Cochrane Database of Systematic Reviews (Protocols) || Oral probiotics for infantile colic

Oral probiotics for infantile colic (Protocol)

Praveen V Praveen S Deshpande G Patole SK

This is a reprint of a Cochrane protocol prepared and maintained by The Cochrane Collaboration and published in The Cochrane

Library 2014 Issue 3

httpwwwthecochranelibrarycom

Oral probiotics for infantile colic (Protocol)

Copyright copy 2014 The Cochrane Collaboration Published by John Wiley amp Sons Ltd

T A B L E O F C O N T E N T S

1HEADER

1ABSTRACT

1BACKGROUND

4OBJECTIVES

4METHODS

10ACKNOWLEDGEMENTS

10REFERENCES

14CONTRIBUTIONS OF AUTHORS

14DECLARATIONS OF INTEREST

iOral probiotics for infantile colic (Protocol)


[Intervention Protocol]

Oral probiotics for infantile colic

Vijayakumar Praveen1 Shama Praveen2 Girish Deshpande3 Sanjay K Patole4

1Mountain View Regional Medical Center Las Cruces NM USA 2Neonatal Perinatal Medicine Pediatrix Medical Group El Paso

Texas USA 3Neonatal Pediatrics Nepean Hospital Sydney and University of Sydney Kingswood Australia 4School of Paediatrics

and Child Health School of Womenrsquos and Infantrsquos Health University of Western Australia King Edward Memorial Hospital Perth

Australia

Contact address Vijayakumar Praveen Mountain View Regional Medical Center 4311 East Lohman Ave Las Cruces NM 88011

USA drpraveenvijayhotmailcom

Editorial group Cochrane Developmental Psychosocial and Learning Problems Group

Publication status and date New published in Issue 3 2014

Citation Praveen V Praveen S Deshpande G Patole SK Oral probiotics for infantile colic Cochrane Database of Systematic Reviews

2014 Issue 3 Art No CD010986 DOI 10100214651858CD010986


A B S T R A C T

This is the protocol for a review and there is no abstract The objectives are as follows

To systematically assess the efficacy and adverse effects of oral probiotics in reducing colic in infants less than six months of age

B A C K G R O U N D

Description of the condition

Infantile colic is defined as paroxysmal (sudden brief and repet-

itive) excessive inconsolable crying for more than three hours a

day at least three days a week for one week or more in an other-

wise healthy baby (Wessel 1954 Roberts 2004 Savino 2007a) It

is most frequently observed in infants between two weeks and four

months of age Colicky infants typically present with excessive and

persistent crying that tends to occur in the evening peaking at six

weeks of age associated with drawing up of the legs tension of

the body flushing of the face and meteorism (the accumulation

of gas in the lumen of the gastrointestinal tract associated with

abdominal distension) The diagnosis is entirely clinical in nature

The infantrsquos discomfort expressed by crying can be due to a vari-

ety of reasons ranging from benign to life threatening (Freedman

2009) Thus all colicky infants should have a complete medical

assessment in order to exclude underlying medical conditions that

may require further evaluation and treatment The natural history

of infantile colic is believed to be self-limiting and symptoms gen-

erally improve by three to four months of age Taking these aspects

into consideration hospital admission for these infants is unnec-

essary and should be discouraged (Savino 2007b) The prevalence

of infantile colic ranges widely from 3 to 40 (Lucassen 2001)

and fewer than 5 of distressed infants have identifiable medical

explanations for their crying (Heine 2008)

Over the years many studies have been conducted to determine

the cause of this condition even though its self-limiting nature has

precluded the use of invasive investigations Although the term

lsquocolicrsquo implies a gastrointestinal disease the aetiology remains elu-

sive and is most likely multifactorial (Savino 2007b) Gupta 2002

suggested roles for both behavioural factors (psychological and so-

cial) and biological components (food hypersensitivity or allergy

or both and gut dysmotility) assuming that certain infants are pre-

disposed to visceral hypersensitivity (enhanced sensation of pain

from the internal organs of the viscera) and hyperalgesia (a state

of abnormally increased sensitivity to pain) in the first weeks of

1Oral probiotics for infantile colic (Protocol)


life In particular it has been observed that a subset of infants with

severe colicky symptoms suffer from cowrsquos milk allergy and in

these infants dietetic treatment should be the first therapeutic ap-

proach (Iacono 2005) Colic has been found to be more frequent

in formula-fed infants than in breast-fed infants (Cohen 2012)

Infant colic not only results in increased crying time but is also

related to long-term outcomes such as maternal sensitivity sepa-

ration anxiety temper tantrums and altered sleep patterns (Stifter

1998) While there appears to be no negative effect of infant colic

on maternal behaviour there is some evidence that mothers are af-

fected personally by their interactions with an inconsolable child

The study by Stifter 1998 also reported that mothers of infants

who had colic rated themselves as less competent than mothers of

infants who did not have colic

Recently data supporting the concept of aberrant gut microbiota

in infants with colic have been presented suggesting its influence

on gut motor function and gas production (Savino 2009) and

possibly emphasising an inflammatory origin for the condition

(Savino 2006) Considering the lack of a unifying theory in the

pathogenesis of infantile colic probiotics may offer a promising

therapeutic direction

Description of the intervention

Various therapeutic interventions have been used for infant colic

including simethicone herbal remedies such as fennel extract and

chamomile sucrose and glucose solutions manipulation (Dobson

2012) massage and reflexology Recently the role of aberrant gut

flora in infant colic has resulted in the study of probiotics in this

area Probiotics are orally administered live organisms with poten-

tial health benefits to the host Lactobacillus and Bifidobacterium

species are the organisms most commonly used as probiotics The

definitions of probiotic and related interventions are as follows

Probiotic an oral supplement or a food product that contains a

sufficient number of viable micro-organisms to alter the microflora

of the host and has the potential for beneficial health effects (CAST

2010 FAO 2010)

Prebiotic an indigestible food ingredient that benefits the host by

selectively stimulating the favourable growth or activity or both

of one or more indigenous probiotic bacteria (Roberfroid 2007

CAST 2010 FAO 2010)

