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Review |

Probiotics to Prevent or Treat Excessive Infant Crying:  Systematic Review and Meta-analysis FREE

Valerie Sung, MPH1,2,3; Sarsha Collett, MPH4; Tanyth de Gooyer, PhD4; Harriet Hiscock, MD1,2,3; Mimi Tang, PhD1,2,5; Melissa Wake, MD1,2,3
[+] Author Affiliations
1Department of Paediatrics, The University of Melbourne, Parkville, Australia
2Murdoch Childrens Research Institute, Parkville, Australia
3Centre for Community Child Health, Royal Children’s Hospital, Parkville, Australia
4Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
5Department of Allergy and Immunology, Royal Children’s Hospital, Parkville, Australia
JAMA Pediatr. 2013;167(12):1150-1157. doi:10.1001/jamapediatrics.2013.2572.
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Published online

Importance  Excessive infant crying is common, distressing, but without proven effective prevention or management options. Probiotics may be a promising solution.

Objective  To examine whether probiotics are effective in the prevention/management of crying (“colic”) in infants 3 months or younger.

Data Sources  A systematic search of MEDLINE, EMBASE, and the Cochrane Library, supplemented by the metaRegister of Controlled Trials.

Study Selection  Studies that randomized infants 3 months or younger to oral probiotics vs placebo or no or standard treatment with the outcome of infant crying, measured as the duration or number of episodes of infant crying/distress or diagnosis of “infant colic.” Twelve of the 1180 initially identified studies were selected.

Data Extraction and Synthesis  This review/meta-analysis was conducted according to guidelines from the Cochrane Handbook for Systematic Reviews of Interventions, with reporting following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Data were independently extracted by 3 of us.

Main Outcome(s) and Measure(s)  Infant crying, measured as the duration or number of episodes of infant crying/distress, or diagnosis of “infant colic.”

Results  Of the 12 trials (1825 infants) reviewed, 6 suggested probiotics reduced crying, and 6 did not. Three of the 5 management trials concluded probiotics effectively treat colic in breastfed babies; 1 suggested possible effectiveness in formula-fed babies with colic, and 1 suggested ineffectiveness in breastfed babies with colic. Meta-analysis of 3 small trials of breastfed infants with colic found that Lactobacillus reuteri markedly reduced crying time at 21 days (median difference, −65 minutes/d; 95% CI, −86 to −44). However, all trials had potential biases. Meanwhile, of 7 prevention trials, 2 suggested possible benefits. Considerable variability in the study populations, study type, delivery mode/dose of probiotic supplementation, and outcomes precluded meta-analysis.

Conclusions and Relevance  Although L reuteri may be effective as treatment for crying in exclusively breastfed infants with colic, there is still insufficient evidence to support probiotic use to manage colic, especially in formula-fed infants, or to prevent infant crying. Results from larger rigorously designed studies applicable to all crying infants will help draw more definitive conclusions.

Figures in this Article

Infant colic, or excessive infant crying/fussing for no apparent cause, is a major medical and public health issue because it is common, distressing, and costly and can have significant long-term consequences. Affecting up to 20% of infants younger than 3 months,1 it is detrimental to maternal mental health and family quality of life2 and is the most common proximal risk factor for child abuse.3 Infants whose crying persists beyond age 3 months are more likely to have later mental health problems4 including anxiety, aggression and hyperactivity, sleep disorders, and allergy.5,6

The etiology of infant colic remains unclear, impeding development of effective prevention and management strategies. Various psychosocial and gastrointestinal causes have been proposed but not proven to contribute to colic. Food allergy has perhaps the strongest association with infant irritability,79 with gut inflammation from cow’s milk protein or alteration of gut microbiota postulated as underlying causes.10

Recently, studies have reported gut microbial differences between infants with and without colic,1113 suggesting these could be responsible for pathophysiological changes such as inflammation, gas production, bloating, and gut dysmotility, in turn leading to infant distress. These new developments are particularly exciting given that systematic reviews have shown other treatments to have either limited efficacy (eg, hypoallergenic or extensively hydrolyzed formula in infants, maternal elimination diets in breastfeeding mothers, improved parental responsiveness, reduced stimulation, and use of sucrose, herbal mixtures, and anticholinergic medications) or be ineffective (eg, simethicone, antireflux medications, antacids, parental counseling, carrying, spinal manipulation, and car ride stimulators).1416 The logical next step is to determine whether intervening to alter gut microbiota can effectively prevent or reduce infant crying.

