ALUMINUM NEUROTOXICITY IN PRETERM INFANTS RECEIVING INTRAVENOUS-FEEDING SOLUTIONS
`
`ALUMINUM NEUROTOXICITY IN PRETERM INFANTS RECEIVING
`INTRAVENOUS-FEEDING SOLUTIONS
`
`NICHOLAS J. BISHOP, M.D., RUTH MORLEY, M.B., B.CHIR., J. PHILIP DAY, PH.D., AND ALAN LUCAS, M.D.
`
`ABSTRACT
`Background Aluminum, a contaminant of com-
`mercial intravenous-feeding solutions, is potentially
`neurotoxic. We investigated the effect of perinatal ex-
`posure to intravenous aluminum on the neurologic
`development of infants born prematurely.
`Methods We randomly assigned 227 premature in-
`fants with gestational ages of less than 34 weeks and
`birth weights of less than 1850 g who required in-
`travenous feeding before they could begin enteral
`feeding to receive either standard or specially consti-
`tuted, aluminum-depleted intravenous-feeding solu-
`tions. The neurologic development of the 182 surviv-
`ing infants who could be tested was assessed by
`using the Bayley Scales of Infant Development at 18
`months of age.
`Results The 90 infants who received the standard
`feeding solutions had a mean (⫾SD) Bayley Mental
`Development Index of 95⫾22, as compared with
`98⫾20 for the 92 infants who received the aluminum-
`depleted solutions (P⫽0.39). In a planned subgroup
`analysis of infants in whom the duration of intrave-
`nous feeding exceeded the median and who did not
`have neuromotor impairment, the mean values for
`the Bayley Mental Development Index for the 39 in-
`fants who received the standard solutions and the 41
`infants who received the aluminum-depleted solu-
`tions were 92⫾20 and 102⫾17, respectively (P⫽0.02).
`The former were significantly more likely (39 percent,
`vs. 17 percent of the latter group; P⫽0.03) to have a
`Mental Development Index of less than 85, increasing
`their risk of subsequent educational problems. For all
`157 infants without neuromotor impairment, increas-
`ing aluminum exposure was associated with a reduc-
`tion in the Mental Development Index (P⫽0.03), with
`an adjusted loss of one point per day of intravenous
`feeding for infants receiving the standard solutions.
`Conclusions
`In preterm infants, prolonged intra-
`venous feeding with solutions containing aluminum
`is associated with impaired neurologic development.
`(N Engl J Med 1997;336:1557-61.)
`©1997, Massachusetts Medical Society.
`
`A
`
`LUMINUM toxicity occurs in adults and
`children with renal insufficiency who are
`treated by dialysis with aluminum-con-
`taminated solutions or oral phosphate-
`binding agents that contain aluminum.1-7 The clin-
`ical manifestations of aluminum toxicity include
`hypochromic, microcytic anemia; bone disease3,5,8-10;
`and progressive dementia with increased concentra-
`tions of aluminum in the brain.7,11,12
`
`Aluminum accumulates in the body when protec-
`tive gastrointestinal mechanisms are bypassed, renal
`function is impaired, and exposure is high. These
`conditions are met in intravenously fed preterm in-
`fants, whose renal function is frequently compro-
`mised during their initial course; some have had
`high plasma aluminum concentrations.13-17 We previ-
`ously reported on a preterm infant who died unex-
`pectedly and whose brain aluminum concentration
`was similar to that of adults who died with alumi-
`num intoxication.18
`We hypothesized that increased aluminum expo-
`sure in this vulnerable population would probably
`have detrimental effects on neurologic development
`in the long term. We undertook this prospective study
`in preterm infants to compare the effect on the in-
`fants’ subsequent neurologic development of stand-
`ard intravenous-feeding solutions, similar to those
`used in routine practice in the United States and Eu-
`rope, and solutions whose aluminum content had
`been reduced.
