target sample size of 64 per group at follow-up would allow a difference of 0.5 SD to be detected at 80% power and 5% signicance. Bone mass was adjusted for size in 3 ways: (1) bone mineral apparent density (BMAD) of the LS, calculated as BMC/BA1.5, BMAD z scores, were calculated for age, gender, and ethnic group using United Kingdom machinespecic reference data11; (2) for WB bone mass, a 2-stage procedure was used; the indices lean/height3 and BMC/lean0.7 were calculated by using the power relationships required to remove any residual association with height determined using log-log regression; and (3) multiple regression was used rst to examine the effect of PN solution assignment on later bone mass at skeletal sites after adjusting for age, gender, pubertal stage, and body size (weight and height) and second to adjust for potential confounding factors, including current physical activity and calcium intake. Continuous

variables were transformed to natural logarithms for regression analyses, allowing coefcients to be expressed as percentages (sympercents12). Relationships between neonatal aluminum exposure and later bone mass were also examined in a nonrandomized manner, by using total neonatal aluminum exposure from PN as both a continuous and a dichotomous variable. Multiple regression was used with backward elimination of nonsignicant variables (P .05), adjusting for potential confounders including PN duration and factors related to neonatal illness severity.

RESULTS
Comparison of Randomly Assigned Groups Fifty-nine children from the original cohort (26% of those randomly assigned; 32% of survivors; 33% of those eligible for follow-up) completed the bone health protocol (Table 2). Children who were followed had signicantly higher birth weight SD score (SDS) than those who were not seen, but there were no other baseline differences (Table 3). Neonatal data for those who were followed up (Table 4) showed that the randomly assigned groups were well matched for birth weight, gestation,

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TABLE 3 Neonatal Data for Those Seen or not Seen at the Current Follow-up
Parameter Birth weight, mean (SD), g Birth weight SDS, mean (SD), g Gestation, mean (SD), wk Male, n (%) Singleton, n (%) Days in study, mean (SD) Days of intravenous feeding, mean (SD) Days to reach full enteral feeds, mean (SD) Days of ventilation, median (25th, 75th centiles)
a

Seen at 15 y (n 59) 1270 (295) 0.10 (0.99) 28.9 (2.0) 27 (46) 42 (71) 41 (18) 15 (9) 15 (9) 5 (3, 8)

Not Seen at 15 y (n 168) 1204 (311) 0.51 (1.20) 29.0 (2.4) 91 (54) 125 (74) 38 (23) 14 (11) 14 (6) 4 (2, 9)

P .163 .013a .758 .291 .883 .355 .552 .273 .192

teral steroids or any other regular medications. AD children had signicantly higher LS BMC and LS BA, with a similar although nonsignicant trend in WB BMC, WB BA, WB BMD, WB BMD z score, LS BMD z score, hip BMC, and hip BA (Table 5). Size-Adjusted Bone Mass We explored whether the increase in LS BMC was attributable to a concomitant increase in bone size in the AD group. Supporting this, we found no difference between groups in (1) LS BMC, after adjusting for height, weight, and LS BA (LS BMC 2.7% lower in group S [95% condence interval (CI): 8.9 to 3.6]), and (2) LS BMAD z scores. There were no group differences in WB BMC and hip BMC adjusted for height, weight, and BA (WB BMC 1.6% lower [95% CI: 4.5 to 1.4]) and hip BMC 2.5% lower [95% CI: 8.5 to 3.5]) in group S or in lean/height and WB BMC/lean ratios. Neonatal Aluminum Exposure and Bone Mass: Nonrandomized Analyses Calculated neonatal aluminum exposure from PN varied with both the type of solution and duration of parenteral feeding. Values for the exposure of infants ( g/kg) by randomized group (Fig 1) showed overlap, with values for 24 infants falling into a common range. Mean (SD), median (25th, 75th centiles), minimum and maximum concentrations in the 2 groups were 3.0 (0.8), 28 (17, 46) and 4 and 152 g/kg for the AD group and 21.3 (7.2), 280 (91, 417), and 19 and 840 g/kg for group S (P .001 for all). The total aluminum exposure from PN as a continuous variable was not a signicant predictor of adjusted BMC at any site, after adjusting for relevant neonatal variables (birth weight, gestation, days of ventilation, and days of intravenous feeding) and follow-up
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days in the trial, and days of intravenous feeding. There were no differences in neonatal peak plasma calcium, minimum phosphate, or maximum alkaline phosphatase (data not shown). Median (25th, 75th centile) peak alkaline phosphatase concentrations were 609 (502, 751) and 606 (438, 705) IU/L in groups AD and S, respectively, with maximum values of 982 and 1087 IU/L. Total neonatal aluminum exposure from PN expressed in g/kg was, by design, signicantly higher in children who received standard feeding solutions. The proportion of breast milk in the diet did not differ between groups. All infants required ventilatory support, with no group differences in duration or time spent in 30% oxygen. Three infants (2 AD and 1 S) devel-

