WHAT IS THE EVIDENCE FOR PROBIOTIC SUPPLEMENTATION?

Transcription

1 WHAT IS THE EVIDENCE FOR PROBIOTIC SUPPLEMENTATION? Roger F. Soll, MD H. Wallace Professor of Neonatology University of Vermont President Vermont Oxford Network 19 th International Symposium on Neonatology Sao Paulo, Brazil

2 Probiotic Supplementation Can probiotic supplementation improve the health of preterm infants? - improve growth and feeding tolerance - decrease the risk of NEC and death

3 Probiotic Supplementation At birth, the infant s gastrointestinal tract (GI tract) is sterile. Colonization of the GI tract starts immediately after birth with the initiation of enteral feeding, and is well established within the first few days of life. Intestinal flora varies widely from person to person. In adults, normal intestinal microflora consists of more than 100,000 billion bacterial cells comprising more than 400 different species.

4 Probiotic Supplementation In formula-fed infants, coliforms, enterococci, and bacteroides predominantly colonize the intestinal tract. Bifidobacterium and Lactobacillus are present occasionally. However, in breastfed infants, Bifidobacterium and Lactobacillus predominate with other enteric organisms being present less frequently.

5 Probiotic Supplementation This pattern of bowel colonization is different in preterm infant in an intensive care setting. Antibiotic use, infection control procedures, and delayed initiation of enteral feeding may influence the type and amount of micro-organisms colonizing the GI tract.

6 Probiotic Supplementation the GI tract of ELBW infants are colonized by fewer than three bacterial species by the 10th day of life species of Bifidobacterium and Lactobacillus are found in the stool of less than 5% of patients studied within the 1st month of life By day 30 of life, predominant organisms were enterobacteriaceae and coagulase-negative staphylococci, which are the most frequent pathogens responsible for nosocomial infection in the NICU. Gewolb and coworkers

7 Probiotic Supplementation Probiotic bacteria are defined as live nonpathogenic bacteria species that normally reside in the GI tract of healthy term infants. It has been postulated that introducing probiotics to preterm infants might be beneficial in order to avoid overgrowth of pathogenic organisms. Probiotics supplementation has been proposed to enhance enteral feeding and prevent NEC and nosocomial infections in preterm infants.

8 Probiotic Supplementation The proposed beneficial effects of probiotic administration come from potentially competing with other organisms for binding sites and substrates in the bowel thereby: increasing the production of anti-inflammatory cytokines, decreasing the production of proinflammatory cytokines, reducing intestinal permeability, enhancing enteral nutrition.

9 Probiotic Supplementation Probiotics products are available in the United States without prescription as nutritional supplements. A variety of probiotic agents may be available for study. Lactobacillus and Bifidobacterium species are available commercially in different forms and concentrations.

10 Probiotic Supplementation For good or for bad. Infant formula with probiotic supplements has recently been marketed for sale to the general public (Nestle Good Start, Natural Cultures ).

11 What about probiotic supplementation?

12 Probiotic Supplementation Over 20 clinical studies of probiotic administration to premature infants have been published. These studies have used different types of probiotics used, different administration regimens (dosage, length of treatment) and have had different clinical endpoints.

13 Probiotic Supplementation Does probiotic supplementation improve growth and feeding tolerance?

14 Probiotic Supplementation Kitajima 1997: single center study randomized controlled trial Intervention: 91 infants were randomized to receive enteral probiotics (Bifidobacterium breve) or control.

15 Probiotic Supplementation Kitajima 1997: Patient Characteristics No of cases Sex (M/F) 24/22 25/20 No of SGA infants 5 7 Gestation (w) 28.2 (2.1) 28.3 (2.3) Birth weight (g) 1026 (205) 1026 (241) IPPV (days) 3 [0-163] 4 [0-244] Duration of antibiotics (days) 7.5 [0-20] 7 [0-28] Kitajima, H. et al. Arch. Dis. Child. Fetal Neonatal Ed. 1997;76:101-F107

