`Evaluating Differences in Aluminum Exposure
`through Parenteral Nutrition in Neonatal Morbidities
`
`Megan Fortenberry 1, Lela Hernandez 2,* and Jacob Morton 3
`1 University of North Carolina Health Care, Chapel Hill, NC 27514, USA;
`megan.fortenberry@unchealth.unc.edu
`2 Wesley Children’s Hospital, 550 N Hillside, Wichita, KS 67214, USA
`3
`Saint Vincent Hospital, 123 Summer St, Worcester, MA 01608, USA; Jacob.morton@stvincenthospital.com
`* Correspondence: lelafung@gmail.com; Tel.: +1-316-962-6095
`
`Received: 2 October 2017; Accepted: 9 November 2017; Published: 16 November 2017
`
`Abstract: Aluminum is a common contaminant in many components of parenteral nutrition,
`especially calcium and phosphate additives. Although long-term effects have been described in
`the literature, short-term effects are not well-known. Currently, the Food and Drug Administration
`recommends maintaining aluminum at <5 mcg/kg/day. This was a single center, retrospective
`case-control study of 102 neonatal intensive care unit patients. Patients were included if they had a
`diagnosis of necrotizing enterocolitis, rickets/osteopenia, or seizures and received at least 14 days
`of parenteral nutrition. Patients were matched 1:1 with control patients by gestational age and
`birth weight. Mean total aluminum exposure for the 14 days of parenteral nutrition was calculated
`using manufacturer label information. Differences in mean aluminum exposure between cases and
`controls, as well as subgroup analysis in those with renal impairment or cholestasis, was conducted.
`Aluminum exposure in patients meeting inclusion criteria closely mirrored the aluminum exposure
`of control patients. The difference in aluminum exposure was not found to be statistically significant,
`except in patients with cholestasis. Although the study found no difference in aluminum exposure
`in short-term complications with neonates, long-term complications are well established and may
`warrant the need to monitor and limit neonatal aluminum exposure.
`
`Keywords: parenteral nutrition; aluminum; neonate
`
`1. Introduction
`
`Aluminum serves no known biological role in the human body. Humans are naturally exposed
`to aluminum through drinking water, foods, medications, dust, and deodorant [1]. Additionally,
`aluminum is a common contaminant in many components of parenteral nutrition, especially calcium
`and phosphate additives. Under normal circumstances, the human body has natural defense
`mechanisms that prevent significant absorption of ingested aluminum. An intact gastrointestinal
`tract typically allows less than 1% absorption of aluminum [1]. Of the aluminum that enters the
`bloodstream, 99% is excreted through the kidneys.
`Preterm infants require high amounts of calcium and phosphate for bone mineralization.
`This, coupled with poor renal function, predispose preterm infants to a high risk for aluminum toxicity
`when fed parenterally. Reports of aluminum toxicity have been described since the 1970s [2]. Potential
`long-term effects of aluminum include neurotoxicity, anemia, bone disease, and cholestasis [3–12].
`As such, the Food and Drug Administration recommends maintaining aluminum exposure at less than
`5 mcg/kg/day [13].
`Currently, there is little research examining the effects of parenteral aluminum exposure on
`neonatal morbidities in an acute inpatient setting. The objective of this study was to determine if
`estimated mean cumulative aluminum exposure as part of parenteral nutrition is increased in neonates
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`Nutrients 2017, 9, 1249; doi:10.3390/nu9111249
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`www.mdpi.com/journal/nutrients
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`with poor outcomes, including necrotizing enterocolitis, rickets/osteopenia, and/or seizures when
`compared with control patients. Diagnoses were selected based on previous literature establishing
`a relationship between aluminum exposure and development of neurotoxicity and inhibition of
`proper bone maturation [3–12,14]. Necrotizing enterocolitis was selected as an inclusion diagnosis
`based on the direct relationship of the disease state with extended parenteral nutrition requirements.
`Secondary outcomes included: evaluation of mean cumulative aluminum exposure in neonates with
`renal dysfunction or cholestasis as well as determination of the doses of aluminum to which more
`cases were exposed, if a significant difference existed between cases and controls.
