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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

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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London.org.pediatrics. MD. Isaacs. Those who were randomly assigned to standard parenteral nutrition solution had lower lumbar spine BMC. Nevertheless.a Elizabeth B. E-mail: m. Fewtrell. hip. as indicated by reduced bone mass. In a randomized trial. It is not known whether aluminum exposure has long-term health consequences. MDa aMedical Research Council Childhood Nutrition Research Centre. UK.6% [95% confidence interval 0. 2010 . PhD. Here. apparently explained by a concomitant decrease in bone size. United Kingdom. Copyright © 2009 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.a and Alan Lucas. P 0. United Kingdom KEY WORDS preterm infant. WHAT THIS STUDY ADDS: Neonates who are exposed to parenteral aluminum may have reduced lumbar spine and hip bone mass during adolescence. PhD.fewtrell@ich. University College London Institute of Child Health. bone health. children who were exposed to neonatal aluminum intakes above the median (55 g/kg) had lower hip BMC (by 7. and whole body were measured with dual radiograph absorptiometry in 13. given our previous finding 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.ucl. MRC Childhood Nutrition Research Centre. 2009 Address correspondence to Mary S.ac.pediatrics. In nonrandomized analyses. 1098-4275). RESULTS: Fifty-nine children (32% of survivors) were followed. Sheffield. and bAcademic Unit of Child Health. in the same cohort. Online.1542/peds. Pediatrics 2009. potential risk factors for later osteoporosis and hip fracture.124:1372–1379 1372 FEWTRELL et al Downloaded from www. UCL Institute of Child Health. Sheffield Children’s NHS Foundation Trust. These findings need confirmation in larger. independent of bone (or body) size. Edmonds. MD.21–13. more detailed studies. we showed reduced neurodevelopmental scores in preterm infants who were previously exposed to aluminum from parenteral nutrition solutions. the potential adverse longterm consequences of early aluminum exposure now deserve renewed attention. The potential adverse long-term consequences of early aluminum exposure deserve renewed attention.8]. abstract OBJECTIVE: Aluminum has known neurotoxicity and may impair shortterm bone health.Aluminum Exposure From Parenteral Nutrition in Preterm Infants: Bone Health at 15-Year Follow-up WHAT’S KNOWN ON THIS SUBJECT: Aluminum has neurotoxicity and may impair short-term bone health. parenteral nutrition.a Nick J.1542/peds. Bishop. London WC1N 1EH. Provided by Indonesia:AAP Sponsored on October 11.org/cgi/doi/10.2009-0783 Accepted for publication Jun 9. 0031-4005.2009-0783 doi:10. uk PEDIATRICS (ISSN Numbers: Print. 30 Guilford St. AUTHORS: Mary S. potential risk factors for later osteoporosis and hip fracture. CONCLUSIONS: Neonates who are exposed to parenteral aluminum may have reduced lumbar spine and hip bone mass during adolescence. We showed reduced neurodevelopmental scores in preterm infants who were previously exposed to aluminum from parenteral nutrition solutions.b Caroline J. aluminum ABBREVIATIONS PN—parenteral nutrition DXA— dual-energy x-ray absorptiometry BMC— bone mineral content BA— bone area BMD— bone mineral density LS—lumbar spine WB—whole body BMAD— bone mineral apparent density SDS—SD score www. Fewtrell. MD.to 15-year-olds who were born preterm and randomly assigned standard or aluminum-depleted parenteral nutrition solutions during the neonatal period. we test the hypothesis that neonatal aluminum exposure also adversely affects long-term bone health.02). METHODS: Bone area (BA) and bone mineral content (BMC) of lumbar spine.