`
`METHODS
`
`Subjects
`We enrolled 227 infants from the neonatal intensive care unit
`of Rosie Maternity Hospital, in Cambridge, United Kingdom,
`from May 1988 to January 1991. The criteria for entry into the
`study were a clinical decision to initiate intravenous feeding, a
`birth weight of less than 1850 g, and a gestational age of less than
`34 weeks. Infants whose mothers were not residents of the Unit-
`ed Kingdom and infants with major congenital malformations
`were excluded from the study.
`Each infant entering the study was randomly assigned by the
`pharmacy according to a multiple permuted-block method to re-
`ceive either the standard or the aluminum-depleted intravenous
`solutions. Investigators and attending staff were unaware of the
`assignments, and no investigator served as an attending physician.
`The study was approved by the relevant ethics committees, and
`parental consent was obtained for each infant.
`
`Feeding Policy
`Intravenous feeding was introduced (typically on postnatal day
`2 or 3) and stopped at the discretion of members of the senior
`attending clinical staff. The proportion by volume of amino acid
`solution (Vamin Infant, Kabi Vitrum, now Pharmacia, Stockholm,
`Sweden) was increased at one- or two-day intervals from 15 per-
`cent to 30 percent in increments of 5 percent. Intravenous fat in-
`
`From the Medical Research Council (MRC) Dunn Nutrition Unit and
`University of Cambridge Department of Paediatrics, Cambridge (N.J.B.);
`the MRC Childhood Nutrition Research Centre, Institute of Child Health,
`London (R.M., A.L.); and the University of Manchester Department of
`Chemistry, Manchester (J.P.D.) — all in the United Kingdom. Address re-
`print requests to Dr. Bishop at the Genetics Unit, Shriners’ Hospital for
`Crippled Children, 1529 Cedar Ave., Montreal, QC H3G 1A6, Canada.
`
`Volume 336 Number 22
`
`ⴢ 1557
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on October 2, 2019. For personal use only. No other uses without permission.
`
` Copyright © 1997 Massachusetts Medical Society. All rights reserved.
`
`1
`
`EXELA 2003
`Eton Pharmaceuticals v. Exela Pharma Sciences
`PGR2020-00086
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`The New England Journal of Medicine
`
`take (Intralipid 20 percent, Kabi Vitrum) was increased from
`0.5 g per kilogram of body weight per day to 3 g per kilogram
`per day as the infant’s clinical condition allowed. The volumes of
`calcium and phosphate solution administered depended on the
`amino acid concentration of the feeding solution. For solutions
`that contained 15 or 20 percent amino acids by volume, the cal-
`cium and phosphate contents were 36 and 18 mg per deciliter,
`respectively. For solutions that contained 25 or 30 percent amino
`acids by volume, the calcium and phosphate contents were 44 and
`25 mg per deciliter, respectively.
`In 19 infants, the decision to initiate intravenous feeding was
`reversed immediately after randomization on clinical grounds (typ-
`ically, metabolic instability or improvement eliminating the need
`for parenteral feeding), and therefore none was given. These in-
`fants remained in the study and their results at the follow-up ex-
`amination are included in the appropriate groups.
`Enteral feeding was increased gradually to 180 ml per kilogram
`every 24 hours, according to tolerance. Mothers were encouraged
`to provide breast milk. If the mother provided no breast milk or
`an insufficient amount, a standard preterm formula was used (Far-
`ley’s Health Products, Kendal, United Kingdom).
`
`Intravenous Solutions
`The compositions of the two types of solution were identical
`except that the aluminum-depleted solutions contained less alu-
`minum and more chloride, reflecting the use of calcium chloride
`instead of calcium gluconate (Table 1). The use of a mixed sodium–
`potassium phosphate solution in place of potassium acid phosphate
`minimized this increase in chloride.
`
`Data Collection
`We collected data on the neonatal course of each infant, includ-
`ing data on intravenous fluid intake and the total volume and type
`of fluid given. Plasma concentrations of sodium, potassium, urea,
`creatinine, glucose, and calcium and acid–base status were meas-
`
`
`OF
`
` A
` C
`
` C
`
` 1.