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`2. Materials and Methods
`
`2.1. Study Design
`
`This was a single center, retrospective, case-control study. All data was collected utilizing
`electronic medical records. Data collected included: gestational age, birth weight, daily weight,
`diagnoses, and parenteral nutrition (PN) formulas. Parenteral nutritional formulas, as well as daily
`weight, were entered into an aluminum calculator developed by investigators in Microsoft Excel©
`(Microsoft Professional Office 2016; Microsoft Corporation, Redmond, WA, USA) utilizing current
`manufacturer labeling to determine daily exposure to aluminum in mcg/kg/day (Table 1).
`
`Table 1. Manufacturer Aluminum Content.
`
`Product
`Dextrose
`Amino Acids
`Sodium Chloride
`Sodium Acetate
`Sodium Phosphate
`Potassium Chloride
`Potassium Acetate
`Potassium Phosphate
`Calcium Gluconate
`Magnesium Sulfate
`Fat Emulsion
`
`Brand
`Hospira
`Hospira
`APP/Fresenius 1
`APP/Fresenius
`APP/Fresenius
`APP/Fresenius or Hospira
`Exela or Hospira
`APP/Fresenius
`American Regent
`American Regent
`APP/Fresenius
`1 APP-American Pharmaceutical Partners.
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`Aluminum Content (mcg/L)
`25
`25
`200
`400
`16,000
`100
`200
`32,800
`12,500
`12,500
`25
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`Each PN formula was entered into the calculator by the primary investigator. Daily aluminum
`exposure over the first 14 days in each patient were added to determine the cumulative aluminum
`exposure in mcg/kg. Data was maintained utilizing a de-identified list. This study was approved by
`the Wichita Medical Research and Education Foundation Institutional Review Board.
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`2.2. Patient Selection
`
`Patients were included in the study sample if they received at least 14 days of parenteral nutrition
`between 1 June 2013 and 30 June 2016. All patients who received 14 days of parenteral nutrition
`during the preselected timeframe were retrieved from the electronic database. From there, cases were
`selected if they had a diagnosis consistent with necrotizing enterocolitis, rickets/osteopenia, or seizures
`based on diagnoses in Neodata® (Isoprime, Lisle, IL, USA). Control patients were selected if they had
`received at least 14 days of parenteral nutrition without development of any of the inclusion diagnoses.
`Controls were selected using a random sequence generator. Cases were matched 1:1 to a control patient
`based on gestational age and birth weight. Patients were excluded if they were diagnosed with any
`inclusion diagnoses prior to the initiation of parenteral nutrition, if they received less than 14 days of
`parenteral nutrition, or if they were small for gestational age. There were no gestational age or birth
`weight requirements for inclusion in the study.
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`2.3. Outcomes
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`The primary outcome of this study was to determine if estimated mean cumulative aluminum
`exposure as part of parenteral nutrition is increased in neonates with poor outcomes, including
`necrotizing enterocolitis, rickets/osteopenia, and/or seizures. Secondarily, the study aimed to evaluate
`the mean cumulative aluminum exposure in neonates with renal dysfunction, defined as serum
`creatinine >1.5 mg/dL, or cholestasis, defined as direct bilirubin >2 mg/dL. An additional secondary
`outcome included determining the doses of aluminum (mcg/kg/day) to which more cases were
`exposed, if a significant difference in exposure existed between cases and controls.
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`2.4. Statistical Analysis
`
`Based on an alpha of 5% and an 80% power to detect a difference in risk of development of
`inclusion diagnoses between cases and control of approximately 2.5 (i.e., odds ratio = 2.5), we calculated
`that 85 cases and 85 controls need to be included [14,15]. Differences in mean aluminum exposure
`between cases and controls were analyzed using a Student’s t-test. If a statistically significant difference
`(p < 0.05) in aluminum exposure was found between cases and controls, a classification and regression
`tree (CART) analysis would be conducted to determine the doses of aluminum for which more cases
`were exposed.
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`3. Results
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`A total of 156 patients were selected between 1 June 2013 and 30 June 2016. Of these, 54 patients
`were excluded due to receiving less than 14 days of parenteral nutrition. The remaining 102 resulted in
`51 matched pairs. There was an even split of male and female patients with 51 of each. Patients were
`on average 27 weeks and 3 days gestational age (24 weeks, 2 days–33 weeks, 6 days) and weighed
`1.029 kg (0.59 kg–2.223 kg) at birth. Thirty-one patients had a diagnosis of seizures, nineteen patients
`had a diagnosis of necrotizing enterocolitis, and twenty-three patients had osteopenia/rickets. Of the
`patients included, twenty had at least two inclusion diagnoses and two patients met all three inclusion
`diagnoses. Regarding secondary endpoints, ten patients met inclusion criteria for renal dysfunction
`and three patients met criteria for cholestasis. Demographic information can be found in Table 2.