4 0. None of these studies tested whether early aluminum exposure might influence long-term bone health and. duced bone formation. and bone disease. pigs.0 1.0 to 4. 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.1 45 g/kg per d 50. METHODS Study subjects were adolescents who were previously randomly assigned to aluminum-depleted versus standard PN solutions during the neonatal period.2 mostly from calcium gluconate solutions stored in glass vials. Our trial.0 — 102 Aluminum Content ( ) Solution Low Aluminum Volume (mL) Aluminum Content ( ) 1. Assigning infants to high levels of aluminum exposure would have been unethical.5 Given the known toxicity of aluminum and the increasing survival of high-risk neonates who require parenteral nutrition (PN).6 1.6 Bone health was not assessed at that stage.3 — — 2. Vitalipid. where complex-forming anions dissolve aluminum from the glass during autoclaving.1. believed to be a key predictor of osteoporosis and fracture risk.1 4. all of which apply frequently to sick or preterm infants.8 — 0.0 0.5 g protein/100 mL. 2010 . we explored whether early exposure to intravenous aluminum has adverse long-term effects on health.3 with high serum. with patchy osteomalacia.3 1. potassium Total aluminum intake at 180 mL/kg per day 50. Using a mixed sodium-potassium phosphate solution instead of potassium acid phosphate further reduced aluminum and minimized the increase in chloride. In this study.0 1. birth weight 1850 g) were recruited from NICUs in Cambridge and Norwich. and tissue levels. therefore.1 1. Provided by Indonesia:AAP Sponsored on October 11. sodium.7 Adults with uremia and those who are on total parenteral nutrition have low bone formation.0 15. and parental consent was obtained. showed that those who were exposed for 10 days to standard solutions had impaired neurologic development at 18 months postterm. excess aluminum accumulates at the mineralization front and is associated with rePEDIATRICS Volume 124. however. in rats. Neotrace was an in-house preparation that contained copper and zinc only. anemia.1 0.1 1. result in reduced bone mass. and Solivito were manufactured by Kabi Vitrum. Randomized Trial A total of 227 preterm infants (gestation 34 weeks. however.1 1.5 0. notably.3 — 8. dogs. United Kingdom. Number 5. a Not available in the United States.org. 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. reflecting use of calcium chloride rather than calcium gluconate. Vitalipid contained fat-soluble vitamins.6 1.1 0.5 15. and Solivito contained water-soluble vitamins. Investigators and staff were blind to the assignments.5 g/kg per d Vamin infant contained essential amino acids without added electrolytes. Parenteral feeding solutions that are used for infants are contaminated with aluminum.4 Increased aluminum concentrations have been observed postmortem in the brain of a parentally fed preterm infant. PN was introduced (typically on postnatal day 2 or 3) and stopped at the discretion of NICU medical staff. infants retain up to 78% of the aluminum.0 0. because standard PN solutions contain significant aluminum.3 0. and adult humans.0 1. The study was approved by the research ethics committee. including detailed records of intravenous fluids 1373 Downloaded from www. Vamin infant. it was ethical for us to conduct a randomized trial to compare these with corresponding solutions specially sourced for low aluminum content. Recognized clinical manifestations of aluminum toxicity. urine.ARTICLES Aluminum is the most common metallic element in the earth’s crust but has no known biological role.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. The composition of the 2 solutions (Table 1) was identical except that the AD solution contained less aluminum and more chloride. renal function is impaired. Data were collected on the neonatal course of each infant. When fed parenterally.pediatrics.2 — — 14. between May 1988 and January 1991.5 102 0. conducted in preterm infants. Intralipid 20%. for instance from older renal dialysis solutions. Infants were eligible for the study when there was a clinical decision to initiate intravenous feeding. 6.0 0. or exposure is high. Intralipid 20% was a fat emulsion that contained 20 g/dL fatty acids. Infants were randomly assigned according to a multiple random permuted-block method to receive either standard (S) or aluminum-depleted (AD) PN solution.0 1.2 2. included progressive dementia. Details are given elsewhere6 but summarized here. It accumulates in the body when protective gastrointestinal mechanisms are bypassed.8 — 38.

