Probiotics for Infantile Colic: A Randomized, Double-Blind, Placebo-Controlled Trial Investigating Lactobacillus reuteri DSM 17938 Kim Chau, MSc1,2, Eddy Lau, MD3,4,5, Saul Greenberg, MD6, Sheila Jacobson, MD2,6, Parvaneh Yazdani-Brojeni, MD2, Natasha Verma, MD2, and Gideon Koren, MD1,2,3,6,7 Objective To investigate the effectiveness of Lactobacillus reuteri DSM 17938 for the treatment of infantile colic in breastfed Canadian infants, compared with placebo.

Study design A randomized, double-blind, placebo-controlled trial was conducted involving 52 infants with colic, according to modified Wessel criteria, who were assigned at random to receive L reuteri DSM 17938 (108 colonyforming units) (n = 24) or placebo (n = 28) for 21 days. Daily crying and fussing times were recorded in a structured diary, and maternal questionnaires were completed to monitor changes in infant colic symptoms and adverse events. Results Total average crying and fussing times throughout the study (from baseline to day 21) were significantly shorter among infants with colic in the probiotic group compared with infants in the placebo group (1719  750 minutes [29  13 hours] vs 2195  764 minutes [37  13 hours]; P = .028) (relative risk, 0.78; 95% CI, 0.58-0.98). Infants given L reuteri DSM 17938 showed a significant reduction in daily crying and fussing times at the end of treatment period compared with those receiving placebo (median, 60 minutes/day [IQR, 64 minutes/day] vs 102 minutes/day [IQR, 87 minutes/day]; P = .045). On day 21, a significantly higher proportion of infants in the L reuteri DSM 17938 group responded to treatment with a $50% crying time reduction compared with infants given placebo (17 vs 6, P = .035; relative risk, 3.3; 95% CI, 1.55-7.03). Conclusion Administration of L reuteri DSM 17938 significantly improved colic symptoms by reducing crying and fussing times in breastfed Canadian infants with colic. (J Pediatr 2014;-:---).

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rying is thought to be normal behavior during infancy, serving as the infant’s means of survival to alert and elicit help to their physiological needs, such as hunger, diaper change, temperature, and discomfort or pain.1,2 Although crying is often considered “normal behavior,” 5%-40% of infants cry inconsolably and excessively, accompanied by bouts of fussiness and gas passing.3-5 Wessel et al6 coined the term “infantile colic” to describe a “fussy” infant with colic as “one who is otherwise healthy and well-fed, had paroxysms of irritability, fussy or crying, lasting for a total of three hours a day, occurring on more than three days in any one week for a period of three weeks.” Fussing is defined as “behavior that is not quite crying but not content either.”7 Infantile colic can manifest as early as 2 weeks of age, with peak crying duration and fussiness typically between 6 and 8 weeks of age, and diminishing between 3 and 4 months of age.1,6,8,9 Paroxysms of crying and fussy/gassy periods can commence and subside without an obvious trigger or cause, making infantile colic difficult to prevent and treat.1,6,7,9 The etiology of infantile colic remains unclear; however, various theories have been proposed, some of which include overproduction of intestinal gas, forceful intestinal contraction, hypersensitivity to cow’s milk protein, transient lactase deficiency, negative or inadequate maternal–infant bonding or parental overstimulation, difficult infant temperament, and insecure parental attachment.2,6,7,9,10 Of importance, studies have implicated a potential role of the intestinal microbiota.11-14 The intestinal microbiota differs drastically between infants with colic and those without colic.12,14,15 Lending support to that role, infants with colic may display inadequate levels of lactobacilli in early infancy, which affects intestinal fatty acid From the Department of Pharmacology and Toxicology, profiles,12 and are more frequently colonized with the gas-forming Clostridium University of Toronto; Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children; difficile, Escherichia spp, and Klebsiella spp.16 It may be that infantile colic is Department of Pediatrics, University of Toronto; Department of Emergency Medicine, The Hospital for related not only to an atypical colonization pattern, but also to the lack of microSick Children; Department of Pediatrics, St Joseph’s 11,17 Health Care; Department of Pediatric Medicine, The bial diversity of the intestinal microbiota in the early days of life. Hospital for Sick Children; and Department of Probiotics are defined as “live microorganisms that, when administered in Physiology and Pharmacology, Schulich School of 18 Medicine and Dentistry, University of Western Ontario, adequate amounts, confer health benefits on the host.” In recent years, growing London, Ontario, Canada evidence suggests that supplementation with probiotics can modulate intestinal Supported by the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation. The probacterial patterns by aiding the colonization of beneficial bacteria.19,20 Probiotics biotic and placebo were supplied by Ferring Canada, Inc. The authors declare no conflicts of interest. can suppress intestinal inflammation by preventing the overgrowth of Registered with ClinicalTrials.gov: NCT01541046. inflammation-inducing microbes and gas-forming coliforms.21-23 Several clin0022-3476/$ - see front matter. Copyright ª 2014 Elsevier Inc. ical trials have been conducted to examine the effectiveness of L reuteri DSM All rights reserved. 17938 vs placebo in the treatment of infantile colic.24-26 Although the results http://dx.doi.org/10.1016/j.jpeds.2014.09.020 1