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`Table 2. Patient Demographic Data.
`
`Average Gestational Age
`Average Birth Weight
`Gender, male
`Seizures
`Necrotizing Enterocolitis
`Osteopenia/Rickets
`
`Case Patients (n = 51)
`27 weeks, 2 days (±1 week, 3 days)
`1.029 kg (±0.32 kg)
`27 (53%)
`31 diagnoses (61%)
`19 diagnoses (19%)
`23 diagnoses (45%
`
`Control Patients (n = 51)
`27 weeks, 3 days (±1 week, 3 days)
`1.029 kg (±0.32 kg)
`24 (47%)
`-
`-
`-
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`Total aluminum exposure in all patients meeting inclusion criteria was 78.8 mcg/kg/day when
`compared with control patients of 79.2 mcg/kg/day (p = 0.87). Patients with a diagnosis of seizures
`had a total aluminum exposure of 78.3 mcg/kg/day when compared with control patients of
`78.7 mcg/kg/day (p = 0.91). Regarding necrotizing enterocolitis, patients with the diagnosis had
`a 79.1 mcg/kg/day while matched control patients had a total exposure of 80.5 mcg/kg/day (p = 0.72).
`Total aluminum exposure in patients with osteopenia or rickets was 80.8 mcg/kg/day when compared
`with controlled patients whose aluminum exposure was 79.6 mcg/kg/day (p = 0.76). Twenty patients
`had multiple inclusion diagnoses. The total aluminum exposure of case patients who had multiple
`inclusion diagnoses was 80.1 mcg/kg/day versus average 78.6 mcg/kg/day (p = 0.75).
`A total of 10 patients met the inclusion criteria for renal dysfunction. The average aluminum exposure
`of these 10 patients was 80.4 mcg/kg/day when compared with 78.9 mcg/kg/day in the 92 patients
`who did not have renal dysfunction (p = 0.7). Three patients met the inclusion criteria for cholestasis.
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`The average aluminum exposure in patients with cholestasis was 91.7 mcg/kg/day compared with
`78.7 mcg/kg/day in the 99 patients who did not meet inclusion criteria for cholestasis (p = 0.04).
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`4. Discussion
`
`The utilization of parenteral nutrition (PN) is a routine practice in the neonatal intensive care
`unit. Aluminum is commonly found as a contaminant in many components of parenteral nutrition,
`especially calcium and phosphate additives. A study conducted by Moreno and colleagues, found that
`parenteral nutrition solutions were the main source of aluminum exposure in neonates, representing
`88.7% of aluminum intake [16]. Reports of aluminum toxicity first appeared in the 1970’s [3]. However,
`to our knowledge this is the first study to assessing the relationship between aluminum exposure
`through parenteral nutrition and acute morbidities in neonatal patients.
`An influential study published by Bishop and colleagues examined 227 infants in the
`neonatal intensive care unit. The infants were randomized to receive either standard aluminum
`or aluminum-depleted intravenous-feeding solutions. In infants who received more than 10 days of
`parenteral nutrition, the Mental Development Index of those receiving the standard aluminum PN was
`found to be statistically lower than those who received the aluminum-depleted intravenous-feeding
`solutions (p = 0.02). In addition, infants who received the standard aluminum intravenous-feeding
`solutions were statistically more likely to have a Mental Development Index below 85 points,
`which could increase their risk of educational impairment (p = 0.03). It was estimated that infants
`would lose around one Mental Development Index point for each day on the standard aluminum
`solution [4]. However, it is important to note that infants with a diagnosis of neuromotor impairment
`were excluded as this impairment could render the assessment of the Bayley Mental Scale inaccurate.
`A follow-up study by Fewtrell and colleagues evaluated what effect the standard aluminum and
`aluminum-depleted intravenous-feeding solutions had on the bone development of infants from the
`Bishop study. Adolescents who had participated in the Bishop study as infants were invited back
`for assessment of bone area, bone mineral content, and bone mineral density. Patients who had a
`high exposure to aluminum (55 mcg/kg/day) had significantly lower hip bone mineral content after
`adjusting for confounding variables (p = 0.02) [12].