Synbiotic a product that contains both probiotics and prebiotics

Evidence for synergy between a specific prebiotic and a probiotic

in the product is not essential Synbiotics may be separate supple-

ments or may exist in functional foods as food additives (CAST

2010 FAO 2010)

Postbiotic a metabolic by-product generated by a probiotic micro-

organism that influences the hostrsquos biological functions (Commane

2005 Falony 2006)

Functional food any modified food or food ingredient that pro-

vides a health benefit beyond that ascribed to any specific nutri-

ent(s) it may contain It must remain a food and demonstrate its

effect in amounts normally expected to be consumed Benefits may

include functions relevant to improving health and well-being or

reducing risk of disease or both Any food that contains probiotics

or prebiotics is a functional food An example of a functional food

is live-culture yogurt that contains probiotic bacteria prebiotics

and other dietary nutrients

Probiotics may also be delivered by means of faecal bacteriotherapy

via the rectal route These probiotics have been studied in adults

but there are no current data on probiotics delivered by the rectal

route in infants

Safety of probiotics

Probiotic sepsis long-term altered immune responses and the de-

velopment of antibiotic resistance are the main concerns with pro-

biotic therapy Hempel 2011 reported a comprehensive survey as-

sessing the safety of Lactobacillus Bifidobacterium Saccharomyces

Streptococcus Enterococcus and Bacillus strains in the prevention

treatment or risk reduction of disease in humans (including chil-

dren adults and the elderly) Their search identified 11977 publi-

cations of which 622 were included in the review In 235 studies

only non-specific safety statements were made the remaining 387

reported the presence or absence of specific adverse events The

studies primarily assessed Lactobacillus alone or in combination

with other genera often Bifidobacterium Many case reports de-

scribed fungaemia and bacteraemia as potentially associated with

probiotic organisms Randomised controlled trials (RCTs) showed

no significant increased risk of adverse events associated with

short-term probiotic use Long-term effects remained largely un-

known There was a lack of assessment and systematic reporting

of adverse events Rare adverse events were difficult to assess They

concluded that the current literature is not well equipped to an-

swer questions on the safety of probiotics with confidence

Ha 1999 systematically reviewed the safety of Lactobacillus and

Bifidobacterium as probiotics Their search revealed many case re-

ports (Husni 1997 Ha 1999 Rautio 1999 Kunz 2004) of sepsis

due to Lactobacillus but none from RCTs of probiotics Systemic

probiotic infection was rarely reported with Bifidobacterium Seri-

ous probiotic infections have been reported mostly in high-risk in-

dividuals particularly those who are debilitated immunocompro-

mised and with indwelling catheters or devices (Broughton 1983

Kalima 1996 Perapoch 2000 Thompson 2001 Salminen 2002

Soleman 2003 Kunz 2004 Salminen 2004 Boyle 2006 Ohishi

2010 Jenke 2012) The American Academy of Pediatrics has also

voiced concern as regards the use of probiotics in children with

such risk factors (Thomas 2010) It is however important to note

that prospective studies indicate the safety of probiotics in im-

munocompromised adults and children with human immunode-

ficiency virus and also in preterm very-low birthweight neonates

(Cunningham-Rundles 2000 Salminen 2004 Alfaleh 2011)

A systematic review (Reddy 2013) has reported that there is in-

sufficient evidence on the effects of probiotics in children with



short bowel syndrome (SBS) where the risk of adverse effects such

as probiotic sepsis is high Overgrowth of commensal lactobacilli

can be a feature of individuals including children with SBS and

is frequently associated with D-lactic acidosis (Bongaerts 1997)

D-Lactic acidosis has been reported in a five-year-old girl with SBS

receiving probiotic supplementation containing Lactobacillus aci-

dophilus (suspected causative agent) Lactobacillus bulgaricus Strep-

tococcus faecalis andStreptococcus faecium (Munakata 2010) which

improved after discontinuing the probiotic Ku 2006 reported a

five-year-old boy with SBS who developed recurrent episodes of

D-lactic acidosis whilst on L acidophilus and Bifidobacterium in-

fantis which resolved when enteral feeds were interrupted He de-

veloped further episodes when his milk formula was inadvertently

changed to one containing L acidophilus and Bifidobacterium spp

(Ku 2006) Consumption of probiotic strains that produce L-lac-

tate exclusively is not likely to present a problem for such infants

and may be useful in their treatment (Vanderhoof 1998)

Probiotic prophylaxis with Lactobacillus rhamnosus GG (LGG)

has been reported to reduce the frequency of atopic dermatitis

(Kalliomaumlki 2001) in neonates However recent trials have re-

ported no such benefits in neonates after supplementation with

LGG and L acidophilus (Ha 1999) Moreover an unexpected in-

crease in recurrent wheezing bronchitis was observed in children

who received LGG (Kopp 2008 Kopp 2009) Taylor 2007 ad-

ministered L acidophilus (LAVRI-A1) to newborns for the first six

months of life There was no effect on the prevention of atopic

dermatitis but an increased rate of sensitisation was observed in

the probiotic group versus the control group However at follow-

up the higher rates of sensitisation seen previously at one year of

age in the probiotic group were no longer apparent after the third

year of life (Taylor 2007 Prescott 2008) Skin prick test (SPT)

responses to three different probiotic preparations (Fiorilacreg Di-

coflorreg and Reuterinreg) were evaluated in addition to relevant

food allergens in children with cowrsquos milk allergy (Bruni 2009)