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from 2 clinical trials have demonstrated the superiority of L reuteri DSM 17938 over placebo,24,26 a recent study from Australia failed to corroborate this effect.25 Given that the country of origin has been shown to strongly affect the development of intestinal microbiota in infants,27 the results of those clinical trials might not be generalizable to North America. Therefore, in this randomized, double-blind, placebo-controlled trial, we sought to determine the effectiveness of the probiotic L reuteri DSM 17938 in treating infantile colic in exclusively breast-fed Canadian infants. We hypothesized that breastfed infants with colic given L reuteri DSM 17938 would exhibit significantly reduced crying and fussing times compared with those receiving placebo.

Methods This randomized, double-blind, placebo-controlled trial was carried out between February 2012 and April 2014 at The Hospital for Sick Children and in pediatric care practices in Toronto, Ontario, Canada. Before study initiation, approval was obtained from The Hospital for Sick Children’s Research Ethics Board and Health Canada. Eligible infants were included in the study after written informed consent was obtained from a parent/guardian. Study participants met the following inclusion criteria: (1) diagnosis of infantile colic (ie, crying or fussy/gassy episodes $3 hours/day for $3 days/7 days, as defined by a modified definition of Wessel criteria) at study commencement; (2) age 3 weeks to 6 months at study commencement (although infantile colic typically manifests between age 2 weeks and 34 months, to capture infants with delayed onset of colic, infants with colic up to 6 months were eligible); (3) exclusively breastfed; (4) term delivery ($37 weeks gestation at birth); (5) 5-minute Apgar score $7; and (6) birth weight $2500 g. Exclusion criteria included: (1) a major medical problem or acute illness, including gastroesophageal reflux, as determined by a pediatrician; (2) history of antibiotic treatment before or during the study; (3) history of probiotic or L reuteri supplementation; (4) history of any allergies to any of the ingredients in the probiotic L reuteri DSM 17938 (freeze-dried, 1  108 per 5 drops; sunflower oil, medium-chain triglyceride oil, and silicon dioxide) or placebo (sunflower oil, medium-chain triglyceride oil, and silicon dioxide); and (5) concurrent participation in another clinical trial. The study’s primary outcome was defined as a reduction in the duration of average crying and fussing times, from baseline (day 0) to end of treatment (day 21), to

Probiotics for infantile colic: a randomized, double-blind, placebo-controlled trial investigating Lactobacillus reuteri DSM 17938.

To investigate the effectiveness of Lactobacillus reuteri DSM 17938 for the treatment of infantile colic in breastfed Canadian infants, compared with ...
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