Safety and Efficacy Profile Of Prebiotic Oligosaccharides In Preterm Infants

Key takeaways

Prematurity-related complications and an immature digestive system remain major cause of infections and neonatal mortality worldwide.^1,2
Prebiotics can modulate gut microbiota, promote gut maturation, and maintain epithelial permeability of the intestine.²
Supplementation of prebiotics like GOS:FOS (9:1) was shown to result in reduced rate of sepsis,^3,4 length of hospital stay,³ mortality,² time to full enteral feeding,³ and necrotizing enterocolitis (NEC).³

Introduction

About 2.5 million infant deaths occur annually worldwide. Global statistics reveal that prematurity-related complications account for 35% of neonatal deaths. A prospective study conducted on three large neonatal cohorts from India showed that 39-54% of neonatal deaths were related to prematurity-related complications.¹ Evidence suggests that a majority of preterm deaths are due to complications like necrotizing enterocolitis (NEC) or sepsis.¹ Figure 1 illustrates the risk factors and impact of prebiotics on preterm morbidity and mortality.

Figure 1. Pathology of prematurity-related complications and effects of prebiotics in preterm infants. ^2,3,5 GOS: Galacto-oligosaccharides; FOS: Fructo-oligosaccharides; NEC: Necrotizing enterocolitis.

Clinical evidence supporting the health benefits of prebiotics in preterm infants

Sepsis and mortality

A prospective study from India reported 19 to 40% of neonatal deaths due to sepsis that can be prevented with appropriate intervention.¹ Particularly, prebiotic supplementation with GOS:FOS (9:1) demonstrated a considerable reduction in sepsis rate (Figure 2).

Figure 2. Effect of prebiotics in reducing sepsis rate in preterm infants. RCT: Randomized clinical trial; GOS: Galacto-oligosaccharides; FOS: Fructo-oligosaccharides; HR: Hazard ratio; CI: Confidence interval

Time to achieve full enteral feeding, hospital stay, and stool frequency

Preterm birth and associated complications like NEC and feeding intolerance often hinder complete enteral feeding.² A meta-analysis demonstrated that prebiotic supplementation reduces the time taken to achieve complete enteral feeding, hospital stay, and improves stool frequency in preterm infants.² Table 1 summarizes the key outcomes of GOS:FOS (9:1) supplementation in preterm infants.

Table 1. Effect of GOS: FOS (9:1) in reducing time to achieve enteral feeding and hospital stay in preterm infants.^3,4

Study	Population/Group	Key outcomes
Hospital stay
Armanian et al., 2014³(RCT)	N=75 GOS:FOS (9:1) vs. control	Meantime hospitalization was shorter in the prebiotic group(16 days) than the control group (25 days), P=0.004.
Enteral feeding time
Modi et al.,2010⁴(RCT)	N=160 GOS:FOS (9:1) vs. standard feed	Meantime to reach full enteral feeding 6 days (GOS: FOS group) vs. 7 days (control group) (P=0.10) at 28 weeks
Stool frequency
Dasopoulou et al., 2015⁶	N=167 GOS:FOS (9:1) vs. control feed	Increased stool frequency Higher stool frequency in the GOS: FOS group (91.9%, P<0.05) compared to the control group (72.5%) on day 16
Westerbreek et al., 2011⁷	N=113 GOS:FOS vs. Placebo 27 days	Higher stool frequency in the GOS:FOS group (3.1 ± 0.8) compared to the placebo group (2.8 ± 0.7) (P = 0.15)
Reduction of pathogenic bacteria
Jan Knol et al., 2005⁸	N= 25 GOS:FOS vs. Placebo	Reduction in the number of pathogens in the group supplemented with GOS:FOS compared to placebo (7.24+0.31 log CFU/g stool vs 7.67+0.58 log CFU/g stool; p=0.039).