Probiotics, defined as live microorganisms that confer health benefits, have emerged as one major contender. Probiotics colonize the bowel, competitively inhibit other bacterial adhesion, strengthen mucosal barriers, suppress intestinal inflammation, and modulate infant gut microbiota.17,18 Animal studies indicate probiotics change pain perception mediated by the gut and dampen gut contractile activity.19,20 Based on these effects, various probiotic bacteria have been evaluated in the treatment and prevention of infant colic.

To our knowledge, this is the first systematic review to determine the effectiveness of probiotics in the prevention and management of infant colic. We hypothesized that probiotic supplementation in these infants will be effective in reducing and preventing infant crying. We aimed to determine whether probiotic supplementation, when compared with no or standard treatment, in randomized trials of infants younger than 3 months is effective in reducing the (1) duration of infant crying/distress, (2) number of episodes of crying/distress, and/or (3) proportions with “infant colic” (crying/fussing ≥3 hours of the day for ≥3 days per week for ≥1 week).

Search Strategy

This systematic review and meta-analysis was conducted according to guidelines from the Cochrane Handbook for Systematic Reviews of Interventions,21 with reporting following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.22 Searches of the databases MEDLINE, EMBASE, and the Cochrane Library, including the Cochrane Central Register of Controlled Trials, were completed in June 2012. Articles from 1950 to June 2012 were initially searched using the following Medical Subject Headings (MeSH) terms and key words and limited to “all infants (birth to 23 months)”: (1) MeSH terms: colic or crying or irritable mood and probiotics or lactobacillus or bifidobacterium or streptococcus or saccharomyces or Escherichia coli or Enterobacteriaceae and (2) key words: colic* or cry* or irritab* and probiotic* or lactobacil* or bifidobac* or streptococ* or saccharomyc* or Escherichia* or bacilli* or enterobacter*. When the initial search suggested that infant crying was frequently a secondary outcome in articles investigating the safety and tolerance of probiotics in infants, a further search was performed using the MeSH terms and key words for the various probiotic strains and the following: (1) MeSH terms: safety or drug tolerance or growth and (2) key words: safe* or toleran* or grow*; a limit of the last 20 years was applied because most studies on probiotic use occurred in this time frame. Furthermore, reference lists from articles were explored for other potential studies. Article authors were contacted by e-mail to clarify any relevant article queries. We also searched for ongoing trials using the terms probiotic and colic through the metaRegister of Controlled Trials on controlled-trials.com, including the National Institutes of Health ClinicalTrials.gov and the International Standard Randomized Controlled Trial Number Registers, in September 2012. Non–English language literature and unpublished data were not included.

Three of us (V.S., S.C., and T.dG.) independently identified appropriate articles through examining relevant abstracts, reviewed trials for eligibility, and assessed the quality of trials. Inconsistencies were resolved by discussions between the 3 of us.

Study Selection

The systematic review included randomized clinical trials involving infants who were younger than 3 months at the commencement of oral probiotic supplementation vs placebo or standard care or no care. Studies were included that investigated the effectiveness of any probiotic given to either mothers or infants in both term and preterm infants. The primary outcome was infant crying/distress, measured as duration or the number of episodes, or the diagnosis of “infant colic,” defined by the modified Wessel criteria of crying/fussing for 3 hours or more of the day for 3 days or more per week for 1 week or more.

Using a standardized data extraction form, the following information was captured for each included study: (1) the characteristics of infants (age at recruitment, sex, gestation, feeding method, delivery type, whether prevention or treatment, and method of diagnosis of colic); (2) the type of intervention (strain, dose, frequency, and duration of probiotic use) vs placebo or vs standard treatment (including dose, frequency, and duration of treatment) or vs no treatment; (3) the outcome measures (crying duration or frequency of bouts of crying or diagnoses of infant colic, whether they were primary vs secondary outcomes, and timing of outcomes measured); and (4) reported adverse effects.

Trial quality and risk of bias were assessed according to the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions.21 This included rating the adequacy of randomization; allocation concealment; blinding of participants, data collectors, and outcome assessors; and extent of loss to follow-up.

