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

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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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The potential adverse long-term consequences of early aluminum exposure deserve renewed attention. 2010 . WHAT THIS STUDY ADDS: Neonates who are exposed to parenteral aluminum may have reduced lumbar spine and hip bone mass during adolescence. Fewtrell. Those who were randomly assigned to standard parenteral nutrition solution had lower lumbar spine BMC.02). United Kingdom. and bAcademic Unit of Child Health. 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. MRC Childhood Nutrition Research Centre.fewtrell@ich.124:1372–1379 1372 FEWTRELL et al Downloaded from www. CONCLUSIONS: Neonates who are exposed to parenteral aluminum may have reduced lumbar spine and hip bone mass during adolescence. Isaacs. 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 as indicated by reduced bone mass. independent of bone (or body) size. Edmonds. University College London Institute of Child Health. Fewtrell. children who were exposed to neonatal aluminum intakes above the median (55 g/kg) had lower hip BMC (by 7. potential risk factors for later osteoporosis and hip 15-year-olds who were born preterm and randomly assigned standard or aluminum-depleted parenteral nutrition solutions during the neonatal period. United Kingdom KEY WORDS preterm infant. Pediatrics 2009.a Elizabeth B. In a randomized trial. potential risk factors for later osteoporosis and hip fracture. MD. In nonrandomized analyses.1542/ Caroline J. in the same cohort. 1098-4275). 30 Guilford St. 0031-4005. Sheffield. AUTHORS: Mary S. METHODS: Bone area (BA) and bone mineral content (BMC) of lumbar spine. We showed reduced neurodevelopmental scores in preterm infants who were previously exposed to aluminum from parenteral nutrition solutions. we showed reduced neurodevelopmental scores in preterm infants who were previously exposed to aluminum from parenteral nutrition solutions.a and Alan Lucas. PhD. Online. MDa aMedical Research Council Childhood Nutrition Research Centre.pediatrics. UK. It is not known whether aluminum exposure has long-term health consequences. RESULTS: Fifty-nine children (32% of survivors) were followed. P 0. London. more detailed studies.8]. Provided by Indonesia:AAP Sponsored on October 11. Nevertheless. 2009 Address correspondence to Mary S. UCL Institute of Child Health.2009-0783 Accepted for publication Jun 9. apparently explained by a concomitant decrease in bone size.2009-0783 doi:10. abstract OBJECTIVE: Aluminum has known neurotoxicity and may impair shortterm bone health. we test the hypothesis that neonatal aluminum exposure also adversely affects long-term bone health. MD. Sheffield Children’s NHS Foundation Trust. Here.21–13. hip.6% [95% confidence interval 0. parenteral nutrition. the potential adverse longterm consequences of early aluminum exposure now deserve renewed attention. E-mail: m. bone health.a Nick MD.1542/peds.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. These findings need confirmation in larger. 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. PhD. Bishop. London WC1N 1EH. uk PEDIATRICS (ISSN Numbers: Print.

and Solivito contained water-soluble vitamins.5 102 0. conducted in preterm infants. Vamin infant.0 0.0 0.ARTICLES Aluminum is the most common metallic element in the earth’s crust but has no known biological role.6 Bone health was not assessed at that stage.0 1. Assigning infants to high levels of aluminum exposure would have been unethical.1 4. and parental consent was obtained.1. Vitalipid contained fat-soluble vitamins. and Solivito were manufactured by Kabi Vitrum. Investigators and staff were blind to the assignments. Vitalipid.4 Increased aluminum concentrations have been observed postmortem in the brain of a parentally fed preterm infant. excess aluminum accumulates at the mineralization front and is associated with rePEDIATRICS Volume 124.6 1. Our trial. and tissue Intralipid 20%.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. 