Use of Probiotics in the NICU
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Transcript of Use of Probiotics in the NICU
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Use of Probiotics in the NICU
Part 1
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Today there will be 1,367 babies born prematurely in the United States…
and human milk feedings offer prevention and benefit for all of these morbidities.
Immunonutrition
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Immunonutrition
“The interaction between the initially sterile
gastrointestinal tract and the microbiota that
colonize it after birth is increasingly being
recognized as a crucial component of postnatal
development.”
Montgomery, RK (2008) Gastroenterology and Nutrition: Neonatology Questions and Controversies.
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Immunonutrition
• Ontogeny of the Gut– Microvilli and biofilm
• Appear at 16 weeks & develop to cover surface area
• Cover the surface of intestinal enterocytes - form brush border
• Significantly increases mucosal surface area
• Site of terminal carbohydrate digestion
• Functions as a massive immune surface preventing bacterial adhesion and penetration – bacterial translocation
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Immunonutrition
Bengt Björkstėn, MD, PhD (2008) Probiotics: Facts, Fiction and Future NASPGHAN
Body Surface Area Skin 2m2
Lungs ~100 m2
Airways 100m2
Gut 300m2
Lungs as
Sheet
Intestines as Sheet
Skin as
Box
Parameter Number
Seating Capacity of the OSU Stadium 102,329
Population of the United States (2011)* 311,077,408
World Population (2011)* 6,909,201,891
GDP of the United States (2010) 14,624,184,000,000
# of Mammalian Cells in your Body 10,000,000,000,000
# of Microbial Cells in/on your Body 100,000,000,000,000
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Total Bacterial Counts (cfu/ml)
stomach 0-103
jejunum 0-105
ileum 103-107
colon 1010-1013
Immunonutrition
• Distribution of Microbiome
1. Harmsen HJ, et al.J Pediatr Gastroenterol Nutr 2000;30:61–67 2. Guarner F, Malagelada JR. Lancet 2003;361:512–519 3. Orrhage K, Nord CE. Acta Paediatr Suppl 1999;88:47–57
Infant ~ 1010 organisms(10,000,000,000)
About 60% of fecal massOver 400 species
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Immunonutrition
• Function of Commensal Organisms– Protection from infection
• Competes with pathogens• Forms bacteriocins
– Metabolism• CHO fermentation• Vitamins, SCFA• Procarcinogens
– Immunity• IgA synthesis• Modulate inflammation
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Immunonutrition
• Colonization of the Gut– First Stage (birth to one week)
• Composition of infants evolving microbiota is initially defined by the mother
• Role of ROM, labor, SVD • Exposes infant to maternal GI flora • Leading to colonization of maternal flora• Changing clinical practices
– Role of mode of delivery– ↑ Elective C/S without ROM & labor – Hyper-hygienic measures– ↑ Use of antibiotics for mother & infant
• "Evolutionary Discordance"
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Immunonutrition
• Colonization of the Infant GI tract– Second Stage (1-4 weeks)
• Role of infant’s diet major factor– Variation in microbiota and organisms seen between
breast fed and formula fed infants– Promotes growth of Lactobacillus & bifidobacterium
species
• Role of human milk– Human milk has lower buffering capacity– Acidic milieu potentiates nonpathogenic bacterial growth
• Role of oligosaccharides– Serve as prebiotics– Support favorable/commensal bacterial populations
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Immunonutrition
0
10
20
30
40
50
60
70
g/L
Lactose Fat Oligosaccharides Protein
1. Boehm G, Stahl B. J Nutr 2007;137 Suppl 2:847S–849S. 2. Coppa G, Bruni S, Morelli L, et al. J Clin Gastroenterol 2004;38 (2):S80-S83. 3. Chaturvedi P. Glycobiology 2001;11:5:365-372. 4. Erney R. J Pediatr Gastroenterol Nutr 2000;30:181-192.
OligosaccharidesLarge variety – well over 100 possible3
>400 samples from women in 10 countries showed great variability 4
70
12
40
10
Third Largest Component of Human
Milk 1,2
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Immunonutrition
• Oligosaccharides– Third largest component of human milk
• Nutritional function is to serve as prebiotics– A carbohydrate molecule composed of 3-20
monosaccharides or simple sugars "feed" the bacteria
• Oligosaccharides in milk are not digestible– Selectively fermented by the desirable gut microflora
• Stimulate developing immune system responses– Act as receptor analogues to prevent attachment of
enteropathogens on the epithelial surface – Support favorable/commensal bacterial populations
Nestle Nutr Workshop Ser Pediatr Program. 2008;62:205-18; discussion 218-22
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Immunonutrition
• Insults Affecting the Premature Gut– Immaturity– Mode of delivery– Luminal starvation – Hypoxic-ischemic reperfusion– Infection/inflammation– Antibiotic exposure
• Insults Result in – Altered GI Colonization – Risk of Bacterial Translocation– Potential for Sespis
Neu J & Bernstein, H Update on host defense and immunonutrients Clinics in Perinatology 29(1); 2002.
