The ProPre-Save Study: Effects of Probiotics and Prebiotics Alone or Combined on Necrotizing Enterocolitis in Very Low Birth Weight Infants

Published:January 13, 2015DOI:


      To test the efficacy of probiotic and prebiotic, alone or combined (synbiotic), on the prevention of necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants.

      Study design

      A prospective, randomized, controlled trial was conducted at 5 neonatal intensive care units in Turkey. VLBW infants (n = 400) were assigned to a control group and 3 study groups that were given probiotic (Bifidobacterium lactis), prebiotic (inulin), or synbiotic (Bifidobacterium lactis plus inulin) added to breastmilk or formula for a maximum of 8 weeks before discharge or death. The primary outcome was NEC (Bell stage ≥2).


      The rate of NEC was lower in probiotic (2.0%) and synbiotic (4.0%) groups compared with prebiotic (12.0%) and placebo (18.0%) groups (P < .001). The times to reach full enteral feeding were faster (P < .001), the rates of clinical nosocomial sepsis were lower (P = .004), stays in the neonatal intensive care unit were shorter, (P = .002), and mortality rates were lower (P = .003) for infants receiving probiotics, prebiotics, or synbiotic than controls. The use of antenatal steroid (OR 0.5, 95% CI 0.3-0.9) and postnatal probiotic (alone or in synbiotic) (OR 0.5, 95% CI 0.2-0.8) decreased the risk of NEC, and maternal antibiotic exposure increased this risk (OR 1.9, 95% CI 1.1-3.6).