The proportion of SPT reactions to all tested probiotic products

was significantly lower than to cowrsquos milk Significantly higher

sensitisation was observed for Fiorilac versus Dicoflor and versus

Reuterin It was recommended that probiotic use in individuals

with cowrsquos milk allergy has to be limited to products that do not

contain milk It was advised that in selected individuals a screen-

ing SPT with the product is important to evaluate its potential

contamination with milk Martiacuten-Muntildeoz 2012 investigated the

safety of probiotics in individuals with food allergies Their results

indicated that commercially available probiotic compounds may

contain hidden food allergens and may not be safe for those with

cowrsquos milk or henrsquos egg protein allergy

Many lactobacilli strains are naturally resistant to vancomycin

(Borriello 2003) The vancomycin resistance genes of Lactobacil-

lus species appear to be chromosomally located and are not easily

transferable to other genera (Tynkkynen 1998) Another potential

concern is the transfer of plasmid-mediated antibiotic resistance

(eg tetracycline resistance through a Lactobacillus reuteri strain

(Rosander 2008) However follow-up studies have not indicated

antibiotic resistance as a concern despite the adoption of probi-

otics on a population level in Finland (Salminen 2002)

Overall the current evidence indicates that probiotic lactobacilli

and bifidobacteria are safe and well tolerated by healthy infants and

children and have no adverse events (Vanderhoof 1998 Pedone

1999 Saavedra 1999 Cunningham-Rundles 2000 Guandalini

2000 Borriello 2003 Petschow 2005) However considering that

their associated risk is not zero monitoring for adverse events

is important even when probiotics are used in otherwise healthy

infants with colic

How the intervention might work

It is hypothesised that infant colic may have medical (organic) or

behavioural causes Among the organic causes a role for intestinal

lactobacilli and a coliform colonisation pattern has been suggested

and proposed in the pathogenesis of infantile colic (Savino 2004

Savino 2005 Rhoads 2009 Savino 2009)

Experimental studies suggest a possible mechanism of action of L

reuteri through an improvement in gut motility and function and

direct effects on visceral pain It has been demonstrated that L

reuteri acts on colon motility by targeting ion channels in enteric

sensory nerves (Kunze 2009) More recentlyL reuteri ingestion

has been shown to enhance the tonic inhibition of rat colon con-

tractile activity by acting via the intermediate conductance cal-

cium-dependent potassium channel IK(Ca) current in myenteric

AH cells (Wang 2010) Modulation of motility via AH cell ex-

citability could be a pathway through which probiotics influence

extrinsic sensory neurones and thus central nervous system activity

(Wang 2010) L reuteri ingestion has been shown to prevent the

hyperexcitability of colonic dorsal root ganglion somas induced by

noxious stimuli (Ma 2009) Finally the effects of L reuteri on the

immune system have been documented showing a suppression of

proinflammatory cytokines in macrophages monocytes and den-

dritic cells and a promotion of regulatory T cells producing in-

terleukin-10 and transforming growth factor-beta The modula-

tion of immune responses is likely to underlie the ability of L

reuteri to reduce intestinal inflammation in several murine colitis

models (Walter 2011) Probiotics such as Bifidobacterium have

been shown to induce varying cytokine production (He 2002)

Probiotics have been studied in another gastrointestinal disorder

characterised by visceral hypersensitivity autonomic dysfunction

motor dysfunction and psychological factors - irritable bowel syn-

drome (Andresen 2006)

Specific data about the differential effects of probiotics versus pro-

biotic-supplemented infant formula are not currently available al-

though LGG (as a part of hydrolysed formula) has been shown to

decrease faecal calprotectin and improve recovery in infants with

blood in their stools and presumptive allergic colitis compared

with hydrolysed formula alone (Baldassarre 2010) Currently two

infant formulas contain probiotics one contains Bifidobacterium



lactis and the other LGG These probiotics are added only to pow-

dered formula at present The overall health benefit of adding

probiotics to infant formula remains to be demonstrated in large

RCTs The effects of probiotics are strain specific (Kirjavainen

1999 Luyer 2005) and their dose-response relationships have been

documented in studies (Gill 2001 Larsen 2006 Gao 2010)

Why it is important to do this review

Infantile colic is a common disorder with a prevalence of 3

to 28 in neonates and infants between two weeks and four

months of age (Keefe 2006 Savino 2010)The pathogenesis of

colic is poorly understood and involves a range of risk factors

Simethicone the best available and most commonly prescribed

treatment for infant colic has been found to be no more effec-

tive than placebo (Garrison 2000 Lucassen 2000 an up-to-date

review of the evidence is being carried out Savino 2012a) Gut

flora has been recently proposed to play an important role in the

pathogenesis of colic (Savino 2007b) Observational studies and

clinical trials report probiotics to be beneficial in the treatment

of colic (Savino 2010) A recent systematic review on nutritional

supplements and complementary medicine in infant colic showed

that although some encouraging results exist for fennel extract

mixed herbal tea and sugar solutions design flaws and the absence

of independent replications preclude practice recommendations

(Perry 2011) The methodology of the Perry 2011 review was not

rigorous and did not include some recent trials

Considering the impact of the condition the increasing scope

of oral probiotics in the field of neonatology (necrotising en-

terocolitis) and paediatrics (allergic enteritis) (Baldassarre 2010

Deshpande 2010 Deshpande 2011) as well as the relatively low

cost and easy availability of probiotics we believe it is important

to evaluate the current evidence of probiotics in the field of infant

colic in terms of both effectiveness and safety using the rigorous

methodology of a Cochrane systematic review

O B J E C T I V E S

To systematically assess the efficacy and adverse effects of oral

probiotics in reducing colic in infants less than six months of age

M E T H O D S

Criteria for considering studies for this review

Types of studies

RCTs and quasi RCTs

Types of participants

Inclusion criteria infants up to six months of age however fed

with a clinical diagnosis of infant colic that satisfies the modified

Wesselrsquos criteria (Wessel 1954) of at least three hours of crying

time per day for at least three days for at least a week prior to

enrolment in a trial

Exclusion criteria i) preterm infants ii) infants with clinical

chronic gastrointestinal illnesses such as gastro-oesophageal reflux

disease iii) infants who have received antibiotics or probiotics dur-

ing the period preceding the administration of trial probiotics

Types of interventions

Oral probiotics of any strain dose or duration in any form (ie

as part of synbiotics or as a functional food in probiotic-supple-

mented infant formula) compared with conventional care (eg

simethicone) placebo or no treatment We will include studies in

which probiotics were delivered in conjunction with conventional

care versus conventional care alone

We will exclude studies that involve (i) dietary modifications to the

motherrsquos diet and (ii) education interventions that instruct such

modifications For further information on these interventions we

direct authors to the following Cochrane Review rsquoDietary modi-

fications for infantile colicrsquo (Savino 2012b)

