EDITORIALS
May 2014
Probiotic Supplementation in Preterm Infants: It Is Time to Change Practice
P
robiotic supplementation in preterm infants is their institution from 10% to 5% (P < .05) with a nonsignifperhaps the best studied yet least used therapy in icant reduction in mortality (10% to 7%).6 They used a pro1,2 neonatal medicine. All recently published metabiotic supplement produced using Good Manufacturing Practice with stringent quality control in facilities registered analyses have reported significant impacts on important clinand inspected by Health Canada. Elsewhere, they note that ical outcomes.3-5 In the updated Cochrane meta-analysis,3 there is a well-defined regulatory pathway which includes 24 trials, there is a signifiSee related article, p 980 for evaluating drugs and devices, but that cant decrease in necrotizing enterocolitis probiotics are neither of these.1 (NEC) (relative risk [RR] 0.43, 95% CI 0.33-0.56; risk difference [RD] 0.03, 95% CI 0.04 to 0.02; P < .00001) and In the US, probiotics are considered either foods or bioall-cause mortality (RR 0.65, 95% CI 0.52-0.81; RD 0.01, logics, depending on their intended use. Most probiotics 95% CI 0.02 to 0.00, P = .01). Length of stay was 3-4 are manufactured as foods by companies that market health days shorter. There was no probiotic-related sepsis, although products to enhance adult well-being. This makes it chalthis is rarely reported outside trials.6 lenging for investigators to meet the requirements of the US Food and Drug Administration (FDA) for an InvestigaProbiotics are still infrequently used in North America. In tional New Drug application (IND).12,13 Filing an IND for 2012, only 8%-9% of very low birth weight (VLBW) infants in 7 the Vermont Oxford Network received probiotics. It is time a probiotic product requires significant human and financial resources and a manufacturer willing to support the proto consider changing guidance and practice.8 The authors of cess.12,13 Substantial delays in access to probiotics have this editorial have differed on whether we have sufficient evidence to introduce prophylactic treatment. Tarnow-Mordi been inevitable because phase I, II, and III studies of existing et al argued in 2010 that “the evidence that probiotics reduce products must be conducted before they can be made availmortality rates is as conclusive as that for surfactant for respiable.12-14 Up to now, all this may have required the investratory distress syndrome, cooling for hypoxic ischemic enment of hundreds of thousands of dollars, which would cephalopathy, or antenatal corticosteroids for threatened have to be recovered in the price of the product. preterm labor.”9 In a companion commentary, Soll argued In respect of probiotics, the FDA must both protect preterm infants, by ensuring the safety, efficacy, and security that the decision was far less clear.10 Trials had used multiple of probiotics, and help parents get the accurate, scienceagents and doses. Few had studied extremely low birth weight based information they need to use probiotics to improve infants, and few infants had received breast milk. their infants’ health.15 Eight years ago, a workshop titled Many of these arguments have now been addressed. Wang reports subgroups of trials using Bifidobacteria alone, Lacto“Developing Probiotics as Foods and Drugs—Scientific and bacilli alone, or the 2 combined.5 In all 3 subgroups, there Regulatory Challenges” proposed that federal agencies provide: (1) transparent guidance on the development of probiwere significant reductions, by about two-thirds, in the RR otic studies; and (2) sufficient resources to sponsors or of NEC. The recently updated Cochrane Review includes investigators who are legally required to file INDs.12,13 The 17 trials of >4900 VLBW infants.3 The RR risk of severe NEC for probiotics versus control was 0.41 (95% CI 0.31first proposal was implemented15 but, to our knowledge, 0.56; RD 0.03, 95% CI 0.05 to 0.02; P < .00001). The not the second. No probiotic product has yet been approved treatment of 33 VLBW infants would prevent 1 case of severe by the FDA.16 If a trial of probiotics to show differences in NEC. The ProPrems study in 1099 very preterm infants in NEC or mortality is ever done in the US,1 its results are likely Australia and New Zealand is the largest ever randomized to be several years away. trial of probiotics.11 Although there was no decrease in sepsis How can clinicians translate current evidence into practice? The rapid introduction of colostrum and fresh human or the control mortality rate of 5.1%, the rate of NEC was milk is a rational strategy, supported by evidence from trials halved (4.4% vs 2.2%; RR 0.46, 95% CI 0.23-0.93; P = .03), in 343 infants and recent observational data.2,17-19 However, even though >95% of infants received breast milk. In this issue of The Journal, Janvier et al report that since routine probiotics could prevent 2500 cases of NEC per introducing probiotics in July 2011, the rate of NEC fell at year in North America, or 200 cases per month,6 assuming a 50% reduction in RR, based on trials in 6000 newborns and routine use in 3000 neonates.2-5,11 This has major FDA IND NEC RD RR VLBW
