SPECIAL ARTICLE
Vitamin A Supplementation in Very Low Birth Weight Neonates:
Rationale and Evidence
Jayant P. Shenai, MD
ABBREVIATIONS. BPD, bronchopulmonary dysplasia; VLBW, very low birth weight; RBD, retinol-binding protein; IU, interna-tional units.
B
ronchopulmonary dysplasia (BPD) is the mostprevalent form of chronic lung disease in in-fancy. Among the 3.9 million births in the United States in 1997, approximately 55 000 newborn infants weighed,1500 g at birth.1Among these very low birth weight (VLBW) infants, 49 000 infants would be expected to be discharged alive at the end of their first hospitalization (Vanderbilt experience 1998). At an estimated incidence of 24% among the VLBW survivors (Vanderbilt experience 1998), 12 000 new cases of BPD would be expected to emerge annually, making BPD the leading cause of chronic lung disease in infancy.
The pathogenesis of BPD involves factors causing injury to an immature lung and factors inhibiting its healing.2,3 The lung injury can result from such in-sults as hyaline membrane disease, barotrauma or volutrauma from mechanical ventilation, oxygen toxicity, and airway infection associated with pro-longed tracheal intubation.4The lung healing can be influenced by nutrients, antioxidants, inflammatory cells, eicosanoids, growth factors, peptide hormones, and components of extracellular matrix.5The role of the essential micronutrient vitamin A (retinol) in the promotion of orderly growth and differentiation of regenerating epithelial tissues makes vitamin A an important nutrient during recovery from lung inju-ry.6,7This review focuses on the pathophysiology of vitamin A deficiency in relation to BPD, examines the evidence for vitamin A deficiency in VLBW ne-onates, and provides guidelines for vitamin A sup-plementation as an approach toward amelioration of lung disease among the VLBW survivors.
RATIONALE FOR VITAMIN A ASSESSMENT
Vitamin A promotes normal growth and differen-tiation of epithelial cells. Vitamin A deficiency, there-fore, affects various organ systems, including the lung.6The histopathologic changes in the respiratory
system generally precede other consequences of vi-tamin A deficiency involving the genitourinary sys-tem, eye, and skin.6
Vitamin A deficiency results in a progressive se-quence of histopathologic changes in the epithelial lining of pulmonary conducting airways.6,8,9In those proximal airways, in which basal cells exist as stem cells for replacement of lining epithelial cells after their attrition from natural causes or injury or dis-ease, basal cell proliferation is stimulated. As these normally discontinuous basal cells become conflu-ent, the normal differentiated ciliated columnar cells and nonciliated secretory cells become displaced from their basement membrane footing, lose their blood supply, and become necrotic. The resultant histopathologic change is described as necrotizing tracheobronchitis and is characteristic of early stages of vitamin A deficiency. In more advanced stages of vitamin A deficiency, the basal cells continue to pro-liferate, lose their phenotypic future, and develop as layers of stratified squames that become keratinized. The resultant histopathologic change is described as squamous metaplasia. The pathophysiologic conse-quences of these changes include: a) loss of normal secretions of goblet cells and of other secretory cells; b) loss of normal water homeostasis across tracheo-bronchial epithelium; c) loss of mucociliary transport with resultant predisposition to airway infection; and d) narrowing of lumina and loss of distensibility of airways with resultant increase in airway resis-tance and work of breathing.3 The histopathologic changes of vitamin A deficiency and associated pathophysiologic consequences are reversible with restoration of normal vitamin A status.7,10
When one examines the tracheobronchial tree of VLBW infants, who after neonatal pulmonary insults undergo an abnormally protracted healing phase, the sequential epithelial changes classically described as BPD are observed.2,5These changes consist of necro-tizing tracheobronchitis in early stages (Fig 1) and squamous metaplasia in advanced stages of the dis-ease (Fig 2). The histopathologic changes of BPD and vitamin A deficiency are remarkably similar. The clinical manifestations, such as recurrent airway in-fections, typically observed in infants with BPD and in children with vitamin A deficiency, can be ex-plained based on the functional alterations caused by the histopathologic changes in the lung and tracheo-bronchial tree.