16 Probiotic Supplementation Kitajima, H. et al. Arch. Dis. Child. Fetal Neonatal Ed. 1997;76:101-F107

17 Probiotic Supplementation Kitajima, H. et al. Arch. Dis. Child. Fetal Neonatal Ed. 1997;76:101-F107

18 Probiotic Supplementation Does probiotic supplementation improve clinical outcome? Sepsis Necrotizing Enterocolitis Mortality

19 Necrotizing Enterocolitis (NEC) Incidence 1 to 5% of all NICU admissions 6 to 7% of infants 500 to 1500 grams preterm > term black > white male > female (?) Mortality 12 to 30% surgical NEC: ~50%

20 Necrotizing Enterocolitis

21 Necrotizing Enterocolitis (NEC) Deterrence/Prevention Breastfed babies have a lower incidence of NEC than formulafed babies. Unclear role of various feeding regimes in the etiology of NEC. Although conventional wisdom recommends slow initiation and advancement of enteral feeds for premature infants, randomized trials do not show an increased incidence of NEC for babies in whom feeds have been started earlier in life or in whom feeding advancement has been more rapid

22 Should placebo-controlled trials continue? Updated Meta-analysis of Probiotics for Preventing Necrotizing Enterocolitis in Preterm Neonates Girish Deshpande, FRACP, Shripada Rao, MD, Sanjay Patole, DrPH, Max Bulsara, PhD Pediatrics 2010;125:

23 Probiotic Supplementation Selection criteria: - Randomized controlled trials of any enteral probiotic supplementation in preterm VLBW infants - started within first 10 days and continued for 7 days - reported on stage 2 NEC or higher (Modified Bell Staging). A total of 11 (N = 2176) trials were eligible for inclusion in the meta-analysis. Deshpande, G. et al. Pediatrics 2010;125:

24 Study BW/GA Probiotic Feeds Kitajima 1997 < 1500 grams BB MM or FM Dani 2002 < 33 week or LB-GG MM, DM, or FM < 1500 grams Costalos week SB FM Bin Nun 2005 < 1500 grams BI, ST, BBB MM or FM Lin 2005 < 1500 grams LB-A, BI MM or DM Manzoni 2006 < 1500 grams LB-C MM or DM Mohan 2006 < 37 week BB-L FM Stratiki to 37 week BB-L FM Lin 2008 < 34 week and BBB, LB-A MM or FM < 1500 grams Samanta 2009 < 34 week and < 1500 grams BBB, BB-L, BI, LB- A MM or FM Rougé 2009 < 32 week and BB-LG, LB GG MM, DM, or FM < 1500 grams

25 PROBIOTICS FOR THE PREVENTION OF NECROTIZING ENTEROCOLITIS IN PRETERM INFANTS EFFECT ON SEPSIS RELATIVE RISK XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX Deshpande, G. et al. Pediatrics 2010;125:

26 PROBIOTICS FOR THE PREVENTION OF NECROTIZING ENTEROCOLITIS IN PRETERM INFANTS EFFECT ON SEVERE NECROTIZING ENTEROCOLITIS RELATIVE RISK XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX Deshpande, G. et al. Pediatrics 2010;125:

27 PROBIOTICS FOR THE PREVENTION OF NECROTIZING ENTEROCOLITIS IN PRETERM INFANTS EFFECT ON MORTALITY RELATIVE RISK XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX Deshpande, G. et al. Pediatrics 2010;125:

28 PROBIOTICS IN VERY LOW BIRTH WEIGHT INFANTS META-ANALYSIS OF 11 RANDOMIZED CONTROLLED TRIALS Outcome (studies) Relative risk Decreased Risk Increased ( 95% CI ) SEPSIS (10) 0.98 (0.81, 1.18) SEVERE NEC (11) 0.35 (0.23, 0.55) MORTALITY (9) 0.42 (0.29, 0.62) 0.2 Deshpande, G. et al. Pediatrics 2010;125: Relative Risk and 95% CI

29 Probiotic Supplementation probiotic supplementation was not associated with any probiotic-related sepsis cases or any other adverse effects.