GE. Children who were followed had significantly higher birth weight SD score (SDS) than those who were not seen. gender. Weight was measured by using digital scales and height by using a portable stadiometer. RESULTS Comparison of Randomly Assigned Groups Fifty-nine children from the original cohort (26% of those randomly assigned. gender. Downloaded from www. including current physical activity and calcium intake. and (3) multiple regression was used first to examine the effect of PN solution assignment on later bone mass at skeletal sites after adjusting for age. gestation. a simple questionnaire determined hours of weight-bearing activity per week. and ethnic group using United Kingdom machinespecific reference data11. Waukesha. and body size (weight and height) and second to adjust for potential confounding factors. calculated as BMC/BA1. including previous and current medications. or no Bayley performed Received no TPN TPN indicates total parenteral nutrition. Lunar Prodigy. 5 much more active). Provided by Indonesia:AAP Sponsored on October 11. (2) for WB bone mass. 2010 . but there were no other baseline differences (Table 3). bone area (BA) and bone mineral density (BMD) at the lumbar spine (LS. The aluminum content of the PN solutions was measured by graphite-furnace atomic-absorption spectrometry (see Bishop et al6 for details). Total radiation exposure was below daily background levels ( 7 Sv/d in the United Kingdom). Children wore light indoor clothing after removing metal objects. The study was approved by the Great Ormond Street Hospital Research Ethics Committee. a 2-stage procedure was used.pediatrics. As recommended by the International 1374 FEWTRELL et al 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.org.5 SD to be detected at 80% power and 5% significance. Relationships between neonatal aluminum exposure and later bone mass were also examined in a nonrandomized manner. and parents rated the child’s activity level compared with his or her peers (rated 1–5: 1 much less active. hips. Bone Densitometry Dual-energy radiograph absorptiometry (DXA. 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). allowing coefficients to be expressed as percentages (sympercents12). the indices lean/height3 and BMC/lean0.and PN. pubertal stage. A food frequency questionnaire quantified current calcium intake (Calquest9). Children with neurologic impairment or a previous Bailey score of 85 were excluded. 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. Multiple regression was used with backward elimination of nonsignificant variables (P . 32% of survivors. were calculated for age.05). Continuous variables were transformed to natural logarithms for regression analyses. WI) was used to measure bone mineral content (BMC). Statistics Groups were compared using t test or 2 test.5. and clinical events. Some variables were transformed to ensure normal distribution. Written informed consent was obtained from a parent and written assent from the child. by using total neonatal aluminum exposure from PN as both a continuous and a dichotomous variable. The target sample size of 64 per group at follow-up would allow a difference of 0. L2–L4). was calculated for each infant from the daily volume of PN solution. Bone mass was adjusted for size in 3 ways: (1) bone mineral apparent density (BMAD) of the LS. and whole body (WB). BMAD z scores. enteral feeds. expressed as g/kg.7 were calculated by using the power relationships required to remove any residual association with height determined using log-log regression. 33% of those eligible for follow-up) completed the bone health protocol (Table 2). Neonatal data for those who were followed up (Table 4) showed that the randomly assigned groups were well matched for birth weight.10 we used “total body less head” values for WB scans. Total aluminum exposure from PN. A general medical and fracture history was taken. adjusting for potential confounders including PN duration and factors related to neonatal illness severity.

