Introduction {#Sec1}
============

Oral vitamin E is used in several childhood diseases, such as for prevention of retinopathy of prematurity (ROP), growth retardation, fat malabsorption (e.g., cystic fibrosis, cholestatic diseases), and other chronic diseases in infants and children with vitamin E deficiency.  In neonates, vitamin E is administered to alter the antioxidant status in order to prevent free-radical damage in cell membranes, to inhibit inflammatory processes by modulating cellular signals, to regulate transcriptions, and to stimulate the infants' immune system \[[@CR1]\].  In children with fat malabsorption, vitamin E is administered to prevent neuropathy, gastrointestinal disturbances, and myopathy caused by vitamin E deficiency. 

Few oral products have been approved by regulatory authorities, resulting in "off-label" or unlicensed use and extempore pharmacy compounding \[[@CR2]--[@CR4]\].  Discussions with physicians and pharmacists revealed different recommendations on doses, formulations, and drug of choice.  The diversity was confirmed in a later survey \[[@CR5]\].  Some oral vitamin E products may contain excipients, such as polyethylene glycol, propylene glycol, ethanol, or polysorbate 80, which have been associated with adverse drug reactions in children. 

"Vitamin E" is a common term for eight lipid-soluble compounds: α-, β-, γ-, and δ-tocopherol, and α-, β-, γ-, and δ-tocotrienol \[[@CR6]\].  In humans, α-tocopherol is the most abundant form in plasma \[[@CR7]\].  Vitamin E compounds differ in stereoisomerism, esterification, and biological activity (Table [1](#Tab1){ref-type="table"}) \[[@CR6], [@CR8]\].  Table 1Content of common vitamin E compounds, in milligrams (mg) and international units (IU) \[[@CR6], [@CR8]\]CompoundmgIUdl-α-tocopheryl acetate11.00d-α-tocopheryl acetate11.36dl-α-tocopherol11.10d-α-tocopherol11.49Tocofersolan10.39--0.45

Vitamin E undergoes passive diffusion from the small intestine \[[@CR7]\].  The absorption rates differ considerably between individuals, ranging from 20--60%, depending on pancreatic function, bile salts, concomitant fat intake, and product properties \[[@CR6], [@CR9]--[@CR11]\].  Preceding absorption, vitamin E and food lipids form micelles in the presence of bile and bile salts.  The vitamin E compound tocofersolan has both hydrophilic and lipophilic properties and may increase the bioavailability of fat-soluble vitamin E in individuals having a low degree of absorption \[[@CR12]\].  The strength conversion factor (Table [1](#Tab1){ref-type="table"}) for tocofersolan is, however, based on the tocopherol content of the molecule, regardless of bioavailability.  Vitamin E is not transformed and is eliminated by fecal excretion or conjugation. 

Our main aim was to review data on therapeutic use of and recommendations for oral vitamin E therapy in neonates and children. 

Methods {#Sec2}
=======

To identify published studies, case reports, and information on therapeutic use of oral vitamin E in children, a literature search was carried out.  Search terms in Medline OVID and EMBASE were Vitamin e.mp, exp Vitamin E/, tocofersolan.mp, or tpgs.mp; limited to human, all child (birth to 18 years) or child.mp; administration, oral or oral.mp; publication year 1980--February 2008.  Publications on other aspects than therapy, such as supplements in formulas or total parenteral nutrition (TPN), were excluded.  Only articles written in English or a Scandinavian language evaluating human subjects were considered. 

Therapy recommendations and product properties were also found in handbooks, such as the British National Formulary for Children (BNF for Children) \[[@CR13]\], Medicines for Children \[[@CR14]\], Pediatric Dosage Handbook \[[@CR11]\], Neonatal Drug Formulary \[[@CR15]\], Neofax \[[@CR16]\], product monographs, and formularies.  In addition to the review of clinical studies on the use of oral vitamin E in children, data from the handbook recommendations are presented as well. 

