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Open Access 01-12-2016 | Study protocol

The N3RO trial: a randomised controlled trial of docosahexaenoic acid to reduce bronchopulmonary dysplasia in preterm infants < 29 weeks’ gestation

Authors: Carmel T. Collins, Robert A. Gibson, Maria Makrides, Andrew J. McPhee, Thomas R. Sullivan, Peter G. Davis, Marta Thio, Karen Simmer, Victor S. Rajadurai, the N3RO Investigative Team

Published in: BMC Pediatrics | Issue 1/2016

Abstract

Background

Bronchopulmonary dysplasia (BPD) is a major cause of mortality and long-term respiratory and neurological morbidity in very preterm infants. While survival rates of very preterm infants have increased over the past two decades there has been no decrease in the rate of BPD in surviving infants. Evidence from animal and human studies has suggested potential benefits of docosahexaenoic acid (DHA), an n-3 long chain polyunsaturated fatty acid, in the prevention of chronic lung disease. This randomised controlled trial aims to determine the effectiveness of supplementary DHA in reducing the rate of BPD in infants less than 29 weeks’ gestation.

Methods/design

This is a multicentre, parallel group, randomised, blinded and controlled trial. Infants born less than 29 weeks’ gestation, within 3 days of first enteral feed and with parent informed consent are eligible to participate. Infants will be randomised to receive an enteral emulsion containing DHA or a control emulsion without DHA. The DHA emulsion will provide 60 mg/kg/day of DHA. The study emulsions will continue to 36 weeks’ postmenstrual age (PMA). The primary outcome is BPD as assessed by the requirement for supplemental oxygen and/or assisted ventilation at 36 weeks’ PMA. Secondary outcomes include the composite of death or BPD; duration of respiratory support and hospitalisation, major neonatal morbidities. The target sample size is 1244 infants (622 per group), which will provide 90 % power to detect a clinically meaningful absolute reduction of 10 % in the incidence of BPD between the DHA and control emulsion (two tailed α =0.05).

Discussion

DHA supplementation has the potential to reduce respiratory morbidity in very preterm infants. This multicentre trial will provide evidence on whether an enteral DHA supplement reduces BPD in very preterm infants.

Trial registration

Australia and New Zealand Clinical Trial Registry: ACTRN12612000503820. Registered 09 May 2012.

Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2001;163:1723–9.CrossRefPubMed

Schulzke SM, Pillow JJ. The management of evolving bronchopulmonary dysplasia. Paediatr Respir Rev. 2010;11:143–8.CrossRefPubMed

Santuz P, Baraldi E, Zaramella P, Filippone M, Zacchello F. Factors limiting exercise performance in long-term survivors of bronchopulmonary dysplasia. Am J Respir Crit Care Med. 1995;152:1284–9.CrossRefPubMed

Doyle LW, Anderson PJ. Long-term outcomes of bronchopulmonary dysplasia. Semin Fetal Neonatal Med. 2009;14:391–5.CrossRefPubMed

Hayes JD, Feola DJ, Murphy BS, Shook LA, Ballard HO. Pathogenesis of bronchopulmonary dysplasia. Respiration. 2010;79:425–36.CrossRefPubMed

Birch EE, Khoury JC, Berseth CL, Castaneda YS, Couch JM, Bean J, et al. The impact of early nutrition on incidence of allergic manifestations and common respiratory illnesses in children. J Pediatr. 2010;156:902–6.CrossRefPubMed

Minns LM, Kerling EH, Neely MR, Sullivan DK, Wampler JL, Harris CL, et al. Toddler formula supplemented with docosahexaenoic acid (DHA) improves DHA status and respiratory health in a randomized, double-blind, controlled trial of US children less than 3 years of age. Prostaglandins Leukot Essent Fatty Acids. 2010;82:287–93.CrossRefPubMed

Biltagi MA, Baset AA, Bassiouny M, Kasrawi MA, Attia M. Omega-3 fatty acids, vitamin C and Zn supplementation in asthmatic children: a randomized self-controlled study. Acta Paediatr. 2009;98:737–42.CrossRefPubMed

Thienprasert A, Samuhaseneetoo S, Popplestone K, West AL, Miles EA, Calder PC. Fish oil n-3 polyunsaturated fatty acids selectively affect plasma cytokines and decrease illness in Thai schoolchildren: a randomized, double-blind, placebo-controlled intervention trial. J Pediatr. 2009;154:391–5.CrossRefPubMed

10.

Smithers LG, Gibson RA, McPhee A, Makrides M. Effect of long-chain polyunsaturated fatty acid supplementation of preterm infants on disease risk and neurodevelopment: a systematic review of randomized controlled trials. Am J Clin Nutr. 2008;87:912–20.PubMed

11.

Martin CR, Dasilva DA, Cluette-Brown JE, Dimonda C, Hamill A, Bhutta AQ, et al. Decreased postnatal docosahexaenoic and arachidonic acid blood levels in premature infants are associated with neonatal morbidities. J Pediatr. 2011;159(5):743–749.e1-2.CrossRefPubMedPubMedCentral

12.

