A comparison of three vitamin a dosing regimens in extremely-low-birth-weight infants

doi:10.1067/mpd.2003.214

The Journal of Pediatrics

Volume 142, Issue 6, June 2003, Pages 656-661

Presented in part at the Pediatric Academic Societies' Meeting, Baltimore, Maryland, May 2002.

https://doi.org/10.1067/mpd.2003.214 Get rights and content

Abstract

Objective Vitamin A supplementation reduces bronchopulmonary dysplasia (BPD)/death in extremely low birth weight neonates. It was hypothesized that compared with the standard regimen of 5000 IU 3 times per week for 4 weeks, (1) a higher dose (10,000 IU 3 × per week) would increase serum retinol and retinol binding protein (RBP) and lower relative dose responses (RDR), and (2) once-per-week dosing (15,000 IU once per week) would lead to equivalent levels, RBP, and RDR. Study design Extremely low birth weight neonates (n = 120) receiving O₂/mechanical ventilation at 24 hours were randomly assigned to (1) standard, (2) higher dose, or (3) once-per-week regimens. Measures of vitamin A deficiency were serum retinol <20 μg/dL, RBP <2.5 mg/dL, and/or RDR >10% on day 28. BPD was defined as O₂/mechanical ventilation at 36 weeks' postmenstrual age. Results Groups were similar at enrollment (median gestational age, 25 weeks; birth weight, 689 g). Possible toxicity was seen in <5%. The higher dose regimen did not increase retinol or RBP, decrease RDR, or improve outcomes. Infants in the once-per-week regimen had lower retinol levels and higher RDR without an effect on outcomes. Conclusions Compared with the standard regimen, once-per-week dosing worsened, and higher doses did not reduce, vitamin A deficiency. Therefore, the standard regimen is recommended. (J Pediatr 2003;142:656-61)

Section snippets

Methods

This study was a randomized, partially masked trial comparing the standard, the higher dose, and the once-per-week regimens. The protocol was approved by the institutional review board, and informed parental consent was obtained before random assignment. The study design was similar to the NICHD Neonatal Network trial with respect to entry criteria, ages at retinol administration, and biochemical and clinical assessment methods (Tyson et al, 1999). Entry criteria were birth weight 401 to 1000 g

Results

ELBW infants (n = 120) were enrolled in the trial from November 1999 to August 2001. A total of 269 ELBW infants were screened for eligibility during this period, and 190 (71%) were found eligible. Of the remaining 79 infants (29%), 55 (20%) were not eligible because they were not receiving mechanical ventilation or supplemental oxygen at 24 hours of age, 22 (8%) died, and 2 had major malformations. Informed consent was obtained in 120 of the 190 infants (63%). Consent was declined by parents

Discussion

This study evaluated three regimens for the intramuscular administration of vitamin A in ELBW neonates. Compared with the standard NICHD regimen (5000 IU 3 × per week for 4 weeks), administration of a higher dose (10,000 IU 3 × per week for 4 weeks) did not increase vitamin A concentrations or reduce biochemical measures of deficiency, whereas once-per-week dosing (15,000 IU once per week for 4 weeks) led to lower retinol concentrations on study day 28.

A limitation of this study is that blood

References (20)

JP Shenai et al.
Plasma vitamin A and retinol-binding protein in premature and term neonates
J Pediatr
(1981)
JP Shenai et al.
Clinical trial of vitamin A supplementation in infants susceptible to bronchopulmonary dysplasia
J Pediatr
(1987)
KA Kennedy et al.
Vitamin A to prevent bronchopulmonary dysplasia in very-low-birth-weight infants: has the dose been too low? The NICHD Neonatal Research Network
Early Hum Dev
(1997)
RD Zachman et al.
Use of the intramuscular relative-dose-response test to predict bronchopulmonary dysplasia in premature infants
Am J Clin Nutr
(1996)
N Montreewasuwat et al.
Serum and liver concentrations of vitamin A in Thai fetuses as a function of gestational age
Am J Clin Nutr
(1979)
J Landman et al.
Comparison of enteral and intramuscular vitamin A supplementation in preterm infants
Early Hum Dev
(1992)
JP Shenai et al.
Vitamin A status of neonates with bronchopulmonary dysplasia
Pediatr Res
(1985)
JE Tyson et al.
Vitamin A supplementation for extremely-low-birth-weight infants: National Institute of Child Health and Human Development Neonatal Research Network
N Engl J Med
(1999)
BA Darlow et al.
Vitamin A supplementation for preventing morbidity and mortality in very low birthweight infants
Cochrane Database Syst Rev
(2000)
JP. Shenai
Vitamin A supplementation in very low birth weight neonates: rationale and evidence
Pediatrics
(1999)

There are more references available in the full text version of this article.

