Proceedings of the Nutrition Society (2011), 70, 299–304
`g The Authors 2011 First published online 10 June 2011
`
`doi:10.1017/S0029665111000498
`
`The Annual Meeting of the Nutrition Society and BAPEN was held at Harrogate International Centre, Harrogate on 2–3 November 2010
`
`Conference on ‘Malnutrition matters’
`
`Symposium 2: Micronutrients under the microscope
`Aluminium exposure from parenteral nutrition in preterm infants and
`later health outcomes during childhood and adolescence
`
`Mary S. Fewtrell1*, Caroline J. Edmonds2, Elizabeth Isaacs1, Nick J. Bishop3 and Alan Lucas1
`1Childhood Nutrition Research Centre, UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK
`2School of Psychology, University of East London, Stratford Campus, Water Lane, London E15 4LZ, UK
`3Academic Unit of Child Health, Sheffield Children’s Hospital, Sheffield S10 2TH, UK
`
`Aluminium is the most common metallic element, but has no known biological role. It accu-
`mulates in the body when protective gastrointestinal mechanisms are bypassed, renal function
`is impaired, or exposure is high – all of which apply frequently to preterm infants. Recognised
`clinical manifestations of aluminium toxicity include dementia, anaemia and bone disease.
`Parenteral nutrition (PN) solutions are liable to contamination with aluminium, particularly
`from acidic solutions in glass vials, notably calcium gluconate. When fed parenterally, infants
`retain > 75 % of the aluminium, with high serum, urine and tissue levels. Later health effects of
`neonatal intravenous aluminium exposure were investigated in a randomised trial comparing
`standard PN solutions with solutions specially sourced for low aluminium content. Preterm
`infants exposed for > 10 d to standard solutions had impaired neurologic development at 18
`months. At 13–15 years, subjects randomised to standard PN had lower lumbar spine bone
`mass; and, in non-randomised analyses, those with neonatal aluminium intake above the
`median had lower hip bone mass. Given the sizeable number of infants undergoing intensive
`care and still exposed to aluminium via PN, these findings have contemporary relevance. Until
`recently, little progress had been made on reducing aluminium exposure, and meeting Food and
`Drug Administration recommendations (< 5 mg/kg per d) has been impossible in patients < 50 kg
`using available products. Recent advice from the UK Medicines and Healthcare regulatory
`Authority that calcium gluconate in small volume glass containers should not be used for
`repeated treatment in children < 18 years, including preparation of PN, is an important step
`towards addressing this problem.
`
`Parenteral nutrition: Aluminium: Preterm: Cognitive outcome: Bone health
`
`ProceedingsoftheNutritionSociety
`
`Aluminium is the most common metallic element and the
`third most common element after oxygen and silicon. Due
`to its reactivity, aluminium exists mostly in the form of
`ores, and free aluminium is rarely found. Historically,
`aluminium was regarded as more precious than gold or
`silver; Napoleon III was said to have served his most
`honoured guests from aluminium plates while less impor-
`tant visitors ate from gold platters. Aluminium is ubiqui-
`tous, but has no known biological role. Although lifetime
`exposure to aluminium is high, this does not pose problems
`for healthy individuals with normal
`renal
`function.
`
`However, aluminium accumulates in the body when pro-
`tective gastrointestinal mechanisms are bypassed, renal
`function is impaired, or exposure is high; all of these
`situations are found frequently in sick preterm infants who
`are receiving parenteral nutrition (PN)(1).
`
`Health effects of aluminium exposure
`
`Clinical manifestations of aluminium toxicity have been
`recognised for many years,
`and include dementia,
`bone disease and anaemia. These problems were initially
`
`Abbreviations: MDI, Mental Development Index; PN, parenteral nutrition.