Results {#Sec3}
=======

As this review focused on oral vitamin E therapy in children, only studies including vitamin E doses, pharmacokinetics, and oral formulations were considered. 

Clinical studies and case reports on oral vitamin E therapy in children are few and heterogeneous regarding the compounds being used, dosing, and indications.  The majority of the studies included a small number of patients, and they rarely specified how doses were chosen, either for prophylaxis or for treatment of current deficiency.  The exact name of the active substance was rarely stated.  Information on the content of excipients was not always provided, and some studies did not describe the formulation at all.  Consequently, overall statistical evaluations of dosing and formulation recommendations for both neonates and older children have not been feasible for this review. 

Published data indicate that an esterified, synthetic racemic mixture, all-rac-α-tocopheryl acetate (formerly dl-α-tocopheryl acetate), and dl-α-tocopherol are commonly used in medicinal products (Table [2](#Tab2){ref-type="table"}).  A water-soluble form, tocofersolan, has also been used \[[@CR5]\].  Tocofersolan contains RRR-α-tocopherol with polyethylene glycol 1000 succinate \[[@CR8]\] and is also called "d-α-tocopheryl PEG 1000 succinate," "d-α-tocopheryl polyethylene glycol succinate," "TPGS," and "vitamin E TPGS."  Table 2Studies on oral vitamin E therapy in sick newborns and premature babies included in the Cochrane review \[[@CR1]\]AuthorsNo.  of patientsPatient ageDoses and duration of therapyVitamin E compoundIndicationsOutcome parametersVitamin E levelsResults, type of study, statistical analysisFerlin et al.  \[[@CR49]\]40; 10 vit.  E, 10 vit.  E/iron, 20 iron or placebo15 days25 IU/day; 2 monthsα-TocopherolPrevention, anemia of prematurityHematological test values, group comparisonsNot measuredDescriptive; no effect on hematology parameters; ADR not mentionedFisher et al.  \[[@CR18]\]28; 17 vit.  E, 11 placebo24 h25 or 50 mg/day; 3 daysTocofersolanProphylaxis, hyperbilirubinemiaHemoglobin, carboxyhemoglobin, carbon monoxide, bilirubinT: 1.85 ± 0.76 mg/dL, C: 0.76 ± 0.49 mg/dLStatistical group comparison; no significant effect on bilirubin levels; ADR not mentionedHittner et al.  \[[@CR17]\]150; 101 analyzed, T: 50 patients24 hT: 100 mg kg^−1^ day^−1^, C: 5 mg kg^−1^ day^−1^ during hospital staydl-α-TocopherolPrevention of retrolental fibroplasiaDisease severity (grade I--IV)T: 1.21 ± 0.79 mg/dL, C: 0.62 ± 0.40 mg/dLStatistical group comparisons, incl.  multivariate analysis; significant reduced incidence of disease grade \>2; ADR not studiedJansson et al.  \[[@CR50]\]57; 33 vit.  E/iron, 24 iron10 days15 mg/day; 8--10 weeksdl-α-Tocopheryl acetateDose finding, vit.  E requirementsHematological test valuesT: 1.22 ± 0.20 mg/dL, C: 0.8 ± 0.28 mg/dLStatistical group comparison; no significant difference in hemoglobin concentration or reticulocyte count; ADR for vit.  E not studiedMelhorn et al.  \[[@CR51]\]186; 47 vit.  E, 50 vit.  E/iron, 89 iron or no supplement8 days25 IU/day; 5 weeksα-Tocopheryl acetatePrematurity, anemia prophylaxisHematological test values, vit.  E deficiencyT: 0.5--1.0 mg/dL, C: 0.2--0.8 mg/dLSignificantly lower hemoglobin, higher reticulocyte count, and increased cell fragility without vit.  E supplement in premature infantsPathak et al.  \[[@CR52]\]30; 15 vit.  E/iron/erythropoietin, 15 iron/erythropoietin24.4 ± 15.5 days50 IU/day until discharge or 8 weeksNot specifiedAnemia of prematurity, with erythropoietin therapyHematological test values, response to erythropoietin/ironT: approx.  65 μmol/L (8 weeks therapy), C: approx.  35 μmol/L (8 weeks therapy)Statistical analysis by Student's*t*-test; no differences among study groups; ADR not mentionedSmith et al.  \[[@CR19]\]30; 17 vit.  E, 13 placebo\< 24 h50 mg/day; 3 daysTocofersolanBilirubin production after vit.  E supplementVit.  E, bilirubin, hemoglobinT: 2.11 ± 0.79 mg/dL, C: 1.71 ± 1.40 mg/dLStatistical group comparison; no significant differences; ADR not mentionedZipursky et al.  \[[@CR53]\] and follow-up \[[@CR1]\]269; 135 vit.  E, 134 placebo2.7 ± 3 days25 IU/day; 6 weeksNot specifiedPrevention of anemiaHematological test valuesSick infants: T : 3.1 ± 2.3 mg/dL, C: 0.87 ± 0.4 mg/dL; healthy infants: T: 2.5 ± 1.4 mg/dL, C: 0.83 ± 0.7 mg/dLDescriptive; no significant difference between supplement and non-supplement; ADR not mentioned*T* Treatment,*C* control,*ADR* adverse drug reaction

