Research Briefings Received: October 1, 2013 Accepted: November 11, 2013 Published online: January 14, 2014
Neonatology 2014;105:182–188 DOI: 10.1159/000357212
Early Postnatal Additional High-Dose Oral Vitamin A Supplementation versus Placebo for 28 Days for Preventing Bronchopulmonary Dysplasia or Death in Extremely Low Birth Weight Infants Sascha Meyer Ludwig Gortner NeoVitaA Trial Investigators
Neonatal Intensive Care Unit, Department of Pediatrics and Neonatology, University Children’s Hospital of Saarland, Homburg, Germany
Abstract Background: Prematurity and the associated risk for bronchopulmonary dysplasia (BPD) remain a significant threat to extremely low birth weight (ELBW) infants. Vitamin A has been considered a therapeutic alternative in reducing the rate of BPD and mortality. Objectives: To investigate whether early postnatal, additional high-dose oral vitamin A supplementation for 28 days is more efficient in reducing BPD or death in ELBW infants than placebo treatment. Methods: This is a multicenter, double-blind RCT comparing postnatal high-dose oral vitamin A supplementation (5,000 IU vitamin A/kg/day vs. placebo) for 28 days in ELBW neonates requiring mechanical ventilation, noninvasive ventilatory support or supplemental oxygen at 24 h of age. The primary end point is the proportion of children who died before 36 weeks’ gestational age or developed moderate or severe BPD. BPD is defined as the need for supplemental oxygen to maintain SaO2 of ≥92% at rest at 36 weeks’ postmenstrual age (PMA). Clinical secondary end points include the following: BPD (including mild form), intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, necrotizing enterocolitis, total number of days of mechanical ventilation
© 2014 S. Karger AG, Basel 1661–7800/14/1053–0182$39.50/0 E-Mail [email protected] www.karger.com/neo
and oxygen supplementation, and safety and tolerability of high-dose vitamin A supplementation. Results and Conclusions: The results of the NeoVitaA trial will provide robust data with regard to the efficacy of high-dose oral vitamin A supplementation in reducing the incidence of BPD or death at 36 weeks’ PMA in ELBW infants. © 2014 S. Karger AG, Basel
Introduction
Bronchopulmonary dysplasia (BPD) affects as many as 35% of extremely low birth weight infants (ELBW; birth weight 40% oxygen, and cannot successfully be weaned from the ventilator. The decision to administer intravenous steroids is at the physician’s discretion at each participating center. In our view, a positive benefit-risk ratio exists for this clinical trial as it can be assumed that high-dose vitamin A administered to ELBW infants reduces the risk for developing BPD or death. Conversely, we consider the risks and inconveniences associated with the trial medication and specific study procedures acceptable and limited.
References
188
10 Röhr SB, Sauer H, Gortner L, Gräber S, Meyer S: Cardiovascular and metabolic side effects associated with hydrocortisone and dexamethasone use in VLBW infants: a single-centre experience. Acta Paediatr 2013; 102:e436. 11 Biesalski HK, Nohr I: Importance of vitamin A for lung function and development. Mol Aspects Med 2003;24:431–440. 12 Metzler MD, Snyder JM: Retinoic acid differentially regulates expression of surfactant associated proteins in human fetal lung. Endocrinology 1993;133:1990–1998. 13 Zile MH: Function of vitamin A in vertebrate embryonic development. J Nutr 2001; 131: 705–708. 14 Darlow BA, Graham PJ: Vitamin A supplementation to prevent mortality and shortand long-term morbidity in very low birthweight infants. Cochrane Database Syst Rev 2011;10:CD000501. 15 Tyson JE, Wright LL, Oh W, Kennedy KA, Mele L, Ehrenkranz RA, Stoll BJ, Lemons JA, Stevenson DK, Bauer CR, Korones SB, Fanaroff AA: Vitamin A supplementation for extremely-low-birth-weight infants. N Engl J Med 1999;340:1962–1968. 16 Kaplan HC, Tabangin ME, McClendon D, Meinzen-Derr J, Margolis PA, Donovan EF: Understanding variation in vitamin A supplementation among NICUs. Pediatrics 2010; 126:e367–e373. 17 Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, et al: Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr 2009;50:85–91. 18 Wardle SP, Hughes A, Chen S, Shaw NJ: Randomised controlled trial of oral vitamin A supplementation in preterm infants to prevent chronic lung disease. Arch Dis Child Fetal Neonatal Ed 2001;84:F9–F13. 19 Seger N, Soll R: Animal derived surfactant extract for treatment of respiratory distress syndrome. Cochrane Database Syst Rev 2009; 2:CD007836. 20 Barrington KJ: The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. BMC Pediatr 2001;1:1. 21 Doyle LW, Halliday HL, Ehrenkranz RA, Davis PG, Sinclair JC: Impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk for chronic lung disease. Pediatrics 2005;115:655–661. 22 Soll RF: Inhaled nitric oxide for respiratory failure in preterm infants. Neonatology 2012; 102:251–253. 23 Tropea K, Christou H: Current pharmacologic approaches for prevention and treatment of bronchopulmonary dysplasia. Int J Pediatr 2012;2012:598606.