`*Corresponding author: Dr Mary S. Fewtrell, fax + 44 2078319903, email m.fewtrell@ich.ucl.ac.uk
`
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`identified in patients with renal impairment exposed to
`high concentrations of aluminium from dialysis solutions
`and phosphate binders, who developed so-called ‘dialysis
`dementia’. Up to 80 % of patients with dialysis dementia
`exhibit motor impairment, with myoclonic jerks, ataxia and
`dyspraxia(2). Cortical atrophy of the frontal lobes has been
`reported on brain scans(3) and autopsy studies of patients
`have shown particularly high concentrations of aluminium
`in grey matter(4). Bolla et al.(5) performed detailed neuro-
`cognitive testing in adults undergoing dialysis, and repor-
`ted that serum aluminium concentrations were predictive
`of visual memory. Associations between aluminium con-
`centrations and tests of frontal lobe function and attention/
`concentration were also seen, although only in subjects
`with lower vocabulary scores. Similar neurological and
`cognitive problems were subsequently identified in adults
`receiving PN solutions, and also in aluminium smelting
`plant workers, especially those exposed before the new
`smoke hoods were introduced in 1972(6).
`Adverse effects of aluminium on bone have been iden-
`tified in adults with uraemia and low turnover osteomala-
`cia(7) and in those with normal renal function undergoing
`long-tern PN(8). Both groups of patients had low bone
`formation on iliac crest biopsy, with patchy osteomalacia.
`Histochemical staining of biopsy samples showed alumi-
`nium accumulation at the mineralisation front, which was
`quantified as surface-stainable aluminium. The latter cor-
`related closely with quantitative measurements of alumi-
`nium in
`bone
`determined
`by
`atomic
`absorption
`spectroscopy. These findings were supported by multiple
`studies in several species of experimental animals includ-
`ing rats(9), piglets(10) and dogs(11).
`
`Aluminium exposure in preterm infants
`Moreno et al.(12) calculated that PN solutions were the
`main source of aluminium exposure in neonates, account-
`ing for 89 % of total aluminium intake. In earlier PN
`solutions (prior to the mid-1990s), aluminium contamina-
`tion occurred mostly from casein hydrolysates and trace
`element components, but the problem with more modern
`PN solutions relates mainly to small-volume acidic solutions
`stored in glass vials, notably calcium gluconate which was
`found to account for 81 % of the contamination in one
`study(13). It has been recognised for some time that, when fed
`parenterally, infants retain > 75 % of the aluminium (com-
`pared to approximately 40 % in adults), with high serum,
`urine and tissue levels(12,14). For example, Sedman et al.(15)
`prospectively studied plasma and urinary aluminium con-
`centrations in eighteen premature infants receiving intra-
`venous therapy and in eight
`term infants receiving no
`intravenous therapy. They also measured bone aluminium
`concentrations in autopsy specimens from twenty-three
`infants, including six who had received at least 3 weeks of
`intravenous therapy. Preterm infants who received intra-
`venous therapy had high plasma and urinary aluminium
`concentrations compared with normal controls. The bone
`aluminium concentration was also ten times higher in infants
`who had received at least 3 weeks of intravenous therapy
`than in those who had received limited intravenous therapy.
`
`Although aluminium exposure and tissue aluminium
`accumulation were well documented in neonates two de-
`cades ago, it was unclear at the time whether this exposure
`had any health consequences. A causal relationship between
`early aluminium exposure and adverse health outcomes
`cannot be established in observational studies, particularly
`in preterm infants in whom the duration of PN (and hence,
`aluminium exposure) is very likely to act as a proxy for
`poor health, which is itself associated with adverse out-
`come. Thus, an experimental study was required, with pre-
`term infants randomised to different aluminium exposure
`and follow-up to measure health outcomes. While it was not
`ethical to randomise a group of infants to receive ‘high’
`aluminium exposure, it was ethical and feasible to rando-
`mise them to receive a lower aluminium exposure than they
`would receive in normal clinical practice.