Types of outcome measures

Primary outcomes

1 A reduction in the duration of crying (post-treatment

versus baseline) Data may be continuous (eg hours per day)

or dichotomous (eg reduction to below a pre-defined threshold

as determined by the trial authors)

Secondary outcomes

1 The number of responders in each group after treatment

Responders will be defined as those who experienced a decrease

in the daily average crying time of 50 from baseline

(dichotomous outcome)

2 Reduction in frequency of crying episodes per 24 hours

(post treatment versus baseline) dichotomous outcome

3 Parental or family quality of life including measures of

parental anxiety stress or depression (continuous outcome)

4 Infant sleep duration per 24 hours at 7 14 21 days (post

treatment versus baseline) (continuous outcome)

5 Parental satisfaction measured by Likert scale or NRS

(Numeric Rating Scale) (continuous outcome)



6 Adverse effects constipation vomiting sepsis (including

probiotic strain sepsis) diarrhoea apnoea ALTE (apparent life

threatening event) (dichotomous variable)

7 Intestinal microflora analysis to determine the effect of the

probiotic on selected intestinal microbiota

Outcomes marked with an asterisk will be used to populate the

rsquoSummary of findingsrsquo table

Search methods for identification of studies

Electronic searches

We will search the following databases

1 Cochrane Central Register of Controlled Trials

(CENTRAL)

2 Ovid MEDLINE

3 Ovid MEDLINE In-Process and Other Non-Indexed

Citations

4 Embase

5 CINAHL

6 PsycINFO

7 Science Citation Index

8 Social Sciences Citation Index

9 Cochrane Database of Systematic Reviews

10 Database of Abstracts of Reviews of Effects (DARE)

11 Conference Proceedings Citation Index-Science

12 Conference Proceedings Citation Index-Social Science and

Humanities

13 WorldCat (limited to theses)

14 Networked Digital Library of Theses and Dissertations (

ndltdorg)

15 DART-Europe E-theses Portal (dart-europeeu)

16 TROVE (limited to theses) (trovenlagovau)

17 MetaRegister of Controlled Trials (controlled-trialscom)

18 ClinicalTrialsgov (clinicaltrialsgov)

19 Australian and New Zealand Clinical Trials Registry (

anzctrorgau)

20 World Health Organization International Trials Registry

Platform (appswhointtrialsearch)

21 PubMed Dietary Supplement Subset (odsodnihgov

ResearchPubMed_Dietary_Supplement_Subsetaspx

The search strategy below will be used in Ovid MEDLINE and

adapted for the other databases

1 colic

2 colic$tw

3 ((stomach or abdominal or abdomen$) adj3 (spasm$ or pain$

or cramp$))tw

4 ((gastric or gastro$) adj3 (spasm$ or pain$ or cramp$))tw

5 crying

6 (cry or crying or cries)tw

7 or1-6

8 probiotics

9 probiotic$tw

10 Complementary Therapies

11 Dietary Supplements

12 Gastrointestinal Agents

13 exp lactobacillaceae

14 lactobacill$tw

15 exp Bifidobacterium

16 Bifidobacter$tw

17 Bifidus$tw

18 exp Saccharomyces

19 Saccharomyces$tw

20 Streptococcus

21 streptococc$tw

22 Lactic acid bacteria$tw

23 (Biogaia or Culturelle or Enflora$ or Florastor or ((Gerber$ or

Nestle$) adj2 (Goodstart or Good Start)) or Nutramigen or VSL

3)tw

24 (Baby$ Bliss or Baby$ Own or Colic Calm or Colic Ease or

colic drops or Colief or Dentinox or Gripe Water or Infacol or

Little Tummy$)tw

25 or8-24

26 exp infant

27 (baby or babies or infant$ or child$ or newborn$ or

neonat$)tw

28 26 or 27

29 7 and 25 and 28

Searching other resources

References from published studies

We will scan the bibliographies of included and excluded studies

for possible references to RCTs

Unpublished literature

In addition to searching the trials registers and theses reposito-

ries listed above we will obtain additional information on unpub-

lished ongoing trials via correspondence with trial authors We

will also contact the manufacturers of relevant probiotics (includ-

ing Biogaiareg Culturellereg Florastorreg Mead Johnsonreg Nes-

tlereg) We will search the world wide web using Bing Google and

Google Scholar using the search criteria described above to iden-

tify grey literature When relevant unpublished or ongoing studies

are identified we will then attempt to obtain sufficient details to

incorporate them in the review

Handsearching



We will handsearch the abstracts of meetings of the Pediatric Aca-

demic Societies - Society for Pediatric Research and Pediatric Gas-

troenterology for further RCTs

Adverse effects

We will search for adverse effects of probiotics used in the treat-

ment of infant colic For common adverse event data we will use

RCT data only Formulating a separate search and strategy for rare

adverse events in studies with other designs is outside the purview

of the current review Any findings will be summarised qualita-

tively in the rsquoDiscussionrsquo section of the review

Language

We will not impose any language restrictions and we will seek

translations where applicable

Data collection and analysis

Selection of studies

Two review authors (VP and SP) will independently select studies

for inclusion in the review We will screen the search results using

titles of papers and abstracts when available We will retrieve the

full text of the selected articles and assess them for inclusion ac-

cording to prespecified selection criteria We will measure inter-

rater reliability using kappa statistics and we will explore reasons

for disagreement between reviewers based on the guidelines pro-

vided in the Cochrane Handbook for Systematic Reviews of Interven-

tions (Higgins 2011a)