oped suspected necrotizing enterocolitis; of these cases, 2 were considered equivocal and 1 (from group AD) was conrmed at surgery. Socioeconomic and educational indices did not differ between groups. At follow-up, there were no group differences in gender distribution, pubertal stages, age, or anthropometric variables, although there was a trend toward greater weight, weight SDS, and BMI in AD children (Table 5). Five group S children and 1 group AD child were using bronchodilators for asthma, and 1 group S child was also receiving inhaled corticosteroids. No other signicant medical conditions were reported in either group, and no children were taking oral or paren-

TABLE 4 Neonatal Data for Children Seen at Follow-up According to Original Randomized Group
Parameter Birth weight, mean (SD), g Gestation, mean (SD), wk Boys, n (%) Singleton, n (%) Days in trial, mean (SD) Days of intravenous feeding, mean (SD) Days to reach enteral full feeds, mean (SD) Total aluminum exposure from PN, mean (SD), g/kg Mean aluminum exposure from PN, mean (SD), g/kg per d Received breast milk, n (%) % of enteral intake as breast milk, median (25th, 75th centile) Days of ventilation, median (25th, 75th centile) Days in 30% O2, median (25th, 75th centile) Suspected NEC, n (%)
NEC indicates necrotizing enterocolitis.

Low Aluminum (n 33) 1290 (281) 29.0 (1.9) 17 (52) 21 (64) 42 (16) 12.5 (8.8) 14 (6) 39.1 (35.6) 3.00 (0.83) 27 (82) 58 (24, 99) 5 (3, 8) 6 (5, 27) 2 (6)

Standard Aluminum (n 26) 1244 (316) 28.8 (2.1) 11 (42) 21 (81) 41 (20) 13.2 (9.2) 15 (6) 280.0 (212.8) 21.30 (7.20) 16 (62) 55 (23, 99) 5 (3, 7) 8 (4, 41) 1 (4)

P .556 .619 .680 .247 .712 .774 .572 .001 .001 .139 .782 .969 .496 .999

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TABLE 5 Anthropometry and Bone Densitometry Data at Follow-up According to Original Randomly
Assigned Group
Parameter Age at follow-up, y Pubertal stage (breast/genital development), n (%) 3 4 5 Missing Reached menarche, n (%) Weight, mean (SD), kg Weight SDS Height, mean (SD), cm Height SDS HC, mean (SD), cm HC SDS BMI, mean (SD), kg/m2 BMI SDS MUAC, mean (SD), cm Waist circumference, mean (SD), cm Bone densitometry data, mean (SD) WB BMC less head, g WB BA less head, cm2 WB BMD less head, g/cm2 WB BMD z score Hip BMC, g Hip BA, cm2 Hip BMD, g/cm2 LS BMC, g LS BA, cm2 LS BMD, g/cm2 LS BMD z score LS BMAD z score Fat mass, kg Lean mass, kg Lean/height3 BMC-head/lean0.7 Low Aluminum 15.29 (0.76) Standard Aluminum 15.15 (0.76) P .482

sure group in both comparisons). No child reported repeated fractures or unusual fragility fractures suggestive of poor bone health.

10 (33) 9 (30) 10 (33) 1 (3) 16 (100) 63.18 (15.84) 0.57 (1.29) 163.6 (8.3) 0.40 (1.03) 55.2 (5.2) 0.48 (3.7) 25.6 (13.2) 1.07 (1.50) 26.9 (6.0) 75.0 (12.9) 1909 (355) 1870 (225) 1.014 (0.079) 0.26 (0.84) 32.4 (5.8) 31.1 (3.3) 1.040 (0.094) 44.9 (8.8) 40.5 (5.4) 1.102 (0.119) 0.23 (1.20) 0.046 (1.000) 18.5 (10.5) 41.8 (9.2) 9.45 (1.27) 0.20 (0.02)

3 (12) 10 (39) 12 (46) 1 (4) 14 (93) 57.38 (14.02) 0.15 (1.14) 162.2 (7.4) 0.42 (0.70) 55.3 (1.8) 0.22 (1.03) 21.8 (4.2) 0.50 (1.17) 26.6 (4.3) 73.9 (11.1) 1739 (339) 1769 (215) 0.976 (0.083) 0.19 (0.94) 29.7 (5.7) 29.8 (3.2) 0.992 (0.130) 39.8 (6.5) 37.8 (3.7) 1.053 (0.149) 0.63 (1.28) 0.081 (1.220) 15.5 (10.1) 39.2 (6.9) 9.14 (0.98) 0.19 (0.03)

