Abstract
There has been a multivitamin infusion (MVI) shortage for the last decade, generating increasing concerns for the neonatal population. This study evaluated a cohort of 4 total parenteral nutrition (TPN)-dependent neonates who presented within a 6-month period with abnormal biochemistry in a complex and unusual pattern. All exhibited findings were suggestive of multiple inherited metabolic disorders (IMD), particularly multiple acyl-CoA dehydrogenase deficiency and maple syrup urine disease. Given the rarity of having 2 IMDs, communication with the primary team was initiated and revealed inadequate MVI in the administered TPN. All biochemical abnormalities could be explained by thiamine (B1), riboflavin (B2), pyridoxine (B6), and/or biotin (B7) deficiency. MVI-deficient TPN as the single unifying etiology is further supported by normal newborn screening (NBS) and resolution of biochemical abnormalities with MVI administration in all neonates. Awareness of this problem is critical to avoid unnecessary testing and initiate prompt treatment with vitamins.
Keywords
Introduction
Inherited metabolic disorders (IMD) can present acutely in the neonatal period with features including lethargy, seizures, vomiting, metabolic acidosis, hypoglycemia, or hyperammonemia. These disorders are a diagnostic consideration in many critically ill infants treated in emergency departments and neonatal intensive care units (NICUs).
Deficiencies of specific vitamins can mimic a variety of IMDs, as many enzymes involved in cellular metabolism depend on vitamins as cofactors to function properly. This includes many B vitamins such as thiamine (B1), riboflavin (B2), pyridoxine (B6), and biotin (B7). For example, thiamine is a cofactor for the branched-chain alpha-keto acid dehydrogenase (BCKDH) complex, which catalyzes the breakdown of branched-chain amino acids (BCAAs). A deficiency in the active BCKDH complex causes maple syrup urine disease (MSUD), leading to elevated BCAAs, including leucine, isoleucine, and valine. Extreme thiamine deficiency can mimic MSUD, even in individuals with an otherwise functional BCKDH complex. 1 A similar dependency exists between multiple acyl-CoA dehydrogenases and riboflavin, as patients with severe riboflavin deficiency can have biochemical features mimicking those of multiple acyl-CoA dehydrogenase deficiency (MADD).2,3
This mimicry is particularly relevant given the current vitamin shortages. According to the American Society for Parenteral and Enteral Nutrition (ASPEN), there has been a multivitamin infusion (MVI) shortage for the last decade, 4 generating concerns for an eventual problem that disproportionately impacts critically ill pediatric and neonatal patients who are unable to receive multivitamins enterally. ASPEN has recommended against the use of pediatric intravenous multivitamins for adults to prevent the worsening of the shortage and resultant vitamin deficiencies in neonatal and pediatric patients and has suggested prioritizing intravenous multivitamins for patients under 2.5 kg or less than 36 weeks gestational age. 5 Likely due to a combination of MVI shortage and limited resources of many community hospitals, severe iatrogenic vitamin deficiencies among total parenteral nutrition (TPN)-dependent neonates appear to be occurring more frequently.
Case Presentations
Over the course of 6 months, a single healthcare center cared for 4 critically ill, TPN-dependent neonates transferred from outside hospitals (OSH) with abnormal biochemical studies suggestive of one or more IMD. All individuals had testing performed by the Stanford Biochemical Genetics Laboratory. All individuals had normal newborn screening (NBS) performed by the California Department of Public Health Newborn Screening Program. In all 4 cases, the biochemical abnormalities were ultimately attributed to iatrogenic vitamin deficiencies secondary to MVI-deficient TPN administration. Research was conducted at Stanford University, Stanford Hospital and Clinics, and Lucile Packard Children’s Hospital, and approved by the institutional review board (IRB #73331).
Case 1: A male infant born at 33 weeks gestation developed cholestasis while on TPN since birth. On day of life (DOL) 28, plasma amino acid (PAA) analysis demonstrated elevations of BCAAs in a pattern consistent with MSUD, including elevated alloisoleucine (Table 1). Acylcarnitine profile (ACP) demonstrated elevation of isovaleryl-/2-methylbutyrylcarnitine (C5), glutarylcarnitine (C5-DC), and 3-hydroxyisovalerylcarnitine (C5-OH), with urine organic acid (UOA) analysis demonstrating elevation of multiple metabolites, including 3-hydroxyisovaleric, ethylmalonic, glutaric, and 2-hydroxyglutaric acids, concerning for MADD (Table 1). Chromosomal microarray and exome sequencing were nondiagnostic. Communication with the OSH suggested inadequate MVI in the previously administered TPN due to formulary shortages. Following the initiation of an adequate dose of MVI, PAA, ACP, and UOA findings were resolved.
