Lutein and Zeaxanthin Supplementation in Preterm Very Low-Birth-Weight Neonates in Neonatal Intensive Care Units: A Multicenter Randomized Controlled Trial

Paolo Manzoni; Roberta Guardione; Paolo Bonetti; Claudio Priolo; Andrea Maestri; Caterina Mansoldo; Michael Mostert; Giovanni Anselmetti; Daniela Sardei; Massimo Bellettato; Paolo Biban; Daniele Farina

doi:10.1055/s-0032-1321494

American Journal of Perinatology, Table of Contents

Am J Perinatol 2013; 30(01): 025-032
DOI: 10.1055/s-0032-1321494

Original Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Lutein and Zeaxanthin Supplementation in Preterm Very Low-Birth-Weight Neonates in Neonatal Intensive Care Units: A Multicenter Randomized Controlled Trial

Paolo Manzoni

¹Neonatology and NICU, S. Anna Hospital, Torino, Italy

,

Roberta Guardione

¹Neonatology and NICU, S. Anna Hospital, Torino, Italy

,

Paolo Bonetti

²Pediatrics/Neonatal Intensive Care Unit, Division of Pediatrics, Azienda Ospedaliera, Verona, Italy

,

Claudio Priolo

¹Neonatology and NICU, S. Anna Hospital, Torino, Italy

,

Andrea Maestri

¹Neonatology and NICU, S. Anna Hospital, Torino, Italy

,

Caterina Mansoldo

²Pediatrics/Neonatal Intensive Care Unit, Division of Pediatrics, Azienda Ospedaliera, Verona, Italy

,

Michael Mostert

³Division of Neonatology and Pediatrics, City Hospital, Thiene, Italy

⁵Department of Pediatrics, University of Torino, Italy

,

Giovanni Anselmetti

⁴Referral Center for ROP of Piedmont, Torino, Italy

,

Daniela Sardei

³Division of Neonatology and Pediatrics, City Hospital, Thiene, Italy

⁵Department of Pediatrics, University of Torino, Italy

,

Massimo Bellettato

³Division of Neonatology and Pediatrics, City Hospital, Thiene, Italy

⁵Department of Pediatrics, University of Torino, Italy

,

Paolo Biban

²Pediatrics/Neonatal Intensive Care Unit, Division of Pediatrics, Azienda Ospedaliera, Verona, Italy

,

Daniele Farina

¹Neonatology and NICU, S. Anna Hospital, Torino, Italy

› Author Affiliations

Abstract

Background Human milk feeding protects against oxidative stress-induced damage in preterm neonates, including severe multifactorial diseases such as retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), and bronchopulmonary dysplasia (BPD). The carotenoids, which are not found in formula milk, might play a key role in these actions.

Methods A multicenter, double-blind, randomized controlled trial was conducted in three tertiary Italian neonatal intensive care units. All preterm infants <32⁺⁶ weeks' gestational age were eligible and were randomized to a single, oral, daily 0.5-mL dose of carotenoid supplementation (0.14 mg lutein + 0.0006 mg zeaxanthin) or placebo (5% glucose solution) from birth till 36 weeks' corrected gestational age. Primary outcomes were threshold ROP, NEC > second stage, and BPD. Surveillance for detection of these diseases and for intolerance/adverse effects was performed.

Results No treatment-related adverse effect was documented in the 229 analyzed infants, whose clinical/demographical characteristics were similar in the two groups. Threshold ROP incidence did not significantly differ in treated (6.2%) versus not treated infants (10.3%; p = 0.18). The same occurred for NEC (1.7% versus 5.1%; p = 0.15) and BPD (4.5% versus 10.3%; p = 0.07). Noteworthy, the progression rate from early ROP stages to threshold ROP was decreased by 50% (0.30 versus 0.44; p = 0.23).

Conclusion Lutein/zeaxanthin supplementation in preterm infants is well tolerated. No significant effect was seen on threshold ROP, NEC, or BPD. The decreasing trends of these outcomes in the treatment group need to be assessed and confirmed on larger sample-sizes.

Keywords

nutrition - lutein - zeaxanthin - preterm neonates - ROP - BPD - NEC - prevention

