Inadequacy of IV vitamin A supplementation of extremely preterm infants?
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Helen Mactier, MD, FRCPCH Peter Galloway, MB, FRCPEd Ruth Hamilton, MSc, CPhys Lawrence Weaver, MD, DSc, FRCP Departments of Child Health, Biochemistry, and Clinical Physics Princess Royal Maternity and Royal Hospital for Sick Children Glasgow, UK YMPD1377 10.1016/j.jpeds.2004.12.036 REFERENCES 1. Ambalavanan N, Kennedy K, Tyson J, Carlo WA. Survey of vitamin A supplementation for extremely-low-birth-weight infants: is clinical practice consistent with the evidence? J Pediatr 2004;145:304-7. 2. Greene HL, Phillips BL, Franck L, Fillmore CM, Said HM, Murrell JE, et al. Persistently low blood retinol levels during and after parenteral administration of very low birth weight infants: examination of losses into intravenous administration sets and a method of prevention by addition to a lipid emulsion. Pediatrics 1987;79:894-900. To the Editor: In their paper, Ambalavanan et al 1 conclude that current clinical practices for vitamin A supplementation in extremely- low-birth-weight (ELBW) infants are inconsistent with available evidence. We disagree. The authors’ support for the use of intramuscular vitamin A in ELBW infants is the metaanalysis by Darlow and Graham, 2 which is largely weighted toward the authors’ own study and includes studies in larger infants and alternate dosages and routes. Of all outcomes analyzed, only 2 showed marginal risk reduction: death or oxygen supplementation at 1 month (0.93; CI, 0.88-0.99) and oxygen need at 36 weeks postmenstrual age (0.87; CI, 0.77-0.99). The conclusion that the number needed to treat (NNT) is ‘‘14 to 20 to prevent adverse pulmonary outcomes’’ is a distortion of the statistics. In reality, these numbers represent mean estimates from 2 different outcomes, not the actual range for a given outcome. Those ranges are: death or oxygen need at 1 month (20;10,100); oxygen need at 36 weeks postmenstrual age (14;7,100). Thus, the NNT may be as high as 100. In their metaanalysis, Darlow and Graham conclude that universal vitamin A supplementation for ELBW infants is not supported by that data, but rather individualized decisions on the basis of local bronchopulmonary dysplasia risk with the ‘‘benefits of a modest reduction in this outcome balanced against lack of other proven benefits and the acceptability of treatment.’’ It appears the survey respondents agree. Finally, more study into the pharmacology of vitamin A is necessary before widespread use is considered. A thera- peutic window has yet to be defined in the ELBW population. Current supplementation practices result in unpredictable serum levels. For a vitamin with known toxicity, supplemen- tation can have significant risks. Unfortunately, neonatology has a history of tragic effects for therapies thought initially to be safe. Todd West, MD James Cummings, MD Department of Pediatrics Neonatal Division East Carolina University Greenville, NC 27834 YMPD1378 10.1016/j.jpeds.2004.12.037 REFERENCES 1. Ambalavanan N, Kennedy K, Tyson J, Carlo W. Survey of vitamin A supplementation for extremely-low-birth-weight infants: is clinical practice consistent with the evidence? J Pediatr 2004;145:304-7. 2. Darlow BA, Graham PJ. Vitamin A supplementation for preventing morbidity and mortality in very low birthweight infants. Cochrane Database Syst Rev 2002;4:CD000501. Reply To the Editor: We appreciate the comments by West and Cummings 1 and Mactier et al 2 on our survey of vitamin A use in extremely- low-birth-weight infants. 3 We agree with Mactier that more research is required on the pharmacology of vitamin A to optimize the dose and route of administration in extremely premature infants and appreciate the caution of West and Cummings in the introduction of new therapies in neonates. We welcome the investigative work of Mactier et al on the intravenous vitamin A formulation. Their results indicate that the manufacturer’s recommended dose of 920 IU/kg/day was not sufficient to maintain adequate plasma retinol levels in most infants. In the National Institute of Child Health and Human Development (NICHD) vitamin A trial, 4 the control group received about 1000 IU/kg/day (enteral plus parenteral) versus 4000 IU/kg/day in the vitamin A group. However, even the higher intake in the supplemented group was associated with low vitamin A levels (serum retinol <20 mcg/dL) in 25% of the infants. Our subsequent study comparing even higher intakes (10,000 IU 3 times a week) to the standard regimen of 5000 IU given intramuscularly 3 times a week showed that the higher doses did not increase vitamin A concentrations or reduce the incidence of vitamin A deficiency. 5 One possible explanation for why these high intakes of vitamin A do not improve serum levels may be that serum levels of the vitamin A transport proteins retinol-binding protein and transthyretin are decreased by inflammation 6 (ie, they are negative acute-phase reactants), and inflammation is common in these extremely premature infants. Better methods may need to be developed to optimize transport and delivery of administered vitamin A to tissues. It also needs to be determined whether improving delivery to the tissues further improves clinical outcomes without introducing toxicity. We consider the evidence for the safety of vitamin A administration to be stronger than the evidence for the Letters 847
Transcript of Inadequacy of IV vitamin A supplementation of extremely preterm infants?