Data extraction and management

Two authors (GD VP) will independently extract the following

data using a standardised data extraction form author year of

publication language study setting funding source definition

and diagnostic criteria for infant colic inclusion and exclusion

criteria for participants participant characteristics (age preterm

or term gender diagnosis) probiotic synbiotic or probiotic-sup-

plemented formula (strain dose frequency duration) outcome

measures (mean daily duration of crying number of inconsolable

crying episodes number of responders at various time periods

intestinal microflora analysis using fluorescence in situ hybridisa-

tion number of adverse events (sepsis vomiting constipation di-

arrhoea) number of participants allocated to each group presence

or absence of intention-to-treat analysis (whether participants for

whom data were available were analysed as randomised) partici-

pants lost to follow up and reasons for loss to follow up informa-

tion about methods of imputation and measures of compliance

When necessary we will individually contact the lead authors of

studies that do not report relevant statistical data such as odds

ratios (OR) and standard errors Any differences of opinion will

be resolved by team authors SP and GD

Assessment of risk of bias in included studies

Two authors (VP and SP) will independently assess the risk of bias

in each included trial for the following six components sequence

generation allocation concealment blinding or masking incom-

plete outcome data selective outcome reporting and other biases

For each of these components we will assign an assessment of risk

of bias as high low or unclear (Higgins 2011b) These assessments

will be analysed independently by the other authors (GP and SP)

We will resolve differences by discussion We will attempt to con-

tact the trial authors for clarification when methodological details

are unclear We will record these assessments in standard rsquoRisk

of biasrsquo tables in Review Manager (RevMan) 5 (Review Manager

2011) and summarise them in a rsquoRisk of biasrsquo figure and graph

We will use these assessments in making judgements about overall

study quality when preparing rsquoSummary of findingsrsquo tables

Sequence generation

We will assess randomisation as at rsquolow risk of biasrsquo if the proce-

dure of sequence generation was explicitly described and consid-

ered adequate to produce comparable groups Examples include

computer-generated random numbers a random numbers table

or coin tossing We will assess randomisation as at rsquohigh risk of

biasrsquo if sequence generation was based on participant record num-

bers date of birth day or week of presentation or alternation If

the authors of the trial mention randomised sequence generation

without completely defining the actual process we will assess the

trial as at rsquounclear risk of biasrsquo

Allocation concealment

We will assess concealment of treatment allocation as at rsquolow risk

of biasrsquo if the procedure was explicitly described and adequate

to ensure that intervention allocations could not be foreseen in

advance of or during enrolment Examples include centralised

randomisation numbered or coded containers or sealed envelopes

We will assign a rsquohigh risk of biasrsquo to studies in which inadequate

procedures were applied such as alternation or references to case

record numbers or dates of birth We will assign an rsquounclear risk

of biasrsquo if there is insufficient information to permit a judgement

of either a rsquolow risk of biasrsquo or a rsquohigh risk of biasrsquo to be made (eg

the use of assignment envelopes is described but it is unclear that

they were sequentially numbered opaque and sealed)

Blinding of participants clinicians and outcome assessors

We will assess the risk of bias associated with the blinding of par-

ticipants clinicians and outcome assessors based on the likelihood

that such blinding is sufficient to ensure that the outcome asses-

sors (usually parents) had no knowledge of which intervention the

infant received Blinding of infants is not of course considered

necessary in the infant study population We will assign a rsquohigh

risk of biasrsquo to studies that used no or incomplete blinding or in



which there is a likelihood that the binding was broken We will

assign an rsquounclear risk of biasrsquo if there is inadequate information

to permit a judgement of either a rsquolow risk of biasrsquo or a rsquohigh risk

of biasrsquo to be made or if the study does not address the outcome

Incomplete outcome data

We will assess the reporting of incomplete outcome data as at

rsquolow risk of biasrsquo if attrition and exclusions were reported reasons

for attrition were reported and any re-inclusions in analyses were

performed by the authors

We will assess the reporting of incomplete outcome data as at rsquohigh

risk of biasrsquo in case of one or more of the following situations

i) if a difference in the proportion of incomplete outcome data

across groups is determined by a participantrsquos true outcomes

ii) if the reasons for missing outcomes differ among the groups

iii) the proportion of missing outcome data when compared to

observed event risk is sufficient to cause clinically relevant bias in

the intervention size estimate

iv) in the case of studies that report rsquoas-treated analysesrsquo with sub-

stantial departure from the intervention assigned at the time of

randomisation

v) in the case of the potentially inappropriate imputation of miss-

ing outcomes data as if they were real measurements


rsquounclear risk of biasrsquo if there is insufficient reporting of attrition or

inclusion data or both to permit a judgement of either a rsquolow risk

of biasrsquo or a rsquohigh risk of biasrsquo to be made (ie if unstated numbers

are randomised or reasons for missing data are not provided or if

the study did not address the outcome)

