title: Original version Date - Neonatal Intensive Care Drug Manual
text: Evidence summary
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  Several systematic reviews and randomised controlled trials have shown that enteral probiotics significantly reduce the risk of NEC (≥ stage II), late onset sepsis, all-cause mortality and time to full enteral feeds. [1-3] (LOE 1, GOR A) Multiple strains of probiotics may be more effective in preventing NEC and mortality than single strains. [9] (LOE I, GOR B)
  Probiotics for prevention of NEC in preterm infants: Enteral probiotic supplementation significantly reduced the incidence of severe NEC (RR 0.43, 95% CI 0.33 to 0.56; 20 studies, 5529 infants) and mortality (typical RR 0.65, 95% CI 0.52 to 0.81; 17 studies, 5112 infants). The included trials reported no systemic infection with the supplemental probiotics organism. Probiotics preparations containing either Lactobacillus alone or in combination with Bifidobacterium were found to be effective. Conclusions: Enteral supplementation of probiotics prevents severe NEC and all-cause mortality in preterm infants. [1, 2, 9] (LOE I GOR A) Infloran containing Bifidobacterium bifidum and Lactobacillus acidophilus has been shown in a RCT to reduce the incidence of death and NEC. [7] Prospective observational studies of routine use of Infloran (B. bifidum and L. acidophilus) in preterm neonates, gestation < 32 weeks and < 1500 g, have documented its safety and potential efficacy. [10, 11]
  Probiotics for prevention of late onset sepsis (LOS) in preterm infants: Enteral probiotics supplementation significantly reduced the incidence of LOS (37 RCTs, 9416 infants; 13.9% vs 16.3%; RR 0.86; 95% CI 0.78–0.94; P = .0007; NNT 44). [2, 3] (LOE I GOR A)
  Safety: None of the included trials have reported probiotic-induced sepsis.[1-3, 9] Case reports of systemic infections caused by probiotic organisms are found in the literature. [8] Most adverse events and serious adverse events were considered unrelated to the study product and there were no major safety concerns.[8]
  Issues related to quality of probiotic products have been reported, including viability and contamination.[12, 13] Food and Drug Administration (FDA) USA issued an alert when a neonate died due to fungal sepsis from contaminated probiotic product.[13] Viability and contamination testing should be performed on every batch of probiotic product.[8]
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  References
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  1. Alfaleh K, Anabrees J, Bassler D, Al-Kharfi T. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev. 2011:CD005496.
  2. Dermyshi E, Wang Y, Yan C, Hong W, Qiu G, Gong X, Zhang T. The "Golden Age" of Probiotics: A Systematic Review and Meta-Analysis of Randomized and Observational Studies in Preterm Infants. Neonatology. 2017;112:9-23.
  3. Rao SC, Athalye-Jape GK, Deshpande GC, Simmer KN, Patole SK. Probiotic Supplementation and Late-Onset Sepsis in Preterm Infants: A Meta-analysis. Pediatrics. 2016;137:e20153684.
  4. Deshpande G, Rao S, Patole S, Bulsara M. Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates. Pediatrics. 2010;125:921-30.
  5. Martin CR, Walker WA. Probiotics: role in pathophysiology and prevention in necrotizing enterocolitis. Semin Perinatol. 2008;32:127-37.
  6. Infloran. Product information. Laboratorio Farmaceutico, Italy. 2002.
  7. Lin HC, Hsu CH, Chen HL, Chung MY, Hsu JF, Lien RI, Tsao LY, Chen CH, Su BH. Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: a multicenter, randomized, controlled trial. Pediatrics. 2008;122:693-700.
  8. Deshpande GC, Rao SC, Keil AD, Patole SK. Evidence-based guidelines for use of probiotics in preterm neonates. BMC medicine. 2011;9:92.
  9. Chang HY, Chen JH, Chang JH, Lin HC, Lin CY, Peng CC. Multiple strains probiotics appear to be the most effective probiotics in the prevention of necrotizing enterocolitis and mortality: An updated meta-analysis. PLoS One. 2017;12:e0171579.
  10. Deshpande G, Shingde V, Downe L, Leroi M, Xiao J. Routine probiotics for preterm neonates: experience in a tertiary australian neonatal intensive care unit. J Paediatr Child Health. 2013;49:50.
  11. Samuels N, Van De Graaf R, Been JV, De Jonge RCJ, Hanff LM, Wijnen RMH, Kornelisse RF, Reiss IKM, Vermeulen MJ. Necrotising enterocolitis and mortality in preterm infants after introduction of routine probiotics in a NICU setting. Eur J Pediatr. 2016;175 (11):1733-4.
  12. Canganella F, Paganani S, Ovidi M, Vettraino AM, Bevilacqua L, Massa S, Trovatelli LD. A microbiological investigation on probiotic pharmaceutical products used for human health. Microbiological research. 1997;152:171-9.
  13. Drago L, Rodighiero V, Celeste T, Rovetto L, De Vecchi E. Microbiological evaluation of commercial probiotic products available in the USA in 2009. J Chemother. 2010;22:373-7.
  12. https://www.fda.gov/food/recallsoutbreaksemergencies/outbreaks/ucm423830.htm.
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