      In VLBW infants, probiotic (Bifidobacterium lactis) and synbiotic (Bifidobacterium lactis plus inulin) but not prebiotic (inulin) alone decrease NEC.
      GI (Gastrointestinal), NEC (Necrotizing enterocolitis), NICU (Neonatal intensive care unit), NS (Nonsensitive), RCT (Randomized controlled trial), VLBW (Very low birth weight)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic and Personal
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The Journal of Pediatrics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Kafetzis D.A.
        • Skevaki C.
        • Costalos C.
        Neonatal necrotizing enterocolitis: an overview.
        Curr Opin Infect Dis. 2003; 16: 349-355
        • Neu J.
        • Walker W.A.
        Necrotizing enterocolitis.
        N Engl J Med. 2011; 364: 255-264
        • Bauer C.R.
        • Morrison J.C.
        • Poole W.K.
        • Korones S.B.
        • Boehm J.J.
        • Rigatto H.
        • et al.
        A decreased incidence of necrotizing enterocolitis after prenatal glucocorticoid therapy.
        Pediatrics. 1984; 73: 682-688
        • Lucas A.
        • Cole T.J.
        Breast milk and neonatal necrotising enterocolitis.
        Lancet. 1990; 336: 1519-1523
        • Caplan M.S.
        • Miller-Catchpole R.
        • Kaup S.
        • Russell T.
        • Lickerman M.
        • Amer M.
        • et al.
        Bifidobacterial supplementation reduces the incidence of necrotizing enterocolitis in a neonatal rat model.
        Gastroenterology. 1999; 117: 577-583
        • Dani C.
        • Biadaioli R.
        • Bertini G.
        • Martelli E.
        • Rubaltelli F.F.
        Probiotics feeding in prevention of urinary tract infection, bacterial sepsis and necrotizing enterocolitis in preterm infants. A prospective double-blind study.
        Biol Neonate. 2002; 82: 103-108
        • Panigrahi P.
        Probiotics and prebiotics in neonatal necrotizing enterocolitis: new opportunities for translational research.
        Pathophysiology. 2014; 21: 35-46
        • Goldmann D.A.
        • Leclair J.
        • Macone A.
        Bacterial colonization of neonates admitted to an intensive care environment.
        J Pediatr. 1978; 93: 288-293
        • Bernet M.F.
        • Brassart D.
        • Neeser J.R.
        • Servin A.L.
        Adhesion of human bifidobacterial strains to cultured human intestinal epithelial cells and inhibition of enteropathogen-cell interactions.
        Appl Environ Microbiol. 1993; 59: 4121-4128
        • Mack D.R.
        • Michail S.
        • Wei S.
        • McDougall L.
        • Hollingsworth M.A.
        Probiotics inhibit enteropathogenic E. coli adherence in vitro by inducing intestinal mucin gene expression.
        Am J Physiol. 1999; 276: G941-G950
        • Alfaleh K.
        • Anabrees J.
        • Bassler D.
        • Al-Kharfi T.
        Probiotics for prevention of necrotizing enterocolitis in preterm infants.
        Cochrane Database Syst Rev. 2011; : CD005496
        • Hoyos A.B.
        Reduced incidence of necrotizing enterocolitis associated with enteral administration of Lactobacillus acidophilus and Bifidobacterium infantis to neonates in an intensive care unit.
        Int J Infect Dis. 1999; 3: 197-202
        • Boehm G.
        • Stahl B.
        Oligosaccharides from milk.
        J Nutr. 2007; 137: 847S-849S
        • Schley P.D.
        • Field C.J.
        The immune-enhancing effects of dietary fibres and prebiotics.
        Br J Nutr. 2002; 87: S221-S230
        • Srinivasjois R.
        • Rao S.
        • Patole S.
        Prebiotic supplementation in preterm neonates: updated systematic review and meta-analysis of randomised controlled trials.
        Clin Nutr. 2013; 32: 958-965
        • Kukkonen K.
        • Savilahti E.
        • Haahtela T.
        • Juntunen-Backman K.
        • Korpela R.
        • Poussa T.
        • et al.
        Long-term safety and impact on infection rates of postnatal probiotic and prebiotic (synbiotic) treatment: randomized, double-blind, placebo-controlled trial.
        Pediatrics. 2008; 122: 8-12
        • Richardson D.K.
        • Corcoran J.D.
        • Escobar G.J.
        • Lee S.K.
        SNAP-II and SNAPPE-II: simplified newborn illness severity and mortality risk scores.
        J Pediatr. 2001; 138: 92-100
        • Haque K.N.
        Definitions of bloodstream infection in the newborn.
        Pediatr Crit Care Med. 2005; 6: S45-S49
        • Walsh M.C.
        • Kliegman R.M.
        • Fanaroff A.A.
        Necrotizing enterocolitis: a practitioner's perspective.
        Pediatr Rev. 1988; 9: 219-226
        • Ehrenkranz R.A.
        • Walsh M.C.
        • Vohr B.R.
        • Jobe A.H.
        • Wright L.L.
        • Fanaroff A.A.
        • et al.
        Validation of the National Institutes of Health consensus definition of bronchopulmonary dysplasia.
        Pediatrics. 2005; 116: 1353-1360
        • Fernandez-Carrocera L.A.
        • Solis-Herrera A.
        • Cabanillas-Ayon M.
        • Gallardo-Sarmiento R.B.
        • Garcia-Perez C.S.
        • Montano-Rodriguez R.
        • et al.
        Double-blind, randomised clinical assay to evaluate the efficacy of probiotics in preterm newborns weighing less than 1500 g in the prevention of necrotising enterocolitis.
        Arch Dis Child Fetal Neonatal Ed. 2013; 98: F5-F9
        • Schwiertz A.
        • Gruhl B.
        • Lobnitz M.
        • Michel P.
        • Radke M.
        • Blaut M.
        Development of the intestinal bacterial composition in hospitalized preterm infants in comparison with breast-fed, full-term infants.
        Pediatr Res. 2003; 54: 393-399
        • Gewolb I.H.
        • Schwalbe R.S.
        • Taciak V.L.
        • Harrison T.S.
        • Panigrahi P.
        Stool microflora in extremely low birthweight infants.
        Arch Dis Child Fetal Neonatal Ed. 1999; 80: F167-F173
        • Guthrie S.O.
        • Gordon P.V.
        • Thomas V.
        • Thorp J.A.
        • Peabody J.
        • Clark R.H.
        Necrotizing enterocolitis among neonates in the United States.
        J Perinatol. 2003; 23: 278-285
        • Deshpande G.
        • Rao S.
        • Patole S.
        • Bulsara M.
        Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates.
        Pediatrics. 2010; 125: 921-930
        • Rojas M.A.
        • Lozano J.M.
        • Rojas M.X.
        • Rodriguez V.A.
        • Rondon M.A.
        • Bastidas J.A.
        • et al.
        Prophylactic probiotics to prevent death and nosocomial infection in preterm infants.
        Pediatrics. 2012; 130: e1113-e1120
        • Jacobs S.E.
        • Tobin J.M.
        • Opie G.F.
        • Donath S.
        • Tabrizi S.N.
        • Pirotta M.
        • et al.
        Probiotic effects on late-onset sepsis in very preterm infants: a randomized controlled trial.
        Pediatrics. 2013; 132: 1055-1062
        • Wagner R.D.
        • Warner T.
        • Roberts L.
        • Farmer J.
        • Balish E.
        Colonization of congenitally immunodeficient mice with probiotic bacteria.
        Infect Immun. 1997; 65: 3345-3351
        • Mihatsch W.A.
        • Hoegel J.
        • Pohlandt F.
        Prebiotic oligosaccharides reduce stool viscosity and accelerate gastrointestinal transport in preterm infants.
        Acta Paediatr. 2006; 95: 843-848
        • Kapiki A.
        • Costalos C.
        • Oikonomidou C.
        • Triantafyllidou A.
        • Loukatou E.
        • Pertrohilou V.
        The effect of a fructo-oligosaccharide supplemented formula on gut flora of preterm infants.
        Early Hum Dev. 2007; 83: 335-339