.155

DISCUSSION
Our study produced 2 principle ndings suggesting that exposure to aluminum from standard PN solutions that are used in the neonatal period may impair long-term bone mineralization. First, children who were born preterm and randomly assigned to an aluminum-depleted PN solution had signicantly higher LS BMC and BA and higher LS BMD, WB BMC, BA, and BMD during adolescence. After adjustment for current body and bone size, these differences between groups were no longer signicant, suggesting that the higher bone mass reects greater skeletal size in the AD group. Second, in nonrandomized analyses relating neonatal aluminum exposure to later bone outcomes, we found that hip BMC was reduced in children with aluminum exposure above the median ( 55 g/kg) than in those with lower exposure. In contrast to the effect on WB and LS bone mass seen in the randomized comparison, the higher hip BMC associated with lower aluminum exposure did not seem to be related to greater bone size. These ndings have potential relevance for later osteoporosis and fracture risk. Short-term adverse effects of aluminum on bone health have been shown in animals and adult humans,7 but no study previously investigated whether such effects persist beyond the period of exposure; however, our work in other areas shows that neonatal inuences may have lasting effects on bone health indices, adding plausibility to our ndings here. For example, we showed that so-called metabolic bone disease of prematurity, as a result of early calcium and phosphorus insufciency, is linked to stunting of linear

.147 .201 .488 .929 .881 .724 .161 .114 .837 .722 .068 .086 .080 .054 .080 .144 .148 .017 .031 .170 .234 .665 .286 .242 .245 .101

HC indicates head circumference; MUAC, mid upper arm circumference.

variables (age, gender, weight, height, and BA); however, to look for a threshold effect, aluminum exposure was categorized as low and high by using the median exposure (55 g/kg) as a cutoff. Children with high exposure had signicantly lower hip BMC (by 7.6% [95% CI: 0.2113.8]; P 0.02). The median was chosen as the cutoff to ensure equal numbers in the 2 groups, considering the relatively small sample size; however, exploratory analyses by using other cutoffs (data not shown) suggested that there was a signicant relationship between aluminum intake and hip BMC only once intake exceeded 45 g/kg. The largest effect size was seen by using a cutoff of 65 g/kg
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(adjusted hip BMC: 9.6% [95% CI: 15.8 to 3.3] lower in group S). Above this level, the effect plateaued. This association was not present for any other skeletal site. For example, by using the median exposure (55 g/kg) as a cutoff, adjusted WB BMC was 2.7% (95% CI: 6.1 to 0.7) and LS BMC was 3.0% (95% CI: 9.8 to 3.9) lower in group S. Current calcium intake and physical activity did not predict size-adjusted bone mass (data not shown). Fracture rates were not inuenced by (1) randomly assigned group or (2) whether aluminum exposure was below or above the median (24% and 23% for lower versus higher aluminum expo-

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FIGURE 1
Calculated total aluminum exposure from PN during the neonatal period according to randomized group. Each symbol represents a single subject.

growth later in childhood.13 More recently, we found an association between greater intakes of breast milk during the neonatal period and higher WB BMC and BA in young adults who were born preterm.14 Our ndings have contemporary relevance. In practice, despite greater recognition of aluminum toxicity, little progress has been made on reducing exposure. Poole et al3 recently concluded that meeting current Food and Drug Administration recommendations to limit aluminum exposure to 5 g/kg per day is impossible in patients who weigh 50 kg by using currently available PN products, and calculated aluminum exposure in infants 3 kg was 30.3 to 59.9 g/kg per dayindeed, somewhat higher than the calculated exposure of infants who
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received standard PN solution in our trial. The mechanism for long-term effects of aluminum on bone health is unclear. A direct toxic effect seems unlikely, because bone tissue will have been replaced more than once by age 13 to 15 years. Possibly, aluminum exposure might program the responsiveness of bone such that, for example, children who are exposed to more aluminum form less bone for a given level of mechanical stimulus. This could explain the apparent site-specic effects. Alternatively, aluminum might have neurotoxic effects, affecting central mechanisms that control bone mass. Indeed, bone remodeling is partly controlled by the central nervous system. In animals, several neuropeptides affect bone formation via the hypothala-