8) Not Seen at 15 y (n 168) 1204 (311) 0. mean (SD). weight SDS. wk Boys. All infants required ventilatory support.496 . 75th centiles) a Seen at 15 y (n 59) 1270 (295) 0. mean (SD).10 (0. mean (SD). 46) and 4 and 152 g/kg for the AD group and 21. The total aluminum exposure from PN as a continuous variable was not a significant predictor of adjusted BMC at any site. 99) 5 (3.758 . by design. mean (SD). 751) and 606 (438.83) 27 (82) 58 (24. g/kg Mean aluminum exposure from PN.ARTICLES TABLE 3 Neonatal Data for Those Seen or not Seen at the Current Follow-up Parameter Birth weight. 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.9 to 3.291 .3 (7. Five group S children and 1 group AD child were using bronchodilators for asthma. and BA (WB BMC 1. after adjusting for relevant neonatal variables (birth weight. Supporting this. n (%) % of enteral intake as breast milk.7% lower in group S [95% confidence interval (CI): 8.8) 14 (6) 39. 75th centile) Suspected NEC. Provided by Indonesia:AAP Sponsored on October 11. 2 were considered equivocal and 1 (from group AD) was confirmed at surgery.99) 28.1 (35.9 (2. with a similar although nonsignificant trend in WB BMC.969 . 75th centile) Days of ventilation. n (%) Days in trial. n (%) Days in study.20) 29.20) 16 (62) 55 (23. of these cases. WB BMD z score. and BMI in AD children (Table 5). Three infants (2 AD and 1 S) devel- oped suspected necrotizing enterocolitis. and days of intravenous feeding) and follow-up 1375 P . n (%) NEC indicates necrotizing enterocolitis.0 (0. 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. November 2009 Downloaded from www.30 (7. weight. respectively.572 . 705) IU/L in groups AD and S. significantly higher in children who received standard feeding solutions. At follow-up. 27) 2 (6) Standard Aluminum (n 26) 1244 (316) 28.619 . The proportion of breast milk in the diet did not differ between groups.774 .org. Socioeconomic and educational indices did not differ between groups. mean (SD) Days to reach enteral full feeds.355 .0) 27 (46) 42 (71) 41 (18) 15 (9) 15 (9) 5 (3. mean (SD). 99) 5 (3. 75th centile) Days in 30% O2.1) 11 (42) 21 (81) 41 (20) 13.782 .139 .2 (9. days in the trial. There were no group differences in WB BMC and hip BMC adjusted for height. gestation.556 .2) 15 (6) 280.6) 3. or maximum alkaline phosphatase (data not shown).0 (2. after adjusting for height. 75th centiles). and LS BA (LS BMC 2. mean (SD). n (%) Singleton. 280 (91.001 for all). 8) 6 (5. pubertal stages.51 (1. weight.013a .00 (0. with values for 24 infants falling into a common range. n (%) Singleton. and (2) LS BMAD z scores.6]). median (25th. with maximum values of 982 and 1087 IU/L. 75th centile) peak alkaline phosphatase concentrations were 609 (502. LS BMD z score.0 (1. WB BMD. 9) P . Number 5. mean (SD) Days of intravenous feeding. days of ventilation. 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. age.273 . hip BMC. Values for the exposure of infants ( g/kg) by randomized group (Fig 1) showed overlap. 41) 1 (4) P . and 1 group S child was also receiving inhaled corticosteroids. median (25th.05.192 teral steroids or any other regular medications. minimum phosphate.pediatrics.5 (8.163 . Total neonatal aluminum exposure from PN expressed in g/kg was.9) 17 (52) 21 (64) 42 (16) 12.4]) and hip BMC 2. we found no difference between groups in (1) LS BMC. mean (SD) Days of ventilation.5% lower [95% CI: 8. mean (SD).6% lower [95% CI: 4. and days of intravenous feeding. mean (SD) Total aluminum exposure from PN. mean (SD) Days to reach full enteral feeds. there were no group differences in gender distribution. 7) 8 (4.8) 21. AD children had significantly higher LS BMC and LS BA.5]) in group S or in lean/height and WB BMC/lean ratios.5 to 3. wk Male. and 19 and 840 g/kg for group S (P . minimum and maximum concentrations in the 2 groups were 3. median (25th. No other significant medical conditions were reported in either group. or anthropometric variables. 28 (17. and hip BA (Table 5). There were no differences in neonatal peak plasma calcium. g Birth weight SDS. with no group differences in duration or time spent in 30% oxygen. Mean (SD).247 .5 to 1.8 (2.712 . 417). although there was a trend toward greater weight. g Gestation. median (25th.4) 91 (54) 125 (74) 38 (23) 14 (11) 14 (6) 4 (2.001 .001 . g/kg per d Received breast milk.680 . Median (25th.999 PEDIATRICS Volume 124. g Gestation.8). median (25th.0 (212. mean (SD) Days of intravenous feeding. Low Aluminum (n 33) 1290 (281) 29. WB BA.883 . 2010 .552 .2).