Meta-analysis

Meta-analysis was performed using version 5.0 of RevMan.23 Identified studies were included in the meta-analysis that (1) reported on the duration of infant crying/distress as minutes per day as the daily crying time or the difference in daily crying time between intervention and control groups; (2) measured the outcome at the same point postintervention; and (3) used the same probiotic strain with the same dosage and route of delivery. The median difference in daily crying time between treatment and control groups at 21 days of intervention was the primary measure of treatment effect, because this outcome measure was available in all trials included in the meta-analysis. The continuous outcomes for individual trials and pooled statistics were reported as median differences and 95% confidence intervals. For trials that did not report the median difference, the median difference was calculated as the difference in median crying time between intervention and control groups. The 95% confidence intervals were calculated from the provided P values using the Altman and Bland method,24 assuming the variance of crying times was the same in both groups. We also pooled results by converting median to mean crying times to investigate whether outcomes may differ. The random-effects model and the inverse variance method were used for pooling data, and statistical heterogeneity between outcomes for trials was evaluated using the t2, χ2, and I2 statistics. I2 of 30% to 60%, 50% to 90%, and 75% to 100% represented moderate, substantial, and considerable heterogeneity, respectively. Heterogeneity was regarded to be substantial if t2 was greater than zero or the P value was low (<.10) in the χ2 test for heterogeneity. The random-effects model was selected as the method to pool data because of important clinical heterogeneity between trials identified a priori. Analysis was repeated using the fixed-effects model to ascertain whether similar conclusions were reached.

Study Selection

The eFigure in the Supplement details the trial selection processes. Eighteen trials were extracted for review of eligibility, comprising 16 from the 1173 potentially relevant studies identified in the database search and a further 2 from a search of the metaRegister of Controlled Trials. Of these 18, 6 were excluded because of unclear outcome measures or inappropriate age groups; the remaining 12 met inclusion and exclusion criteria, and of these, 3 also met inclusion criteria for a single meta-analysis. Five authors were contacted for clarification of details of the outcome measures, but no additional relevant information was able to be obtained.

Study Characteristics

Table 1 summarizes the characteristics of each of the 12 included trials. eTable 1 in the Supplement describes the characteristics of the excluded trials.

Table Graphic Jump LocationTable 1.  Characteristics of Individual Included Trials
Population

All included studies were randomized clinical trials. Five trials examined the effectiveness of probiotics in the management of infant colic18,25,3032 and 7, the effectiveness of probiotics in the prevention of infant crying.2629,3335 The included trials totaled 1825 infants, of whom 271 were term infants with the diagnosis of colic, 1534 were term infants without colic, and 20 were preterm newborns without colic. Study sample sizes ranged from 9 to 1018. Six trials studied formula-fed infants only,25,26,29,3335 3 included breastfed infants only,18,28,32 1 examined both breastfed and formula-fed infants,27 and 2 investigated breastfed infants with mothers on dairy-free diets.30,31

Interventions

Two studies included 1050 mother-infant pairs with high risk of allergy, where the intervention was given to both pregnant mothers antenatally during the last 4 weeks of pregnancy and postnatally to mothers or infants for 6 months as capsules or capsule contents suspended in liquid.27,28 The remaining trials involved postnatal probiotic supplementation to infants younger than 3 months as drops,3032 capsule contents suspended in liquid,18 or formula.25,26,29,34,35 Six trials used a single probiotic,26,28,3033 5 included multiple probiotics,18,25,27,34,35 and 1 trial used a probiotics/prebiotics mixture.29

The dosage of probiotics varied widely between trials, in particular when probiotics were administered within formula because the amount of formula ingested by infants could vary greatly. The duration of intervention ranged from 2 weeks to 6 months. All but 1 trial compared a probiotic intervention with placebo; this trial compared a probiotic with simethicone,30 a medication known to be ineffective in the management of colic.36,37

Outcomes

The most common outcome reported was daily infant crying time (mean or median duration), which was the primary outcome in 3 trials3032 and a secondary outcome in 6 trials.18,26,28,29,33,34 The remaining 3 trials each reported a different crying-related outcome: number of infants with a 25% reduction in daily crying duration,25 number of infants diagnosed with infant colic,27 and number of episodes of crying per day.35 Most trials used diaries completed by participant parents as a measure of crying time; however, 2 used questionnaires,27,35 1 involved an interview,29 and in 2, the method of measure was unclear.18,33 Six trials measured outcomes at 1 month26,29,30,32,33,35 and 3 measured outcomes at all of 7, 14, and 21 days.3032

