POSITION PAPER Supplementation of Infant Formula With Probiotics and/or Prebiotics: A Systematic Review and Comment by the ESPGHAN Committee on Nutrition ESPGHAN Committee on Nutrition: ÃChristian Braegger, Ã3Anna Chmielewska, yTamas Decsi, zSanja Kolacek, zzWalter Mihatsch, §Luis Moreno, Ã3Małgorzata Pies´cik, jjJohn Puntis, ô1Raanan Shamir, #Hania Szajewska, ÃÃ2Dominique Turck, and yyJohannes van Goudoever ABSTRACT intake durations, as well as provide more information about the long-term Infant formulae are increasingly supplemented with probiotics, prebiotics, or safety of probiotics and/or prebiotics. Because most of the trials were synbiotics despite uncertainties regarding their efficacy. The present article, company funded, independent trials, preferentially financed jointly by developed by the Committee on Nutrition of the European Society for national/governmental/European Union bodies and other international organ- Paediatric Gastroenterology, Hepatology, and Nutrition, systematically isations, would be desirable. reviews published evidence related to the safety and health effects of the administration of formulae supplemented with probiotics and/or prebiotics Key Words: feeding, microbiota, modification, paediatric nutrition compared with unsupplemented formulae. Studies in which probiotics/pre- (JPGN 2011;52: 238–250) biotics were not administered during the manufacturing process, but thereafter, for example in capsules, the contents of which were supplemented to infant formula or feeds, were excluded. On the basis of this review, available scientific data suggest that the administration of currently evaluated probiotic- INTRODUCTION and/or prebiotic-supplemented formula to healthy infants does not raise safety nfant formulae are increasingly being supplemented with pro- concerns with regard to growth and adverse effects. The safety and clinical biotics, prebiotics, or synbiotics despite uncertainties regarding effects of 1 product should not be extrapolated to other products. At present, theirI efficacy (1–4). Previously, 2 position papers related to this issue there is insufficient data to recommend the routine use of probiotic- and/or were published by the Committee on Nutrition of the European prebiotic-supplemented formulae. The Committee considers that the supple- Society for Paediatric Gastroenterology, Hepatology, and Nutrition. mentation of formula with probiotics and/or prebiotics is an important field of The first one, published in 2004, commented on probiotic bacteria (5). research. There is a need in this field for well-designed and carefully On the basis of the evidence obtained in a search up to July 2003, the conducted randomised controlled trials, with relevant inclusion/exclusion Committee concluded that clinical trials have provided only limited criteria and adequate sample sizes. These studies should use validated clinical data on the safety and clinical effects of adding probiotic preparations outcome measures to assess the effects of probiotic and/or prebiotic supple- to infant formulae, follow-on formulae, and special medical foods. mentation of formulae. Such trials should also define the optimal doses and The Committee also concluded that there is no published evidence of any long-term clinical benefits of infant formula supplementation Received August 8, 2010; accepted August 8, 2010. with probiotic bacteria. The second position paper, also published in From the ÃUniversity Children’s Hospital, Zurich, Switzerland, the 2004, commented on the addition of prebiotic oligosaccharides to yDepartment of Paediatrics, University of Pecs, Hungary, the infant and follow-on formulae (6). On the basis of evidence obtained zUniversity Children’s Hospital, Zagreb, Croatia, the §Escuela Univer- in a search up to January 2004, the Committee concluded that only sitaria de Ciencias de la Salud, Universidad de Zaragoza, Spain, the limited studies have evaluated the effects of the addition of prebiotic jjLeeds General Infirmary, UK, the ôSchneider Children’s Medical substances to dietetic products for infants. The Committee stated that Center of Israel, Sackler Faculty of Medicine, Tel-Aviv University, # although the administration of prebiotic oligosaccharides has the Israel, the Department of Paediatrics, Medical University of Warsaw, potential to increase the total number of bifidobacteria in faeces and Poland, the ÃÃJeanne de Flandre Children’s Hospital, Lille University Faculty of Medicine, France, the yyErasmus MC/Sophia Children’s may also soften stools, there is no published evidence of any clinical Hospital, Rotterdam, The Netherlands, and the zzDepartment of Pae- benefits of adding prebiotic oligosaccharides to dietetic products for diatrics, Diakonieklinikum, Germany. infants. Of note, according to the Commission Directive 2006/141/ Address correspondence and reprint requests to Hania Szajewska, MD, EC of 22 December 2006 on infant formulae and follow-on formulae, Department of Paediatrics, Medical University of Warsaw, 01-184 fructooligosaccharides (FOS) and galactooligosaccharides (GOS) Warsaw, Dzialdowska 1, Poland (e-mail: [email protected]). may be voluntarily added to infant formulae if their content does 1 Committee Chair. 