Oral vitamin E in sick newborns and premature infants {#Sec4}
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In this patient category, oral vitamin E may be used for treatment or for prevention of vitamin E deficiency, anemia, or for prevention of ROP caused by oxygen therapy.  However, the interpretation of data is limited by several factors, as the methodologies, choice of drugs and doses, outcomes, and ADR assessments have been less than optimal.  Vitamin E was initiated as an oral formulation in only a few studies, and the doses were heterogeneous.  A Cochrane review on vitamin E supplementation for prevention of morbidity and mortality in preterm infants included 26 published studies that fulfilled the Cochrane quality and entry criteria of primary and secondary outcomes analysis; infants with gestational age less than 37 weeks or birth weight less than 2,500 g were included \[[@CR1]\].  Most studies were carried out with other administration forms, such as parenteral, intramuscular/intravenous, or parenteral in combination with oral.  Eight of these studies refer to oral therapy alone and form the basis for our review in this patient category (Table [2](#Tab2){ref-type="table"}). 

No recent studies on vitamin E treatment in neonates were identified.  The majority of the studies on oral vitamin E administration in neonates describe the use of α-tocopherol or α-tocopheryl acetate for prevention of anemia.  Only one study addresses prevention of ROP \[[@CR17]\].  For tocofersolan, we identified two small studies on the effect on bilirubin levels \[[@CR18], [@CR19]\]. 

It is worth noting the diversity of doses, indications, and choices of compounds in the studies.  Vitamin E absorption may differ among formulations \[[@CR10]\].  Existing studies on absorption were published several years ago, with suboptimal designs and products no longer available.  Systematic, comparative dose-finding studies for any vitamin E compound within this patient group were not identified.  Serum concentrations have been demonstrated to differ widely even after equal doses \[[@CR20], [@CR21]\]. 