`
`Randomised trial of aluminium exposure from
`parenteral nutrition in preterm infants
`
`To investigate the short- and long-term health effects of
`neonatal intravenous aluminium exposure, a randomised
`double-blind trial was initiated in 1988, comparing stan-
`dard PN solutions with solutions specially sourced for low
`aluminium content. Details of the original trial design are
`reported elsewhere but summarised briefly here(1). Two
`hundred and twenty-seven preterm infants with birthweight
`< 1850 g were recruited from a neonatal unit in Cambridge,
`UK. Infants were eligible if a clinical decision was made to
`start PN, and were randomly assigned to receive either
`standard PN solution or a specially sourced low-aluminium
`solution. Details of the composition of the two solutions
`are shown in Table 1, together with the measured alumi-
`nium concentrations in each solution. The solutions were
`identical except that the aluminium-depleted solution con-
`tained calcium chloride instead of calcium gluconate. The
`use of a mixed sodium–potassium phosphate solution in
`place of potassium acid phosphate minimised the increase
`in chloride. By design, the total aluminium intake when the
`infant received 180 ml/kg per d differed markedly; 45 mg/kg
`per d for the standard solution compared with only 4–5 mg/
`kg per d for the aluminium-depleted solution. All decisions
`on infant feeding were made by the clinicians responsible
`for the care of the infant; the study team were not involved in
`this aspect. Data were collected on the clinical course of
`each infant, detailed records of exact intravenous and oral
`intake, daily blood samples for electrolytes, calcium and
`acid-base status, and weekly samples for plasma chloride.
`
`Cognitive outcome at 18 months post-term(1)
`
`At 18 months corrected age, all surviving infants were
`invited for a follow-up examination. A single investigator,
`blind to the PN allocation, assessed cognitive development
`using the Mental Scale of the Bayley Scales of Infant
`development(16),
`from which the Mental Development
`Index (MDI) was derived. The number of days of intra-
`venous feeding for infants tested at 18 months did not
`differ by randomised group. Overall, there was no differ-
`ence in MDI between randomised groups and no difference
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`301
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`Table 1. Composition and aluminium content of
`
`the standard and aluminium-depleted intravenous feeding solutions used in a
`randomised trial(15)
`
`Solution
`
`Volume (ml)
`
`Al content (mg)
`
`Volume (ml)
`
`Aluminium content (mg)
`
`Standard
`
`Aluminium-depleted
`
`Vamin infant
`Intralipid 20 %
`Vitalipid
`Solivito
`Neotrace
`Potassium acid phosphate
`Polyfusor phosphate
`Calcium gluconate
`Calcium chloride
`Dextrose, sodium, potassium
`Total aluminium intake at 180 ml/kg per d
`
`50
`15
`1
`1
`1.6
`1.3
`–
`8.0
`–
`102
`45 mg/kg per d
`
`1.5
`0.1
`0.3
`< 0.1
`1.2
`2.8
`–
`38.8
`–
`< 0.1
`
`50
`15
`1
`1
`1.6
`–
`14.4
`–
`2.1
`102
`4.0–4.5 mg/kg per d
`
`1.5
`0.1
`0.3
`< 0.1
`1.2
`–
`0.3
`–
`0.5
`< 0.1
`
`Vamin infant contained essential amino acids without added electrolytes. Intralipid 20 % was a fat emulsion containing 20 g fatty acids/dl. Vitalipid contained
`fat-soluble vitamins and Solivito contained water-soluble vitamins. Neotrace was an in-house preparation containing Cu and Zn only. Vamin infant, intralipid
`20 %, vitalipid and solivito were manufactured by Kabi Vitrum.
`
`1000
`
`800
`
`600
`
`400
`
`200
`
`0
`
`Total neonatal aluminium exposure (µg/kg)
`
`Aluminium-depleted
`PN solution (n 33)
`
`Standard
`PN solution (n 26)
`
`Fig. 1. Neonatal aluminium exposure for subjects studied at
`13–15 years, according to randomised parenteral nutrition (PN)
`solution in a randomised trial(15).
`
`suggesting they were a ‘lower risk’ group in terms of later
`adverse outcomes. The total duration of intravenous feeding
`for subjects followed up was not significantly different from
`randomised groups (12.5 (SD 8.8) days for aluminium-
`depleted v. 13.2 (SD 9.2) for controls, P = 0.8). However, as
`expected, mean, median (25th, 75th centiles), minimum and
`maximum exposure in the two groups were significantly
`different (3.0 (SD 0.8), 28 (17, 46), 4, 152 mg/kg for the
`aluminium-depleted group and 21.3 (SD 7.2), 280 (91, 417),
`19, 840 mg/kg for the control group (P< 0.001 for all)).