2010 . Recognized clinical manifestations of aluminum toxicity.5 15. included progressive dementia.8 — 38. showed that those who were exposed for 10 days to standard solutions had impaired neurologic development at 18 months postterm. infants retain up to 78% of the aluminum. Infants were eligible for the study when there was a clinical decision to initiate intravenous feeding. where complex-forming anions dissolve aluminum from the glass during autoclaving. The composition of the 2 solutions (Table 1) was identical except that the AD solution contained less aluminum and more chloride.3 1. METHODS Study subjects were adolescents who were previously randomly assigned to aluminum-depleted versus standard PN solutions during the neonatal period. reflecting use of calcium chloride rather than calcium gluconate. birth weight 1850 g) were recruited from NICUs in Cambridge and Norwich.2 — — 14. Provided by Indonesia:AAP Sponsored on October 11.1 0. anemia.5 Given the known toxicity of aluminum and the increasing survival of high-risk neonates who require parenteral nutrition (PN). Infants were randomly assigned according to a multiple random permuted-block method to receive either standard (S) or aluminum-depleted (AD) PN solution. The study was approved by the research ethics committee. Data were collected on the neonatal course of each infant. urine. United Kingdom.3 with high serum.5 0. None of these studies tested whether early aluminum exposure might influence long-term bone health and.5 g/kg per d Vamin infant contained essential amino acids without added electrolytes. Number 5.0 to 4. however. Neotrace was an in-house preparation that contained copper and zinc only. Randomized Trial A total of 227 preterm infants (gestation 34 weeks. and bone disease.0 — 102 Aluminum Content ( ) Solution Low Aluminum Volume (mL) Aluminum Content ( ) 1.1 45 g/kg per d 50. dogs.8 — 0.3 — 8.6 1. we explored whether early exposure to intravenous aluminum has adverse long-term effects on health. duced bone formation. it was ethical for us to conduct a randomized trial to compare these with corresponding solutions specially sourced for low aluminum content. notably. in rats. 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. believed to be a key predictor of osteoporosis and fracture risk. When fed parenterally. result in reduced bone mass. however.0 0.5 g protein/100 mL. all of which apply frequently to sick or preterm infants.1 1. with patchy osteomalacia. renal function is impaired.0 15. Parenteral feeding solutions that are used for infants are contaminated with aluminum. 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.0 1.3 0.2 mostly from calcium gluconate solutions stored in glass vials. and adult humans.1 0.1 1.2 2.1 1. 6. Intralipid 20% was a fat emulsion that contained 20 g/dL fatty acids. a Not available in the United States. It accumulates in the body when protective gastrointestinal mechanisms are bypassed.0 1. PN was introduced (typically on postnatal day 2 or 3) and stopped at the discretion of NICU medical staff.3 — — 2. In this study.4 0. potassium Total aluminum intake at 180 mL/kg per day 50.0 1. or exposure is high. because standard PN solutions contain significant aluminum. therefore. Using a mixed sodium-potassium phosphate solution instead of potassium acid phosphate further reduced aluminum and minimized the increase in chloride. Details are given elsewhere6 but summarized here.7 Adults with uremia and those who are on total parenteral nutrition have low bone formation.pediatrics. for instance from older renal dialysis solutions. between May 1988 and January 1991. including detailed records of intravenous fluids 1373 Downloaded from www. sodium. pigs.

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