Food and Drug Administration Investigational New Drug application Necrotizing enterocolitis Risk difference Relative risk Very low birth weight
The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.12.050
959
THE JOURNAL OF PEDIATRICS
www.jpeds.com
implications for improved growth and development,20 and follow-up studies will therefore be important.17 Many clinicians may wish to establish protocols, supported by local microbiologists, drug and therapeutics committees, Institutional Review Boards, and parent representative groups, to introduce probiotics using peerreviewed guidelines.6,14 Protocols evaluating growth and development as primary outcomes can be undertaken without an IND.15,19,21,22 Probiotics should be produced under stringent quality control by Good Manufacturing Practice, as in the ProPrems trial (ABC Dophilus Probiotic Powder for Infants; Solgar, Leonia, New Jersey11), or the cohort study by Janvier et al (FloraBABY; ReNew Life, Palm Harbor, Florida).6 Local laboratories should confirm taxonomy, colony counts, and exclusion of contaminants in the reconstituted product; that they can grow the constituent bacterial species and recognize their Gram stain and phenotypic appearances in different media; and the need for extended incubation times in anaerobic conditions, or that a regional service is available for these functions and, if necessary, for precise identification of species by DNA analysis.6,14 Last, if the results of research are to be implemented in a timely fashion with, rather than simply for the community,23,24 it will be important to seek the perspectives of parent representative groups,25 after openly sharing the pros2 and cons.17 Their support could help avoid years of therapeutic inertia for a much studied and effective, but underused, intervention. n William Tarnow-Mordi, BA, MBChB, DCH, FRCPCH WINNER Centre for Newborn Research, NHMRC Clinical Trials Centre University of Sydney Camperdown, New South Wales, Australia Roger F. Soll, MD Department of Neonatology Fletcher Allen Health Care University of Vermont Burlington, Vermont Reprint requests: William Tarnow-Mordi, BA, MBChB, DCH, FRCPCH, NHMRC Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia. E-mail: [email protected]
References 1. Janvier A, Lantos J, Barrington K. The politics of probiotics: probiotics, necrotizing enterocolitis and the ethics of neonatal research. Acta Paediatr 2013;102:116-8. 2. Ofek Shlomai N, Deshpande G, Rao S, Patole S. Probiotics for preterm neonates: what will it take to change clinical practice? Neonatology 2013; 105:64-70. 3. Alfaleh K, Bassler D. Probiotics for prevention of necrotizing enterocolitis in preterm infants (updated 2013). Cochrane Database Syst Rev. in press.
960
Vol. 164, No. 5 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. Wang Q, Dong J, Zhu Y. Probiotic supplement reduces risk of necrotizing enterocolitis and mortality in preterm very low-birth-weight infants: an updated meta-analysis of 20 randomized, controlled trials. J Pediatr Surg 2012;47:241-8. 6. Janvier A, Lantos J, Barrington K. Cohort study of probiotics in a North American neonatal intensive care unit. J Pediatr 2014;164:980-5. 7. Vermont Oxford Network of Very Low Birth Weight Infants. Burlington, VT: Vermont Oxford Network, 2012. Nightingale Internet Reporting System, www.vtoxford.org accessed on January 29, 2014. 8. Thomas DW, Greer FR. Probiotics and prebiotics in pediatrics. Pediatrics 2010;126:1217-31. 9. Tarnow-Mordi WO, Wilkinson D, Trivedi A, Brok J. Probiotics reduce all-cause mortality and necrotizing enterocolitis: it is time to change practice. Pediatrics 2010;125:1068-70. 10. Soll RF. Probiotics: are we ready for routine use? Pediatrics 2010;125: 1071-2. 11. Jacobs SE, Tobin JM, Opie GF, Donath S, Tabrizi SN, Pirotta M, et al. Probiotic effects on late-onset sepsis in very preterm infants: a randomized controlled trial. Pediatrics 2013;132:1055-62. 12. Hibberd PL, Davidson L. Probiotic foods and drugs: impact of US regulatory status on design of clinical trials. Clin Infect Dis 2008; 46(Suppl 2):S137-40. discussion S44-51. 13. Hoffman FA, Heimbach JT, Sanders ME, Hibberd PL. Executive summary: scientific and regulatory challenges of development of probiotics as foods and drugs. Clin Infect Dis 2008;46(Suppl 2): S53-7. 14. Deshpande GC, Rao SC, Keil AD, Patole SK. Evidence-based guidelines for use of probiotics in preterm neonates. BMC Med 2011;9:92. 15. FDA. http://www.fda.gov/AboutFDA/WhatWeDo/default.htm. 16. Neu J. Routine probiotics for premature infants: let’s be careful!. J Pediatr 2011;158:672-4. 