`
`Cognitive outcome
`
`As at 18 months of age, no significant differences in cog-
`nitive outcome were found between randomised groups
`during adolescence. Non-randomised analyses were also
`performed to assess the impact of aluminium exposure,
`because an infant’s actual exposure depended not only on
`the PN solution received but also on the duration of intra-
`venous feeding, which varied considerably. The actual
`neonatal exposure to aluminium (shown in Fig. 1) covered
`
`in the proportion of infants considered to have neuromotor
`impairment. However, preterm infants exposed for > 10 d
`to standard solutions had impaired neurologic development
`at 18 months, and were significantly more likely to have
`MDI< 85 (n 41 for aluminium-depleted group and n 39 for
`standard group), placing them at increased risk for sub-
`sequent educational problems. For the 157 infants without
`neuromotor impairment,
`increasing neonatal aluminium
`exposure was associated with a reduction in the Bayley
`MDI, with an adjusted loss of one point per day of intra-
`venous feeding with the standard solution. These findings
`strongly suggested that prolonged exposure to PN solutions
`that are routinely contaminated with aluminium might have
`lasting adverse consequences for cognitive outcome in this
`vulnerable group.
`
`Follow-up at 13–15 years
`
`To test the hypothesis that neonatal aluminium exposure
`would have persisting adverse effects on cognitive out-
`come during adolescence, and adverse effects on bone
`health, fifty-nine subjects from the original cohort (26 % of
`those randomised; 32 % of survivors; 33 % of those eligible
`for follow-up) were invited for follow-up at age 13–15
`years. Subjects with neuromotor impairment or with Bay-
`ley MDI< 85 at 18-month follow-up were excluded,
`because children with an existing impairment would be
`unable to complete the cognitive tests in the follow-up
`protocol. A detailed battery of tests was administered,
`evaluating overall cognitive level (intelligence quotient
`(IQ))(17) and also specific functions hypothesised to be
`potentially affected by early aluminium exposure, includ-
`ing tests of academic attainment(18,19), different aspects of
`memory functions(20–22), and higher level functions such as
`planning and organising behaviour(23). Bone mass was
`measured using dual X-ray absorptiometry at the lumbar
`spine, hip and whole body. Fifty-nine subjects were seen
`for follow-up at age 13–15 years; thirty-three from the
`aluminium-depleted group and twenty-six from the standard
`group. Compared with subjects not seen, those who were
`followed up had significantly higher birthweight SDS,
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`Table 2. How can neonatal aluminium exposure from parenteral nutrition (PN) solutions be minimised using currently available solutions?
`Potential methods and barriers to implementation
`
`Solution
`
`1. Use calcium gluconate packaged
`in plastic rather than glass vials
`
`2. Use calcium chloride in place of
`calcium gluconate
`
`3. Use organic phosphate salts
`4. Substitute potassium acid phosphate
`with sodium phosphate salts that
`have less aluminium contamination
`
`Barrier to implementation
`
`Currently, only 10 ml plastic vials are available, so making up rather than large
`volumes of PN solutions requires opening an unfeasible number of vials per day
`This issue should be addressed by manufacturers following the recent Medicines and Healthcare
`regulatory Authority recommendation(32)
`Theoretical concerns about risk of metabolic acidosis due to the higher chloride intake
`(not realised in randomised controlled trial that used this strategy(1)
`Chloride intake can be reduced by replacing other chloride salts with alternatives, e.g. sodium and
`potassium acetate, magnesium sulfate
`Products are expensive and are not available currently in the US
`
`a wide range, with considerable overlap between ran-
`domised groups. No significant differences were found
`when comparing subjects with total neonatal aluminium
`exposure above or below the median (55 mg/kg).
`These findings must be considered in the context of the
`fact that the subjects seen at 13–15 years were a selected
`group, excluding those with known neuromotor impair-
`ment at 18 months or a Bayley MDI< 85; they also had
`higher birthweight SDS than subjects who were not fol-
`lowed. Hence, it could be argued that the findings show no
`evidence of longer-term cognitive effects in this relatively
`lower risk cohort who had normal cognitive outcome at
`18 months post-term, but cannot perhaps be generalised to
`smaller infants who already have evidence of neurocogni-
`tive impairment apparent in infancy: in effect, the follow-
`up protocol may have excluded the children already
`adversely affected by neonatal aluminium exposure. How-
`ever, the sub-group of subjects studied at 13–15 years
`(particularly those subjects who had received more than
`10 d of PN) showed the same trend towards higher Bayley
`MDI at 18 months in the aluminium-depleted group as
`observed in the larger cohort. Statistical significance was
`not reached for this comparison, possibly due to the small
`sample sizes available for the analyses; nevertheless these
`data suggest
`that
`the children followed-up were fairly
`representative of all subjects seen at 18 months in terms of
`the effects of aluminium exposure on cognitive outcome.