`T
`LUMINUM
`AND
`OMPOSITION
`ONTENT
`ABLE
` S
`
` A
`-D
` I
`
`THE
`TANDARD
`AND
`LUMINUM
`EPLETED
`NTRAVENOUS
`F
` S
`.
`EEDING
`OLUTIONS
`
`S
`OLUTION
`
`*
`
`S
`TANDARD
`
`VOLUME
`(ml)
`
` S
`OLUTIONS
`ALUMINUM
`CONTENT
`(
`g)
`m
`
`50
`Vamin Infant
`15
`Intralipid 20%
`1
`Vitlipid
`1
`Solivito
`1.6
`Neotrace
`1.3
`Potassium acid phosphate
`—
`Polyfusor phosphate
`8.0
`Calcium gluconate
`—
`Calcium chloride
`Dextrose, sodium, potassium 102
`Total aluminum intake
`45
`at 180 ml/kg/day
`
`m
`
`1.5
`0.1
`0.3
`0.1
`⬍
`1.2
`2.8
`—
`38.8
`—
`1.0
`⬍
`g/kg/day
`
`-D
`A
`EPLETED
`LUMINUM
`S
`OLUTIONS
`
`
`
`VOLUME
`(ml)
`
`50
`15
`1
`1
`1.6
`—
`14.4
`—
`2.1
`102
`4.0–5.0
`
`ALUMINUM
`
`CONTENT
`(
`g)
`m
`
`⬍
`
`1.5
`0.1
`0.3
`0.1
`1.2
`—
`0.3
`—
`0.5
`1.0
`g/kg/day
`
`⬍
`
`m
`
`*Vamin Infant contained essential amino acids without added electro-
`lytes. Intralipid 20% was a fat emulsion containing 20 g of fatty acids per
`deciliter. Vitlipid contained fat-soluble vitamins, and Solivito contained wa-
`ter-soluble vitamins. Neotrace was an in-house preparation containing cop-
`per and zinc only. Vamin Infant, Intralipid 20%, Vitlipid, and Solivito were
`manufactured by Kabi Vitrum.
`
`1558
`
`ⴢ
`
`May 29, 1997
`
`ured daily, and plasma chloride weekly. Cranial ultrasonography
`was performed weekly. Extensive social, demographic, and ob-
`stetrical data were collected from the mothers by trained research
`nurses unaware of treatment-group assignments. Social class was
`coded according to the British Registrar General’s Classification of
`Occupations, on the basis of the occupation of the income-provid-
`ing parent or the father’s occupation if both parents were earning.
`The mother’s education was coded according to her formal educa-
`tional attainment (1 for mothers with no certificates to 5 for those
`with a university degree or similar educational level).
`
`Neurodevelopmental Assessments
`All the surviving children were invited to have a follow-up ex-
`amination at the post-term age of 18 months. The examination
` and an evaluation
`consisted of a standard neurologic assessment
`19
`of development by a single experienced investigator unaware of
`the children’s group assignments, using the Mental Scale of the Bay-
` from which the Mental De-
`ley Scales of Infant Development,
`20
`velopment Index was derived (mean [
`SD] for normal children,
`⫾
`100
`16; possible range, 50 to 150).
`⫾
`A diagnosis of neuromotor impairment was made if the physi-
`cal examination revealed abnormalities of tone or of the move-
`ment of limbs, trunk, head, or neck. The reference ranges used
` Since any
`were from the schema of Amiel-Tison and Stewart.
`19
`degree of impairment can influence the assessment of develop-
`ment with the Bayley Mental Scale (which depends heavily on
`age-appropriate fine-motor skills), the severity of the impairment
`was not taken into account in the analyses.
`
`Measurement of Aluminum
`The aluminum content of the intravenous-feeding solutions
`was measured by graphite-furnace atomic-absorption spectrome-
`try, with the use of Zeeman-effect background correction (model
`Z3030, Perkin Elmer, Beaconsfield, United Kingdom). Analyte
`materials were diluted appropriately (with a minimum of a four-
`fold dilution) with 0.1 percent Triton X-100 and 0.1 M nitric
`acid (BDH AnalaR and Aristar grade, respectively) and calibrated
`by using a standard solution of aluminum (1 mg per liter) in 0.1
`M nitric acid (coefficient of variation, 6 to 8 percent). All meas-
`urements were performed in quadruplicate.