Adverse Effects

None of the studies reported adverse effects of probiotic supplementation. Three trials did not include adverse effects as outcomes.18,30,32 The others concluded no adverse effects in gastrointestinal tolerance, growth, or infections.2529,31,3335

Risk of Bias Within Trials

The process of determining risk of bias for each individual trial is described in eTable 2 in the Supplement. Five trials adequately described the process of randomization sequence generation,27,29,31,32,34 6 defined the procedures of allocation concealment,26,27,29,3133 and 3 adequately blinded participants, research personnel, and outcomes.27,29,32 The 2010 Savino et al trial31 blinded participants and research personnel, but the statistician who generated the randomization list was not blinded to the outcome. The 2007 Savino et al trial30 was inadequately blinded, because the control group received a medication at a different dosing regimen than the intervention group. The remaining trials did not describe the blinding processes. Ten trials reported rates of incomplete outcome data as less than 20%.25,2735 All trials presented outcomes appropriately and avoided selective outcome reporting.

Three trials did not describe baseline characteristics.25,26,35 Because the reported outcome in 2 of these trials26,35 was total duration of crying in each group, this could result in important bias if the baseline crying time was by chance remarkably different in each group. Three trials reported markedly different baseline characteristics between groups.28,32,33 In the Rinne et al trial,28 fewer infants were born by cesarean section in the probiotic than the placebo group, and this was not adjusted for in the analysis. This may affect results because the gut microbiota profile is known to be different in infants born by cesarean section from those born by vaginal delivery.38 In the Szajewska et al trial,32 the probiotic group had a higher percentage of infants with a family history of allergy than the control group, and this was not adjusted for in the analysis.32 In Vendt et al trial,33 the placebo group had higher baseline crying time than the probiotic group; however, the reported outcome was change in crying time. Overall, only 2 trials27,29 had low risk of bias.

Study Results

Table 2 summarizes the results of each trial reviewed, by the type of study and probiotics used. Of the 7 prevention trials, 2 reported the mean daily crying time to be less in the probiotic compared with the placebo group.26,29 In one, formula-fed preterm infants were supplemented with the probiotic Lactobacillus reuteri26; in the other, term infants received a combination of probiotics and prebiotics in an α-lactalbumin–enriched formula.29 None of the other 5 prevention trials found a significant difference between the probiotic and control groups.

Of the 5 management trials for infant colic, 3 trials3032 reported a significant reduction in median daily crying time in the probiotic compared with the placebo group3032 and were sufficiently homogenous to meta-analyze (see later). The Dupont et al trial25 could not be included in the meta-analysis because of its dichotomized outcome; although it found no difference between groups in the number of infants with a reduction of daily crying time of more than 25% at 2 weeks, irritability and agitation without crying decreased more in the probiotic than the control group. The Mentula et al trial18 reported no difference in crying duration between the 2 groups at 2 weeks; it could not be included in the meta-analysis because of the vastly different intervention (a combination of different probiotics), dosing of intervention, mode of intervention delivery (capsules), unclear measure of crying outcomes used, and small sample size (n = 9).18

The 3 trials included in the meta-analysis3032 examined the effectiveness of the probiotic L reuteri in the management of colic in term infants. All 209 infants were breastfed only, and in 2 trials, mothers were also on dairy-free diets.30,31 All used the same dose of L reuteri at 109 colony-forming units per day, in the form of 5 drops per day; the controls received a placebo in 2 trials and simethicone in the third. All 3 trials reported the median daily crying time at 21 days of intervention as the primary outcome.

Figure 1 shows results of the meta-analysis. Supplementation with L reuteri in breastfed term infants with colic reduced the daily crying time at day 21 of intervention by a median difference of 65.10 minutes per day (95% CI, −85.82 to −44.38) compared with the placebo group (z = 6.16; P < .001) (Figure 1A). However, there was substantial heterogeneity (I2 = 55%) between the few included trials (P = .11) in the random-effects model. Results were very similar when median crying times were converted to means to pool results using mean difference as the primary measure of treatment effect (Figure 1B). Results were also similar when the fixed-effects model was explored (Figure 2).

Place holder to copy figure label and caption
Figure 1.
Meta-analyses of Treatment Trials Using a Random-Effects Model

A, Meta-analysis of treatment trials using median difference as the primary outcome, with a random-effects model. B, Meta-analysis of treatment trials using mean difference as the primary outcome, with a random-effects model. IV indicates inverse variance.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Meta-analyses of Treatment Trials Using a Fixed-Effects Model

A, Meta-analysis of treatment trials using median difference as the primary outcome, with a fixed-effects model. B, Meta-analysis of treatment trials using mean difference as the primary outcome, with a fixed-effects model. IV indicates inverse variance.