Dosing recommendations and indications differ among handbooks (Table [3](#Tab3){ref-type="table"}).  Table 3Summary of handbook dosing recommendations for oral vitamin ESourceProductIndicationsDosagesCommentsNeonatal Drug Formulary \[[@CR15]\]Aquasol E (tocopherol acetate)Investigational: treatment or prevention of anemia of prematurityAdequate nutritional intake of vitamin E as the only actionMonitor serum levels when pharmacologic doses of vitamin E are administered; liquid preparation is very hyperosmolar and should be dilutedAll neonates with birthweight \<1,000 g100 mg kg^−1^ day^−1^ beginning at admission in the ward (adjusted to maintain the level 0.5--3.5 mg/dL)Retinopathy of prematurity (ROP)Prophylaxis: 25--50 units/day until 2--3 months, treatment: 50--200 units/day for 2 weeksBroncho-pulmonary dysplasia (BPD)Intraventricular hemorrhage (IVH)Neofax \[[@CR16]\]Aquavit E (tocopherol acetate)Prevention of vitamin E deficiency; may be indicated in babies receiving erythropoietin and high iron dosages5--25 IU/dayHyperosmolar; contains polysorbate 80 and propylene glycol; higher doses to reduce oxidant-induced injury (ROP, BPD, IVH) remain controversialPediatric Dosage Handbook \[[@CR11]\]Aquasol E, Aquavit EVitamin E deficiencyPremature LBW neonates: 25--50 units/dayNormal levels within 1 week of therapyPrevention of vitamin E deficiencyLBW neonates: 5 units/day, full-term: 5 units/L formula ingestedNEC has been associated with oral administration of large dosages (e.g., \>200 units/day) of hyperosmolar vitamin E preparation in LBW neonatesInvestigational: prevention of ROP or BPD secondary to oxygen therapy15--30 units kg^−1^ day^−1^ to maintain plasma levels at 1.5--2 μg/mL; neonates may need as high as 100 units kg^−1^ day^−1^Cystic fibrosis100--400 units/dayBeta-thalassemia750 units/daySickle cell anemia450 units/dayMalabsorption syndrome1 unit kg^−1^ day^−1^ of water-miscible vitamin EBNF for Children \[[@CR13]\]Vitamin E suspensionVitamin E deficiencyNeonate 10 mg kg^−1^ day^−1^Consider dilution in neonates due to high osmolality; increased risk of NEC in preterm neonatesChild 1 month--18 years: 2--10 mg/kg daily, up to 20 mg/kg has been usedCystic fibrosisChild 1 month--1 year: 50 mg once daily, adjusted as necessaryChild 1--12 years: 100 mg once daily, adjusted as necessaryChild 12--18 years: 200 mg once daily, adjusted as necessaryCholestasis and severe liver diseaseNeonate: 10 mg/kg dailyChild 1 month--12 years: initially 100 mg daily, adjusted according to response; up to 200 mg/kg daily may be requiredChild 12--18 years: initially 200 mg daily, adjusted according to response; up to 200 mg/kg daily may be requiredPrevention of abnormally low vitamin E levels in abetalipoproteinaemiaNeonate: 100 mg/kg once dailyChild 1 month--18 years: 50--100 mg/kg once dailyLBW Low birth weight, NEC necrotizing enterocolitis