` Multiple batches of
`21
`calcium gluconate (from four manufacturers) and calcium chlo-
`ride (two manufacturers) were analyzed; concentrations of alumi-
`num were consistently high for gluconate (4810
`440
`g per
`⫾
`m
`liter) and low for chloride (210
`10
`g per liter). All other compo-
`⫾
`m
`nents were analyzed on multiple occasions; the values shown in Ta-
`ble 1 are the mean values. Aluminum intake (component volume
`times component aluminum concentration) was calculated daily
`for each infant.
`
`Statistical Analysis
`Our primary hypothesis was that neurologic development would
`be better in infants receiving the aluminum-depleted solutions.
`However, two factors were likely to confound the analysis: the dif-
`ficulty of accurately assessing mental development in children with
`neuromotor impairment and the variation in the duration of in-
`travenous feeding and hence in aluminum intake.
`The Bayley Mental Scale, like most tests of mental ability in
`young children, requires age-appropriate fine-motor skills; there-
`fore, scores do not usually reflect the level of intellectual ability of
`children with neuromotor impairment. For this reason, the main
`analyses were performed as reported previously
` and as planned
`22
`here by using Student’s t-test, excluding the 25 children with ev-
`idence of neuromotor impairment at the time of testing. However,
`data on these infants were included in a separate analysis, in which
`children with neuromotor impairment arbitrarily received a score
`of 50 points and the data were analyzed as randomized by the
`Mann–Whitney–Wilcoxon test. Two infants could not be tested,
`because one was blind and the other completely uncooperative.
`We also planned stratified analyses to take into account the
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on October 2, 2019. For personal use only. No other uses without permission.
`
` Copyright © 1997 Massachusetts Medical Society. All rights reserved.
`
`2
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`ALUMINUM NEUROTOXICITY IN PRETERM INFANTS RECEIVING INTRAVENOUS-FEEDING SOLUTIONS
`
`duration of aluminum exposure — since once randomized, some
`infants would receive little intravenous feeding — and to seek
`threshold effects. The simplest stratification envisaged was to sub-
`divide each group into two according to the duration of paren-
`teral feeding (longer or shorter than the overall median), neces-
`sarily decreasing group numbers but maintaining similar numbers
`in each group. The effect of other variables known to influence
`developmental outcome was evaluated by multiple regression
`analysis.
`
`RESULTS
`The characteristics of the infants in each group are
`shown in Table 2; daily aluminum intake was sub-
`stantially greater in the infants receiving the standard
`solutions than in those receiving the aluminum-
`SD], 19
`8 vs. 3
`1
`g
`depleted solutions (mean [
`⫾
`⫾
`⫾
`m
`per kilogram per day; P
`0.001). The numbers of
`⬍
`deaths, handicapped survivors, and children lost to
`follow-up are shown in Table 3.
`Among the infants with no neuromotor impair-
`ment, the mean (
`SD) Mental Development Index
`⫾
`values for the groups receiving the standard and alu-
`minum-depleted solutions were 98
`20 and 101
`18,
`⫾
`⫾
`respectively (Table 4). The Mental Development In-
`dex values for all the groups of infants who received
`intravenous feeding for 10 days (median duration of
`exposure) or less were similar. However, for the
`
`group of infants receiving the standard solutions for
`more than 10 days, the Mental Development Index
`was 10 points less than for those receiving the alu-
`minum-depleted solutions (P
`0.02). This difference
`⫽
`was reflected in the significantly greater proportion
`of infants who received the standard solutions for
`more than 10 days and whose Mental Development
`Index values were below 85 points — 15 of 39 (38
`percent) as compared with 7 of 41 (17 percent,
`P
`0.03).
`⫽
`The corresponding analyses, including the chil-
`dren with neuromotor impairment, are also shown
`in Table 4. The results are weakened by the difficulty
`of obtaining realistic measurements of mental devel-
`opment in children with neuromotor impairment.