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• Late Onset Blood Stream Infection– An episode of blood stream infection after
72 hours of life– Associated with high mortality– Associated with high morbidity
• Acute respiratory failure• Hypotension• Thrombocytopenia/Anemia• Feeding intolerance
– Staphlococcus aureus & Gram (-) organisms• Constitute 15% of late onset infections and have
particularly high morbidity and mortality in the preterm population
Immunonutrition
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• Long term morbidity of Late Onset Sepsis– Bronchopulmonary dysplasia (BPD)
• No BPD: in room air by 28d PNA
• Mild BPD: in oxygen at 28d PNA but in room air at 36 weeks PMS
• Oxygen therapy at 36 weeks PMA
– Moderate BPD• In oxygen but <30% or <100ml/min at 36 weeks PMA
– Severe BPD• In oxygen >30% or >100 ml/min at 36 weeks PMA
– Associated morbidity• Increased LOS, Periventricular leukomalacia (PVL)
Immunonutrition
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Immunonutrition
• Risk of NEC, Translocation and Sepsis
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Immunonutrition
“ Lack of breast
milk may be the commonest
immunodeficiency
of infancy.”
Tarnow-Mordi W et al Adjunctive immunologic interventions in neonatal sepsis. In Clinics in Perinatology 37(2) (2010) Hanson LA. Session 1: Feeding and infant development breastfeeding and immune function. Proc Nutr Soc 2007; 66(3): 384-
96.
"Adjunctive Immunologic Interventions in Neonatal Sepsis“
Listed with major clinical strategies , immunologic & pharmacologic therapies
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Immunonutrition
• ImmunonutritionThe modulation of the immune and inflammatory responses in critically ill patients with the use of enteral feedings enriched with immune-enhancing ingredients.
Neu J & Bernstein, H Update on host defense and immunonutrients Clinics in Perinatology 29(1); 2002.
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• Benefits of Probiotics– Resistance to colonization
• Reduction in bacterial translocation• Production of antimicrobial substances
– Immunomodulation• Modification of host response to microbial products• Modification of toxins or toxin receptors• Promote intestinal motor function• Inhibition of adhesion augmentation of IGA • Anti-inflammatory signaling within the epithelium
Immunonutrition
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Immunonutrition
Lin et al (2005). Oral Probiotics Reduce the Incidence and Severity of Necrotizing Enterocoloitis in Very Low Birth Weight Infants. Pediatrics, 115:1-4
• Probiotics and NEC– Prospective, masked, randomized trial– 367 VLBW (<1500g) with similar demographic & clinical
variables were enrolled then randomized– Study group (180) fed Infloran (Lactobacillus
acidophilus & Bifodobacterium infantis) with BM bid– Controls (187) fed BM alone – Both groups followed until discharge– Primary outcome: death or NEC (≥ stage 2)
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Immunonutrition
• Lin et al (2005). Oral Probiotics Reduce the Incidence and Severity of Necrotizing Enterocoloitis in Very Low Birth Weight Infants. Pediatrics, 115:1-4
• Incidence of death or NEC (≥ stage 2) – Significantly lower in study group (2 of 180 vs 10 of 187 controls)– Six cases of severe NEC (Bell stage 3) in the control group – No cases of severe NEC in the study group– No positive blood cultures for Lactobacillus or Bifidobacterum
Probiotics Control P value
Death, n% 7 (3.9) 10 (10.7) .009
Death or NEC cases, n (%) 9(5) 24(12.8) .009
NEC, stage 2 or 3, n(%) 2(1.1) 10(5.3) .04
Sepsis, n(%) 22(12.2) 36(19.3) .03
NEC or sepsis, n(%) 24(13.3) 46(24.6) .03
NEC, sepsis or death, n(%) 31(17.2) 60(32.1) .009
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Immunonutrition• Probiotics in the NICU
– Three separate meta-analyses of probiotics on the reduction of NEC in premature infants were published in 2010
– All three meta-analyses found probiotic supplementation significantly reduced the incidence of NEC and overall mortality
– Based on the robust evidence from their data, Deshpande, Rao, Patole, and Bulsara stated probiotic supplementation should be routinely used in the NICU and additional placebo studies would be unethical
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Immunonutrition
• 2010 Recommendations for Probiotics – In their meta-analysis, Guthmann et al found
• Studies using a multi-strain probiotic had the best results compared to the studies using a single-strain probiotic
– American Academy of Pediatrics• Suggest more research is needed to determine the
appropriate probiotic species and dosing in this population with an emphasis on the extremely low birth weight infants
• Lack of heterogeneity of the probiotic organisms used • Lack of FDA regulation on probiotics • Insufficient evidence for safety in infants <1000 grams • Although probiotic supplementation is not without absolute
risk, the overwhelming evidence of its benefits may outweigh the risks
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Immunonutrition• Deshpande G, Rao S, Paole S & Bulsara M Updated Meta-analysis of Probiotics for
Preventing Necrotizing Enterocolitis in Preterm Neonates. Pediatrics published online Apr 19, 2010. DOI: 10,1542/peds.2009-1301
• Probiotics– A meta-analysis of 11 randomized, controlled trials
that involved 2176 infants treated with oral probiotics• Significant reductions in all-cause mortality and NEC are
reported• Risk of NEC (typical relative risk: 0.35 [95% confidence
interval: 0.23– 0.55])• Death (typical relative risk: 0.42 [95% confidence interval:
0.29–0.62])
– Results reflect on the growing body of evidence that probiotics are effective in the preterm patient population.
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Immunonutrition• Deshpande G, Rao S, Paole S & Bulsara M Updated Meta-analysis of Probiotics for
Preventing Necrotizing Enterocolitis in Preterm Neonates. Pediatrics published online Apr 19, 2010. DOI: 10,1542/peds.2009-1301
• Number Needed to Treat – The number needed to treat with prophylactic
probiotics to prevent 1 case of NEC in this population is 25
– Determined by all three separate meta-analyses in 2010
– The potential benefits of probiotic supplementation in premature infants should be seriously considered by NICU staff