Case 2: A female infant born at 23 weeks gestation on TPN since birth developed metabolic acidosis, prompting biochemical genetics evaluation. On DOL 23, ACP demonstrated the elevation of multiple short- and medium-chain acylcarnitine species (Table 1), concerning for MADD. These normalized on repeat ACP after initiating adequate dosing of MVI.
Case 3: A male infant born at 31 weeks gestation with biliary atresia had been receiving TPN since birth. UOA analysis performed on DOL 13 showed an elevation of glycine conjugates along with glutaric, ethylmalonic, and dicarboxylic acids (Table 1), concerning for MADD. Biochemical abnormalities normalized on repeat UOA on DOL 22 after initiating adequate dosing of MVI.
Case 4: A female infant born at 35 weeks gestation developed cholestasis while on TPN since birth. Biochemical evaluation performed on DOL 20 was notable for elevated BCAAs by PAA analysis, with UOA analysis demonstrating elevation of branched-chain alpha-keto acids, 3-hydroxyisovaleric, ethylmalonic, glutaric, 2-hydroxyglutaric, and dicarboxylic acids (Table 1). There was also an elevation of vanillactic acid (Table 1), concerning for aromatic L-amino acid decarboxylase deficiency. By DOL 28, all biochemical abnormalities had normalized after initiating adequate dosing of MVI.
Vitamins as Cofactors for Enzymes and Their Respective Inherited Metabolic Disorders (IMD) and Biomarkers, in Addition to the Laboratory Findings of 4 Neonates Before and After Inclusion of a Multivitamin in the Parenteral Nutrition.
Abbreviations: 3MCC, 3-methyl-crotonyl-CoA; AADC, aromatic L-amino acid decarboxylase; MADD, multiple acyl-CoA dehydrogenase deficiency; MSUD, maple syrup urine disease; PC, pyruvate carboxylase; PDH, pyruvate dehydrogenase.
Discussion
We have described a cohort of 4 patients who underwent biochemical studies for various reasons that all showed evidence of one or more IMD. All abnormalities can be explained by deficient thiamine, riboflavin, pyridoxine, and/or biotin administration, as deficiencies of these cofactors alter specific enzymatic activities, leading to metabolic derangements that mimic one or more IMD. MVI-deficient TPN as the single unifying etiology is further supported by normal newborn screening and resolution of biochemical abnormalities with MVI administration in all neonates. One infant underwent molecular genetic testing that was nondiagnostic. This testing, along with the normal NBS, make the chance of a vitamin-responsive IMD much less likely.
The recent increase in these cases has been alarming. In addition to our cases described here, there are additional cases recently reported in California. 6 Of note, these clinical cases had several commonalities that contributed to their vitamin deficiencies and subsequent metabolic derangements; all had experienced prolonged TPN administration prior to transfer for prematurity and/or other co-morbidities, and all were cared for in community hospital NICUs. This study only includes cases that were evaluated at 1 institution, but these results are likely generalizable to other areas inside and outside of the United States.
Critical evaluation of MVI preparations used in the neonatal population is important. Awareness of this issue in the broader medical community is vital to prioritize pediatric MVI for infants, as recommended by ASPEN, 5 specifically in critically ill infants most at risk for nutritional deficiencies, to avoid unnecessary testing and to initiate prompt treatment with appropriate vitamins. Vitamin deficiencies should be considered in the differential diagnosis for at-risk patients, including those with dietary or eating restrictions, TPN dependency, or intestinal malabsorption. This is of particular importance due to the parenteral vitamin shortages likely disproportionately impacting patients, specifically neonates, cared for at community hospitals across the United States and worsening known healthcare disparities in lower socioeconomic and rural communities.
Footnotes
Author Contributions
Reva Frankel and Courtney Verscaj drafted the manuscript. Christina Tise and Kristina Cusmano-Ozog conceptualized, reviewed, and edited the manuscript.
Data Availability Statement
Relevant data is included in this paper. Additional data is not publicly available as it is protected by HIPAA. Further inquiries can be directed to the corresponding author.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval
Ethical approval to report this case series was obtained from the Stanford University institutional review board (IRB #73331).
Informed Consent
Informed consent for patient information to be published in this article was not obtained because the IRB has determined that this project does not meet the definition of research as defined in 45 CFR 46.102(d), nor the definition of clinical investigation as defined in 21 CFR 50.3(c). A waiver of consent was approved by the IRB due to its retrospective minimal-risk nature.
