Oral vitamin A supplementation in very low birth weight neonates: a randomized controlled trial
This randomized double-blind placebo-controlled trial evaluated the effects of early postnatal oral vitamin A supplementation (VAS) in 196 inborn very-low birth weight (VLBW) infants requiring respiratory support at 24 h of age. Eligible infants were randomized to receive aqueous syrup of vitamin A (10,000 IU of retinol/dose; n = 98) or placebo (n = 98) on alternate days for 28 days. Primary outcome variable was composite incidence of all-cause mortality and/or oxygen requirement for 28 days. Secondary outcome variables were safety/tolerability of VAS, serum retinol concentration at recruitment and day 28, duration of oxygen requirement and respiratory support and incidences of complications. On intention-to-treat analysis, composite incidence of all-cause mortality and oxygen requirement for 28 days was significantly lower in vitamin A group (relative risk (95% confidence interval), 0.440 (0.229–0.844); p < 0.05, number needed to benefit, 7). Requirement and duration of oxygen supplementation and non-invasive respiratory support, incidences of late-onset sepsis, patent ductus arteriosus, and duration of hospital stay were also significantly lower in vitamin A group. Serum retinol concentration improved significantly after VAS. No major adverse effect was observed.
Conclusions: Early postnatal oral VAS was associated with better composite outcome of all-cause mortality and oxygen requirement without any major adverse effects.
What is Known:
• Postnatal intramuscular vitamin A supplementation improves the survival, respiratory outcome and other morbidities in very low birth weight neonates without major adverse effects.
• Limited studies on oral vitamin A supplementation did not document substantial benefits.
What is New:
• Early postnatal alternate-day oral vitamin A supplementation at the dose of 10,000 IU/dose for 28 days improves the composite outcome of death and oxygen requirement in very low birth weight neonates with respiratory distress
• No major adverse effects were documented
KeywordsNeonate Oral Very low birth weight Vitamin A supplementation
Continuous positive airway pressure
Clinical Trial Registry of India
Denever Developmental Screening Test
High flow nasal cannula
Hemodynamically significant patent ductus arteriosus
Inter quartile range
Low and middle income countries
National Institute of Child Health and Human Development
Neonatal intensive care unit
Number needed to treat for benefit
Respiratory distress syndrome
Retinopathy of prematurity
Very low birth weight
Vitamin A supplementation
Vitamin A and placebo oral solutions were procured from the Apex Pharmaceuticals Private Limited, Chennai, India, though the manufacturer who did not have any control over study design or outcome.
Prof Sriparna Basu and Prof Ashok Kumar conceptualized and designed the study, coordinated and supervised data collection, drafted the initial manuscript, and reviewed and revised the manuscript. Dr. Parul Khanna designed the data collection instruments, collected data, carried out the initial analyses, and reviewed and revised the manuscript. Dr. Ragini Srivastava supervised the data collection, did the biochemical analysis, reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
Compliance with ethical statements
Conflict of interest
The authors declare that they have no conflict of interest.
The trial was ethically approved by the Institute Ethics Committee of All India Institute of Medical Sciences, Rishikesh, India.
Informed consent was obtained from all individual participants included in the study.
- 4.Bental RY, Cooper PA, Cummins RR, Sandler DL, Wainer S, Rotschild A (1994) Vitamin A therapy - effects on the incidence of bronchopulmonary dysplasia. Afr J Food Agric Nutr Dev 6:141–145Google Scholar
- 5.Bessey OA, Lowry OH, Brock MJ, Lopez JA (1946) The determination of vitamin A and carotene in small quantities of blood serum. J Biol Chem 166:177–188Google Scholar
- 8.Calisici E, Yarci E, Degirmencioglu H, Oncel MY, Oguz SS, Uras N, Dilmen U (2014) PO-0731 the effects of early oral vitamin A treatment on the prevention of bronchopulmonary dysplasia in low birth weight infants. Arch Dis Child 99:A494Google Scholar
- 11.Darlow BA, Graham PJ, Rojas-Reyes MX (2016) Vitamin A supplementation to prevent mortality and short- and long-term morbidity in very low birth weight infants. Cochrane Database of Syst Rev 8:CD000501Google Scholar
- 14.Giridhar S, Kumar J, Attri SV, Dutta S, Kumar P (2019) Intramuscular followed by oral vitamin A supplementation in neonates with birth weight from 750 to 1250 g: a randomized controlled trial. Ind J Clin Biochem First Online 03 January https://doi.org/10.1007/s12291-018-0807-1
- 17.Haider BA, Sharma R, Bhutta ZA (2017) Neonatal vitamin A supplementation for the prevention of mortality and morbidity in term neonates in low and middle income countries. Cochrane Database of Syst Rev 2:CD006980Google Scholar
- 21.Kennedy KA, Stoll BJ, Ehrenkranz RA, Oh W, Wright LL, Stevenson DK, Lemons JA, Sowell A, Mele L, Tyson JE, Verter J (1997) 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 49:19–31CrossRefGoogle Scholar
- 22.Kiatchoosakun P, Jirapradittha J, Panthongviriyakul MC, Khampitak T, Yongvanit P, Boonsiri P (2014) Vitamin A supplementation for prevention of bronchopulmonary dysplasia in very-low-birth-weight premature Thai infants: a randomized trial. J Med Assoc Thail 97:S82–S88Google Scholar
- 24.Koletzko B, Goulet O, Hunt J, Krohn K, Shamir R, Parenteral Nutrition Guidelines Working Group (2005) Guidelines on paediatric parenteral nutrition of the European society of paediatric gastroenterology, hepatology and nutrition (ESPGHAN) and the European society for clinical nutrition and metabolism (ESPEN), supported by the European society of paediatric research (ESPR). J Pediatr Gastroenterol Nutr 41:S47–S53CrossRefGoogle Scholar
- 27.Morales S, Chung AW, Lewis JM, Messina A, Holt LE Jr (1950) Absorption of fat and vitamin A in premature infants: II effect of particle size on the absorption of these substances. Pediatrics. 6:644–649Google Scholar
- 33.Tyson JE, Wright LL, Oh W, Kennedy KA, Mele L, Ehrenkranz RA, Stoll BJ, Lemons JA, Stevenson DK, Bauer CR, Korones SB, Donovan EF, Carlo WA, Shankaran S, Stark AR, Papile LA, Jobe A, Stacewicz-Sapuntzakis M, Verter J, Fanaroff AA (1999) Vitamin A supplementation for extremely-low-birth-weight infants: National Institute of Child Health and Human Development neonatal research network. N Engl J Med 340:1962–1968CrossRefGoogle Scholar
- 37.WHO (1996) Indicators for assessing vitamin A deficiency and their application in monitoring and evaluation intervention programmes. World Health Organization, GenevaGoogle Scholar
- 38.World Health Organization (2009) Global prevalence of vitamin A deficiency in populations at risk 1995–2005. In: WHO Global Database on Vitamin A Deficiency. WHO, GenevaGoogle Scholar