Accepted Manuscript Probiotics in neonates – what do we know? Sunil Rangarajan, MBBS PII:

S0899-9007(14)00040-9

DOI:

10.1016/j.nut.2014.01.001

Reference:

NUT 9199

To appear in:

Nutrition

Received Date: 27 November 2013 Revised Date:

25 December 2013

Accepted Date: 7 January 2014

Please cite this article as: Rangarajan S, Probiotics in neonates – what do we know?, Nutrition (2014), doi: 10.1016/j.nut.2014.01.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Editorial – Probiotics in neonates – what do we know? Author:

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Sunil Rangarajan, MBBS Affiliation: Division of Nephrology, University of Alabama at Birmingham 701 19th Street South, LHRB 452,

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Birmingham, Alabama - 35233

Email – [email protected] Word count of the editorial: 751 Number of figures – 0

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Number of tables – 0

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Phone - 205-934-5783

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This editorial has not been previously published and is not submitted elsewhere for publication.

The additions to the text have been highlighted as blue text. Accordingly, references have been updated too.

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The intestinal microbiotic environment is both complex and fascinating, and the balance attained in this milieu is of utmost importance in neonates. Earlier, it was thought that a neonate is born with a sterile gut. However, recent evidence has uncovered a mechanism by which bacterial

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colonization of the gut can happen by fetal exposure to microbes through the amniotic fluid in utero (1). The bacterial colonization that follows is dependent on a number of factors, including and not limited to the mode of delivery, gestational age, timing and type of initiation of enteral

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overall long term health outcome of the child is well known.

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feeds and treatment with antibiotics (2). The central effect this has on the innate health and the

The use of probiotics in neonates, which alter the host microbiota, is debatable. Probiotics usually contain lactobacilli, bifidobacteria and streptococci. In addition to the proposed mechanisms of physical and immunological barrier function, effect on mucus production and improving intestinal motility, probiotics have a “post biotic” effect; as the byproducts of the

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metabolic reactions of these bacteria exercise the much researched immunomodulatory effects (3). While keeping in mind the most precious and natural probiotic source in the world, the human breast milk, it is also important to note that probiotics have been used in infants and

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children of varying ages in the prevention and treatment of necrotizing enterocolitis (NEC),

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antibiotic associated diarrhea, acute viral gastroenteritis, prevention of atopic diseases, and Crohn’s disease. NEC is the most extensively studied disease in this field. In preterm neonates, enteral feeds are often delayed and antibiotic usage is also quite common. This has served as the rationale behind clinical trials using probiotics in the prevention and treatment of NEC, as both these factors have been proved to be contributory to the pathogenesis of NEC in preemies. Currently, the level of evidence is at level 1a for the routine use of probiotics in preterm infants only. However, we are still at level 2a of evidence to suggest the use of probiotics in specific

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type and dosing maybe beneficial in conditions of high NEC (4). Recently, routine use of probiotics in two cohorts of preemies showed reduced rate of NEC as well as isolated rectal bleeding (5). Recent meta-analysis data in very low birth preterm neonate has shown that

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probiotic supplementation reduces the risk of NEC (6, 7). However, these reviews, like many others, analyze a diverse mix of studies and one must be cautious not to generalize these results. In another study, titrated doses of probiotics have been administered to healthy term infants with

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slight improvement in colic and reduced need for use of antibiotics. However, this study did not

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include sick or low birth weight infants (8).

The need to exercise caution while administering probiotics, especially in sick preterm or low birth weight infants is higher, as the organisms that often cause sepsis in these groups come from the infants’ indigenous flora, essentially increased by probiotics (9). Moreover, there are also occasional case reports in the literature which have reported the probiotics themselves acting

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directly as the source of the sepsis such sick and immunocompromised children. In view of lack of adequate evidence about timing and dosage supporting the use of probiotics as a norm, we should also be mindful about the ecological impact, potential microbial adaptations secondary to

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interventions (10).

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use of probiotics, impact of unintended cross colonizations and intercations with other preventive

It is to be expected that, for the foreseeable future, at least 500,000 HIV-infected infants will be born each year, most of them in low-income countries with generalized epidemics (11). Little is known about infants that were exposed to and not infected with HIV and even lesser data is available on the growth outcomes of these infants, and how probiotic supplementation affects these anthropometric parameters. The study conducted by Van Niekerk et al features a randomized double blinded placebo controlled trial that studied effect of probiotics in very low

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birth weight HIV-exposed and HIV-unexposed neonates. According to this study, probiotic supplementation did not affect growth outcomes or feeding tolerance in either of the groups. However, this study looked at a very specific group of neonates and excluded septic, and

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otherwise immunocompromised neonates. Supplementation of probiotics to sick neonates has risks of devastating complications like sepsis and requires more studies. Larger RCTs are required in the future to establish guidelines for the usage of probiotics in premature neonates in

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view of the potential adverse effects as well as a cost benefit analysis.

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References: 1.

DiGiulio DB, Romero R, Amogan HP, Kusanovic JP, Bik EM, Gotsch F, et al. Microbial

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prevalence, diversity and abundance in amniotic fluid during preterm labor: a molecular and culture-based investigation. PloS one. 2008;3(8):e3056. 2.

Yoshioka H, Iseki K, Fujita K. Development and differences of intestinal flora in the

neonatal period in breast-fed and bottle-fed infants. Pediatrics. 1983;72(3):317-21.

Commane DM, Shortt CT, Silvi S, Cresci A, Hughes RM, Rowland IR. Effects of

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3.

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fermentation products of pro- and prebiotics on trans-epithelial electrical resistance in an in vitro model of the colon. Nutrition and cancer. 2005;51(1):102-9. 4.

Murguia-Peniche T, Mihatsch WA, Zegarra J, Supapannachart S, Ding ZY, Neu J.

Intestinal mucosal defense system, Part 2. Probiotics and prebiotics. The Journal of pediatrics. 2013;162(3 Suppl):S64-71.

Bonsante F, Iacobelli S, Gouyon JB. Routine probiotic use in very preterm infants:

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retrospective comparison of two cohorts. American journal of perinatology. 2013;30(1):41-6. 6.

Bernardo WM, Aires FT, Carneiro RM, Sa FP, Rullo VE, Burns DA. Effectiveness of

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probiotics in the prophylaxis of necrotizing enterocolitis in preterm neonates: a systematic

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review and meta-analysis. Jornal de pediatria. 2013;89(1):18-24. 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. Journal of pediatric surgery. 2012;47(1):241-8. 8.

Saavedra JM, Abi-Hanna A, Moore N, Yolken RH. Long-term consumption of infant

formulas containing live probiotic bacteria: tolerance and safety. The American journal of clinical nutrition. 2004;79(2):261-7.

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9.

Salminen MK, Rautelin H, Tynkkynen S, Poussa T, Saxelin M, Valtonen V, et al.

Lactobacillus bacteremia, clinical significance, and patient outcome, with special focus on probiotic L. rhamnosus GG. Clinical infectious diseases : an official publication of the Infectious

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Diseases Society of America. 2004;38(1):62-9.

Millar M, Wilks M, Fleming P, Costeloe K. Should the use of probiotics in the preterm

be routine? Archives of disease in childhood Fetal and neonatal edition. 2012;97(1):F70-4. World Health Organization. Progress on global access to HIV antiretroviral therapy: a

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report on "3 by 5" and beyond. 2006.

Probiotics in neonates: What do we know?

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