VLBW neonates are susceptible to acute, subacute,
From the Department of Pediatrics, Vanderbilt University School of Medi-cine, Nashville, Tennessee.
Received for publication Jun 26, 1999; accepted Jun 26, 1999.
and chronic lung injury.2When the pulmonary con-ducting airways are injured, the stimulus to epithe-lial regeneration is triggered, possibly under the in-fluence of growth factors such as epidermal growth factor.11 Simultaneous with this injury, if vitamin A deficiency of such severity as to preclude orderly differentiation of proliferating basal cells were present, normal healing would not occur, and chronic BPD would be the result. Conversely, the potential role of vitamin A in influencing orderly differentiation of regenerating airways would have a favorable effect on the healing process, resulting in reduced pulmonary morbidity. This rationale pro-vides the basis for studying vitamin A status in re-lation to BPD in VLBW neonates.
EVIDENCE OF VITAMIN A DEFICIENCY
Measurement of plasma concentration of vitamin A is the most commonly used biochemical marker of
vitamin A status. In healthy adult humans, the plasma vitamin A concentration ranges from 20 to 80
mg/dL.12In children, including infants, a plasma vi-tamin A concentration ,20 mg/dL is considered to be indicative of vitamin A deficiency.13Most VLBW neonates are born with plasma vitamin A concentra-tions that are in the deficient range.14,15
Measurement of plasma concentration of retinol-binding protein (RBP), the specific carrier protein of vitamin A, is another biochemical marker of vitamin A status. In healthy adult humans, the plasma RBP concentration averages 4.6 mg/dL (6SD 1.0 mg/ dL).16The plasma RBP concentrations in infants and children are approximately 60% of the adult values,17 and those,2.5 mg/dL are considered to be indica-tive of vitamin A deficiency.18Most VLBW neonates are born with plasma RBP concentrations that are in the deficient range.15,19
Inasmuch as 90% of the total body reserve of vita-Fig 1. Photomicrograph of lung from
a VLBW neonate who died in the early stages of BPD. Necrosis of lining epi-thelium and sloughing of necrotic debris into the lumen of an airway, characteristic of necrotizing tracheo-bronchitis, are evident.
min A is normally stored in the liver, measurement of vitamin A concentration in a liver tissue sample taken at autopsy gives an accurate indication of vi-tamin A status.13 The liver vitamin A concentration ranges from 100 to 300 mg/g in healthy adult hu-mans,20 and varies with age in children, being low during infancy relative to later childhood.21,22A liver vitamin A concentration,40mg/g is considered to be indicative of low vitamin A reserve and that,20
mg/g is considered deficient.23Most VLBW neonates are born with low liver vitamin A stores.22,24 –27In the absence of an adequate intake of vitamin A in the postnatal period, therefore, these infants are at an added risk for becoming vitamin A-deficient.
Plasma RBP response to vitamin A administration is a useful functional measure of vitamin A status.28 RBP is largely synthesized in the liver and secreted into plasma as the retinol:RBP complex.29In vitamin A-deficient animals, RBP secretion is blocked, lead-ing to its accumulation in the liver and resultlead-ing in high liver and low plasma concentrations of RBP.30,31 When these animals are given vitamin A, mobiliza-tion of RBP from the liver occurs, which leads to a rapid decrease in the liver RBP concentration and a concomitant increase in the plasma RBP concentra-tion.30 In vitamin A-sufficient animals, on the other hand, RBP does not accumulate in the liver, and minimal or no change in plasma RBP concentration is observed after vitamin A administration.30 The per-cent increase in plasma RBP conper-centration (D-RBP) from its baseline value in response to vitamin A administration, therefore, is useful for determining vitamin A status.28 A high D-RBP value (.8%) is considered to be indicative of vitamin A deficiency.28 In VLBW neonates, the plasma RBP response to vi-tamin A administration, characterized by high
D-RBP values, provides further evidence that these infants are vitamin A-deficient at birth.28 It is likely that the VLBW neonates are vitamin A-deficient at birth because of deprivation of transplacental vita-min A supply resulting from their delivery at an early gestational age.