Oral vitamin E in children with liver or biliary tract disease {#Sec5}
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We did not identify any evidence-based review for these patient categories.  The clinical studies and case reports have differing dosing approaches, choices of compound, and outcome parameters (Table [4](#Tab4){ref-type="table"}).  Table 4Publications on oral vitamin E therapy in children with liver or biliary diseaseAuthorsNo.  of patientsPatient ageDosesVitamin E compoundsIndicationsOutcome parametersVitamin E levelsCommentsChowers et al.  \[[@CR54]\]137--36 years100 mg kg^−1^ day^−1^"Vitamin E"; unspecifiedAbeta/hypobetalipoproteinemiaRetinal degeneration0.03--0.35 mg/dLDescriptive long-term follow-up; oral vitamin A and E; retinal changes foundClark et al.  \[[@CR55]\]116.1 ± 5.2 years20--100 IU/dayα-Tocopheryl acetateCholestasisComparison of screening resultsNot describedAssessment of monitoring methodologyGuggenheim et al.  \[[@CR56]\]116 years400 mg/dayα-Tocopheryl acetateCholestasis, neuromuscular diseaseNeurological improvement4.5--8.5 mg/g cholesterolCase reportHegele and Angel \[[@CR57]\]116 years800 mg/day"Vitamin E"; unspecifiedAbetalipo proteinemia, neuropathyNeurological improvement331 µmol/mg triglyceride in adipose tissueCase reportLubrano et al.  \[[@CR58]\]103.4 years (2--6 years)300 mg/dayα-Tocopheryl acetateCholestasisErythrocyte membrane lipid peroxidation, hematology parametersT: 8.35 ± 4.92, C: 11.70 ± 0.9115-day trial to assess oxidative damageMuller et al.  \[[@CR59]\]8Not described100 mg kg^−1^ day^−1^α-Tocopheryl acetateAbetalipoproteinemiaNeurological sequelaeOnly examplesDescriptive long-term follow-upNakagawa et al.  \[[@CR60]\]311 months--14 years20--125 mg kg^−1^ day^−1^α-Tocopheryl acetateCholestasisEffect on neurological diseaseRange: 0.07--0.72 mg/dLCase reportsRoma et al.  \[[@CR61]\]14.5 years120, then 60 mg kg^−1^ day^−1^"Vitamin E"; unspecifiedHypobetalipoproteinemiaSymptom improvement, neurological function"Normal"Case reportRoongpraiwan et al.  \[[@CR62]\]112--18 months100, then 50 IU kg^−1^ day^−1^α-Tocopheryl acetateCholestasisVitamin E levelsDescribed for dose and patientDescriptive studySocha et al.  \[[@CR63]\]159 months--3.4 years20 IU/kgTocofersolanCholestasisVitamin E levels9.7 (7.2--14.9) mg/LComparative study with control groupSokol et al.  \[[@CR64]\]1419 months--17.5 years100--200 IU kg^−1^ day^−1^dl-α-TocopherolCholestasisNeurological function, vitamin E levelsAdditional i.m.  injection due to lack of responseDescriptive study, mixed administration routesSokol et al.  \[[@CR65]\]600.5--20 years25 IU kg^−1^ day^−1^TocofersolanCholestasisNeurological function, safety profile21.6--39.9 µmol/LDescriptive studyTraber et al.  \[[@CR66]\]18 years100 mg kg^−1^ day^−1^TocofersolanCholestasisAbsorption, plasma level10.5--18.1 µg/mLCase report*T* Treatment,*C* control

Neonates and children with bile duct atresia or chronic intrahepatic cholestasis have insufficient bile secretion.  Vitamin E treatment is therefore indicated due to reduced ability to dissolve dietary fat and vitamins.  Serum concentrations may, however, still be lower than expected \[[@CR22], [@CR23]\].  Some studies describe the use of tocofersolan in children with obstructive bile disease \[[@CR24], [@CR63], [@CR65], [@CR66]\], and a medicinal product was recently approved by the European Medicines Agency under exceptional circumstances \[[@CR67]\].  The total daily dose is stated as 17 mg/kg of d-alpha-tocopherol in the form of tocofersolan.  Sokol and co-workers analyzed serum concentrations in 22 children with hepatic/biliary disease who had vitamin E deficiency \[[@CR24]\].  All patients were switched from tocopheryl acetate to tocofersolan, and all of them needed a significant dose reduction in order to maintain the target serum concentration.  On average, doses were reduced by 83% (range: 64.3--93.5%).  A larger study from the same authors included 60 children aged 0.5--20 years.  All children needed a dose reduction when tocopherol or tocopheryl acetate 70--200 IU kg^−1^ day^−1^ was replaced with tocofersolan 20--25 IU kg^−1^ day^−1^ \[[@CR65]\].  Dose reductions of 40--77% are also described after changing from α-tocopherol to tocofersolan in children with biliary stasis \[[@CR63], [@CR66]\].  Despite the paucity of data, these results indicate that patients with absorption disturbances may need considerable dose reduction when treated with tocofersolan compared to α-tocopherol or α-tocopheryl acetate. 

Dosage recommendations in handbooks range from "water-miscible vitamin E" 1 IU kg^−1^day^−1^ \[[@CR11]\] to 100--200 mg α-tocopheryl acetate/day \[[@CR13]\] (Table [3](#Tab3){ref-type="table"}). 