17. Modi N. Probiotics and necrotising enterocolitis: the devil (as always) is in the detail. Commentary on N. Ofek Shlomai et al.: Probiotics for preterm neonates: what will it take to change clinical practice? (Neonatology 2014;105:64-70). Neonatology 2014;105:71-3. 18. McGuire W, Anthony MY. Donor human milk versus formula for preventing necrotising enterocolitis in preterm infants: systematic review. Arch Dis Child Fetal Neonatal Ed 2003;88:F11-4. 19. Seigel JK, Smith PB, Ashley PL, Cotten CM, Herbert CC, King BA, et al. Early administration of oropharyngeal colostrum to extremely low birth weight infants. Breastfeeding Med 2013;8:491-5. 20. Schulzke SM, Deshpande GC, Patole SK. Neurodevelopmental outcomes of very low-birth-weight infants with necrotizing enterocolitis: a systematic review of observational studies. Arch Pediatr Adolesc Med 2007;161: 583-90. 21. Underwood MA, Salzman NH, Bennett SH, Barman M, Mills DA, Marcobal A, et al. A randomized placebo-controlled comparison of 2 prebiotic/probiotic combinations in preterm infants: impact on weight gain, intestinal microbiota, and fecal short-chain fatty acids. J Pediatr Gastroenterol Nutr 2009;48:216-25. 22. Al-Hosni M, Duenas M, Hawk M, Stewart LA, Borghese RA, Cahoon M, et al. Probiotics-supplemented feeding in extremely low-birth-weight infants. J Perinatol 2012;32:253-9. 23. Washington AE, Lipstein SH. The Patient-Centered Outcomes Research Institute: promoting better information, decisions, and health. N Engl J Med 2011;365:e31. 24. INVOLVE. National Institute of Health Research www.invo.org. uk. 2013. 25. Tarnow-Mordi WO, Cruz M, Wilkinson D. Evaluating therapeutic hypothermia: parental perspectives should be explicitly represented in future research. Arch Pediatr Adolesc Med 2012;166:578-9.
May 2014
Probiotic Supplementation in Preterm Infants: It Is Time to Change Practice
P
robiotic supplementation in preterm infants is their institution from 10% to 5% (P < .05) with a nonsignifperhaps the best studied yet least used therapy in icant reduction in mortality (10% to 7%).6 They used a pro1,2 neonatal medicine. All recently published metabiotic supplement produced using Good Manufacturing Practice with stringent quality control in facilities registered analyses have reported significant impacts on important clinand inspected by Health Canada. Elsewhere, they note that ical outcomes.3-5 In the updated Cochrane meta-analysis,3 there is a well-defined regulatory pathway which includes 24 trials, there is a signifiSee related article, p 980 for evaluating drugs and devices, but that cant decrease in necrotizing enterocolitis probiotics are neither of these.1 (NEC) (relative risk [RR] 0.43, 95% CI 0.33-0.56; risk difference [RD] 0.03, 95% CI 0.04 to 0.02; P < .00001) and In the US, probiotics are considered either foods or bioall-cause mortality (RR 0.65, 95% CI 0.52-0.81; RD 0.01, logics, depending on their intended use. Most probiotics 95% CI 0.02 to 0.00, P = .01). Length of stay was 3-4 are manufactured as foods by companies that market health days shorter. There was no probiotic-related sepsis, although products to enhance adult well-being. This makes it chalthis is rarely reported outside trials.6 lenging for investigators to meet the requirements of the US Food and Drug Administration (FDA) for an InvestigaProbiotics are still infrequently used in North America. In tional New Drug application (IND).12,13 Filing an IND for 2012, only 8%-9% of very low birth weight (VLBW) infants in 7 the Vermont Oxford Network received probiotics. It is time a probiotic product requires significant human and financial resources and a manufacturer willing to support the proto consider changing guidance and practice.8 The authors of cess.12,13 Substantial delays in access to probiotics have this editorial have differed on whether we have sufficient evidence to introduce prophylactic treatment. Tarnow-Mordi been inevitable because phase I, II, and III studies of existing et al argued in 2010 that “the evidence that probiotics reduce products must be conducted before they can be made availmortality rates is as conclusive as that for surfactant for respiable.12-14 Up to now, all this may have required the investratory distress syndrome, cooling for hypoxic ischemic enment of hundreds of thousands of dollars, which would cephalopathy, or antenatal corticosteroids for threatened have to be recovered in the price of the product. preterm labor.”9 In a companion commentary, Soll argued In respect of probiotics, the FDA must both protect preterm infants, by ensuring the safety, efficacy, and security that the decision was far less clear.10 Trials had used multiple of probiotics, and help parents get the accurate, scienceagents and doses. Few had studied extremely low birth weight based information they need to use probiotics to improve infants, and