VLBW neonates who have BPD often manifest clinical, biochemical, and histopathologic evidence of vitamin A deficiency.5,32,33In contrast to infants with no lung disease, those with BPD, in the absence of vitamin A supplementation, typically show a bipha-sic pattern of plasma vitamin A concentrations.33The initial phase is characterized by declining plasma vitamin A concentrations, which reach their nadir at approximately 4 weeks’ postnatal age and are mark-edly below the optimal level. The subsequent phase is characterized by improving plasma vitamin A con-centrations, which nonetheless remain suboptimal for extended periods. Vitamin A deficiency in VLBW neonates with BPD is largely attributed to an inade-quate intake of vitamin A in the postnatal period. Vitamin A value of a diet is expressed in interna-tional units (IU); 1 IU of vitamin A is equal to .3mg of preformed retinol.12A vitamin A intake of at least 1500 IU/kg/d is necessary for normalization of plasma concentrations of vitamin A in VLBW neo-nates.33 Although vitamin A supplementation in VLBW neonates can normalize plasma
concentra-tions of vitamin A and RBP, the plasma RBP re-sponse to vitamin A administration may continue to reflect persistence of vitamin A deficiency, particu-larly among the more immature infants with signif-icant lung disease.28,34It is possible that the require-ment of vitamin A in infants with BPD relative to those with no lung disease is higher because of the ongoing need for regenerative healing from lung injury. It is also possible that the more immature the infant and the more injured the lung, the less efficient is the utilization of available vitamin A at the cellular level.
VITAMIN A SUPPLEMENTATION TRIALS
Several clinical trials have tested the efficacy of vitamin A supplementation in preventing the devel-opment of BPD in VLBW neonates. A randomized, blinded, placebo-controlled clinical trial35 from Vanderbilt University showed that vitamin A sup-plementation (intramuscular retinyl palmitate 2000 IU on alternate days for 28 days) from early postnatal life in VLBW neonates can improve their vitamin A status and also ameliorate the lung disease, as evi-denced by a decreased incidence of BPD and of the associated morbidity. Another randomized, blinded, placebo-controlled clinical trial36 from Greece showed a similar beneficial effect of vitamin A sup-plementation in VLBW neonates. The infants in this trial received intramuscular retinyl palmitate 4000 IU on alternate days until their extubation and place-ment in room air. Together, these trials showed that vitamin A supplementation at the dosages used was associated with a 31% reduction in relative risk and a 25% reduction in incidence of BPD.37
In contrast to the Vanderbilt trial and the trial from Greece, 2 other trials showed no beneficial effect of vitamin A supplementation in prevention of BPD. A randomized, blinded, placebo-controlled clinical tri-al38 from North Carolina showed that vitamin A supplementation (intramuscular retinyl palmitate 2000 IU on alternate days for 28 days) from early postnatal life in VLBW neonates improved their plasma vitamin A concentrations, but did not reduce the incidence of BPD. Another randomized, un-blinded, nonplacebo-controlled preliminary trial39 from South Africa showed a similar lack of beneficial effect of vitamin A supplementation on the incidence of BPD in VLBW neonates.