Helen Mactier, MD, FRCPCHPeter Galloway, MB, FRCPEdRuth Hamilton, MSc, CPhys
Lawrence Weaver, MD, DSc, FRCPDepartments of Child Health, Biochemistry, and Clinical PhysicsPrincess Royal Maternity and Royal Hospital for Sick Children
Glasgow, UKYMPD1377
10.1016/j.jpeds.2004.12.036
REFERENCES1. Ambalavanan N, Kennedy K, Tyson J, Carlo WA. Survey of vitamin A
supplementation for extremely-low-birth-weight infants: is clinical practice
consistent with the evidence? J Pediatr 2004;145:304-7.
2. Greene HL, Phillips BL, Franck L, Fillmore CM, Said HM, Murrell
JE, et al. Persistently low blood retinol levels during and after parenteral
administration of very low birth weight infants: examination of losses into
intravenous administration sets and a method of prevention by addition to
a lipid emulsion. Pediatrics 1987;79:894-900.
Reply
To the Editor:We appreciate the comments by West and Cummings1
andMactier et al2 on our survey of vitamin A use in extremely-low-birth-weight infants.3 We agree with Mactier that moreresearch is required on the pharmacology of vitamin A tooptimize the dose and route of administration in extremelypremature infants and appreciate the caution of West andCummings in the introduction of new therapies in neonates.
We welcome the investigative work of Mactier et al onthe intravenous vitamin A formulation. Their results indicatethat the manufacturer’s recommended dose of 920 IU/kg/daywas not sufficient to maintain adequate plasma retinol levels inmost infants. In the National Institute of Child Health andHuman Development (NICHD) vitamin A trial,4 the controlgroup received about 1000 IU/kg/day (enteral plus parenteral)versus 4000 IU/kg/day in the vitamin A group. However, eventhe higher intake in the supplemented group was associatedwith low vitamin A levels (serum retinol <20 mcg/dL) in 25%of the infants. Our subsequent study comparing even higherintakes (10,000 IU 3 times a week) to the standard regimen of5000 IU given intramuscularly 3 times a week showed that thehigher doses did not increase vitamin A concentrations orreduce the incidence of vitamin A deficiency.5 One possibleexplanation for why these high intakes of vitamin A do notimprove serum levels may be that serum levels of the vitamin Atransport proteins retinol-binding protein and transthyretin aredecreased by inflammation6 (ie, they are negative acute-phasereactants), and inflammation is common in these extremelypremature infants. Better methods may need to be developedto optimize transport and delivery of administered vitamin Ato tissues. It also needs to be determined whether improvingdelivery to the tissues further improves clinical outcomeswithoutintroducing toxicity.
We consider the evidence for the safety of vitaminA administration to be stronger than the evidence for the
To the Editor:In their paper, Ambalavanan et al1 conclude that current
clinical practices for vitamin A supplementation in extremely-low-birth-weight (ELBW) infants are inconsistent withavailable evidence. We disagree.
The authors’ support for the use of intramuscularvitamin A in ELBW infants is the metaanalysis by Darlowand Graham,2 which is largely weighted toward the authors’own study and includes studies in larger infants and alternatedosages and routes. Of all outcomes analyzed, only 2 showedmarginal risk reduction: death or oxygen supplementation at1 month (0.93; CI, 0.88-0.99) and oxygen need at 36 weekspostmenstrual age (0.87; CI, 0.77-0.99). The conclusion thatthe number needed to treat (NNT) is ‘‘14 to 20 to preventadverse pulmonary outcomes’’ is a distortion of the statistics.In reality, these numbers represent mean estimates from 2different outcomes, not the actual range for a given outcome.Those ranges are: death or oxygen need at 1 month(20;10,100); oxygen need at 36 weeks postmenstrual age(14;7,100). Thus, the NNT may be as high as 100.
In their metaanalysis, Darlow and Graham concludethat universal vitamin A supplementation for ELBW infantsis not supported by that data, but rather individualizeddecisions on the basis of local bronchopulmonary dysplasiarisk with the ‘‘benefits of a modest reduction in this outcomebalanced against lack of other proven benefits and theacceptability of treatment.’’ It appears the survey respondentsagree.
Finally, more study into the pharmacology of vitaminA is necessary before widespread use is considered. A thera-peutic window has yet to be defined in the ELBW population.Current supplementation practices result in unpredictableserum levels. For a vitamin with known toxicity, supplemen-tation can have significant risks. Unfortunately, neonatology
Letters
has a history of tragic effects for therapies thought initially tobe safe.
Todd West, MDJames Cummings, MD
Department of Pediatrics Neonatal DivisionEast Carolina UniversityGreenville, NC 27834
YMPD137810.1016/j.jpeds.2004.12.037
REFERENCES1. Ambalavanan N, Kennedy K, Tyson J, Carlo W. Survey of vitamin A
supplementation for extremely-low-birth-weight infants: is clinical practice
consistent with the evidence? J Pediatr 2004;145:304-7.
2. Darlow BA, Graham PJ. Vitamin A supplementation for preventing
morbidity and mortality in very low birthweight infants. Cochrane Database
Syst Rev 2002;4:CD000501.
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