`Such children were thus given nominal scores of 50
`points. When the results for the infants receiving in-
`travenous feeding for more than 10 days were then
`compared by a nonparametric Mann–Whitney–Wil-
`coxon test, the difference between the groups was
`statistically significant (P
`0.04).
`⫽
`In a further, explanatory analysis to assess the in-
`dependent contribution of aluminum intake to the
`developmental outcome, multiple regression analysis
`with the Bayley Mental Development Index as the
`
` G
`
` P
`
` D
` C
`
` I
`
`
`T
` 2.
`THE
`IN
`THE
`OF
`EMOGRAPHIC
`HARACTERISTICS
`RETERM
`NFANTS
`ROUPS
`ABLE
`R
` S
`
` A
`-D
` F
` S
`.*
`EPLETED
`ECEIVING
`TANDARD
`AND
`LUMINUM
`EEDING
`OLUTIONS
`
`C
`HARACTERISTIC
`
`I
`NFANTS
`
` R
`ANDOMIZED
`
`
` T
`I
`ESTED
`NFANTS
`N
`EURODEVELOPMENTALLY
`
`Total no.
`Sex (M/F)
`Birth weight (g)
`Gestation (wk)
`Mechanical ventilation (days)
`Median
`Interquartile range
`Birth weight (no.)
`Appropriate for gestation
`Small for gestation
`Intraventricular hemorrhage
`Total
`Parenchymal
`Periventricular leukomalacia
`Parenteral nutrition (days)
`Median
`Interquartile range
`Aluminum intake (mg)†
`Median
`Interquartile range
`Mother’s expressed breast milk
`(% of enteral intake)
`Preterm formula (% of enteral intake)
`
`STANDARD
`SOLUTIONS
`
`112
`55/57
`299
`1227
`⫾
`29.1⫾2.3
`
`-
`
`ALUMINUM
`DEPLETED
`SOLUTIONS
`
`115
`63/52
`1216
`318
`⫾
`28.9⫾2.3
`
`STANDARD
`SOLUTIONS
`
`90
`42/48
`
`1260⫾294
`29.1⫾2.2
`
`4.5
`2–8
`
`89
`23
`
`28
`6
`4
`
`9
`5–15
`
`187
`70–350
`31
`
`45
`
`5
`2–8
`
`92
`23
`
`32
`8
`7
`
`10
`6–16
`
`28
`11–49
`32
`
`45
`
`4
`2–8
`
`75
`15
`
`18
`4
`3
`
`9.5
`5–15
`
`194
`82–360
`31
`
`44
`
`-
`
`ALUMINUM
`DEPLETED
`SOLUTIONS
`
`92
`50/42
`1234⫾295
`29.1⫾2.0
`
`5
`2–7.5
`
`73
`19
`
`21
`1
`2
`
`10
`6–16
`
`32
`14–48
`32
`
`45
`
`SD.
`*Plus–minus values are means
`⫾
`†There was no statistically significant difference (P
`⬍
`ence in aluminum intake (P
`0.001).
`⬍
`
`0.05) among the groups except for the differ-
`
`Volume 336 Number 22
`
`ⴢ
`
`1559
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on October 2, 2019. For personal use only. No other uses without permission.
`
` Copyright © 1997 Massachusetts Medical Society. All rights reserved.
`
`3
`
`

`

`The New England Journal of Medicine
`
`dependent variable was carried out for the group of
`157 infants with no evidence of neuromotor impair-
`ment at 18 months of age. The independent vari-
`ables entered were birth weight, gestational age, sex,
`maternal educational attainment, social class, dura-
`tion of intravenous feeding (days), duration of ven-
`tilation (days), aluminum intake (micrograms per
`kilogram), and the presence or absence of intraven-
`tricular hemorrhage (and whether parenchymal or
`not). The variables not significantly associated with
`the Mental Development Index in the model were
`removed stepwise. The duration of intravenous feed-
`ing was entered into the final analysis so that alu-
`minum exposure did not become a proxy for the
`duration or severity of illness. Maternal educational
`attainment (P⬍0.001), birth weight (P⫽0.01), alu-
`
`TABLE 3. NUMBERS OF INFANTS IN THE GROUPS
`RECEIVING THE STANDARD AND ALUMINUM-
`DEPLETED FEEDING SOLUTIONS AT STUDY ENTRY
`AND AT THE TIME OF TESTING FOR THE BAYLEY
`MENTAL DEVELOPMENT INDEX.