cm HC SDS BMI.046 (1.724 .5 (10.28) 0.201 .147 .053 (0. g/cm2 LS BMD z score LS BMAD z score Fat mass.976 (0.19 (0.84) 0.5 (5.119) 0. Second.76) P .881 . however.9 (11.6 (8.2) 0.000) 18.1) 39.144 .0 (12.7 Low Aluminum 15. and BA).15 (0. mean (SD). kg Lean mass. the higher hip BMC associated with lower aluminum exposure did not seem to be related to greater bone size.4) 1.8 to 3.70) 55.17) 26. by using the median exposure (55 g/kg) as a cutoff.03) 21.6% [95% CI: 15.101 HC indicates head circumference.080 .1 to 0.50) 26.4 (5. These findings have potential relevance for later osteoporosis and fracture risk.242 .5 (10. g Hip BA. In contrast to the effect on WB and LS bone mass seen in the randomized comparison.234 . height.23 (1.068 .3) 0.9) lower in group S. gender. considering the relatively small sample size.017 .7) 29.8) 31.7) 1.” as a result of early calcium and phosphorus insufficiency. Current calcium intake and physical activity did not predict size-adjusted bone mass (data not shown).29) 163. 2010 .8 (3. MUAC.2 (6. cm2 Hip BMD.pediatrics.086 .7 but no study previously investigated whether such effects persist beyond the period of exposure. This association was not present for any other skeletal site.22 (1. the effect plateaued.18 (15.76) Standard Aluminum 15.27) 0. and BMD during adolescence.5) 41.15 (1.286 .26 (0. P 0. children who were born preterm and randomly assigned to an aluminum-depleted PN solution had significantly higher LS BMC and BA and higher LS BMD.45 (1.2) 0. g LS BA.083) 0.02). First.2) 0.9) 9. The median was chosen as the cutoff to ensure equal numbers in the 2 groups. however.63 (1.102 (0.7 (5. exploratory analyses by using other cutoffs (data not shown) suggested that there was a significant relationship between aluminum intake and hip BMC only once intake exceeded 45 g/kg. adding plausibility to our findings here. kg Weight SDS Height.220) 15.5) 37.665 . we showed that so-called “metabolic bone disease of prematurity.014 (0.org.20) 0.8].07 (1.14 (0. For example. kg Lean/height3 BMC-head/lean0.8 to 3. cm Bone densitometry data. n (%) 3 4 5 Missing Reached menarche.19 (0.992 (0.7) 25. Above this level.040 (0. mean (SD).079) 0.6 (13.114 . mid upper arm circumference.149) 0. Provided by Indonesia:AAP Sponsored on October 11.929 .488 .6% [95% CI: 0. y Pubertal stage (breast/genital development). Short-term adverse effects of aluminum on bone health have been shown in animals and adult humans.94) 29.170 . Children with high exposure had significantly lower hip BMC (by 7.7) and LS BMC was 3. these differences between groups were no longer significant.9 (8.02) 3 (12) 10 (39) 12 (46) 1 (4) 14 (93) 57.98) 0. to look for a “threshold” effect. After adjustment for current body and bone size.4) 0.TABLE 5 Anthropometry and Bone Densitometry Data at Follow-up According to Original Randomly Assigned Group Parameter Age at follow-up. kg/m2 BMI SDS MUAC.2 (5. adjusted WB BMC was 2.03) . n (%) Weight.080 .094) 44.3 (1.8 (4.2) 9.14) 162. cm Height SDS HC. variables (age. For example. No child reported repeated fractures or unusual fragility fractures suggestive of poor bone health.3] lower in group S).8 (3. aluminum exposure was categorized as “low” and “high” by using the median exposure (55 g/kg) as a cutoff.8 (9. g/cm2 WB BMD z score Hip BMC.8) 40.38 (14. WB BMC. cm2 WB BMD less head. cm2 LS BMD.0) 75.2 (7. suggesting that the higher bone mass reflects greater skeletal size in the AD group.02) 0. mean (SD).245 .2) 1.155 DISCUSSION Our study produced 2 principle findings suggesting that exposure to aluminum from standard PN solutions that are used in the neonatal period may impair long-term bone mineralization. mean (SD). mean (SD). BA. in nonrandomized analyses relating neonatal aluminum exposure to later bone outcomes.837 . 10 (33) 9 (30) 10 (33) 1 (3) 16 (100) 63.40 (1. cm Waist circumference.1) 1739 (339) 1769 (215) 0.9) 1909 (355) 1870 (225) 1.482 sure group in both comparisons). g/cm2 LS BMC.3) 73. The largest effect size was seen by using a cutoff of 65 g/kg 1376 FEWTRELL et al (adjusted hip BMC: 9.20 (0.57 (1. Fracture rates were not influenced 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- Downloaded from www.50 (1.1 (3.8 (6.3) 1.031 .9 (6.7% (95% CI: 6. mean (SD).42 (0. is linked to stunting of linear . g WB BA less head.6 (4.8) 0.0% (95% CI: 9.054 .161 .130) 39. however.081 (1.722 .21–13.48 (3.84) 32. we found that hip BMC was reduced in children with aluminum exposure above the median ( 55 g/kg) than in those with lower exposure. mean (SD) WB BMC less head. weight. our work in other areas shows that neonatal influences may have lasting effects on bone health indices.148 .29 (0.03) 55.