Graphic Jump Location

Whether probiotics have any role in the prevention of infant colic is unclear, because existing trials differ vastly in their populations of infants, probiotic strains supplemented, and types and points of outcome measures. Supplementation with the probiotic L reuteri in breastfed term infants younger than 3 months with colic may appear to be effective in reducing crying; however, this conclusion is tempered by the presence of substantial heterogeneity in the 3 treatment trials included in the meta-analysis and some methodological concerns that may bias outcomes, including inadequate blinding of the intervention,30,31 unequal baseline characteristics,32 and lack of information about sequence generation and allocation concealment.30 Further, the measure of crying using “diaries” was unclear in all 3 trials and possibly prone to recall bias; no study used a validated cry diary such as the Barr et al diary.39 Two of the 3 trials30,31 involved infants whose mothers were on dairy-free diets so their results may not generalize to breastfed infants whose mothers are on unrestricted diets, because cow’s milk protein allergy is a known cause of distress in some infants.79 Of the 2 trials with low risk of bias, both were prevention trials that did not examine infant crying as a primary outcome; 1 suggested the probiotic group to have less crying/agitation than the placebo group,29 and the other concluded no difference between groups.27

To our knowledge, this is the first systematic review to investigate the effectiveness of probiotic supplementation for the management and prevention of infant colic. It involved a rigorous review process with adherence to internationally recognized Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Conclusions were able to be drawn from pooled data of randomized clinical trials using probiotic supplementation for the management of infant colic in a meta-analysis. A possible limitation is the exclusion of non–English language trials, when probiotic effects could potentially differ in children from different racial or cultural backgrounds.

This review reflects current general consensus that, even though the use of a specific strain of probiotic (L reuteri) in breastfed term infants with colic is promising, there is still insufficient evidence to support the general use of probiotics in all infants with colic or to recommend its use in preventing colic. Larger and more rigorously designed randomized clinical trials are needed to examine the efficacy of the probiotic L reuteri in the management of breastfed and particularly formula-fed infants with colic and in the prevention of colic in healthy term infants. Currently, at least 5 unpublished trials in progress in different parts of the world are designed to examine the effects of probiotics in the management of breastfed and formula-fed infants with colic.40 The pending results will better inform future meta-analyses that may be able to provide more definitive conclusions about the management of such an important clinical condition.

Corresponding Author: Valerie Sung, MPH, Centre for Community Child Health, Royal Children’s Hospital, Flemington Road, Parkville, Victoria 3052, Australia (valerie.sung@rch.org.au).

Accepted for Publication: March 27, 2013.

Published Online: October 7, 2013. doi:10.1001/jamapediatrics.2013.2572.

Author Contributions: Dr Sung had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Sung, Collett, de Gooyer, Wake.

Acquisition of data: Sung, Collett, de Gooyer.

Analysis and interpretation of data: All authors.

Drafting of the manuscript: Sung, Hiscock, Tang, Wake.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Sung, Collett, de Gooyer.

Administrative, technical, or material support: Sung, Wake.

Study supervision: Hiscock, Tang, Wake.

Conflict of Interest Disclosures: Dr Tang is a member of the Nestlé Nutrition Institute Medical Advisory Board Oceania and the Nutricia Medical Advisory Board Australasia and received honoraria for speaking at symposia sponsored by the Nestlé Nutrition Institute and Nutricia (Danone). She also received probiotic and placebo research products from Nestlé Research Centre Switzerland and Dicofarm Italy for studies unrelated to this systematic review. No other conflicts of interest were reported.

Funding/Support: Dr Sung is supported by National Health and Medical Research Council Postgraduate Scholarship 607447, and Drs Hiscock and Wake are supported by National Health and Medical Research Council Population Health Career Development Awards (grants 607351 and 546405). Murdoch Childrens Research Institute is supported by the Victorian Government’s Operational Infrastructure Support Program.

Role of the Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Michael Abramson, PhD, and Andrew Forbes, PhD, Monash University, John Carlin, PhD, University of Melbourne, and Michael Coory, PhD, Murdoch Childrens Research Institute, for advice on statistical measures.