Neonatology 2014;105:182–188 DOI: 10.1159/000357212
24 Gortner L, Felderhoff-Müser U, Monz D, Bieback K, Klüter H, Jellema R, Kramer BW, Keller M, Reiss I, Horn PA, Giebel B: Regenerative therapies in neonatology: clinical perspectives. Klin Padiatr 2012;224:233–240. 25 Tropea KA, Leder E, Aslam M, Lau AN, Raiser DM, Lee JH, Balasubramaniam V, Fredenburgh LE, Alex Mitsialis S, Kourembanas S, Kim CF: Bronchioalveolar stem cells increase after mesenchymal stromal cell treatment in a mouse model of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2012; 302:L829–L837. 26 Fawke J, Lum S, Kirkby J, Hennessy E, Marlow N, Rowell V, Thomas S, Stocks J: Lung function and respiratory symptoms at 11 years in children born extremely preterm: the EPICure study. Am J Respir Crit Care Med 2010;182:237–245. 27 Humphrey JH, Agoestina T, Wu L, Usman A, Nurachim M, Subardja D, Hidayat S, Tielsch J, West KP Jr, Sommer A: Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr 1996;128:489– 496. 28 Rahmathallah L, Tielsch JM, Thulasiraj RD, Katz J, Coles C, Devi S, John R, Prakash K, Sadanand AV, Edwin N, Kamaraj C: Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomized trial in southern India. BMJ 2003;327:254–257. 29 World Bank: The World Bank World Development Report 1993: Investing in Health. Oxford, Oxford University Press, 1993. 30 Humphrey JH, Rice AL: Vitamin A supplementation of young infants. Lancet 2000;356: 422–424. 31 Mactier H, Weaver LT: Vitamin A and preterm infants: what we know, what we don’t know, and what we need to know. Arch Dis Child Fetal Neonatal Ed 2005;90:F103–F108. 32 Mactier H, Mokaya MM, Farrell L, Edwards CA: Vitamin A provision for preterm infants: are we meeting current guidelines? Arch Dis Child Fetal Neonatal Ed 2011;96:F286–F289. 33 Inder TE, Graham PJ, Winterbourn CC, Austin NC, Darlow BA: Plasma vitamin A levels in the very low birthweight infant: relationship to respiratory outcome. Early Hum Dev 1998;52:155–168. 34 Peeples JM, Carlson SE, Werkmen SH, Cooke RJ: Vitamin A status of preterm infants during infancy. Am J Clin Nutr 1991;53:1455–1459.