`
`INFANTS
`
`SOLUTIONS
`ALUMINUM-
`DEPLETED
`
`STANDARD
`
`Total
`Died
`Lost to follow-up
`Untestable*
`Neurologically impaired
`Never received intravenous feeding†
`With normal neuromotor function,
`tested for Bayley Mental Develop-
`ment Index
`
`112
`14
`8
`0
`12
`8
`78
`
`115
`14
`7
`2
`13
`11
`79
`
`*One child was blind, the other completely uncooperative.
`†These infants entered the study but were found not to
`need intravenous feeding. They were tested developmentally.
`
`minum exposure (P⫽0.02), and sex (advantage for
`female sex, P⫽0.02) were the factors that, in com-
`bination, most strongly predicted the Bayley Mental
`Development Index. There was no interaction be-
`tween aluminum intake and the other factors. Thus,
`the apparent effect of aluminum was unrelated to
`birth weight or sex; that is, for a given level of intake,
`the effect on the Mental Development Index was
`the same in large and small infants. Gestational age,
`duration of ventilation, and the presence or absence
`of intraventricular hemorrhage were not significantly
`associated with the Mental Development Index.
`We estimate that for infants receiving full intrave-
`nous feeding with a mean aluminum intake of 45 mg
`per kilogram per day, the expected reduction in the
`Bayley Mental Development Index would be, on av-
`erage, one point per day of intravenous feeding.
`There was no significant difference in clinical
`course or plasma biochemical results between the two
`groups. Despite the increased chloride load attend-
`ant on the use of the aluminum-depleted solutions,
`there were no episodes of hyperchloremia among in-
`fants receiving these solutions. There was no differ-
`ence in the number of episodes of extravasation re-
`sulting in cutaneous damage between the two groups.
`No infant required flushing of, or surgery on, an ex-
`travasation site.
`
`DISCUSSION
`The results of this study suggest that aluminum
`intake in preterm infants is associated with reduced
`developmental attainment at the corrected post-
`term age of 18 months. The infants who received
`the standard intravenous feeding solutions (provid-
`ing 25 mg of aluminum per deciliter) had a lower
`mean Bayley Mental Development Index than those
`who received aluminum-depleted solutions (provid-
`ing 2.2 mg of aluminum per deciliter), although this
`difference did not reach statistical significance. How-
`
`TABLE 4. VALUES ON THE BAYLEY MENTAL DEVELOPMENT INDEX FOR INFANTS WITHOUT NEUROMOTOR
`IMPAIRMENT AND FOR ALL INFANTS ACCORDING TO THE DURATION OF INTRAVENOUS FEEDING.*
`
`GROUP
`
`STANDARD
`SOLUTIONS
`
`VALUES FOR
`INFANTS WITHOUT NEUROMOTOR IMPAIRMENT
`ALUMINUM-
`DEPLETED
`SOLUTIONS
`
`DIFFERENCE
`
`P
`VALUE
`
`VALUES FOR ALL INFANTS
`ALUMINUM-
`DEPLETED
`SOLUTIONS
`
`DIFFERENCE
`
`STANDARD
`SOLUTIONS
`
`As randomized
`
`⭐10 days TPN
`
`⬎10 days TPN
`
`98⫾20
`(n⫽78)
`105⫾19
`(n⫽39)
`92⫾20
`(n⫽39)
`
`101⫾18
`(n⫽79)
`101⫾20
`(n⫽38)
`102⫾17
`(n⫽41)
`
`2.9
`
`⫺3.9
`
`9.9
`
`0.34
`
`0.36
`
`0.02
`
`95⫾22
`(n⫽90)
`99⫾23
`(n⫽50)
`90⫾21
`(n⫽40)
`
`98⫾20
`(n⫽92)
`100⫾20
`(n⫽47)
`96⫾21
`(n⫽45)
`
`2.7
`
`1.0
`
`5.4
`
`P
`VALUE
`
`0.39
`
`0.83
`
`0.24
`
`*Values are given as means ⫾SD. TPN denotes total parenteral nutrition. Ten days was the median duration of total
`parenteral nutrition for the whole population as randomized (see Table 2).