our protocol excluded children with known neurologic impairment or with a Bayley score 85. Possibly. somewhat higher than the calculated exposure of infants who PEDIATRICS Volume 124. 2010 . Although the effects of high aluminum exposure on LS BMC seemed to be related primarily to reduced bone size (BA). for example.15 Plausibly. Provided by Indonesia:AAP Sponsored on October 11. This could explain the apparent site-specific effects. aluminum might have neurotoxic effects. Alternatively. It is widely recognized that interventions may have differential effects at different skeletal sites.9 g/kg per day—indeed. Indeed. 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. aluminum exposure might “program” the responsiveness of bone such that. exercise typically 1377 Downloaded from www.org. November 2009 received standard PN solution in our trial. the effects observed here might be another facet of early aluminum neurotoxicity rather than reflect a direct effect on bone. 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 findings have contemporary relevance. In animals. bone remodeling is partly controlled by the central nervous system. by design. affecting central mechanisms that control bone mass.3 to 59. and calculated aluminum exposure in infants 3 kg was 30. little progress has been made on reducing exposure. A direct toxic effect seems unlikely. because bone tissue will have been replaced more than once by age 13 to 15 years. growth later in childhood.pediatrics. If so. For example. because.ARTICLES FIGURE 1 Calculated total aluminum exposure from PN during the neonatal period according to randomized group. effects on hip BMC seemed unrelated to any corresponding stunting of hip bone growth. The mechanism for long-term effects of aluminum on bone health is unclear. In practice. Each symbol represents a single subject. despite greater recognition of aluminum toxicity. children who are exposed to more aluminum form less bone for a given level of mechanical stimulus.13 More recently. with signal transmission to bone cells via the sympathetic nervous system. Number 5. several neuropeptides affect bone formation via the hypothala- mus. then our study may have underestimated the effect of aluminum exposure.