Meyer/Gortner/NeoVitaA Trial Investigators
Downloaded by: Chinese University of Hong Kong 137.189.170.231 - 2/22/2015 1:13:51 AM
1 Stichtenoth G, Demmert M, Bohnhorst B, Stein A, Ehlers S, Heitmann F, Rieger-Fackeldey E, Olbertz D, Roll C, Emeis M, Mögel M, Schiffmann H, Wieg C, Wintgens J, Herting E, Göpel W, Härtel C: Major contributors to hospital mortality in very-low-birth-weight infants: data of the birth year 2010 cohort of the German Neonatal Network. Klin Padiatr 2012;224:276–281. 2 Gortner L, Misselwitz B, Milligan D, et al: Rates of bronchopulmonary dysplasia in very preterm neonates in Europe: results from the MOSAIC cohort. Neonatology 2011; 99: 112– 117. 3 Smith VC, Zupancic JA, McCormick MC, Croen LA, Greene J, Escobar GJ, Richardson DK: Trends in severe bronchopulmonary dysplasia rates between 1994 and 2002. J Pediatr 2005;146:469–473. 4 Thomas W, Speer CP: Management of infants with bronchopulmonary dysplasia in Germany. Early Hum Dev 2005;81:155–163. 5 Jobe AH, Bancalari E: Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 163:1723–1729. 6 Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whitfield MF, Trial of Indomethacin Prophylaxis in Preterms (TIPP) Investigators: Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birthweight infants at 18 months: results from the Trial of Indomethacin Prophylaxis in Preterms. JAMA 2003;289:1124–1129. 7 Van Marter LJ, Kuban KC, Allred E, Bose C, Dammann O, O’Shea M, Laughon M, Ehrenkranz RA, Schreiber MD, Karna P, Leviton A, ELGAN Study Investigators: Does bronchopulmonary dysplasia contribute to the occurrence of cerebral palsy among infants born before 28 weeks of gestation? Arch Dis Child Fetal Neonatal Ed 2011;96:F20–F29. 8 Mercier JC, Hummler H, Durrmeyer X, Sanchez-Luna M, Carnielli V, Field D, Greenough A, Van Overmeire B, Jonsson B, Hallman M, Baldassarre J, EUNO Study Group: Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet 2010;376:346–354. 9 Watterberg KL, American Academy of Pediatrics: Committee on Fetus and Newborn Policy statement – postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Pediatrics 2010;126:800–808.
Neonatology 2014;105:182–188 DOI: 10.1159/000357212
Early Postnatal Additional High-Dose Oral Vitamin A Supplementation versus Placebo for 28 Days for Preventing Bronchopulmonary Dysplasia or Death in Extremely Low Birth Weight Infants Sascha Meyer Ludwig Gortner NeoVitaA Trial Investigators
Neonatal Intensive Care Unit, Department of Pediatrics and Neonatology, University Children’s Hospital of Saarland, Homburg, Germany
Abstract Background: Prematurity and the associated risk for bronchopulmonary dysplasia (BPD) remain a significant threat to extremely low birth weight (ELBW) infants. Vitamin A has been considered a therapeutic alternative in reducing the rate of BPD and mortality. Objectives: To investigate whether early postnatal, additional high-dose oral vitamin A supplementation for 28 days is more efficient in reducing BPD or death in ELBW infants than placebo treatment. Methods: This is a multicenter, double-blind RCT comparing postnatal high-dose oral vitamin A supplementation (5,000 IU vitamin A/kg/day vs. placebo) for 28 days in ELBW neonates requiring mechanical ventilation, noninvasive ventilatory support or supplemental oxygen at 24 h of age. The primary end point is the proportion of children who died before 36 weeks’ gestational age or developed moderate or severe BPD. BPD is defined as the need for supplemental oxygen to maintain SaO2 of ≥92% at rest at 36 weeks’ postmenstrual age (PMA). Clinical secondary end points include the following: BPD (including mild form), intraventricular hemorrhage, periventricular leukomalacia, retinopathy of prematurity, necrotizing enterocolitis, total number of days of mechanical ventilation
© 2014 S. Karger AG, Basel 1661–7800/14/1053–0182$39.50/0 E-Mail [email protected] www.karger.com/neo
and oxygen supplementation, and safety and tolerability of high-dose vitamin A supplementation. Results and Conclusions: The results of the NeoVitaA trial will provide robust data with regard to the efficacy of high-dose oral vitamin A supplementation in reducing the incidence of BPD or death at 36 weeks’ PMA in ELBW infants. © 2014 S. Karger AG, Basel
Introduction
Bronchopulmonary dysplasia (BPD) affects as many as 35% of extremely low birth weight infants (ELBW; birth weight 40% oxygen, and cannot successfully be weaned from the ventilator. The decision to administer intravenous steroids is at the physician’s discretion at each participating center. In our view, a positive benefit-risk ratio exists for this clinical trial as it can be assumed that high-dose vitamin A administered to ELBW infants reduces the risk for developing BPD or death. Conversely, we consider the risks and inconveniences associated with the trial medication and specific study procedures acceptable and limited.