30 Probiotics Reduce All-Cause Mortality and Necrotizing Enterocolitis: It Is Time to Change Practice Is more evidence needed before introducing this inexpensive, apparently safe and effective treatment? It is possible that further trials would overturn the evidence of benefit of probiotics, as occurred for magnesium in myocardial infarction. However, the evidence that probiotics reduce mortality rates is as conclusive as that for surfactant for respiratory distress syndrome, cooling for hypoxic ischemic encephalopathy, or antenatal corticosteroids for threatened preterm labor. Should placebo-controlled trials continue? W. Tarnow-Mordi 2010

31 Probiotic Supplementation Maybe not.. R. Soll Pediatrics 2010

32 PROBIOTICS FOR THE PREVENTION OF NECROTIZING ENTEROCOLITIS IN PRETERM INFANTS FUNNEL PLOT: PUBLICATION BIAS UNLIKELY XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX Deshpande, G. et al. Pediatrics 2010;125:

33 PROBIOTICS FOR THE PREVENTION OF NECROTIZING ENTEROCOLITIS IN PRETERM INFANTS EFFECT ON NECROTIZING ENTEROLCOLITIS: RELATIVE RISK

34 PROBIOTICS FOR THE PREVENTION OF NECROTIZING ENTEROCOLITIS IN PRETERM INFANTS EFFECT ON NECROTIZING ENTEROLCOLITIS: RELATIVE RISK

35 Probiotic Supplementation Current studies of probiotics: Multiple agents Multiple dosing strategies Few extremely low birth weight infants Few exclusively breast fed No product that has cleared regulatory hurdles

36 PROBIOTICS NECROTZING ENTEROCOLITIS AND MORTALITY Outcome Relative Risk Decreased Risk Increased ( 95% CI ) BIFIDOBACTERIA - NECROTIZING ENTEROCOLITIS (8) 0.30 ( ) - MORTALITY (3) 0.74 ( ) LACTOBACILLUS + BIFIDOBACTERIA - NECROTIZING ENTEROCOLITIS (6) 0.33 ( ) - MORTALITY (5) 0.47 ( ) LACTOBACILLUS - NECROTIZING ENTEROCOLITIS (4) 0.37 ( ) - MORTALITY (4) 0.61 ( ) Wang Relative Risk and 95% CI

37 Recent Studies of Probiotic Supplementation Prophylactic Probiotics to Prevent Death and Nosocomial Infection in Preterm Infants Rojas and colleagues. Pediatrics 2012; 130: e Objective: to determine whether prophylactic administration of Lactobacillus reuteri to preterm infants reduces the incidence of the composite outcome of death or nosocomial infection (NI). Methods: multicenter, double-blinded, randomized, placebo-controlled trial was conducted in 9 NICUs from 4 major cities in Colombia from 2008 to Participants: 750 preterm infants birth weight 2000 g (Probiotics 372 / Placebo 378) Intervention: randomly assigned during the first 48 hours of life to either daily probiotic administration (Lactobacillus reuteri) or placebo

38 PROBIOTICS NECROTZING ENTEROCOLITIS AND MORTALITY Outcome Relative Risk Decreased Risk Increased ( 95% CI ) SEPSIS - META-ANALYSIS 0.98 ( ) - ROJAS ( ) NECROTIZING ENTEROCOLITIS - META-ANALYSIS 0.35 ( ) - ROJAS ( ) MORTALITY - META-ANALYSIS 0.42 ( ) - ROJAS ( ) Relative Risk and 95% CI

39 Probiotic Supplementation Cane toad Serratia marcescens

40 Probiotic Supplementation The results are promising but remain inconclusive. We need to : - Have a viable commercial product that meets FDA standards - conduct large trials with that produc to assess clinically meaningful outcomes (NEC, sepsis, death)

41 Probiotic Supplementation A real world experience A prospective cohort study of probiotics among very preterm infants in a Canadian NICU Keith J Barrington, MB ChB, Josianne Malo, B.Pharm., M.Sc. and Annie Janvier, MD CHU Ste Justine, Montreal, QC, Canada

42 A prospective cohort study of probiotics among very preterm infants in a Canadian NICU Objective: To determine if introduction of routine probiotic administration would lead to a reduction in Necrotizing Enterocolitis (NEC) using a preparation which is commercially available. Design/Methods: Starting in July 2011 we have administered a preparation containing a mix of 4 bifidobacteria (b breve, bifidum, infantis and longum) and a lactobacillus rhamnosus (Florababy (tm) holder of a Natural Product Number from Health Canada).