Dahlia Haroun for practical help with the study. Although these obstacles have inhibited progress. which provides no information on bone geometry or structure—likely determinants of bone strength and fracture risk. nevertheless. The long-term clinical significance of the observed effects of early aluminum exposure on bone mass at 13 to 15 years cannot currently be quantified. to consider further reducing aluminum in modern PN solutions. The estimated effect was sizable: hip bone mass was 7. Hence. CONCLUSIONS Neonates who are exposed to parenteral aluminum may have reduced LS and hip bone mass during adolescence. Second. if not greater.pediatrics. 2010 . bias. albeit our subjects were only 5 to 8 years from attaining peak bone mass. considered a powerful predictor of outcome. This is complex1 and may involve 1 of 3 generic approaches: (1) changing (with research and product filing if required) existing PN components to alternatives with lower aluminum. although biologically relevant. perhaps through differential influences on trabecular and cortical bone. yet we recognize that such studies require many years to undertake. who performed and analyzed the DXA scans. potential risk factors for later osteoporosis and hip fracture. children from this cohort who were exposed to higher aluminum intakes had reduced developmental scores. and the children and parents who participated. with an estimated loss of 1 developmental quotient point per day of standard PN. Our findings must be interpreted in the context of the relatively small sample size and multiple comparisons performed and should be confirmed on a larger sample and with additional tools to investigate bone indices. Regarding selection bias. such as organic phosphorus sources (the latter are not currently available in the United States. by the parenteral route. Provided by Indonesia:AAP Sponsored on October 11. if normally distributed. At 18 months of follow-up. 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. This would not be expected to influence the bone outcome differences seen between randomly assigned groups. mineral salts) in plastic vials to reduce contamination from glass. Our randomized trial with long-term follow-up is.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. for instance from occasional albumin infusions. we suggest that it would be prudent.org. used here. Of potential relevance here.7 SD and might have missed smaller. even with existing knowledge. before significant cohort attrition. the only 1 in this area.6% lower when aluminum exposure was above the median. a follow-up rate typical of that reported in other recent long-term cohort studies. if adverse effects of aluminum exposure were seen in these larger infants. We could test only 33% of eligible children (32% of survivors).7 SD lower— 14% of population variance. then the effects on smaller. we note that Hernandez19 suggested that the strongest predictor of osteoporosis risk is peak bone mass. and generalizability. ACKNOWLEDGMENTS This study was supported by a research grant from UK Medical Research Council. The major limitation of our study relates to the inevitable cohort attrition over 15 years since study initiation. and its potential hazards when given unphysiologically. LS BMC was 0. calcium salts).16 whereas leptin has different effects on the trabecular and appendicular skeleton. Aluminum has no known biological purpose. 1378 FEWTRELL et al Downloaded from www. effects. and (3) repackaging of PN components (eg. are widely recognized in other contexts. children who were followed here tended to be those with higher birth weight SDSs.18 With 60 children.affects only loaded bones. given to many thousands of preterm and high-risk infants each year. we had the power to detect a difference of 0. and reappraisal of current practice is now needed.17 Such differential effects cannot be studied by DXA. but we cannot exclude an effect in the nonrandomized analyses. Prof Tim Cole for helpful statistical advice. Tony Murphy for helpful discussions on the formulation of PN. to our knowledge. we suggest that future explanatory studies require additional techniques such as hip structural analysis or pQCT. Given our new findings. increasing safety concerns should now lead to reevaluation of aluminum exposure in current PN. We thank Catherine Wilson. estimating that a 10% increase would delay the onset of osteoporosis by 10 years. more vulnerable infants might be at least as large. we did not quantify all possible sources of parenteral aluminum. and in those who were randomly assigned to standard PN solutions.