References
188
10 Röhr SB, Sauer H, Gortner L, Gräber S, Meyer S: Cardiovascular and metabolic side effects associated with hydrocortisone and dexamethasone use in VLBW infants: a single-centre experience. Acta Paediatr 2013; 102:e436. 11 Biesalski HK, Nohr I: Importance of vitamin A for lung function and development. Mol Aspects Med 2003;24:431–440. 12 Metzler MD, Snyder JM: Retinoic acid differentially regulates expression of surfactant associated proteins in human fetal lung. Endocrinology 1993;133:1990–1998. 13 Zile MH: Function of vitamin A in vertebrate embryonic development. J Nutr 2001; 131: 705–708. 14 Darlow BA, Graham PJ: Vitamin A supplementation to prevent mortality and shortand long-term morbidity in very low birthweight infants. Cochrane Database Syst Rev 2011;10:CD000501. 15 Tyson JE, Wright LL, Oh W, Kennedy KA, Mele L, Ehrenkranz RA, Stoll BJ, Lemons JA, Stevenson DK, Bauer CR, Korones SB, Fanaroff AA: Vitamin A supplementation for extremely-low-birth-weight infants. N Engl J Med 1999;340:1962–1968. 16 Kaplan HC, Tabangin ME, McClendon D, Meinzen-Derr J, Margolis PA, Donovan EF: Understanding variation in vitamin A supplementation among NICUs. Pediatrics 2010; 126:e367–e373. 17 Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D, Decsi T, et al: Enteral nutrient supply for preterm infants: commentary from the European Society of Paediatric Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J Pediatr Gastroenterol Nutr 2009;50:85–91. 18 Wardle SP, Hughes A, Chen S, Shaw NJ: Randomised controlled trial of oral vitamin A supplementation in preterm infants to prevent chronic lung disease. Arch Dis Child Fetal Neonatal Ed 2001;84:F9–F13. 19 Seger N, Soll R: Animal derived surfactant extract for treatment of respiratory distress syndrome. Cochrane Database Syst Rev 2009; 2:CD007836. 20 Barrington KJ: The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. BMC Pediatr 2001;1:1. 21 Doyle LW, Halliday HL, Ehrenkranz RA, Davis PG, Sinclair JC: Impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk for chronic lung disease. Pediatrics 2005;115:655–661. 22 Soll RF: Inhaled nitric oxide for respiratory failure in preterm infants. Neonatology 2012; 102:251–253. 23 Tropea K, Christou H: Current pharmacologic approaches for prevention and treatment of bronchopulmonary dysplasia. Int J Pediatr 2012;2012:598606.