Selective reporting

If all of the outcomes mentioned in the Methods section of the

study article have been reported in the Results section then we will

assess selective reporting to be at rsquolow risk of biasrsquo We will also

look at different reported versions of the same study including

protocols and examine them for any evidence of selective outcome

reporting We will assign a rsquohigh risk of biasrsquo if not all of the

studyrsquos prespecified outcomes are reported outcomes are reported

using subscales that were not prespecified or if key outcomes are

excluded The criterion for a judgement of an rsquounclear risk of biasrsquo

will be insufficient information to permit a judgement of either a

rsquohigh risk of biasrsquo or a rsquolow risk of biasrsquo to be made

Other potential threats to validity

We will assess other threats to validity as at rsquolow risk of biasrsquo if the

study appears to be free of other sources of bias such as the study

being stopped prematurely due to a data-dependent process or a

baseline imbalance between the groups Where the risk of bias is

rsquounclearrsquo from published information we will attempt to contact

authors for clarification If this is not forthcoming we will assess

the study as at rsquounclear risk of biasrsquo A rsquohigh risk of biasrsquo will be

assigned if the study has a potential source of bias relating to a

specific type of study design or if the study was claimed to have

been fraudulent The review authors will not be blinded to the

titles of the journals or the identities of the authors as they are

familiar with the field

Measures of treatment effect

For dichotomous outcomes we shall use OR and 95 confidence

intervals (CI)

For continuous outcomes assessed using the same rating scale in all

studies in the comparison we shall use the mean difference with

95 CI where different rating scales have been used to measure

the same outcome for a comparison we shall extract the mean

values and their standard deviations and combine them using the

standardised mean difference (SMD)

Unit of analysis issues

Cluster-randomised trials

We shall use the statistical methods described by Higgins 2008 if

cluster-randomised trials are included in this review If included

trials are randomised by clusters and the results have been adjusted

for clustering then we will combine the adjusted measures of

effects of these cluster-randomised trials If results have not been

adjusted for clustering we will attempt to adjust the results for

clustering by multiplying the standard errors of the estimates by

the square root of the design effect where the design effect is

calculated as DEff = 1 + (M - 1) ICC where M is the average

cluster size and ICC is the intra-cluster coefficient (an estimate

of the relative variability within and between clusters within the

studies) (Donner 1980) We will attempt to obtain the ICC from

the article and if it is not available we will use external estimates

obtained from similar studies Subsequently the estimates and

their corrected standard errors from the cluster-randomised trials

will be combined with those from parallel-group designs using the

generic inverse variance method in RevMan 5 (Review Manager

2011) If necessary we shall seek statistical advice from the editorial

base of the Cochrane Developmental Psychosocial and Learning

Problems Group (CDPLPG)

Cross-over trials

Data from cross-over trials will be pooled according to the meth-

ods described in the Cochrane Handbook for Systematic Reviews of

Interventions (Higgins 2011c) The mean of the within-participant

difference and the standard error of the mean difference will be

entered into RevMan 5 (Review Manager 2011) using the generic

inverse outcome type Where the standard error of the difference

in means is not reported the original data will be requested from

study authors or the value will be imputed Correlation coefficients

will be calculated from studies where sufficient data are available

and if consistent will be used to calculate the missing standard

errors for other studies



The analysis of a cross-over trial should take advantage of the

within-person design and use some form of paired analysis

(Elbourne 2002) In the presence of carry-over in cross-over trials

a common strategy is to base the analysis on only the first period

Although the first period of a cross-over trial is in effect a parallel-

group comparison use of data from only the first period will be

biased if as is likely the decision to do so is based on a statistically

significant test of carry-over Cross-over trials for which only first

period data are available will be considered to be at risk of bias

especially when the two-stage strategy is used This lsquotwo stage anal-

ysisrsquo has been discredited (Freeman 1989) but is still used Also

use of the first period data only removes the main strength of the

cross-over design the ability to compare treatments within indi-

viduals

Although trial authors may have analysed paired data poor pre-

sentation may make it impossible for review authors to extract

paired data Unpaired data may be available and generally will

be unrelated to the estimated treatment effect or statistical signif-

icance While this is not a source of bias it usually leads to a trial

getting (much) less than its due weight in a meta-analysis

Dealing with missing data

We shall attempt to obtain unreported missing data from the trialrsquos

corresponding author Where possible we will extract data to allow

an intention-to-treat analysis in which all randomised participants

are analysed in the groups to which they were originally assigned

regardless of whether or not they received the allocated interven-

tion If there is discrepancy in the numbers randomised and in the

numbers analysed in each treatment group we will calculate and

report the percentage lost to follow-up in each group If dropouts

exceed 10 for any trial we shall assign a worse outcome to those

lost to follow-up for dichotomous outcomes and assess the impact

of this in sensitivity analyses with the results of completers

For continuous data that are missing standard deviations we will

either calculate these from other available data such as standard

errors (SE) or we will enter them using methods suggested by

Higgins 2011b We shall not make any assumptions about losses

to follow-up for continuous data and we shall analyse results for

those who complete the trial We will perform a sensitivity analysis

by calculating the treatment effect including and excluding the

imputed data to determine whether they altered the outcome of

the analysis Where studies do not report response rates values

will be imputed using the method described in Furukawa 2005

If the relevant studies do not report OR or standard errors or

both then we will contact the authors for raw data (numbers of

events and denominators for outcomes of interest) for both arms

of the study) and use these to derive the summary data such as

OR (Odds ratio) RR (Relative risk) and 95 CI

Where it is not possible to obtain missing data we will record this

in the Data Collection Form report it in the rsquoRisk of biasrsquo table

and discuss the extent to which the missing data could alter the

results of the review

We will look for attrition in all of the included studies and we

will explore the impact of including studies with high levels of

missing data in the overall assessment of treatment effect by using

sensitivity analyses

Assessment of heterogeneity

We will assess the following sources of heterogeneity clinical het-

erogeneity (eg differences in study participants interventions)

methodological heterogeneity (eg differences in study design

randomisation concealment blinding of outcome assessment

losses to follow up) and statistical heterogeneity

We will assess heterogeneity between the trials by visually exam-

ining the forest plot to check for overlapping CI using the Chi2

test for homogeneity with a 10 level of significance and the I2 statistic (Higgins 2002) to assess inconsistency (the percentage

of the variability in effect estimates that is due to heterogeneity

rather than sampling error)