`
`1560 ⴢ May 29, 1997
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on October 2, 2019. For personal use only. No other uses without permission.
`
` Copyright © 1997 Massachusetts Medical Society. All rights reserved.
`
`4
`
`

`

`ALUMINUM NEUROTOXICITY IN PRETERM INFANTS RECEIVING INTRAVENOUS-FEEDING SOLUTIONS
`
`ever, a substantial number of infants received little or
`no intravenous feeding after randomization, and ex-
`planatory analysis showed that the effect of alumi-
`num exposure was dose-related. Aluminum exposure
`from the standard intravenous solutions was calculat-
`ed to be associated with a mean loss of one point on
`the Bayley Mental Development Index per day of
`full intravenous feeding, after adjustment for poten-
`tially confounding factors. In infants fed intravenous-
`ly for 10 or more days, those receiving the standard
`solutions had a major (10 point) deficit in their Men-
`tal Development Index and were twice as likely to
`have a Mental Development Index below 85. These
`results provide support for our hypothesis that in-
`travenous aluminum may have neurotoxic effects,
`with longer-term consequences for neurologic de-
`velopment.
`Aluminum is the most common metallic element
`in the earth’s crust23 but has no clear biologic role.
`When intake is not controlled, aluminum causes se-
`vere neurotoxic effects in adults and children with
`renal failure.6,7,11,12 Previous studies of aluminum ex-
`posure in preterm infants revealed increased plasma
`concentrations or urinary excretion of aluminum,
`and those who died had high tissue aluminum con-
`centrations.13-18,24-26 Our findings are therefore plau-
`sible in the light of the previous work on aluminum
`neurotoxicity and on the deposition of aluminum in
`tissues, including the brain, of preterm infants.
`We chose to carry out a randomized study because
`in a nonrandomized study it would have been diffi-
`cult to identify any effects of aluminum among the
`many other factors that could influence neurologic
`development in preterm infants. Indeed, manifesta-
`tions of aluminum toxicity — anemia and bone dis-
`ease — arise frequently in premature infants for rea-
`sons other than aluminum exposure. In our previous
`studies of preterm infants we found that by 18
`months of age, cognitive performance on the Bayley
`Mental Development Index has some value in pre-
`dicting the later intelligence quotient. However, the
`correlation is considerably greater for group mean
`scores than for individual infants (⬎0.9 rather than
`⬎0.5, unpublished data). Whether exposure to alumi-
`num affects intelligence later in life is unknown.
`In conclusion, aluminum has no known biologic
`role and is potentially neurotoxic. Some degree of
`aluminum exposure in preterm infants fed intrave-
`nously seems unavoidable; the duration of such ex-
`posure is necessarily uncertain. Our findings suggest
`that the use of aluminum-depleted solutions for in-
`travenous feeding in these infants may result in im-
`proved neurologic development.
`
`Supported by the United Kingdom Medical Research Council and the
`Wellcome Trust.
`
`We are indebted to the nurses and doctors of the Rosie Maternity
`Hospital neonatal intensive care unit; to Ms. Sarah Churchill, Ms.
`Penny Lucas, and Ms. Corina Adams for data collection; and to the
`pharmacy staff, particularly Ms. Naval Vyse.
`
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`Volume 336 Number 22
`
`ⴢ 1561
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on October 2, 2019. For personal use only. No other uses without permission.
`
` Copyright © 1997 Massachusetts Medical Society. All rights reserved.
`
`5
`
`