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Savino  F, Pelle  E, Palumeri  E, Oggero  R, Miniero  R.  Lactobacillus reuteri (American Type Culture Collection Strain 55730) versus simethicone in the treatment of infantile colic: a prospective randomized study. Pediatrics. 2007;119(1):e124-e130.
PubMed   |  Link to Article
Savino  F, Cordisco  L, Tarasco  V,  et al.  Lactobacillus reuteri DSM 17938 in infantile colic: a randomized, double-blind, placebo-controlled trial. Pediatrics. 2010;126(3):e526-e533.
PubMed   |  Link to Article
Szajewska  H, Gyrczuk  E, Horvath  A.  Lactobacillus reuteri DSM 17938 for the management of infantile colic in breastfed infants: a randomized, double-blind, placebo-controlled trial. J Pediatr. 2013;162(2):257-262.
PubMed   |  Link to Article
Vendt  N, Grünberg  H, Tuure  T,  et al.  Growth during the first 6 months of life in infants using formula enriched with Lactobacillus rhamnosus GG: double-blind, randomized trial. J Hum Nutr Diet. 2006;19(1):51-58.
PubMed   |  Link to Article
Vlieger  AM, Robroch  A, van Buuren  S,  et al.  Tolerance and safety of Lactobacillus paracasei ssp. paracasei in combination with Bifidobacterium animalis ssp. lactis in a prebiotic-containing infant formula: a randomised controlled trial. Br J Nutr. 2009;102(6):869-875.
PubMed   |  Link to Article
Weizman  Z, Alsheikh  A.  Safety and tolerance of a probiotic formula in early infancy comparing two probiotic agents: a pilot study. J Am Coll Nutr. 2006;25(5):415-419.
PubMed   |  Link to Article
Metcalf  TJ, Irons  TG, Sher  LD, Young  PC.  Simethicone in the treatment of infant colic: a randomized, placebo-controlled, multicenter trial. Pediatrics. 1994;94(1):29-34.
PubMed
Danielsson  B, Hwang  CP.  Treatment of infantile colic with surface active substance (simethicone). Acta Paediatr Scand. 1985;74(3):446-450.
PubMed   |  Link to Article
Biasucci  G, Benenati  B, Morelli  L, Bessi  E, Boehm  G.  Cesarean delivery may affect the early biodiversity of intestinal bacteria. J Nutr. 2008;138(9):1796S-1800S.
PubMed
Barr  RG, Kramer  MS, Boisjoly  C, McVey-White  L, Pless  IB.  Parental diary of infant cry and fuss behaviour. Arch Dis Child. 1988;63(4):380-387.
PubMed   |  Link to Article
metaRegister of Controlled Trials: registered trials ISRCTN95287767, NCT01067027, NCT01279265, NCT01541046, and NCT01017991. http://www.controlled-trials.com/mrct/. Accessed September 10, 2012.

Figures

Place holder to copy figure label and caption
Figure 1.
Meta-analyses of Treatment Trials Using a Random-Effects Model

A, Meta-analysis of treatment trials using median difference as the primary outcome, with a random-effects model. B, Meta-analysis of treatment trials using mean difference as the primary outcome, with a random-effects model. IV indicates inverse variance.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
Meta-analyses of Treatment Trials Using a Fixed-Effects Model

A, Meta-analysis of treatment trials using median difference as the primary outcome, with a fixed-effects model. B, Meta-analysis of treatment trials using mean difference as the primary outcome, with a fixed-effects model. IV indicates inverse variance.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Characteristics of Individual Included Trials