Cited by (70)

Systematic review and meta-analysis of the relative dose-response tests to assess vitamin a status
2021, Advances in Nutrition
Vitamin A (VA) is an essential nutrient often lacking in the diets of people in developing countries. Accurate biomarkers of VA status are vital to inform public health policy and monitor interventions. The relative dose-response (RDR) and modified-RDR (MRDR) tests are semi-quantitative screening tests for VA deficiency that have been used in Demographic and Health Surveys and VA intervention studies. A systematic review and meta-analysis of sensitivity and specificity were conducted to summarize the physiological evidence to support the RDR tests as methods to assess VA status and investigate the impact of different pathological and physiological states on the tests. A total of 190 studies were screened for inclusion, with 21 studies comparing the RDR tests with the gold-standard biomarker, liver VA concentration (68% and 80% sensitivity and 85% and 69% specificity for the RDR and MRDR, respectively). Nearly all studies with VA interventions in VA-deficient populations demonstrated a response of the tests to VA intake that would be expected to improve VA status. The impacts of chronic liver disease, protein malnutrition, age, pregnancy and lactation, infection and inflammation, and various other conditions were examined in 51 studies. The RDR and MRDR tests were reported to have been used in 39 observational studies, and the MRDR has been used in at least 6 national micronutrient surveys. The RDR and MRDR are sensitive tests for determining population VA status and assessing VA interventions. Although they are robust to most physiological and pathological states, caution may be warranted when using the tests in neonates, individuals with chronic liver disease, and those with protein or iron malnutrition. Research on further improvements to the tests to increase accessibility, such as sampling breast milk instead of blood or using intramuscular doses in subjects with malabsorption, will allow wider adoption. This review was registered with PROSPERO as CRD42019124180.
ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Vitamins
2018, Clinical Nutrition
Pharmacologic interventions for the prevention and treatment of retinopathy of prematurity
2016, Seminars in Perinatology
Citation Excerpt :
Retinal vitamin A allows adequate rhodopsin availability for phototransduction and protects the photoreceptors from the harmful effects of hypoxia and hyperoxia.68 Studies show a trend for decreased incidence of threshold ROP in ELBW infants treated with 10,000 IU intramuscular vitamin A three times a week (0%) compared with 16% in those who received half this dose.69 A recent double-blind, randomized controlled trial of early high-dose intramuscular vitamin A supplementation for infants at risk of ROP showed improved retinal function at 36 weeks PMA.68
Retinopathy of prematurity (ROP), a significant morbidity in prematurely born infants, is the most common cause of visual impairment and blindness in children and persists till adulthood. Strict control of oxygen therapy and prevention of intermittent hypoxia are the keys in the prevention of ROP, but pharmacologic interventions have decreased risk of ROP. Various drug classes such as methylxanthines (caffeine), VEGF inhibitors, antioxidants, and others have decreased ROP occurrence. The timing of pharmacologic intervention remains unsettled, but early prevention rather than controlling disease progression may be preferred. These drugs act through different mechanisms, and synergistic approaches should be considered to maximize efficacy and safety.
Vitamin A for preterm infants; where are we now?
2013, Seminars in Fetal and Neonatal Medicine
In the 35 years since low plasma vitamin A levels were first described in premature infants, much effort has gone into attempting to describe the functional consequences of vitamin A deficiency in this population. Supplementation of extremely low birth weight infants with intramuscular (i.m.) vitamin A has a significant but modest beneficial effect upon the development of chronic lung disease (NNT 13), most likely due to reduced production of pro-inflammatory cytokines. Early high dose i.m. vitamin A also improves retinal development and there are limited clinical and laboratory data suggesting a role for vitamin A in prevention of retinopathy of prematurity. Despite evidence of benefit, there is reluctance to give routine i.m. vitamin A in the neonatal intensive care unit, but current intravenous supplementation is almost certainly inadequate. Further work is required to identify the optimal dose and most appropriate route of administration of vitamin A for preterm infants.
Vitamin D, vitamin A, maternal-perinatal considerations: Old concepts, new insights, new questions
2013, Journal of Pediatrics
Citation Excerpt :
One trial compared different intramuscular dosing regimens (5000 IU 3 times weekly for 4 weeks, 10 000 IU 3 times weekly for 4 weeks, or 15 000 IU weekly for 4 weeks) in infants weighing <1000 g. The optimal dose appeared to be 5000 IU 3 times weekly for 4 weeks; however, even with this dose, more than 25% of the infants had evidence of vitamin A deficiency.33,34 Higher doses or a better mode of delivery may be needed.
Vitamins A and D are essential nutrients that play important roles in growth and development. Preterm and low birth weight infants have low levels of these nutrients and are at risk for developing detrimental health consequences associated with vitamin A and vitamin D deficiencies. Preliminary data suggest that vitamin A and D supplementation is needed to prevent deficiency. More work is needed to define optimal doses, timing, and modes of administration to ensure that an adequate supply of these vitamins is available to meet the critical needs during pregnancy and in high-risk neonates.
Select micronutrients for the preterm neonate
2023, Nutrition in Clinical Practice

View all citing articles on Scopus

^☆: Reprints not available from the authors. Address correspondence to: Namasivayam Ambalavanan, MD, 525 New Hillman Bldg, 619 S 19th St, University of Alabama at Birmingham, Birmingham, AL 35249. E-mail: [email protected] .

View full text

Original ArticlesA comparison of three vitamin a dosing regimens in extremely-low-birth-weight infants☆

Abstract

Section snippets

Methods

Results

Discussion

J Pediatr

J Pediatr

Early Hum Dev

Am J Clin Nutr

Am J Clin Nutr

Early Hum Dev

Vitamin A status of neonates with bronchopulmonary dysplasia

Pediatr Res

Vitamin A supplementation for extremely-low-birth-weight infants: National Institute of Child Health and Human Development Neonatal Research Network

N Engl J Med

Vitamin A supplementation for preventing morbidity and mortality in very low birthweight infants

Cochrane Database Syst Rev

Vitamin A supplementation in very low birth weight neonates: rationale and evidence

Pediatrics

Original Articles
A comparison of three vitamin a dosing regimens in extremely-low-birth-weight infants☆