Kennedy K. et al. 14(10):843 9. ´ The effect of leptin on bone: an evolving concept of action. Osteoporos Int. 1989.19(22):3109 –3125 Fewtrell MS. Provided by Indonesia:AAP Sponsored on October 11. N Engl J Med. Fuller N. Neonatal factors predicting childhood height in preterm infants: evidence for a persisting effect of early metabolic bone disease? J Pediatr. Primary Prevention by Nutrition Intervention in Infancy and Childhood. Arch Biochem Biophys. Poole RL. Aluminum exposure from pediatric parenteral nutrition: meeting the new FDA regulation. Lucas A. Increased concentration of aluminum in the brain of a parenterally fed preterm infant. Physiol Res.336(22):1557–1561 7. 2000. Zajickova K. Hague GF. 14. et al. Switzerland: Karger. 2008. Cole TJ. Robinson MJ. Day JP. 2009. Bunker VW. 2008. et al. 2009 Cole TJ. Sampson HA.11(1):29 – 42 Crabtree NJ. Kerner JA. Lucas A. Puder M. Accessed September 23. Fewtrell MS. Elefteriou F. Nestle Nutrition Workshop Series Pediatric Program 57. Stat Med. Sympercents: symmetric percentage differences on the 100 log(e) scale simplify the presentation of log transformed data. 11. J Hum Nutr Diet. Theoretical analysis of the relative influences of peak BMD. Hewitt CD. age-related bone loss and menopause on the development of osteoporosis.137(5):668 – 673 Fewtrell MS.45(1):142–149 15. Aluminum neurotoxicity in preterm infants receiving intravenous-feeding solutions. How much loss to follow-up is acceptable in long-term randomised trials and prospective studies? Arch Dis Child. 1994. Morley R. Beyer M. McGraw M. Bishop NJ. Cooper C.com/content/fy43tewe1x4w91x1/ fulltext.9(3):239 –246 2. Mackenzie NI. Braillon P. Number 5. Hintz SR. Fewtrell MS. 2008. Dominguez C. 2010 1379 . 2003.64(9):1316 –1317 6. Aluminum content of milk formulae and intravenous fluids used in infants. Early diet and peak bone mass: 20 year follow-up of a randomized trial of early diet in infants born preterm. 1985. Lancet. O’Hara M. Bishop NJ.135–152 17. Singhal A. 1(8473):157 4.83(1):25–29 5. Curr Opin Clin Nutr Metab Care. Dualenergy X-ray absorptiometry assessment in children and adolescents with diseases that may affect the skeleton: the 2007 ISCD Pediatric Official Positions. Bone. Ballabriga A. Nutrition. springerlink. Metabolic bone disease of total parenteral nutrition. Bishop NJ. 1997. Jameson R. 2004. 1998. Recent developments in aluminum contamination of products used in parenteral nutrition. Arch Dis Child.1(1):115–127 Bishop N. Sedman AB. eds. Murgatroyd PR. 2008. Moreno A.pediatrics. 32(3):242–246 3. Osteoporos Int.93(6): 458 – 461 19. Cirmanova V. JPEN J Parenter Enteral Nutr.org. Acta Paediatr. Singhal A. Gura KM.pdf. Oldroyd B. Switzerland: Nestec Ltd. Regulation of bone remodelling by the central and peripheral nervous system.ARTICLES REFERENCES 1. 1988. Evidence of aluminum loading in infants receiving intravenous therapy.14(1): 149 –152 8. N Engl J Med. Williams JE. 13. Aluminum in the neonate related to parenteral nutrition. Osteoporosis: is primary prevention possible? In: Lucas A. et al. Russell MD. J Clin Densitom. Vevey. November 2009 Downloaded from www. UK Paediatric reference data (GE Lunar Prodigy).57(suppl 1):S143–S151 18. Burnham J. 10. 2000.473(2): 231–236 16. Calcium intake in the elderly: validation of a dietary questionnaire. 1986. 2006. Lucas A. Starka L. Available at: www.312(21):1337–1343 Nelson M. Lendon M. Klein GL. Klein G. Basel. Bishop N. Day JP. 2008. et al. 2006. Hernandez CJ. PEDIATRICS Volume 124. 12. Truscott JG.

Provided by Indonesia:AAP Sponsored on October 11.2009-0783 Updated Information & Services References including high-resolution figures.1372-1379.pediatrics.org/cgi/content/full/124/5/1372 This article cites 17 articles. Bishop. can be found at: http://www.124. tables) or in its entirety can be found online at: http://www.shtml Information about ordering reprints can be found online: http://www.org/misc/reprints. 2009.Aluminum Exposure From Parenteral Nutrition in Preterm Infants: Bone Health at 15-Year Follow-up Mary S. Elizabeth B. Caroline J. appears in the following collection(s): Therapeutics & Toxicology http://www. DOI: 10. Nick J.pediatrics.pediatrics. Fewtrell.pediatrics. along with others on similar topics.1542/peds. Isaacs and Alan Lucas Pediatrics 2009.pediatrics. originally published online Oct 26.org. 2010 . 3 of which you can access for free at: http://www.org/misc/Permissions. Edmonds.shtml Subspecialty Collections Permissions & Licensing Reprints Downloaded from www.org/cgi/content/full/124/5/1372#BIBL This article.pediatrics.org/cgi/collection/therapeutics_and_toxico logy Information about reproducing this article in parts (figures.