Other indications for oral vitamin E therapy {#Sec6}
--------------------------------------------

Vitamin E has also been used in children with diseases such as abetalipoproteinemia (Table [3](#Tab3){ref-type="table"}), cystic fibrosis \[[@CR25]--[@CR27]\] , β-thalassemia, sickle cell anemia \[[@CR11], [@CR13]\], inborn errors of metabolism \[[@CR28]\], epidermolysis bullosa \[[@CR29]\], glucose-6 phosphate dehydrogenase deficiency \[[@CR30]\], and focal segmental glomerulosclerosis \[[@CR31]\].  Many studies do not state the rationale for the dose size, and dosing regimes are not evaluated systematically.  This is demonstrated by the cystic fibrosis studies in children.  Doses differed among the studies: 5.5--47.4 IU kg^−1^ day^−1^, 5--10 mg kg^−1^ day^−1^, and 50--100 IU/day.  The vitamin E compounds used in the studies were described as tocopheryl acetate, tocopherol, tocofersolan, or vitamin E. Despite this, dose recommendations are listed in handbooks (Table [3](#Tab3){ref-type="table"}). 

Recently, vitamin E has been studied in children with obesity-related liver disease \[[@CR32]--[@CR34]\].  Outcome parameters included changes in laboratory findings such as aminotransferases and alkaline phosphatase (ALP).  A cohort study of 11 children aged 8.3--14.3 years found a normalization of serum aminotransferase and ALP after treatment \[[@CR32]\].  However, two other studies, including 28 and 90 children, respectively, found diet and/or exercise to be more efficient than vitamin E therapy alone \[[@CR33], [@CR34]\]. 

Dosing implications for co-administration with other drugs {#Sec7}
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Tocopherol/tocopheryl acetate and tocofersolan appear to differ in their potential for drug interactions.  Tocofersolan may increase the bioavailability of other drugs, such as amprenavir \[[@CR35]\], paclitaxel \[[@CR36]\], vancomycin \[[@CR37]\], and cyclosporine \[[@CR38]\], due to its combined lipophilic and hydrophilic nature.  In children with a liver transplant, tocofersolan has been found to increase cyclosporine serum concentrations significantly \[[@CR39]\].  This may increase the risk of ADRs when tocofersolan and cyclosporine are used simultaneously \[[@CR40]\].  Some studies suggest that vitamin E may increase the risk of hemorrhages due to reduction of prothrombin levels and may affect platelet function, particularly in patients with vitamin K deficiency, such as neonates with sepsis, or in patients treated with antithrombotic medicines such as warfarin and acetylsalicylic acid \[[@CR13], [@CR41], [@CR42]\].  Decreased vitamin E plasma levels have been reported after use of phenobarbital and phenytoin \[[@CR43]\].  Drugs that interfere with the reuptake of bile acids may reduce the uptake of fat-soluble vitamins such as vitamin E \[[@CR44]\]. 

Handbook information on drug interactions with vitamin E is not consistent, and the information differs among books and other literature. 

Discussion {#Sec8}
==========

Overall, the body of evidence was limited due to the small number of studies.  The lack of supportive information on oral vitamin E dosing recommendations in children is a major concern.  This review shows that oral vitamin E dosing regimens for children differ considerably, and few randomized clinical trials have been published.  Information on vitamin E pharmacokinetics in children is lacking, and data regarding doses, compounds, and outcome parameters are heterogeneous.  There are no existing evaluations of dose--effect relationships, therapeutic windows, safety profiles, and optimum duration of therapy for the various vitamin E compounds across age groups or disease states.  Many studies incorporate various forms of vitamin E therapy in their treatment of neonates and older children, such as oral, intravenous, and intramuscular administration and as supplement in total parenteral nutrition.  Consequently, there is very little documentation to support an evidence-based choice of oral therapeutic dose or compound. 

Vitamin E compounds may differ in biological activity and bioavailability.  Most clinical data in children are available for α-tocopherol or tocopherol esters, such as α-tocopheryl acetate.  While a tocofersolan product recently received a marketing authorization in the EU for use in children with cholestasis, this product is contraindicated in premature infants.  In newborns, most evaluations on efficacy and safety are based on studies with intravenous or intramuscular tocopheryl acetate.  Assessment on the risk/benefit profile has not yet been done for oral vitamin E in neonates and children. 