wk Male. g Birth weight SDS. median (25th. 8) Not Seen at 15 y (n 168) 1204 (311) 0. and 19 and 840 g/kg for group S (P . median (25th. minimum and maximum concentrations in the 2 groups were 3. and days of intravenous feeding. of these cases.001 for all).774 . 75th centile) peak alkaline phosphatase concentrations were 609 (502.83) 27 (82) 58 (24.2).5 (8. g/kg Mean aluminum exposure from PN. 417). with maximum values of 982 and 1087 IU/L.619 .3 (7. with a similar although nonsignificant trend in WB BMC.8) 14 (6) 39.9) 17 (52) 21 (64) 42 (16) 12. AD children had significantly higher LS BMC and LS BA. 2 were considered equivocal and 1 (from group AD) was confirmed at surgery.883 . There were no group differences in WB BMC and hip BMC adjusted for height.0 (212. Provided by Indonesia:AAP Sponsored on October 11. n (%) NEC indicates necrotizing enterocolitis. g Gestation.8).291 .pediatrics.6% lower [95% CI: 4. n (%) Days in trial. after adjusting for relevant neonatal variables (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. Total neonatal aluminum exposure from PN expressed in g/kg was. Mean (SD).5% lower [95% CI: 8. 41) 1 (4) P . 9) P . Median (25th. and hip BA (Table 5).5]) in group S or in lean/height and WB BMC/lean ratios. n (%) % of enteral intake as breast milk. 7) 8 (4.20) 16 (62) 55 (23.8) 21. n (%) Singleton.9 to 3. days of ventilation. weight SDS. The proportion of breast milk in the diet did not differ between groups. 46) and 4 and 152 g/kg for the AD group and 21. there were no group differences in gender distribution. mean (SD).ARTICLES TABLE 3 Neonatal Data for Those Seen or not Seen at the Current Follow-up Parameter Birth weight. 75th centile) Days in 30% O2. and LS BA (LS BMC 2.4]) and hip BMC 2. and (2) LS BMAD z scores. 280 (91. Values for the exposure of infants ( g/kg) by randomized group (Fig 1) showed overlap. or anthropometric variables.5 to 3.05. 751) and 606 (438.758 . wk Boys. mean (SD) Days of intravenous feeding.51 (1. All infants required ventilatory support. n (%) Singleton.001 .556 . WB BMD z score.355 . mean (SD) Total aluminum exposure from PN.10 (0. Supporting this.782 .013a .9 (2. and 1 group S child was also receiving inhaled corticosteroids. 75th centiles) a Seen at 15 y (n 59) 1270 (295) 0.7% lower in group S [95% confidence interval (CI): 8. The total aluminum exposure from PN as a continuous variable was not a significant predictor of adjusted BMC at any site. g Gestation. 75th centiles). mean (SD). and days of intravenous feeding) and follow-up 1375 P .192 teral steroids or any other regular medications. mean (SD). mean (SD) Days of intravenous feeding.969 . days in the trial. mean (SD) Days of ventilation.572 .680 . WB BA.6]). and BMI in AD children (Table 5). median (25th. WB BMD. with no group differences in duration or time spent in 30% oxygen. mean (SD).4) 91 (54) 125 (74) 38 (23) 14 (11) 14 (6) 4 (2.99) 28. by design.496 . 99) 5 (3. mean (SD). significantly higher in children who received standard feeding solutions. Number 5.6) 3. 28 (17. 75th centile) Days of ventilation. No other significant medical conditions were reported in either group.0 (1.999 PEDIATRICS Volume 124. mean (SD) Days to reach full enteral feeds. LS BMD z score.712 . 75th centile) Suspected NEC.139 . and BA (WB BMC 1.001 .30 (7. 2010 .552 . n (%) Days in study. November 2009 Downloaded from www. respectively. with values for 24 infants falling into a common range.163 . pubertal stages. 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. Five group S children and 1 group AD child were using bronchodilators for asthma. median (25th.5 to 1. hip BMC. although there was a trend toward greater weight. 27) 2 (6) Standard Aluminum (n 26) 1244 (316) 28. age. 99) 5 (3. There were no differences in neonatal peak plasma calcium. Socioeconomic and educational indices did not differ between groups.2 (9.00 (0. At follow-up. 8) 6 (5.273 . mean (SD) Days to reach enteral full feeds. 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. 705) IU/L in groups AD and S.0 (0. gestation.247 . g/kg per d Received breast milk.1) 11 (42) 21 (81) 41 (20) 13.1 (35.8 (2. mean (SD).2) 15 (6) 280. Low Aluminum (n 33) 1290 (281) mean (SD). Three infants (2 AD and 1 S) devel- oped suspected necrotizing enterocolitis. weight.0) 27 (46) 42 (71) 41 (18) 15 (9) 15 (9) 5 (3.0 (2. or maximum alkaline phosphatase (data not shown). after adjusting for height.20) 29. median (25th. weight. minimum phosphate. we found no difference between groups in (1) LS BMC.