few infants had received breast milk. their infants’ health.15 Eight years ago, a workshop titled Many of these arguments have now been addressed. Wang reports subgroups of trials using Bifidobacteria alone, Lacto“Developing Probiotics as Foods and Drugs—Scientific and bacilli alone, or the 2 combined.5 In all 3 subgroups, there Regulatory Challenges” proposed that federal agencies provide: (1) transparent guidance on the development of probiwere significant reductions, by about two-thirds, in the RR otic studies; and (2) sufficient resources to sponsors or of NEC. The recently updated Cochrane Review includes investigators who are legally required to file INDs.12,13 The 17 trials of >4900 VLBW infants.3 The RR risk of severe NEC for probiotics versus control was 0.41 (95% CI 0.31first proposal was implemented15 but, to our knowledge, 0.56; RD 0.03, 95% CI 0.05 to 0.02; P < .00001). The not the second. No probiotic product has yet been approved treatment of 33 VLBW infants would prevent 1 case of severe by the FDA.16 If a trial of probiotics to show differences in NEC. The ProPrems study in 1099 very preterm infants in NEC or mortality is ever done in the US,1 its results are likely Australia and New Zealand is the largest ever randomized to be several years away. trial of probiotics.11 Although there was no decrease in sepsis How can clinicians translate current evidence into practice? The rapid introduction of colostrum and fresh human or the control mortality rate of 5.1%, the rate of NEC was milk is a rational strategy, supported by evidence from trials halved (4.4% vs 2.2%; RR 0.46, 95% CI 0.23-0.93; P = .03), in 343 infants and recent observational data.2,17-19 However, even though >95% of infants received breast milk. In this issue of The Journal, Janvier et al report that since routine probiotics could prevent 2500 cases of NEC per introducing probiotics in July 2011, the rate of NEC fell at year in North America, or 200 cases per month,6 assuming a 50% reduction in RR, based on trials in 6000 newborns and routine use in 3000 neonates.2-5,11 This has major FDA IND NEC RD RR VLBW
Food and Drug Administration Investigational New Drug application Necrotizing enterocolitis Risk difference Relative risk Very low birth weight
The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.12.050
959
THE JOURNAL OF PEDIATRICS
www.jpeds.com
implications for improved growth and development,20 and follow-up studies will therefore be important.17 Many clinicians may wish to establish protocols, supported by local microbiologists, drug and therapeutics committees, Institutional Review Boards, and parent representative groups, to introduce probiotics using peerreviewed guidelines.6,14 Protocols evaluating growth and development as primary outcomes can be undertaken without an IND.15,19,21,22 Probiotics should be produced under stringent quality control by Good Manufacturing Practice, as in the ProPrems trial (ABC Dophilus Probiotic Powder for Infants; Solgar, Leonia, New Jersey11), or the cohort study by Janvier et al (FloraBABY; ReNew Life, Palm Harbor, Florida).6 Local laboratories should confirm taxonomy, colony counts, and exclusion of contaminants in the reconstituted product; that they can grow the constituent bacterial species and recognize their Gram stain and phenotypic appearances in different media; and the need for extended incubation times in anaerobic conditions, or that a regional service is available for these functions and, if necessary, for precise identification of species by DNA analysis.6,14 Last, if the results of research are to be implemented in a timely fashion with, rather than simply for the community,23,24 it will be important to seek the perspectives of parent representative groups,25 after openly sharing the pros2 and cons.17 Their support could help avoid years of therapeutic inertia for a much studied and effective, but underused, intervention. n William Tarnow-Mordi, BA, MBChB, DCH, FRCPCH WINNER Centre for Newborn Research, NHMRC Clinical Trials Centre University of Sydney Camperdown, New South Wales, Australia Roger F. Soll, MD Department of Neonatology Fletcher Allen Health Care University of Vermont Burlington, Vermont Reprint requests: William Tarnow-Mordi, BA, MBChB, DCH, FRCPCH, NHMRC Clinical Trials Centre, University of Sydney, Camperdown, New South Wales, Australia. E-mail: [email protected]
References 1. Janvier A, Lantos J, Barrington K. The politics of probiotics: probiotics, necrotizing enterocolitis and the ethics of neonatal research. Acta Paediatr 2013;102:116-8. 2. Ofek Shlomai N, Deshpande G, Rao S, Patole S. Probiotics for preterm neonates: what will it take to change clinical practice? Neonatology 2013; 105:64-70. 3. Alfaleh K, Bassler D. Probiotics for prevention of necrotizing enterocolitis in preterm infants (updated 2013). Cochrane Database Syst Rev. in press.