Makrides M, Gibson RA, McPhee AJ, Collins CT, Davis PG, Doyle LW, et al. Neurodevelopmental outcomes of preterm infants fed high-dose docosahexaenoic acid: a randomized controlled trial. JAMA. 2009;301:175–82.CrossRefPubMed

13.

Serhan CN, Chiang N, Van Dyke TE, Serhan CN, Chiang N, Van Dyke TE. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev Immunol. 2008;8:349–61.CrossRefPubMedPubMedCentral

14.

Calder PC. Polyunsaturated fatty acids and inflammatory processes: new twists in an old tale. Biochimie. 2009;91:791–5.CrossRefPubMed

15.

Schwartz J. Role of polyunsaturated fatty acids in lung disease. Am J Clin Nutr. 2000;71:393S–6S.PubMed

16.

Cotogni P, Muzio G, Trombetta A, Ranieri VM, Canuto RA. Impact of the ω-3 to ω-6 polyunsaturated fatty acid ratio on cytokine release in human alveolar cells. JPEN J Parenter Enteral Nutr. 2011;35:114–21.CrossRefPubMed

17.

Manley BJ, Makrides M, Collins CT, McPhee AJ, Gibson RA, Ryan P, et al. High-dose docosahexaenoic acid supplementation of preterm infants: respiratory and allergy outcomes. Pediatrics. 2011;128:e71–77.CrossRefPubMed

18.

Henriksen C, Haugholt K, Lindgren M, Aurvag AK, Ronnestad A, Gronn M, et al. Improved cognitive development among preterm infants attributable to early supplementation of human milk with docosahexaenoic acid and arachidonic acid. Pediatrics. 2008;121:1137–45.CrossRefPubMed

19.

Rogers LK, Valentine CJ, Pennell M, Velten M, Britt RD, Dingess K, et al. Maternal docosahexaenoic acid supplementation decreases lung inflammation in hyperoxia-exposed newborn mice. J Nutr. 2011;141:214–22.CrossRefPubMedPubMedCentral

20.

Ma L, Li N, Liu X, Shaw L, Li Calzi S, Grant MB, et al. Arginyl-glutamine dipeptide or docosahexaenoic acid attenuate hyperoxia-induced lung injury in neonatal mice. Nutrition. 2012;28:1186–91.CrossRefPubMed

21.

Velten M, Britt Jr RD, Heyob KM, Tipple TE, Rogers LK. Maternal dietary docosahexaenoic acid supplementation attenuates fetal growth restriction and enhances pulmonary function in a newborn mouse model of perinatal inflammation. J Nutr. 2014;144:258–66.CrossRefPubMedPubMedCentral

22.

Chao AC, Ziadeh BI, Diau G-Y, Wijendran V, Sarkadi-Nagy E, Hsieh AT, et al. Influence of dietary long-chain PUFA on premature baboon lung FA and dipalmitoyl PC composition. Lipids. 2003;38:425–9.CrossRefPubMed

23.

Blanco P, Freedman S, Lopez M, Ollero M, Comen E, Laposata M, et al. Oral docosahexaenoic acid given to pregnant mice increases the amount of surfactant in lung and amniotic fluid in preterm fetuses. Am J Obstet Gynecol. 2004;190:1369–74.CrossRefPubMed

24.

Collins CT, Sullivan TR, McPhee AJ, Stark MJ, Makrides M, Gibson RA. A dose response randomised controlled trial of docosahexaenoic acid (DHA) in preterm infants. Prostaglandins Leukot Essent Fatty Acids. 2015;99:1–6.CrossRefPubMed

25.

Walsh MC, Yao Q, Gettner P, Hale E, Collins M, Hensman A, et al. Impact of a physiologic definition on bronchopulmonary dysplasia rates. Pediatrics. 2004;114:1305–11.CrossRefPubMed

26.

Dargaville PA, Kamlin CO, De Paoli AG, Carlin JB, Orsini F, Soll RF, et al. The OPTIMIST-A trial: evaluation of minimally-invasive surfactant therapy in preterm infants 25–28 weeks gestation. BMC Pediatr. 2014;14:213.CrossRefPubMedPubMedCentral

27.

Benaron DA, Benitz WE. Maximizing the stability of oxygen delivered via nasal cannula. Arch Pediatr Adolesc Med. 1994;148:294–300.CrossRefPubMed

28.

ANZNN (Australian and New Zealand Neonatal Network). Report of the Australian and New Zealand Neonatal Network 2007. Sydney; 2011

Title: The N3RO trial: a randomised controlled trial of docosahexaenoic acid to reduce bronchopulmonary dysplasia in preterm infants < 29 weeks’ gestation
Authors: Carmel T. Collins
Robert A. Gibson
Maria Makrides
Andrew J. McPhee
Thomas R. Sullivan
Peter G. Davis
Marta Thio
Karen Simmer
Victor S. Rajadurai
the N3RO Investigative Team
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: BMC Pediatrics / Issue 1/2016
Electronic ISSN: 1471-2431
DOI: https://doi.org/10.1186/s12887-016-0611-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

The N3RO trial: a randomised controlled trial of docosahexaenoic acid to reduce bronchopulmonary dysplasia in preterm infants < 29 weeks’ gestation

Abstract

Background

Methods/design

Discussion

Trial registration

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods/design

Discussion

Trial registration

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