Neonatology 2014;105:182–188 DOI: 10.1159/000357212
24 Gortner L, Felderhoff-Müser U, Monz D, Bieback K, Klüter H, Jellema R, Kramer BW, Keller M, Reiss I, Horn PA, Giebel B: Regenerative therapies in neonatology: clinical perspectives. Klin Padiatr 2012;224:233–240. 25 Tropea KA, Leder E, Aslam M, Lau AN, Raiser DM, Lee JH, Balasubramaniam V, Fredenburgh LE, Alex Mitsialis S, Kourembanas S, Kim CF: Bronchioalveolar stem cells increase after mesenchymal stromal cell treatment in a mouse model of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2012; 302:L829–L837. 26 Fawke J, Lum S, Kirkby J, Hennessy E, Marlow N, Rowell V, Thomas S, Stocks J: Lung function and respiratory symptoms at 11 years in children born extremely preterm: the EPICure study. Am J Respir Crit Care Med 2010;182:237–245. 27 Humphrey JH, Agoestina T, Wu L, Usman A, Nurachim M, Subardja D, Hidayat S, Tielsch J, West KP Jr, Sommer A: Impact of neonatal vitamin A supplementation on infant morbidity and mortality. J Pediatr 1996;128:489– 496. 28 Rahmathallah L, Tielsch JM, Thulasiraj RD, Katz J, Coles C, Devi S, John R, Prakash K, Sadanand AV, Edwin N, Kamaraj C: Impact of supplementing newborn infants with vitamin A on early infant mortality: community based randomized trial in southern India. BMJ 2003;327:254–257. 29 World Bank: The World Bank World Development Report 1993: Investing in Health. Oxford, Oxford University Press, 1993. 30 Humphrey JH, Rice AL: Vitamin A supplementation of young infants. Lancet 2000;356: 422–424. 31 Mactier H, Weaver LT: Vitamin A and preterm infants: what we know, what we don’t know, and what we need to know. Arch Dis Child Fetal Neonatal Ed 2005;90:F103–F108. 32 Mactier H, Mokaya MM, Farrell L, Edwards CA: Vitamin A provision for preterm infants: are we meeting current guidelines? Arch Dis Child Fetal Neonatal Ed 2011;96:F286–F289. 33 Inder TE, Graham PJ, Winterbourn CC, Austin NC, Darlow BA: Plasma vitamin A levels in the very low birthweight infant: relationship to respiratory outcome. Early Hum Dev 1998;52:155–168. 34 Peeples JM, Carlson SE, Werkmen SH, Cooke RJ: Vitamin A status of preterm infants during infancy. Am J Clin Nutr 1991;53:1455–1459.
Meyer/Gortner/NeoVitaA Trial Investigators
Downloaded by: Chinese University of Hong Kong 137.189.170.231 - 2/22/2015 1:13:51 AM
1 Stichtenoth G, Demmert M, Bohnhorst B, Stein A, Ehlers S, Heitmann F, Rieger-Fackeldey E, Olbertz D, Roll C, Emeis M, Mögel M, Schiffmann H, Wieg C, Wintgens J, Herting E, Göpel W, Härtel C: Major contributors to hospital mortality in very-low-birth-weight infants: data of the birth year 2010 cohort of the German Neonatal Network. Klin Padiatr 2012;224:276–281. 2 Gortner L, Misselwitz B, Milligan D, et al: Rates of bronchopulmonary dysplasia in very preterm neonates in Europe: results from the MOSAIC cohort. Neonatology 2011; 99: 112– 117. 3 Smith VC, Zupancic JA, McCormick MC, Croen LA, Greene J, Escobar GJ, Richardson DK: Trends in severe bronchopulmonary dysplasia rates between 1994 and 2002. J Pediatr 2005;146:469–473. 4 Thomas W, Speer CP: Management of infants with bronchopulmonary dysplasia in Germany. Early Hum Dev 2005;81:155–163. 5 Jobe AH, Bancalari E: Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 163:1723–1729. 6 Schmidt B, Asztalos EV, Roberts RS, Robertson CM, Sauve RS, Whitfield MF, Trial of Indomethacin Prophylaxis in Preterms (TIPP) Investigators: Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birthweight infants at 18 months: results from the Trial of Indomethacin Prophylaxis in Preterms. JAMA 2003;289:1124–1129. 7 Van Marter LJ, Kuban KC, Allred E, Bose C, Dammann O, O’Shea M, Laughon M, Ehrenkranz RA, Schreiber MD, Karna P, Leviton A, ELGAN Study Investigators: Does bronchopulmonary dysplasia contribute to the occurrence of cerebral palsy among infants born before 28 weeks of gestation? Arch Dis Child Fetal Neonatal Ed 2011;96:F20–F29. 8 Mercier JC, Hummler H, Durrmeyer X, Sanchez-Luna M, Carnielli V, Field D, Greenough A, Van Overmeire B, Jonsson B, Hallman M, Baldassarre J, EUNO Study Group: Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet 2010;376:346–354. 9 Watterberg KL, American Academy of Pediatrics: Committee on Fetus and Newborn Policy statement – postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Pediatrics 2010;126:800–808.