In general we shall interpret an I2 value of 50 or greater as de-

noting significant heterogeneity but we will be guided by Higgins

that I2 values of 30 to 60 may represent moderate heterogene-

ity (Higgins 2008) Hence we will also interpret significant het-

erogeneity for values of I2 greater than 30 if there are inconsis-

tencies in the magnitude and direction of effect estimates between

studies and if the CI overlap minimally

The classic measure of heterogeneity is Cochranrsquos Q which is cal-

culated as the weighted sum of squared differences between indi-

vidual study effects and the pooled effect across studies with the

weights being those used in the pooling method Q is distributed

as a Chi2 statistic with k (number of studies) minus 1 degrees of

freedom Q has low power as a comprehensive test of heterogeneity

(Gavaghan 2000) especially when the number of studies is small

as for most meta-analyses Conversely Q has too much power as

a test of heterogeneity if the number of studies is large (Higgins

2003) Cochran Q forms part of the DerSimonian Laird random-

effects pooling method (DerSimonian 1986)

We will use the random-effects model This assumes that the ef-

fects being estimated in the different studies are not identical but

follow some distribution The model will represent our lack of

knowledge about why real or apparent intervention effects differ

by considering the differences as if they were random The centre

of the distribution will describe the average of the effects and its

width the degree of heterogeneity RevMan implements a version

of random-effects meta-analysis as described by DerSimonian and

Laird (DerSimonian 1986)

Assessment of reporting biases

We will assess all included studies for the adequacy of reporting

of data for prestated outcomes and for selective reporting of out-

comes We will attempt to obtain the results of any unpublished



studies in order to compare results extracted from published jour-

nal reports with results obtained from other sources We will base

our judgements on the risk of selective reporting in the rsquoRisk of

biasrsquo tables for each included study We will assess the likelihood

of potential publication bias using funnel plots (Egger 1997) as

recommended in the Cochrane Handbook of Systematic Reviews of

Interventions (Sterne 2008) provided that there are at least 10 tri-

als in a forest plot assessing a particular outcome Asymmetry in

a funnel plot may be due to reasons other than publication bias

such as small-study effects heterogeneity and chance We will then

apply the Eggerrsquos test

Data synthesis

If two or more studies prove suitable for inclusion (ie are similar

in i) type of probiotic species ii) type of primary outcome and

iii) type of colic) we will perform a meta-analysis of the results

In other words if two or more studies assess the effects of a pro-

biotic in otherwise healthy infants with colic and both measure

daily crying time then we will perform a meta-analysis If there

are common characteristics we will group studies and further in-

vestigate by using subgroup analyses (see below) As we anticipate

clinical heterogeneity to impact our results given the wide scope

of the types of interventions included we will use the random-

effects methods as described in the Cochrane Handbook for System-

atic Reviews of Interventions (Higgins 2008)

For continuous variables we will use a meta-analysis of change

scores because ldquoit removes a component of between-person vari-

ability from the analysisrdquo (Higgins 2008) and we will apply the

mean difference approach where data allow If studies measure the

same outcome using different scales we will apply the SMD ap-

proach

For dichotomous outcomes we will perform a meta-analysis of OR

and a calculation of the number needed to treat for an additional

beneficial outcome since these (in combination) provide good

consistency mathematical properties and ease of interpretation

(Higgins 2008)

If both continuous and dichotomous outcome data are available

for a particular outcome then we will include only continuous

data in the primary analysis If one study reports outcome data

as dichotomous data while another reports the same outcome as

continuous data we will convert the former from OR to SMD

provided the continuous data have an approximate normal or lo-

gistic distribution If not normally or logistically distributed then

we will conduct separate analyses

We will base the assumed control-group risks on an assessment

of typical risks calculated from the control groups in different

participant groups if appropriate or at different lengths of follow

up If there is little variation in baseline risk we will use the median

control-group risk across the studies

If the studies are too heterogeneous to preclude data synthesis then

we will conduct a narrative analysis on the different studies and

explore the reasons for such differences in the studies

Skewed data we will look at the availability of transformed data in

a log scale if reported by the trials We will collect appropriate data

summaries and individual participant data from the trialists and

consult the statistician of the CDPLPG for appropriate analysis

strategies

We will carry out statistical analysis using RevMan software

(Review Manager 2011)

Subgroup analysis and investigation of heterogeneity

If moderate heterogeneity is detected and if data permit the fol-

lowing subgroup analyses will be carried out for each comparison

and outcome

1 Type of probiotic synbiotic or probiotic-supplemented

infant formula

2 Dosage of probiotic

3 Type of feeding infants on both breast milk and formula

feeds will be grouped according to the predominant type of feed

A) infants receiving more than 85 feeds comprising breast milk

will be grouped as predominantly breast-fed babies B) infants

receiving more than 85 feeds comprising formula will be

grouped as predominantly formula-fed babies

4 Outcome time points based on the clinical course of infant

colic we will define outcome time points as short term if the

infant is younger than six months of age and long term if the

infant is older than six months of age

Sensitivity analysis

Where data permit we will conduct sensitivity analyses to deter-

mine whether findings are sensitive to restricting inclusion to stud-

ies judged to be at low risk of bias In these analyses we will limit

inclusion to those studies that have a low risk of selection bias

(associated with sequence generation or allocation concealment)

performance bias (associated with issues of blinding) and attrition

bias (associated with completeness of data) and are published

We shall undertake sensitivity analyses if trials report dropout rates

of 10 or greater in order to ascertain differences in outcomes

between intention-to-treat analyses (all dropouts will be assigned

to the worst outcome for dichotomous outcomes) and analyses of

completers If the results of these analyses differ significantly with

relation to direction of effect we shall perform two additional

analyses

bull a best-case scenario favouring probiotics (ie none of the

dropouts from the probiotics arm had the unfavourable outcome

but all dropouts from the control group had the outcome)

bull a worst-case scenario favouring the control (ie all the


but none from the control group had this poor outcome)

