Use of Probiotics in the NICU

Part 1

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

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.

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

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

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

Immunonutrition

• Function of Commensal Organisms– Protection from infection

• Competes with pathogens• Forms bacteriocins

– Metabolism• CHO fermentation• Vitamins, SCFA• Procarcinogens

– Immunity• IgA synthesis• Modulate inflammation

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"

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

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

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

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.

• 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

• 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

Immunonutrition

• Risk of NEC, Translocation and Sepsis

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

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.

• 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

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)

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

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

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

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.

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