In contrast to the effect on WB and LS bone mass seen in the randomized comparison.9 (8. however.4 (5.992 (0.2) 0. This association was not present for any other skeletal site.76) Standard Aluminum 15.8 (3.081 (1. BA. 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.7 (5. cm2 Hip BMD.18 (15.02) 0. we showed that so-called “metabolic bone disease of prematurity.8) 31.26 (0. After adjustment for current body and bone size.20) 0.57 (1. however.130) 39. considering the relatively small sample size.5 (10.03) . gender. aluminum exposure was categorized as “low” and “high” by using the median exposure (55 g/kg) as a cutoff.03) 21.881 .5) 37.9) lower in group S.488 .8 to 3. is linked to stunting of linear . kg Lean mass. suggesting that the higher bone mass reflects greater skeletal size in the AD group.6 (8.119) 0.2 (6.28) 0.3) 73.76) P .149) 0.84) . in nonrandomized analyses relating neonatal aluminum exposure to later bone outcomes. 2010 .2) 0.1 to 0.2 (5.19 (0.0 (12. 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.07 (1. g/cm2 LS BMC.42 (0.7) and LS BMC was 3.7) 29. g LS BA.02) 3 (12) 10 (39) 12 (46) 1 (4) 14 (93) 57.7) 1. y Pubertal stage (breast/genital development). adding plausibility to our findings here.9) 1909 (355) 1870 (225) 1. For example.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.170 . we found that hip BMC was reduced in children with aluminum exposure above the median ( 55 g/kg) than in those with lower exposure.040 (0. First. to look for a “threshold” effect.19 (0. our work in other areas shows that neonatal influences may have lasting effects on bone health indices.63 (1.23 (1.083) 0.21–13.70) 55.102 (0.TABLE 5 Anthropometry and Bone Densitometry Data at Follow-up According to Original Randomly Assigned Group Parameter Age at follow-up.6% [95% CI: 15.94) 29.9 (11. g WB BA less head.14) 162. by using the median exposure (55 g/kg) as a cutoff.148 . n (%) Weight.079) 0.7 Low Aluminum 15.665 . kg Lean/height3 BMC-head/lean0.5 (5.22 (1.017 . and BMD during adolescence. mean (SD).14 (0.8 (4. 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.2 (7.101 HC indicates head circumference. 10 (33) 9 (30) 10 (33) 1 (3) 16 (100) 63. and BA).7 but no study previously investigated whether such effects persist beyond the period of exposure.286 . The largest effect size was seen by using a cutoff of 65 g/kg 1376 FEWTRELL et al (adjusted hip BMC: 9.3) 1.722 .48 (3.929 . cm2 LS BMD. Children with high exposure had significantly lower hip BMC (by 7. weight.6 (13.17) 26.15 (0. adjusted WB BMC was 2.3) 0.” as a result of early calcium and phosphorus insufficiency.2) 9.114 . however.8 (9.2) 1.7% (95% CI: 6.080 .8 to 3.8 (6. MUAC.9) 9. mean (SD). variables (age.7) 25.080 . cm Height SDS HC. Provided by Indonesia:AAP Sponsored on October 11. height.45 (1. mean (SD). WB BMC.976 (0. mean (SD).220) 15.29) 163. mean (SD). Second.482 sure group in both comparisons).9 (6.20 (0.144 . cm HC SDS BMI.pediatrics. the higher hip BMC associated with lower aluminum exposure did not seem to be related to greater bone size.2) 0.40 (1. mean (SD).38 (14. mid upper arm circumference.068 .1) 39.6% [95% CI: 0.50 (1. kg/m2 BMI SDS MUAC.245 . g/cm2 LS BMD z score LS BMAD z score Fat mass. Above this level.27) 0.5 (10. the effect plateaued.094) 44. The median was chosen as the cutoff to ensure equal numbers in the 2 groups. n (%) 3 4 5 Missing Reached menarche.8) 0.6 (4. P 0. Short-term adverse effects of aluminum on bone health have been shown in animals and adult humans.1 (3. g/cm2 WB BMD z score Hip BMC.201 . mean (SD) WB BMC less head.242 .014 (0. These findings have potential relevance for later osteoporosis and fracture risk.1) 1739 (339) 1769 (215) 0.234 .054 .147 . g Hip BA. kg Weight SDS Height.000) 18.046 (1.086 . cm Waist circumference.29 (0.053 (0. No child reported repeated fractures or unusual fragility fractures suggestive of poor bone health.02). For example.161 .031 .84) 0. Current calcium intake and physical activity did not predict size-adjusted bone mass (data not shown).724 .8]. cm2 WB BMD less head.0) 75.8 (3.8) 40. these differences between groups were no longer significant. cm Bone densitometry data.15 (1.4) 0.5) 41.3] lower in group S).50) 26.4) 1.98) 0.03) 55.0% (95% CI: 9.3 (1.