GOS: Galacto-oligosaccharides; FOS: Fructo-oligosaccharides

Necrotizing enterocolitis (NEC)

A randomized control trial (RCT) evaluated the efficacy of GOS:FOS (9:1) in reducing NEC-incidence in neonates with very low birth-weight. The study reported that supplementation of GOS:FOS mixture (9:1) significantly reduced (P=0.002; HR: 0.49 95% CI: 0.29-0.84) the NEC-incidence (1; 4.0%) compared to the control arm (11; 22.0%).³

Safety of GOS:FOS (9:1) in preterm infants

A meta-analysis involving 18 RCTs demonstrated that prebiotic administration in preterm infants is safe and well-tolerated.²
Modi et al. reported the safety of GOS:FOS (9:1) supplementation in preterm infants and benefits in achieving enteral feeding tolerance.⁴
An RCT conducted on 133 preterm infants reported that supplementation of 1.5 g/kg/day of GOS:FOS (9:1) for 27 days is safe, well-tolerated, and improved stool characteristics.^2,7
Another RCT involving 113 preterm infants with identical baseline characteristics also demonstrated the safety and tolerability of the prebiotic mixture. This study reported that supplementation of the prebiotic mixture [GOS:FOS (80%:20%) pectin-derived acidic oligosaccharides] did not show any adverse effects in preterm infants.⁹

Conclusion

Prebiotics mixture GOS:FOS (9:1) can modulate gut microbiota, promote gut maturation, and help maintain epithelial permeability of the intestine.⁵ Sizable evidence suggests that supplementation of the mixture resulted in reduced incidence of sepsis, length of hospital stay, mortality, time to full enteral feeding, and NEC.^2-4,6,7

References

Jain K, Sankar MJ, Nangia S, Ballambattu VB, Sundaram V, Ramji S, Plakkal N, Kumar P, Jain A, Sivanandan S, Vishnubhatla S. Causes of death in preterm neonates (< 33 weeks) born in tertiary care hospitals in India: analysis of three large prospective multicentric cohorts. Journal of Perinatology. 2019 Sep;39(1):13-9.
Chi C, Buys N, Li C, Sun J, Yin C. Effects of prebiotics on sepsis, necrotizing enterocolitis, mortality, feeding intolerance, time to full enteral feeding, length of hospital stay, and stool frequency in preterm infants: a meta-analysis. European journal of clinical nutrition. 2019 May;73(5):657-70.
Armanian AM, Sadeghnia A, Hoseinzadeh M, Mirlohi M, Feizi A, Salehimehr N, Saee N, Nazari J. The effect of neutral oligosaccharides on reducing the incidence of necrotizing enterocolitis in preterm infants: a randomized clinical trial. International journal of preventive medicine. 2014 Nov;5(11):1387.
Modi N, Uthaya S, Fell J, Kulinskaya E. A randomized, double-blind, controlled trial of the effect of prebiotic oligosaccharides on enteral tolerance in preterm infants (ISRCTN77444690). Pediatric research. 2010 Nov;68(5):440-5.
McKeen S, Young W, Mullaney J, Fraser K, McNabb WC, Roy NC. Infant complementary feeding of prebiotics for the microbiome and immunity. Nutrients. 2019 Feb;11(2):364.
Dasopoulou M, Briana DD, Boutsikou T, Karakasidou E, Roma E, Costalos C, Malamitsi‐Puchner A. Motilin and Gastrin Secretion and Lipid Profile in Preterm Neonates Following Prebiotics Supplementation: A Double‐Blind Randomized Controlled Study. Journal of Parenteral and Enteral Nutrition. 2015 Mar;39(3):359-68.
Westerbeek EA, Hensgens RL, Mihatsch WA, Boehm G, Lafeber HN, Van Elburg RM. The effect of neutral and acidic oligosaccharides on stool viscosity, stool frequency and stool pH in preterm infants. Acta Paediatrica. 2011 Nov;100(11):1426-31.
Knol J, Boehm G, Lidestri M, Negretti F, Jelinek J, Agosti M, Stahl B, Marini A, Mosca F. Increase of faecal bifidobacteria due to dietary oligosaccharides induces a reduction of clinically relevant pathogen germs in the faeces of formula‐fed preterm infants. Acta paediatrica. 2005 Oct;94:31-3.
van den Berg JP, Westerbeek EA, van der Klis FR, Berbers GA, Lafeber HN, van Elburg RM. Neutral and acidic oligosaccharides supplementation does not increase the vaccine antibody response in preterm infants in a randomized clinical trial. PloS One. 2013 Aug 8;8(8):e70904.