`those with Bayley MDI> 85 in
`One possibility is that
`infancy were able to compensate subsequently for any
`adverse effect of early aluminium exposure.
`
`Bone outcomes(24)
`
`Subjects randomised to the aluminium-depleted PN solu-
`tion during the neonatal period had significantly higher
`lumbar spine bone mineral content and bone area at age
`13–15 years, apparently reflecting larger bones with a
`concomitant increase in bone mineral. In non-randomised
`analyses, aluminium exposure as a continuous variable was
`not associated with later bone mass. However, there was
`evidence of a threshold effect. Subjects with neonatal alu-
`minium exposure above the median (55 mg/kg) had sig-
`nificantly lower hip bone mass, independent of their bone
`
`or body size. This effect was not seen at the lumbar spine
`or for whole body bone mass.
`The mechanism for the observed effects of early alumi-
`nium exposure on later bone health is unclear. A direct
`effect on bone structure is unlikely since the skeleton will
`have remodelled more than once in the intervening years.
`It is possible that aluminium modifies the response of bone
`cells to external stimuli such as subsequent loading from
`physical activity or nutritional exposure. This could also
`explain the apparent site-specificity of effects, with effects
`on lumbar spine bone mass in the randomised comparison,
`but a threshold effect observed on hip bone mass. It is well
`recognised that interventions may have differential effects
`at different skeletal sites. For example, exercise interven-
`tions typically affect only the loaded bones(25), while leptin
`has been shown to have different effects on the trabecular
`and appendicular skeleton, possibly related to differential
`effects on cortical and trabecular bone(26). An alternative
`explanation is that bone effects are another manifestation
`of aluminium neurotoxicity; it is now recognised that bone
`remodelling is partly under the control of the central ner-
`vous system(27). In animals, a number of neuropeptides
`affect bone formation via the hypothalamus, with signal
`transmission to bone cells via the sympathetic nervous
`system. If this is the mechanism, the observed adverse
`effects on bone may represent another facet of neurotoxi-
`city.
`
`Study limitations
`
`The main limitation of the most recent follow-up study was
`the attrition rate, with only 30 % of the original cohort seen
`at 13–15 years. This limits the power of the follow-up
`study, allowing detection of a difference of approximately
`0.7 SD between randomised groups at 5 % significance. In
`the event, this may not have been an issue, because the
`effect size for lumbar spine was of this magnitude. Sub-
`jects seen for
`follow-up also had significantly higher
`birthweight SD scores than those not seen, and one would
`suppose that any effect of aluminium seen in the follow-up
`study might be greater in more vulnerable, smaller infants
`who were not studied. The follow-up study also ex-
`cluded subjects already identified as having abnormal
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`development at age 18 months, who would be regarded as
`more vulnerable and potentially at greater risk of adverse
`effects on cognitive outcome or bone health. It may
`therefore have underestimated any effect of aluminium
`exposure.
`
`Interpretation and practical implications of the findings
`
`Data from this clinical trial suggest that neonatal alumi-
`nium exposure from PN in the high-risk preterm infant
`may have adverse effects on later bone health, as well as
`short-term cognitive outcome. Although there was no
`strong evidence for effects on later cognitive outcome, the
`group of subjects followed at 13–15 years were a selected
`population with normal development at 18 months; it is
`unclear whether persistent or additional adverse effects
`would be apparent in the subjects who already demon-
`strated sub-optimal development at 18 months of age. The
`observed effects are plausible given the known toxicity of
`aluminium for brain and bone seen in adults and in animal
`models. This is the only experimental study to system-
`atically examine the health effects of aluminium in any
`population with high exposure and, despite its limitations,
`it seems unlikely that it will be repeated.