References

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Pärtty  AK, Kalliomäki  M, Endo  A, Salminen  S, Isolauri  E.  Compositional development of Bifidobacterium and Lactobacillus microbiota is linked with crying and fussing in early infancy. PLoS One. 2012;7(3):e32495.
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Mentula  S, Tuure  T, Koskenala  R, Korpela  R, Kononen  E.  Microbial composition and fecal fermentation end products from colicky infants: a probiotic supplementation pilot. Microb Ecol Health Dis. 2008;20(1):37-47. doi:10.1080/08910600801933846.
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Ma  X, Mao  Y-K, Wang  B, Huizinga  JD, Bienenstock  J, Kunze  W.  Lactobacillus reuteri ingestion prevents hyperexcitability of colonic DRG neurons induced by noxious stimuli. Am J Physiol Gastrointest Liver Physiol. 2009;296(4):G868-G875.
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Dupont  C, Rivero  M, Grillon  C, Belaroussi  N, Kalindjian  A, Marin  V.  Alpha-lactalbumin-enriched and probiotic-supplemented infant formula in infants with colic: growth and gastrointestinal tolerance. Eur J Clin Nutr. 2010;64(7):765-767.
PubMed   |  Link to Article
Indrio  F, Riezzo  G, Raimondi  F, Bisceglia  M, Cavallo  L, Francavilla  R.  The effects of probiotics on feeding tolerance, bowel habits, and gastrointestinal motility in preterm newborns. J Pediatr. 2008;152(6):801-806.
PubMed   |  Link to Article
Kukkonen  K, Savilahti  E, Haahtela  T,  et al.  Long-term safety and impact on infection rates of postnatal probiotic and prebiotic (synbiotic) treatment: randomized, double-blind, placebo-controlled trial. Pediatrics. 2008;122(1):8-12.
PubMed   |  Link to Article
Rinne  M, Kalliomäki  M, Salminen  S, Isolauri  E.  Probiotic intervention in the first months of life: short-term effects on gastrointestinal symptoms and long-term effects on gut microbiota. J Pediatr Gastroenterol Nutr. 2006;43(2):200-205.
PubMed   |  Link to Article
Rozé  JC, Barbarot  S, Butel  MJ,  et al.  An α-lactalbumin-enriched and symbiotic-supplemented v. a standard infant formula: a multicentre, double-blind, randomised trial. Br J Nutr. 2012;107(11):1616-1622.
PubMed   |  Link to Article
Savino  F, Pelle  E, Palumeri  E, Oggero  R, Miniero  R.  Lactobacillus reuteri (American Type Culture Collection Strain 55730) versus simethicone in the treatment of infantile colic: a prospective randomized study. Pediatrics. 2007;119(1):e124-e130.
PubMed   |  Link to Article
Savino  F, Cordisco  L, Tarasco  V,  et al.  Lactobacillus reuteri DSM 17938 in infantile colic: a randomized, double-blind, placebo-controlled trial. Pediatrics. 2010;126(3):e526-e533.
PubMed   |  Link to Article
Szajewska  H, Gyrczuk  E, Horvath  A.  Lactobacillus reuteri DSM 17938 for the management of infantile colic in breastfed infants: a randomized, double-blind, placebo-controlled trial. J Pediatr. 2013;162(2):257-262.
PubMed   |  Link to Article
Vendt  N, Grünberg  H, Tuure  T,  et al.  Growth during the first 6 months of life in infants using formula enriched with Lactobacillus rhamnosus GG: double-blind, randomized trial. J Hum Nutr Diet. 2006;19(1):51-58.
PubMed   |  Link to Article
Vlieger  AM, Robroch  A, van Buuren  S,  et al.  Tolerance and safety of Lactobacillus paracasei ssp. paracasei in combination with Bifidobacterium animalis ssp. lactis in a prebiotic-containing infant formula: a randomised controlled trial. Br J Nutr. 2009;102(6):869-875.
PubMed   |  Link to Article
Weizman  Z, Alsheikh  A.  Safety and tolerance of a probiotic formula in early infancy comparing two probiotic agents: a pilot study. J Am Coll Nutr. 2006;25(5):415-419.
PubMed   |  Link to Article
Metcalf  TJ, Irons  TG, Sher  LD, Young  PC.  Simethicone in the treatment of infant colic: a randomized, placebo-controlled, multicenter trial. Pediatrics. 1994;94(1):29-34.
PubMed
Danielsson  B, Hwang  CP.  Treatment of infantile colic with surface active substance (simethicone). Acta Paediatr Scand. 1985;74(3):446-450.
PubMed   |  Link to Article
Biasucci  G, Benenati  B, Morelli  L, Bessi  E, Boehm  G.  Cesarean delivery may affect the early biodiversity of intestinal bacteria. J Nutr. 2008;138(9):1796S-1800S.
PubMed
Barr  RG, Kramer  MS, Boisjoly  C, McVey-White  L, Pless  IB.  Parental diary of infant cry and fuss behaviour. Arch Dis Child. 1988;63(4):380-387.
PubMed   |  Link to Article
metaRegister of Controlled Trials: registered trials ISRCTN95287767, NCT01067027, NCT01279265, NCT01541046, and NCT01017991. http://www.controlled-trials.com/mrct/. Accessed September 10, 2012.

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eTable 1. Characteristics of individual excluded trial.

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