Tocofersolan may have increased bioavailability compared to other vitamin E compounds.  This has resulted in therapeutic serum levels despite considerable dose reductions when switching from tocopheryl acetate in children with malabsorption diseases \[[@CR24], [@CR65]\].  Conversely, absorption of tocopheryl acetate in healthy adults may be similar or even superior to tocofersolan \[[@CR45]\].  A change of therapy from α-tocopheryl acetate to tocofersolan may have consequences for dosing recommendations and the ADR profile, but it is not known whether this is the case for all patient groups or whether differences in intestinal absorption are less pronounced in infants without malabsorption disorders.  The pharmacokinetic properties of tocofersolan indicate that therapeutic monitoring may be advisable in children to avoid adverse reactions. 

The relative biological activities of vitamin E compounds have been determined by a rat model, founded on the fact that vitamin E depletion after conception causes death and embryo resorption \[[@CR6]\].  However, the rat model cannot be used to detect differences in biological activity or bioavailability in immature, human intestines, such as in premature babies, sick neonates, or in patients with gastrointestinal disturbances.  To our knowledge, the mg/IU ratio for tocofersolan is based on a calculation of the tocopherol content of the molecule and not the bioavailability of the molecule. 

Toxicity and ADRs, such as sepsis, NEC, and hemorrhages have been reported after vitamin E therapy \[[@CR1]\].  The risk of such events appears to be associated with low birth weight and serum levels above 3.5 mg/dL. No follow-up studies in neonates or older children have been found. 

Some oral vitamin E products may contain excipients, such as polyethylene glycol, propylene glycol, ethanol, or polysorbate 80, which have been associated with ADRs in children.  Few vitamin E products have a marketing authorization for oral administration in children.  Therefore, extempore pharmacy compounding may be the only option.  There are, however, few product specifications.  In the 1980s, reports of deaths and serious ADRs, including thrombocytopenia and kidney and liver failure, were linked to the use of an intravenous vitamin E product \[[@CR46]\] and may have been caused by dose-related toxicity of α-tocopherol, the emulsifier polysorbate or both.  Oral administration of vitamin E has been associated with an increased risk of NEC, possibly related to dose, polysorbate content, or hyperosmolar products \[[@CR47]\].  The polyethylene glycol component of tocofersolan may put children at risk as it accumulates in patients with immature kidneys \[[@CR65]\].  In Norway, an extempore formulation containing 20% alcohol, originally intended for veterinary use, has been widely used "off-label" in neonates and older children \[[@CR5]\].  The alcohol content of 60 mg 96% ethanol per 15 mg tocopheryl acetate in a 1,000-g premature baby is equivalent to 10 mL 45% ethanol in a 70-kg adult.  While data on pediatric alcohol exposure due to excipients are limited, there is a potential risk of adverse effects, especially in neonates and premature infants \[[@CR48]\]. 

Several handbooks carry a warning for hyperosmolar products.  However, information on the osmolality of the various pharmacy-compounded products is not provided. 

The choice of formulation should be based on the principle of suitability for the most vulnerable patients (premature neonates), degree of documentation for pediatric patients, pharmacokinetic predictability/reliability, and suitable strengths for the intended patient groups.  The most obvious factor for achieving a suitable formulation would be to keep the content of alcohol and other excipients to a minimum and to make a critical appraisal of the need for each ingredient. 

Regarding the active ingredient, both tocopheryl acetate and tocofersolan have advantages and disadvantages.  Using tocofersolan eliminates the need for ethanol.  In some patients, the bioavailability may be more predictable.  The disadvantages of tocofersolan are the lack of documentation, unclarified dosage equivalency, and presence of polyethylene glycol. 