dexamethasone in the postnatal period. Surfactant treatment influences the course of hyaline membrane disease, neonatal survival, and the incidence and severity of BPD among VLBW survivors.41Postnatal dexamethasone treatment causes a significant in-crease in plasma concentrations of vitamin A and RBP in newborn infants, independent of their nutri-tional intake,42and thus confounds the interpretation with respect to vitamin A status. Vitamin A intake from enteral and intravenous sources was about two-fold to threetwo-fold higher in the trial from North Caro-lina, relative to that in the Vanderbilt trial. This high intake of vitamin A accounted for the observed low incidence of vitamin A deficiency among infants in the North Carolina trial. Any potential beneficial effect of vitamin A supplementation, therefore, might have been masked by the reduced prevalence of vitamin A deficiency in this patient population. The question of whether vitamin A supplementation should be routinely implemented in the nutritional management of VLBW neonates at risk for BPD has persisted, because the evidence so far has been based on trials from single institutions with inherently lim-ited study sample sizes and individual variations in subject populations. Until now, that is.
A recent multicenter trial43 of vitamin A supple-mentation sheds further light on this important nu-trient in relation to lung disease in VLBW neonates. This trial, sponsored by the National Institute of Child Health and Human Development Neonatal Research Network, involved 14 centers in the United States, a large study sample size of 807 infants, and a randomized, blinded, nonplacebo-controlled study design. Infants who weighed 401 to 1000 g at birth and who received mechanical ventilation or supple-mental oxygen at 24 hours after birth were studied. Vitamin A supplementation (intramuscular retinyl palmitate 5000 IU 3 times a week for 4 weeks) in this trial was effective in lowering the incidence of death or chronic lung disease with need for supplemental oxygen at 36 weeks’ postmenstrual age from 62% in the unsupplemented controls to 55% in the sup-plemented infants. This difference was statistically significant and yielded a relative risk of .89 (95% confidence intervals: .80 –.99) in favor of the supple-mented group. Expressed another way, vitamin A supplementation was associated with 1 additional survivor without chronic lung disease for every 14 to 15 supplemented infants. Most important, careful monitoring for potential signs of vitamin A toxicity confirmed the safety of vitamin A supplementation. Using the dosage regimen in this trial, the cost of vitamin A supplementation is estimated to be a mod-est $27 per infant for a 4-week course of treatment (D. Gregory, personal communication, June 1999).
In light of these findings, the question is not whether vitamin A supplementation is important in VLBW neonates at risk for BPD, but how best to provide optimal vitamin A nutrition in these infants. To that effect, I summarize below the guidelines for vitamin A supplementation in VLBW neonates at risk for BPD followed at Vanderbilt University.
VITAMIN A SUPPLEMENTATION GUIDELINES Subjects
VLBW neonates meeting the following criteria are eligible for vitamin A supplementation: birth weight
,1250 g, estimated gestational age at birth ,31 weeks, appropriate growth for gestational age, need for mechanical ventilation at 24 hours postnatal age, and no major congenital anomalies. These criteria are similar to those proposed by Bancalari et al44 for identification of infants at high risk for BPD.
Vitamin A Intake
Vitamin A intake of each infant is calculated daily. The standard sources of vitamin A are intravenous and enteral. The intravenous vitamin A is from par-enteral nutrition solution estimated to contain 920 IU/dL of vitamin A. The enteral vitamin A is from human milk or preterm infant formula estimated to contain 300 IU/dL or 970 IU/dL of vitamin A, re-spectively.
Vitamin A Supplements
For intramuscular supplementation, a water-mis-cible preparation (Aquasol A Parenteral, Astra, Westboro, MA) containing 50 000 IU/mL of vitamin A as retinyl palmitate is used. This preparation is unstable when diluted and therefore is used in its undiluted form. A unit dose of this preparation is dispensed from pharmacy in a plastic insulin syringe (U100 Becton Dickinson, Franklin Lakes, NJ). For orogastric supplementation, a vitamin A preparation (Pharmaceutical Compounding Centers of America, Houston, TX) containing 10 000 IU/mL of vitamin A as retinyl palmitate is used. A unit dose of this prep-aration is dispensed from pharmacy in a plastic oral dispenser (Exacta-Med, Baxa Corporation, Engle-wood, CA). All unit doses are administered to the infants within 30 minutes of dispensing. To prevent photodegradative loss of vitamin A,45each unit dose is shielded from light until administration.