mus, with signal transmission to bone cells via the sympathetic nervous system.15 Plausibly, the effects observed here might be another facet of early aluminum neurotoxicity rather than reect a direct effect on bone. If so, then our study may have underestimated the effect of aluminum exposure, because, by design, our protocol excluded children with known neurologic impairment or with a Bayley score 85. Although the effects of high aluminum exposure on LS BMC seemed to be related primarily to reduced bone size (BA), effects on hip BMC seemed unrelated to any corresponding stunting of hip bone growth. It is widely recognized that interventions may have differential effects at different skeletal sites. For example, exercise typically
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affects only loaded bones,16 whereas leptin has different effects on the trabecular and appendicular skeleton, perhaps through differential inuences on trabecular and cortical bone.17 Such differential effects cannot be studied by DXA, used here, which provides no information on bone geometry or structurelikely determinants of bone strength and fracture risk. Hence, we suggest that future explanatory studies require additional techniques such as hip structural analysis or pQCT. The major limitation of our study relates to the inevitable cohort attrition over 15 years since study initiation. We could test only 33% of eligible children (32% of survivors), a follow-up rate typical of that reported in other recent long-term cohort studies.18 We recently discussed the implications of cohort attrition for data analysis and interpretation and emphasized the importance of explicitly considering effects on study power, bias, and generalizability.18 With 60 children, we had the power to detect a difference of 0.7 SD and might have missed smaller, although biologically relevant, effects. Regarding selection bias, children who were followed here tended to be those with higher birth weight SDSs; nevertheless, if adverse effects of aluminum exposure were seen in these larger infants, then the effects on smaller, more vulnerable infants might be at least as large, if not greater. Second, we did not quantify all possible sources of parenteral aluminum, for instance from occasional albumin infusions. This would not be expected to inuence the bone outcome differences seen between randomly assigned groups, but we

cannot exclude an effect in the nonrandomized analyses. The long-term clinical signicance of the observed effects of early aluminum exposure on bone mass at 13 to 15 years cannot currently be quantied, albeit our subjects were only 5 to 8 years from attaining peak bone mass, considered a powerful predictor of outcome. The estimated effect was sizable: hip bone mass was 7.6% lower when aluminum exposure was above the median, and in those who were randomly assigned to standard PN solutions, LS BMC was 0.7 SD lower 14% of population variance, if normally distributed. Of potential relevance here, we note that Hernandez19 suggested that the strongest predictor of osteoporosis risk is peak bone mass, estimating that a 10% increase would delay the onset of osteoporosis by 10 years.

CONCLUSIONS
Neonates who are exposed to parenteral aluminum may have reduced LS and hip bone mass during adolescence, potential risk factors for later osteoporosis and hip fracture. Our randomized trial with long-term follow-up is, to our knowledge, the only 1 in this area. Our ndings must be interpreted in the context of the relatively small sample size and multiple comparisons performed and should be conrmed on a larger sample and with additional tools to investigate bone indices, yet we recognize that such studies require many years to undertake, and reappraisal of current practice is now needed. At 18 months of follow-up, before signicant cohort attrition, children from this cohort who were exposed to higher aluminum intakes had reduced developmental scores, with

an estimated loss of 1 developmental quotient point per day of standard PN. Aluminum has no known biological purpose, and its potential hazards when given unphysiologically, by the parenteral route, are widely recognized in other contexts. Given our new ndings, we suggest that it would be prudent, even with existing knowledge, to consider further reducing aluminum in modern PN solutions. This is complex1 and may involve 1 of 3 generic approaches: (1) changing (with research and product ling if required) existing PN components to alternatives with lower aluminum, such as organic phosphorus sources (the latter are not currently available in the United States, and calcium chloride must be used judiciously to avoid precipitation when attempting to provide high intakes of calcium and phosphate); (2) use of new methods for aluminum removal from PN products (eg, calcium salts); and (3) repackaging of PN components (eg, mineral salts) in plastic vials to reduce contamination from glass. Although these obstacles have inhibited progress, increasing safety concerns should now lead to reevaluation of aluminum exposure in current PN, given to many thousands of preterm and high-risk infants each year.

ACKNOWLEDGMENTS This study was supported by a research grant from UK Medical Research Council. We thank Catherine Wilson, who performed and analyzed the DXA scans, Prof Tim Cole for helpful statistical advice, Tony Murphy for helpful discussions on the formulation of PN, Dahlia Haroun for practical help with the study, and the children and parents who participated.

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Aluminum Exposure From Parenteral Nutrition in Preterm Infants: Bone Health at 15-Year Follow-up Mary S. Fewtrell, Nick J. Bishop, Caroline J. Edmonds, Elizabeth B. Isaacs and Alan Lucas Pediatrics 2009;124;1372-1379; originally published online Oct 26, 2009; DOI: 10.1542/peds.2009-0783
Updated Information & Services References including high-resolution figures, can be found at: http://www.pediatrics.org/cgi/content/full/124/5/1372 This article cites 17 articles, 3 of which you can access for free at: http://www.pediatrics.org/cgi/content/full/124/5/1372#BIBL This article, along with others on similar topics, appears in the following collection(s): Therapeutics & Toxicology http://www.pediatrics.org/cgi/collection/therapeutics_and_toxico logy Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://www.pediatrics.org/misc/Permissions.shtml Information about ordering reprints can be found online: http://www.pediatrics.org/misc/reprints.shtml

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