43 A prospective cohort study of probiotics among very preterm infants in a Canadian NICU Control Cohort. Between July 2010 and June 2011 there were 190 infants less than 32 completed weeks gestation admitted who survived for more than 7 days. Mean gestational age (GA) 28.3 (SD 2.5) wk mean birth weight 1288 (SD 447) g. Intervention Cohort. The first 6 months of utilization of probiotics saw 93 admissions <32 weeks who survived more than 7 days and who received probiotics. The mean GA was 28.4 (SD 2.5) wk, mean BW 1188 (SD353) g. Enteral nutrition was started at 35 (SD26) hours of age and probiotics at 4 (SD 4) days of age.

44 A prospective cohort study of probiotics among very preterm infants in a Canadian NICU NEC BEFORE AND AFTER INTRODUCUCTION OF PROBIOTICS 20% % CASES 10% 12.6% 0% NEC BEFORE PROBIOTICS 4.3% AFTER PROBIOTICS

45 Probiotic Supplementation Registries? Conventional Randomized Controlled Trials? Cluster Trials?

46 Prebiotic Supplementation nondigestible food components that beneficially affect the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon and thereby improving host health Oligosaccharides that are contained in human breast milk are considered to be the prototype of prebiotics, since they have been shown to facilitate the growth of bifidobacteria and lactobacilli in the colon of breast-fed neonates.

47 Prebiotic Supplementation Prebiotic supplementation of formula in preterm neonates: a systematic review and meta analysis of randomized controlled trials Srinivasjois R, Rao S, Patole S. Clinical Nutrition Volume 28, Issue 3, June 2009, Pages

48 Prebiotic Supplementation Four RCTs that qualified for inclusion in the review A total of only 126 preterm infants were included in the review. Sample sizes in the studies ranged from 20 to 56 infants. The prebiotic oligosaccharides used in these studies were fructooligosaccharides in one RCT and galactooligosaccharides/fructooligosaccharides in 3 RCTs. The duration of supplementation ranged from 14 to 30 to 33 days.

49 Prebiotic Supplementation Authors of 2 RCTs reported that NEC did not occur in any of their infants. Authors of the other 2 RCTs did not report data related to NEC or sepsis. Meta-analysis of the data from 3 RCTs (n=106) showed no significant difference in weight gain between the prebiotic and control groups (weighted mean difference [WMD] 1.6 g/day, 95% CI 3.76 to 0.57).

50 Lactoferrin Lactoferrin is a glycoprotein found in significant concentrations in human colostrum and in lower concentrations in human milk, tears, saliva, seminal fluid and secondary granules of neutrophils. Lactoferrin has broad-spectrum antimicrobial activity against bacteria, fungi, viruses and protozoa, which results from either its ability to sequester iron or because of a direct lytic effect on microbial cell membranes.

51 Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial Prospective, multicenter, double blind, placebo-controlled, randomized trial. Participants: Premature neonates with birth weight < 1500 g within the first 3 days of life. Setting: Eleven Italian neonatal intensive care units, from October 1, 2007 through July 31, Manzoni and coworkers. JAMA 2009;302(13):

52 Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial Intervention: Bovine lactoferrin (100 mg/day) alone or bovine lactoferrin (100 mg/day) with Lactobacillus rhamnosus LGG (6 x 109CFU/ml) or placebo. The interventions were diluted in milk feeds. If the infants were not being fed, the interventions were administered through an orogastric tube. Manzoni and coworkers. JAMA 2009;302(13):

53 Late onset sepsis Lactoferrin

54 Late onset sepsis Lactoferrin + LGG

55 Necrotizing Enterocolitis (stage II or greater) Lactoferrin Lactoferrin + LGG

56 What should we feed to decrease morbidity and mortality in high risk neonates? Probiotics? Prebiotics? Lactoferrin?

57 Probiotics (and prebiotics?): They are not just for breakfast anymore!

58 Questions? Questions?