Dosage
This orogastric dosage of supplemental vitamin A is based on the trial by Landman et al,48 in which orogastric supplements (5000 IU daily) were demon-strated to be comparable to intramuscular supple-ments (2000 IU on alternate days) in normalizing plasma vitamin A indexes. In the event enteral feed-ing is withheld because of evidence of intolerance, orogastric administration of supplemental vitamin A is discontinued and substituted by intramuscular supplementation until resumption of enteral feeding.
Biochemical Monitoring
Plasma concentrations of vitamin A and RBP are monitored weekly throughout the period of vitamin A supplementation. Plasma vitamin A concentration is determined by spectrofluorometry,49 and plasma RBP concentration by quantitative radial immuno-diffusion (Binding Site, Inc, San Diego, CA). The desired range of plasma vitamin A concentrations is 30 to 60mg/dL, and the desired plasma RBP concen-tration is .2.5 mg/dL.28,34,35 Vitamin A toxicity has not been reported in humans when the plasma vita-min A concentration is,100mg/dL.50The dosage of supplemental vitamin A is adjusted weekly based on plasma vitamin A concentrations.
Clinical Monitoring
Each infant is monitored throughout the period of vitamin A supplementation by careful physical ex-amination for evidence of vitamin A toxicity. Typical clinical manifestations of vitamin A toxicity include mucocutaneous lesions, bone and joint abnormali-ties, hepatomegaly and jaundice, and increased in-tracranial pressure.51 In addition, blood chemistry profiles, including liver function tests, and hemato-logic indexes are evaluated periodically. With these guidelines for vitamin A supplementation, monitor-ing of plasma vitamin A indexes, and clinical evalu-ation for potential toxicity, the goal is to optimize vitamin A nutrition in these infants.
Other Measures
Dexamethasone, a glucocorticosteroid hormone, is being used increasingly in the postnatal treatment of VLBW neonates with BPD.52 Postnatal dexametha-sone treatment causes a significant, yet short-term, increase in plasma concentrations of vitamin A and RBP in newborn infants.42 Thus, in the event dexa-methasone treatment is initiated, supplemental vita-min A is withheld throughout the course of the dexa-methasone treatment. This precautionary measure is intended to avoid the potential risk of vitamin A toxicity associated with dexamethasone treatment.
CONCLUSION
In summary, BPD is a disease of multiple causes, and its incidence among VLBW neonates is unac-ceptably high. In addition to the prevention of pre-maturity as the primary perinatal health care goal, the strategies for reducing the occurrence of BPD among VLBW survivors are clearly warranted. These strategies involve the modulation of a delicate bal-ance between injury and healing of the immature lung. Optimal vitamin A nutrition is one such
strat-egy to complement a host of other approaches. Al-though with clinical trials to date, significant strides have been made toward understanding the role of vitamin A in BPD among VLBW neonates, much remains to be studied. The precise requirement of vitamin A in these infants, and the optimal mode and duration of its administration warrant further inves-tigation. Diagnostic measures that can evaluate mo-lecular mechanisms of vitamin A action in the devel-oping lung need to be explored for their clinical applications. Likewise, the therapeutic role of vita-min A metabolites, including retinoic acid, in pro-moting lung healing awaits further investigation.
ACKNOWLEDGMENTS
I thank Mildred Stahlman for initiating the series of investiga-tions on vitamin A; Frank Chytil for sharing his expertise on vitamin A; Mark Hunt for his enthusiastic technical assistance in the laboratory; and Joyce Johnson for providing the illustrations.
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DOI: 10.1542/peds.104.6.1369
1999;104;1369
Pediatrics
Jayant P. Shenai
Evidence
Vitamin A Supplementation in Very Low Birth Weight Neonates: Rationale and
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DOI: 10.1542/peds.104.6.1369
1999;104;1369
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Jayant P. Shenai
Evidence
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