Full Text

References

References
1 Stoll BJ, Hansen NI, Bell EF , et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Neonatal outcomes of extremely preterm infants from the NICHD Neonatal Research Network. Pediatrics 2010; 126: 443-456
2 Dani C, Giannini L, Bertini G , et al. Changes of nitric oxide, carbon monoxide and oxidative stress in term infants at birth. Free Radic Res 2007; 41: 1358-1363
3 Buonocore G, Groenendaal F. Anti-oxidant strategies. Semin Fetal Neonatal Med 2007; 12: 287-295
4 Schanler RJ, Lau C, Hurst NM, Smith EO. Randomized trial of donor human milk versus preterm formula as substitutes for mothers' own milk in the feeding of extremely premature infants. Pediatrics 2005; 116: 400-406
5 Hylander MA, Strobino DM, Pezzullo JC, Dhanireddy R. Association of human milk feedings with a reduction in retinopathy of prematurity among very low birthweight infants. J Perinatol 2001; 21: 356-362
6 Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet 1990; 336: 1519-1523
7 Lindmark-Månsson H, Akesson B. Antioxidative factors in milk. Br J Nutr 2000; 84 (Suppl. 01) S103-S110
8 Perrone S, Longini M, Marzocchi B , et al. Effects of lutein on oxidative stress in the term newborn: a pilot study. Neonatology 2010; 97: 36-40
9 Sommerburg O, Meissner K, Nelle M, Lenhartz H, Leichsenring M. Carotenoid supply in breast-fed and formula-fed neonates. Eur J Pediatr 2000; 159: 86-90
10 GRAS Notice No. GNR 000140 issued by CFSAN/Office of Food Additive Safety. Available at: http://www.accessdata.fda.gov/scripts/fcn/gras_notices/GRN000385.pdf . Accessed June 22, 2012
11 Bell MJ, Ternberg JL, Feigin RD , et al. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Ann Surg 1978; 187: 1-7
12 Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med 2001; 163: 1723-1729
13 Good WV, Hardy RJ, Dobson V , et al; Early Treatment for Retinopathy of Prematurity Cooperative Group. The incidence and course of retinopathy of prematurity: findings from the early treatment for retinopathy of prematurity study. Pediatrics 2005; 116: 15-23
14 Manzoni P, Rinaldi M, Cattani S , et al; Italian Task Force for the Study and Prevention of Neonatal Fungal Infections, Italian Society of Neonatology. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial. JAMA 2009; 302: 1421-1428
15 Manzoni P, Stolfi I, Pugni L , et al; Italian Task Force for the Study and Prevention of Neonatal Fungal Infections; Italian Society of Neonatology. A multicenter, randomized trial of prophylactic fluconazole in preterm neonates. N Engl J Med 2007; 356: 2483-2495
16 Ascioglu S, Rex JH, de Pauw B , et al; Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer; Mycoses Study Group of the National Institute of Allergy and Infectious Diseases. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 2002; 34: 7-14
17 Manzoni P, Pedicino R, Stolfi I , et al; Task Force per le infezioni fungine neonatali del GSIN; Socieà Italiana di Neonatologia. [Criteria for the diagnosis of systemic fungal infections in newborns: a report from the Task Force on neonatal fungal infections of the GSIN]. Pediatr Med Chir 2004; 26: 89-95
18 Papile LA, Burstein J, Burstein R, Koffler H. Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1,500 gm. J Pediatr 1978; 92: 529-534
19 Alderson P, Green S, Higgins JPT , Eds. Cochrane Reviewers' Handbook 4.2.2. Available at: http://www.mv.helsinki.fi/home/hemila/karlowski/handbook_4_2_2_Karlowski.pdf . Accessed June 2012
20 Bettler J, Zimmer JP, Neuringer M, DeRusso PA. Serum lutein concentrations in healthy term infants fed human milk or infant formula with lutein. Eur J Nutr 2010; 49: 45-51
21 Tacken KJ, Vogelsang A, van Lingen RA, Slootstra J, Dikkeschei BD, van Zoeren-Grobben D. Loss of triglycerides and carotenoids in human milk after processing. Arch Dis Child Fetal Neonatal Ed 2009; 94: F447-F450
22 Capeding R, Gepanayao CP, Calimon N , et al. Lutein-fortified infant formula fed to healthy term infants: evaluation of growth effects and safety. Nutr J 2010; 9: 22
23 Okamoto T, Shirai M, Kokubo M , et al. Human milk reduces the risk of retinal detachment in extremely low-birthweight infants. Pediatr Int 2007; 49: 894-897
24 Thörne A, Aberg W, Carneheim C, Olivecrona T, Nordenström J. Influence of trauma on plasma elimination of exogenous fat and on lipoprotein lipase activity and mass. Clin Nutr 2005; 24: 66-74
25 Mares-Perlman JA, Millen AE, Ficek TL, Hankinson SE. The body of evidence to support a protective role for lutein and zeaxanthin in delaying chronic disease. Overview. J Nutr 2002; 132: 518S-524S
26 Sato J, O'Brien T, Katusic ZS , et al. Dietary antioxidants preserve endothelium dependent vasorelaxation in overfed rats. Atherosclerosis 2002; 161: 327-333
27 Vogelsang A, van Lingen RA, Slootstra J , et al. Antioxidant role of plasma carotenoids in bronchopulmonary dysplasia in preterm infants. Int J Vitam Nutr Res 2009; 79: 288-296
28 Dwyer JH, Navab M, Dwyer KM , et al. Oxygenated carotenoid lutein and progression of early atherosclerosis: the Los Angeles atherosclerosis study. Circulation 2001; 103: 2922-2927
29 Eye Disease Case-Control Study Group. Antioxidant status and neovascular age-related macular degeneration. Arch Ophthalmol 1993; 111: 104-109
30 Gale CR, Hall NF, Phillips DI, Martyn CN. Lutein and zeaxanthin status and risk of age-related macular degeneration. Invest Ophthalmol Vis Sci 2003; 44: 2461-2465