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 our protocol excluded children with known neurologic impairment or with a Bayley score 85.3 to 59. with signal transmission to bone cells via the sympathetic nervous system. Each symbol represents a single subject. The mechanism for long-term effects of aluminum on bone health is unclear. then our study may have underestimated the effect of aluminum exposure. Indeed.13 More recently. growth later in childhood.9 g/kg per day—indeed. Provided by Indonesia:AAP Sponsored on October 11. Possibly. Number 5. 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. Alternatively. affecting central mechanisms that control bone mass.15 Plausibly. 2010 . For example. despite greater recognition of aluminum toxicity. Although the effects of high aluminum exposure on LS BMC seemed to be related primarily to reduced bone size (BA). little progress has been made on reducing exposure. It is widely recognized that interventions may have differential effects at different skeletal sites. and calculated aluminum exposure in infants 3 kg was 30. for example. aluminum exposure might “program” the responsiveness of bone such that. effects on hip BMC seemed unrelated to any corresponding stunting of hip bone growth. If so. somewhat higher than the calculated exposure of infants who PEDIATRICS Volume 124.14 Our findings have contemporary relevance. bone remodeling is partly controlled by the central nervous system. This could explain the apparent site-specific effects. because. several neuropeptides affect bone formation via the hypothala- mus. In practice. A direct toxic effect seems unlikely. In animals. children who are exposed to more aluminum form less bone for a given level of mechanical stimulus.ARTICLES FIGURE 1 Calculated total aluminum exposure from PN during the neonatal period according to randomized group. exercise typically 1377 Downloaded from www. aluminum might have neurotoxic effects.pediatrics. the effects observed here might be another facet of early aluminum neurotoxicity rather than reflect a direct effect on bone. November 2009 received standard PN solution in our trial. by design. because bone tissue will have been replaced more than once by age 13 to 15 years.

calcium salts). considered a powerful predictor of outcome. are widely recognized in other contexts. CONCLUSIONS Neonates who are exposed to parenteral aluminum may have reduced LS and hip bone mass during adolescence. Given our new findings. we did not quantify all possible sources of parenteral aluminum. 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. Our randomized trial with long-term follow-up is. with an estimated loss of 1 developmental quotient point per day of standard PN. effects. we suggest that future explanatory studies require additional techniques such as hip structural analysis or pQCT.7 SD and might have missed smaller. Provided by Indonesia:AAP Sponsored on October 11.18 We recently discussed the implications of cohort attrition for data analysis and interpretation and emphasized the importance of explicitly considering effects on study power. potential risk factors for later osteoporosis and hip fracture. and generalizability. and calcium chloride must be used judiciously to avoid precipitation when attempting to provide high intakes of calcium and phosphate). who performed and analyzed the DXA scans.affects only loaded bones. and (3) repackaging of PN components (eg. 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. albeit our subjects were only 5 to 8 years from attaining peak bone mass. and its potential hazards when given unphysiologically. LS BMC was 0. Dahlia Haroun for practical help with the study. we had the power to detect a difference of 0. Hence. bias.17 Such differential effects cannot be studied by DXA. estimating that a 10% increase would delay the onset of osteoporosis by 10 years. if adverse effects of aluminum exposure were seen in these larger infants. before significant cohort attrition. This would not be expected to influence the bone outcome differences seen between randomly assigned then the effects on smaller. for instance from occasional albumin infusions. a follow-up rate typical of that reported in other recent long-term cohort studies. if not greater. but we cannot exclude an effect in the nonrandomized analyses. (2) use of new methods for aluminum removal from PN products (eg. children from this cohort who were exposed to higher aluminum intakes had reduced developmental scores. Of potential relevance here. Tony Murphy for helpful discussions on the formulation of 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. We could test only 33% of eligible children (32% of survivors). although biologically relevant. which provides no information on bone geometry or structure—likely determinants of bone strength and fracture risk. We thank Catherine Wilson. Prof Tim Cole for helpful statistical advice. we note that Hernandez19 suggested that the strongest predictor of osteoporosis risk is peak bone mass. we suggest that it would be prudent. and in those who were randomly assigned to standard PN solutions. 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. Although these obstacles have inhibited progress.7 SD lower— 14% of population variance. Aluminum has no known biological purpose.6% lower when aluminum exposure was above the median. if normally distributed. The estimated effect was sizable: hip bone mass was 7. Second. to consider further reducing aluminum in modern PN solutions. The major limitation of our study relates to the inevitable cohort attrition over 15 years since study initiation. even with existing knowledge. mineral salts) in plastic vials to reduce contamination from glass. At 18 months of follow-up. by the parenteral route. more vulnerable infants might be at least as large. to our knowledge. and reappraisal of current practice is now needed. children who were followed here tended to be those with higher birth weight SDSs. the only 1 in this area. and the children and parents who participated. nevertheless.18 With 60 children. yet we recognize that such studies require many years to undertake.16 whereas leptin has different effects on the trabecular and appendicular skeleton. 2010 . 1378 FEWTRELL et al Downloaded from www. used here.pediatrics. such as organic phosphorus sources (the latter are not currently available in the United States. Regarding selection bias. ACKNOWLEDGMENTS This study was supported by a research grant from UK Medical Research Council. perhaps through differential influences on trabecular and cortical bone.