2 Committee Secretary. 3 Guest. not exceed 0.8 g/100 mL of a combination of 90% oligogalactosyl- Supplemental digital content is available for this article. Direct URL citations lactose and 10% high-molecular-weight oligofructosyl-saccharose. appear in the printed text, and links to the digital files are provided in the Other combinations and maximum levels of FOS and GOS may be HTML text of this article on the journal’s Web site (www.jpgn.org). The authors report no conflicts of interest other than that reported on the used provided their suitability has been demonstrated through a ESPGHAN Web site. systematic review of the available data related to the expected Copyright # 2011 by European Society for Pediatric Gastroenterology, benefits and safety considerations (7). Hepatology, and Nutrition and North American Society for Pediatric A number of studies related to the use of probiotic-/prebiotic- Gastroenterology, Hepatology, and Nutrition supplemented products for infants have been published in recent DOI: 10.1097/MPG.0b013e3181fb9e80 years. Given this, and in conjunction with the interest on the part 238 JPGN Volume 52, Number 2, February 2011 Copyright 2011 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited. JPGN Volume 52, Number 2, February 2011 Supplementation of Infant Formula With Probiotics and/or Prebiotics of caregivers, health care professionals, and regulatory bodies of probiotics provided in infant formulae by referring to the culture regarding the benefits and risks related to such supplementation, collections and strain number. The doses of probiotics varied con- particularly in very young infants, the Committee decided to update siderably. Doses ranged from 1 Â 107 colony-forming units (CFU)/g and review the published evidence related to the safety and health (25–27) to 108 CFU/g (14,39) to 6 Â 109 CFU/100 mL (8,9) for single effects of the administration of formulae supplemented with pro- probiotics; the dose was 106 CFU/g (11,15) for a combination of biotics and/or prebiotics compared with unsupplemented formulae. probiotics. The supplementation periods varied from 15 days (13) to The Committee considers that there are some major issues related to 8 months (19). A number of RCT described the same study population the addition of probiotic bacteria and/or prebiotics to dietetic but reported different outcome measures (eg, 8 and 9; 16 and 22; 18 products for infants. First, timing, that is, the administration often and 19). One study reported in 2 publications was a cluster RCT begins in early infancy, sometimes at birth when the gut microbiota (18,19). Another study (20) had 3 arms comparing 2 doses of B lactis is not fully established, and factors that influence microbiota may and S thermophilus with placebo. A number of studies had >2 arms permanently affect the development of the ecosystem. Second, comparing different probiotics (18,19,26,27). duration, that is, the daily administration of such products is often prolonged (several weeks or months). Last but not least, delivery is Summary of Reported Results in the form of a specific matrix (infant formula) that could be the only source of feeding of an infant. ADMINISTRATION OF PROBIOTIC-SUPPLEMENTED This document is intended for practitioners, researchers, and FORMULA STARTED IN INFANTS 4MONTHSOF regulatory bodies. It also aims to identify needs for future research. AGE (OR 6 MONTHS OF AGE PROVIDED THAT THEY This document replaces the earlier 2 position papers related to HAVE NOT STARTED COMPLEMENTARY FEEDING) probiotics and prebiotics published in 2004 by the Committee. AND CONTINUED FOR AT LEAST 2 WEEKS (Table 4 at http://links.lww.com/MPG/A33) MATERIALS AND METHODS The Committee carried out a systematic review of random- ised controlled trials (RCT) according to the guidelines from the Growth Cochrane Collaboration. Only studies that compared use of infant formula or follow-on formula supplemented with probiotics and/or B lactis prebiotics during the manufacturing process were included. Studies The impact of B lactis administration on weight and growth in which probiotics/prebiotics were not administered during the was studied in 3 trials (23,24,27). Two of those trials (23,24) were manufacturing process, but thereafter, for example in capsules, the carried out in healthy