Two different formulations may be necessary, due to the differences in doses between premature neonates and school-age hepatobiliary patients/post-liver transplant children.  Increasing doses with age may necessitate increasing strengths and corresponding increases in alcohol content to increase the solubility.  This would represent a lesser problem in older children than in the smallest ones.  Sick neonates having septicemia and other concurrent diseases have several battles to fight.  The metabolic pathways for drugs are under development (transition from intrauterine to extrauterine life), they have reduced capacity for drug metabolism, and ultimately the degree of the disease may affect drug metabolism to a greater extent at this time than for older children. 

In summary, the evidence regarding the use of oral vitamin E in children is limited and largely of poor methodological quality.  Several types of studies are needed.  A survey study would increase our knowledge of current therapeutic practice.  The objective should be to discover to what extent vitamin E is being used for neonates and older children in European countries, the U.S.A., and Japan, for which patient groups, and which products and doses are the most commonly used.  In addition, indications for prescribing the particular drug, existing guidelines in hospitals, and the basis for existing practice could be examined.  Furthermore, there is a need for well-designed pharmacokinetic studies including different formulations of tocopherol, tocopheryl acetate, and tocofersolan.  The studies should include relevant patient groups such as premature neonates, patients with congenital bile atresia before and after surgical therapy, and children after liver transplantation. 

At present, most clinical data refer to tocopheryl acetate.  Randomized, controlled trials should be done to examine the optimum doses and therapeutic equivalency of tocopherol/tocopheryl acetate and tocofersolan.  There are, however, certain methodological challenges regarding choice of treatment and control groups.  When treatment is regarded as essential, placebo controls would be unethical.  To our knowledge some hospitals in Europe do not include oral vitamin E treatment in, e.g., neonates on respirators or those on oxygen therapy.  Consequently, it would be possible to do comparative studies.  Comparison of different therapy regimens with the various forms of vitamin E might be a possible option in children already on therapy.  Other options include case series from hospitals or cohort studies, depending on the information desired.  Comparisons of patients from two hospitals with different treatment regimens would have to be examined carefully due to possible confounding factors.  Data collection from patients who currently receive an oral vitamin E product, including therapeutic monitoring, would be the most readily available method to gather readily accessible material.  When a clinical, comparative study is feasible, we would suggest monitoring outcome parameters as analyzed in the Cochrane metaanalysis with primary outcomes being mortality/survival and long-term morbidity, and secondary outcomes being bronchopulmonary dysplasia, patent ductus arteriosus, sepsis, ROP, NEC, hemoglobin, bilirubin, platelets, and coagulation parameters.  Visual assessments at 3 and 6 months should be included. 

Conclusions {#Sec9}
===========

Oral vitamin E compounds have been used for decades to treat a number of conditions in children.  There are few data to suggest solid guidelines on oral vitamin E therapy.  The present data do not provide sufficient evidence of dosing and products to make recommendations for oral vitamin E use in children.  Most data are available on therapeutic use of α-tocopherol or tocopherol esters, such as α-tocopheryl acetate. 

There are no systematic safety data or documentation on long-term effects.  Extensive use of oral vitamin E in premature infants and neonates solely for prophylactic purposes needs to be evaluated.  Systematic evaluations based on clinical trials would be a better foundation for therapeutic use in premature infants and neonates, regarding both indication for therapy and prevention.  Further research, including comparative, dose-finding studies, is required to ensure evidence-based dosing recommendations for neonates and older children. 

We thank professor Thor Willy Ruud Hansen at the University of Oslo, Section on Neonatology, Oslo University Hospital, Rikshospitalet, Oslo, Norway, for valuable feedback on the manuscript. 

**Open Access** This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. 

ADR(s)

:   Adverse drug reaction(s)

ALP

:   Alkaline phosphatase

BPD

:   Bronchopulmonary dysplasia

NEC

:   Necrotizing enterocolitis

PEG

:   Polyethylene glycol

ROP

:   Retinopathy of prematurity

TPGS

:   Tocopheryl polyethylene glycol succinate

TPN

:   Total parenteral nutrition

BNF

:   British National Formulary