2008. McGraw M. Dominguez C. 12. Starka L. Truscott JG. Mackenzie NI. Singhal A. Lancet. 2009 Cole TJ. 2008. Zajickova K. Day JP. Acta Paediatr. 13. Switzerland: Karger. Nutrition. Oldroyd B. 1998. et al. 1(8473):157 4. Burnham J. Arch Biochem Biophys. Klein G. Puder M. Metabolic bone disease of total parenteral nutrition. Hernandez CJ. Sedman AB.57(suppl 1):S143–S151 18. Bone. et al.336(22):1557–1561 7. J Clin Densitom. Accessed September 23. Kerner JA. Nestle Nutrition Workshop Series Pediatric Program fulltext. Hague GF. eds. Murgatroyd PR. Robinson MJ. How much loss to follow-up is acceptable in long-term randomised trials and prospective studies? Arch Dis Child. 1986. Recent developments in aluminum contamination of products used in parenteral nutrition. Physiol Res. Theoretical analysis of the relative influences of peak BMD.93(6): 458 – 461 19.312(21):1337–1343 Nelson M. Switzerland: Nestec Ltd. 2000.473(2): 231–236 16. Morley R. Bishop NJ. November 2009 Downloaded from www. 2006. N Engl J Med. et al. Calcium intake in the elderly: validation of a dietary questionnaire. Cirmanova V. Bishop NJ. Bunker VW. Williams JE. Elefteriou F. Hewitt CD. ´ The effect of leptin on bone: an evolving concept of action. 1989.14(1): 149 –152 8. Primary Prevention by Nutrition Intervention in Infancy and Childhood. Hintz SR.1(1):115–127 Bishop N. PEDIATRICS Volume –1317 6. Neonatal factors predicting childhood height in preterm infants: evidence for a persisting effect of early metabolic bone disease? J Pediatr. 32(3):242–246 3. 2004. O’Hara M. 1994. 2003. Curr Opin Clin Nutr Metab Care. Moreno A. Bishop N. 1997. Aluminum in the neonate related to parenteral nutrition. 10. N Engl J Med. Fewtrell MS. Basel. Fewtrell MS. Sampson HA. Russell MD. Regulation of bone remodelling by the central and peripheral nervous system.83(1):25–29 5. 1985. Lucas A. 2006. Poole RL. Aluminum neurotoxicity in preterm infants receiving intravenous-feeding solutions. Aluminum exposure from pediatric parenteral nutrition: meeting the new FDA regulation. Osteoporosis: is primary prevention possible? In: Lucas A. Kennedy K. Dualenergy X-ray absorptiometry assessment in children and adolescents with diseases that may affect the skeleton: the 2007 ISCD Pediatric Official Positions. Gura KM. 11. Fuller N. Lucas A. Osteoporos Int.9(3):239 –246 2. 2000. et al. Stat Med. Vevey. Ballabriga A. 14(10):843 9. Braillon P.19(22):3109 –3125 Fewtrell MS. 2008. 14. Sympercents: symmetric percentage differences on the 100 log(e) scale simplify the presentation of log transformed data. Lendon M. age-related bone loss and menopause on the development of osteoporosis. Increased concentration of aluminum in the brain of a parenterally fed preterm infant. Available at: www. Cole TJ.135–152 17. 2008. 2009. Lucas A. 2010 1379 . JPEN J Parenter Enteral Nutr. Jameson R. 2008. Osteoporos Int. Beyer M.11(1):29 – 42 Crabtree NJ.pdf. Evidence of aluminum loading in infants receiving intravenous therapy.137(5):668 – 673 Fewtrell MS. Cooper C. Early diet and peak bone mass: 20 year follow-up of a randomized trial of early diet in infants born preterm.ARTICLES REFERENCES 1. Provided by Indonesia:AAP Sponsored on October 11.45(1):142–149 15. Bishop NJ. et al. springerlink. Klein GL. UK Paediatric reference data (GE Lunar Prodigy). Aluminum content of milk formulae and intravenous fluids used in infants. Arch Dis Child. Singhal A. Day JP. Number 5. 1988.pediatrics. J Hum Nutr Diet.

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

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