`It is important to consider the likely practical signi-
`ficance of the observed effect of aluminium exposure on
`bone mass. This is difficult to quantify since there are no
`data directly relating bone mass at age 13–15 years to later
`fracture risk. Hip bone mass was 7.6 % lower in subjects
`with neonatal aluminium exposure above the median,
`while the difference in lumbar spine bone mineral content
`was approximately 0.7 SD between groups (representing
`approximately 14 % of population variance assuming a
`normal distribution), and the difference in lumbar spine
`bone mineral density was 0.36 SD (representing approxi-
`mately 7 % of population variation). These figures can be
`considered in the context of the study of Hernandez(28),
`who estimated that the peak bone mass was a better pre-
`dicter of osteoporosis risk than either the age at menopause
`or the rate of age-related bone loss later in life, and cal-
`culated that a 10 % increase in peak bone mass would
`delay the onset of osteoporosis by 10 years. Given the
`sizeable number of contemporary infants undergoing
`intensive care and still exposed to aluminium via PN, these
`findings have contemporary relevance. PN is also used
`more aggressively in modern neonatal units, starting earlier
`and with more rapid advancement than was typical at the
`time of the clinical trial; hence neonatal aluminium expo-
`sure may be greater. Furthermore, recommended mineral
`intakes for preterm infants are now higher than what it was
`20 years ago, so preterm infants are exposed to greater
`volumes of calcium gluconate, the main offender in terms
`of aluminium intake.
`
`Regulatory aspects of aluminium exposure
`
`Potential methods for lowering aluminium exposure from
`PN solutions are given in Table 2. Despite widespread
`recognition of the problem, until recently little progress
`had been made on reducing exposure. Following a review
`
`the Food and Drug Administration
`the literature,
`of
`recommended that daily aluminium intakes should not
`exceed 5 mg/kg per d in vulnerable patients(29), including
`preterm infants. Manufacturers were required to ensure
`that large volume parenterals do not contain more than
`25 mg/l of aluminium and to label
`them as such. No
`restrictions were placed on the aluminium content of small
`volume parenterals, but manufacturers were required to
`label them with the estimated aluminium content at expiry.
`While this represented an advance, Poole et al.(30) calcu-
`lated that meeting the Food and Drug Administration
`recommendations was currently impossible in patients
`< 50 kg using available products. Furthermore, calculated
`aluminium intake in patients < 3 kg in their study was
`30–60 mg/kg per d – higher than in the randomised trial
`discussed in this paper. In a more recent study, the same
`investigators measured the actual aluminium content of
`PN solutions being administered to forty preterm infants
`and found that intakes were still three to five times the
`recommended Food and Drug Administration limit,
`although significantly less than the intake calculated using
`manufacturers’ values on product labels(31). Most recently
`(2010), following a review of available data,
`the UK
`Medicines and Healthcare Regulatory Authority recom-
`mended that calcium gluconate in small volume glass
`containers should not be used for repeated or prolonged
`treatment in children < 18 years, including preparation of
`PN(32). Manufacturers should now be required to address
`the issue at
`least for this particular component of PN
`solutions, and this represents an important step towards
`addressing the problem of aluminium exposure and toxi-
`city in vulnerable infants and children.
`
`Acknowledgements
`
`This study was supported by a research grant from UK
`Medical Research Council. The authors declare no con-
`flicts of interest with respect to this paper. M. F. wrote the
`manuscript and was co-principal investigator for the fol-
`low-up study of the clinical
`trial, responsible for the
`design, analysis and interpretation of bone outcomes. C. E.
`was co-principal
`investigator
`for
`the follow-up study,
`responsible for the design and analysis of cognitive out-
`comes and contributed to the drafting and revision of this
`paper. E. I. contributed to the design of the cognitive parts
`of the follow-up study, analysis of cognitive data and
`drafting of this manuscript. N. B. was designer and princi-
`pal investigator for the original randomised controlled trial
`and contributed to the drafting of this paper. A. L. was co-
`designer of the original randomised controlled trial and
`contributed to the drafting of this paper.
`
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`https://www.cambridge.org/core/terms. https://doi.org/10.1017/S0029665111000498
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