`In addition, the rate of parenteral nutrition-associated cholestasis ranges from 7.4% to 84% [2].
`Previous research has shown that hepatic aluminum concentrations were between 5 and 27 times
`higher than normal concentrations in infants receiving parenteral nutrition [17]. Further studies in
`animals found that animals who were exposed to parenteral nutrition had significant increases in
`both the serum bile acids and alkaline phosphatase levels when compared with animals who had not
`received parenteral nutrition [18,19]. Rats who had received parenteral nutrition for 14 days had higher
`concentrations of serum bile acids than those who had received parenteral nutrition for 7 days [19].
`Of the rats who received the parenteral nutrition for 14 days, the group that received high doses of
`aluminum (5 mg/kg/day) had a 33% reduction in biliary flow [19].
`A previous study demonstrated that approximately 90% of pediatric patients between the ages
`of 6 months and 17 years receiving parenteral nutrition had plasma aluminum concentrations above
`the reference range of 0–371 mmol/L [20]. Of these patients, approximately 20% of patients had an
`aluminum concentration 5–8 times the upper limit of normal [20]. Due to the retrospective nature of this
`study, aluminum exposure was calculated versus drawn serum levels. A previous study showed that
`there is no difference in aluminum serum concentrations with various levels of aluminum exposure [21].
`However, at our institution serum aluminum levels are not routinely drawn, limiting our ability to
`evaluate true total aluminum exposure.
`For consistency within our study, the aluminum content listed by the manufacturer was used to
`build the aluminum calculator. However, in 2012 Poole and colleagues demonstrated that components of
`parenteral nutrition may contain less aluminum than labeled by the manufacturer [22]. Despite finding
`that parenteral nutrition components contained less aluminum than the label indicated, Poole and
`colleagues identified that neonatal compounded parenteral nutrition still contained 3–5 times more than
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`the United States Food and Drug Administration (FDA) recommended “safe limit.” The study concluded
`that even when making a conscious effort to use the least contaminated parenteral nutrition products,
`daily aluminum exposure still totaled to 8.8–12.9 mcg/kg/day [22]. Notably, the highest measured and
`calculated aluminum content was found among the smallest patients.
`Despite literature describing the complications associated with aluminum exposure, our study
`supports previous claims of the inability to provide nutrition and maintain aluminum exposure less
`than 5 mcg/kg/day. In fact, of the 1428 parenteral nutrition formulas analyzed during the study
`period, only seven formulas contained aluminum in amounts below the FDA “safe limit.” However,
`in spite of providing aluminum beyond the FDA limit in the majority of our patients, mean cumulative
`aluminum exposures were similar in those with and without the outcomes of interest. There were a
`few limitations with our study. In some instances, the neonates involved in our study did not receive
`all 14 of their PN days consecutively. In addition, only the first 14 days of parenteral nutrition was
`evaluated, so it is possible the total cumulative aluminum exposure may differ between patients with
`diagnoses versus control patients if patients with inclusion diagnoses had received more total days of
`parenteral nutrition. Other limitations of this study include that patients were only matched on weight
`and gestational age, which may not account for all compounding factors. Specific amounts of calcium
`and phosphate were not evaluated in related to osteopenia/rickets diagnoses. Finally, the study fell
`short of enrolling enough patients to meet predefined power.
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`5. Conclusions
`
`In conclusion, mean cumulative aluminum exposure in neonates receiving at least 14 days of
`parenteral nutrition was similar among those with and without necrotizing enterocolitis, seizures, and/or
`osteopenia/rickets. The majority of patients were exposed to aluminum concentrations above the current
`FDA limit. However, larger, high-quality studies are needed to further assess the relationship between
`aluminum exposure and morbidity.
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`Author Contributions: Lela Hernandez and Megan Fortenberry conceived and designed the experiments;
`Megan Fortenberry performed the experiments; Lela Hernandez, Megan Fortenberry, and Jacob Morton analyzed
`the data; Megan Fortenberry wrote the paper; Lela Hernandez, Megan Fortenberry, and Jacob Morton edited and
`approved of final manuscript.
`Conflicts of Interest: The authors declare no conflict of interest.
`
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`© 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
`article distributed under the terms and conditions of the Creative Commons Attribution
`(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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