960
Vol. 164, No. 5 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. Wang Q, Dong J, Zhu Y. Probiotic supplement reduces risk of necrotizing enterocolitis and mortality in preterm very low-birth-weight infants: an updated meta-analysis of 20 randomized, controlled trials. J Pediatr Surg 2012;47:241-8. 6. Janvier A, Lantos J, Barrington K. Cohort study of probiotics in a North American neonatal intensive care unit. J Pediatr 2014;164:980-5. 7. Vermont Oxford Network of Very Low Birth Weight Infants. Burlington, VT: Vermont Oxford Network, 2012. Nightingale Internet Reporting System, www.vtoxford.org accessed on January 29, 2014. 8. Thomas DW, Greer FR. Probiotics and prebiotics in pediatrics. Pediatrics 2010;126:1217-31. 9. Tarnow-Mordi WO, Wilkinson D, Trivedi A, Brok J. Probiotics reduce all-cause mortality and necrotizing enterocolitis: it is time to change practice. Pediatrics 2010;125:1068-70. 10. Soll RF. Probiotics: are we ready for routine use? Pediatrics 2010;125: 1071-2. 11. Jacobs SE, Tobin JM, Opie GF, Donath S, Tabrizi SN, Pirotta M, et al. Probiotic effects on late-onset sepsis in very preterm infants: a randomized controlled trial. Pediatrics 2013;132:1055-62. 12. Hibberd PL, Davidson L. Probiotic foods and drugs: impact of US regulatory status on design of clinical trials. Clin Infect Dis 2008; 46(Suppl 2):S137-40. discussion S44-51. 13. Hoffman FA, Heimbach JT, Sanders ME, Hibberd PL. Executive summary: scientific and regulatory challenges of development of probiotics as foods and drugs. Clin Infect Dis 2008;46(Suppl 2): S53-7. 14. Deshpande GC, Rao SC, Keil AD, Patole SK. Evidence-based guidelines for use of probiotics in preterm neonates. BMC Med 2011;9:92. 15. FDA. http://www.fda.gov/AboutFDA/WhatWeDo/default.htm. 16. Neu J. Routine probiotics for premature infants: let’s be careful!. J Pediatr 2011;158:672-4. 17. Modi N. Probiotics and necrotising enterocolitis: the devil (as always) is in the detail. Commentary on N. Ofek Shlomai et al.: Probiotics for preterm neonates: what will it take to change clinical practice? (Neonatology 2014;105:64-70). Neonatology 2014;105:71-3. 18. McGuire W, Anthony MY. Donor human milk versus formula for preventing necrotising enterocolitis in preterm infants: systematic review. Arch Dis Child Fetal Neonatal Ed 2003;88:F11-4. 19. Seigel JK, Smith PB, Ashley PL, Cotten CM, Herbert CC, King BA, et al. Early administration of oropharyngeal colostrum to extremely low birth weight infants. Breastfeeding Med 2013;8:491-5. 20. Schulzke SM, Deshpande GC, Patole SK. Neurodevelopmental outcomes of very low-birth-weight infants with necrotizing enterocolitis: a systematic review of observational studies. Arch Pediatr Adolesc Med 2007;161: 583-90. 21. Underwood MA, Salzman NH, Bennett SH, Barman M, Mills DA, Marcobal A, et al. A randomized placebo-controlled comparison of 2 prebiotic/probiotic combinations in preterm infants: impact on weight gain, intestinal microbiota, and fecal short-chain fatty acids. J Pediatr Gastroenterol Nutr 2009;48:216-25. 22. Al-Hosni M, Duenas M, Hawk M, Stewart LA, Borghese RA, Cahoon M, et al. Probiotics-supplemented feeding in extremely low-birth-weight infants. J Perinatol 2012;32:253-9. 23. Washington AE, Lipstein SH. The Patient-Centered Outcomes Research Institute: promoting better information, decisions, and health. N Engl J Med 2011;365:e31. 24. INVOLVE. National Institute of Health Research www.invo.org. uk. 2013. 25. Tarnow-Mordi WO, Cruz M, Wilkinson D. Evaluating therapeutic hypothermia: parental perspectives should be explicitly represented in future research. Arch Pediatr Adolesc Med 2012;166:578-9.