We shall report the results of all such analyses



In addition we shall undertake sensitivity analyses for any out-

comes from cluster-randomised trials where ICCs were used from

external sources or where missing standard errors of the differ-

ences in means from cross-over trials were imputed

A C K N O W L E D G E M E N T S

The protocol was produced within the CDPLPG

R E F E R E N C E S

Additional references

Alfaleh 2011

Alfaleh K Anabrees J Bassler D Al-Kharfi T Probiotics for

prevention of necrotizing enterocolitis in preterm infants

Cochrane Database of Systematic Reviews 2011 Issue 3

[DOI 10100214651858CD005496pub3]

Andresen 2006

Andresen V Camilleri M Irritable bowel syndrome recent

and novel therapeutic approaches Drugs 200666(8)

1073ndash88

Baldassarre 2010

Baldassarre ME Laforgia N Fanelli M Laneve A Grosso

R Lifschitz C Lactobacillus GG improves recovery in

infants with blood in the stools and presumptive allergic

colitis compared with extensively hydrolyzed formula alone

Journal of Pediatrics 2010156(3)397ndash401

Bongaerts 1997

Bongaerts GP Tolboom JJ Naber AH Sperl WJ Severijnen

RS Bakkeren JA et alRole of bacteria in the pathogenesis

of short bowel syndrome-associated D-lactic acidemia

Microbial Pathogenesis 199722(5)285ndash93

Borriello 2003

Borriello SP Hammes WP Holzapfel W Marteau P

Schrezenmeir J Vaara M Safety of probiotics that contain

lactobacilli or bifidobacteria Clinical Infectious Diseases

200336(3)775ndash80

Boyle 2006

Boyle RJ Robins-Browne RM Tang ML Probiotic use in

clinical practice what are the risks American Journal of

Clinical Nutrition 200683(6)1256ndash64

Broughton 1983

Broughton RA Gruber WC Haffar AA Baker CJ Neonatal

meningitis due to Lactobacillus Pediatric Infectious Disease

19832(5)382ndash4

Bruni 2009

Bruni FM Piacentini GL Peroni DG Bodini A Fasoli

E Boner AL Cowrsquos milk allergic children can present

sensitisation to probiotics Acta Paediatricia 200998(2)

321ndash3

CAST 2010

Council for Agricultural Science and Technology

Probiotics their potential to impact human health

wwwcast-scienceorgpublicationsprobiotics_their_

potential_to_impact_human_healthampshow=productamp

productID=2930 2010 (accessed 21 October 2013)

Cohen 2012

Cohen EA Hadash A Shehadeh N Pillar G Breastfeeding

may improve nocturnal sleep and reduce infantile colic

potential role of breast milk melatonin European Journal of

Pediatrics 2012171(4)729ndash32

Commane 2005

Commane DM Shortt CT Silvi S Cresci A Hughes RM

Rowland IR Effects of fermentation products of pro- and

prebiotics on trans-epithelial electrical resistance in an in

vitro model of the colon Nutrition and Cancer 200551(1)

102ndash9

Cunningham-Rundles 2000

Cunningham-Rundles S Ahrne S Bengmark S Johann-

Liang R Marshall F Metakis L et alProbiotics and immune

response American Journal of Gastroenterology 200095(1

Suppl)S22ndash5

DerSimonian 1986

DerSimonian R Laird N Meta-analysis in clinical trials

Controlled Clinical Trials 19867(3)177ndash88

Deshpande 2010

Deshpande G Rao S Patole S Bulsara M Updated meta-

analysis of probiotics for preventing necrotizing enterocolitis

in preterm neonates Pediatrics 2010125(5)921ndash30

Deshpande 2011

Deshpande G Rao S Patole S Progress in the field of

probiotics year 2011 Current Opinion in Gastroenterology

201127(1)13ndash8

Dobson 2012

Dobson D Lucassen PLBJ Miller JJ Vlieger AM Prescott

P Lewith G Manipulative therapies for infantile colic


[DOI 10100214651858CD004796pub2]

Donner 1980

Donner A Koval JJ The estimation of intraclass correlation

in the analysis of family data Biometrics 198036(1)19ndash23



Egger 1997

Egger M Davey Smith G Schneider M Minder C Bias

in meta-analysis detected by a simple graphical test BMJ

1997315(7109)629ndash34

Elbourne 2002

Elbourne DR Altman DG Higgins JPT Curtin F

Worthington HV Vaillancourt JM Meta-analyses involving

cross-over trials methodological issues International

Journal of Epidemiology 200231(1)140ndash9

Falony 2006

Falony G Vlachou A Verbrugghe K De Vuyst L Cross-

feeding between Bifidobacterium longum BB536 and

acetate-converting butyrate-producing colon bacteria

during growth on oligofructose Applied and Environmental

Microbiology 200672(12)7835ndash41

FAO 2010

Food Agriculture Organization of the United Nations

World Health Organization Guidelines for the evaluation

of probiotics in food wwwfdagovohrmsdocketsdockets

95s031695s-0316-rpt0282-tab-03-ref-19-joint-faowho-

vol219pdf 2010 (accessed 21 October 2013)

Freedman 2009

Freedman SB Al-Harthy N Thull-Freedman J The

crying infant diagnostic testing and frequency of serious

underlying disease Pediatrics 2009123(3)841ndash8

Freeman 1989

Freeman PR The performance of the two-stage analysis

of two-treatment two-period cross-over trials Statistics in

Medicine 19898(12)1421ndash32

Furukawa 2005

Furukawa TA Cipriani A Barbui C Brambilla P

Watanabe N Imputing response rates from means and

standard deviations in meta-analyses International Clinical

Psychopharmacology 200520(1)49ndash52

Gao 2010

Gao XW Mubasher M Fang CY Reifer C Miller LE

Dose-response efficacy of a proprietary probiotic formula of

Lactobacillus acidophilus CL1285 and Lactobacillus casei

LBC80R for antibiotic-associated diarrhea and Clostridium

difficile-associated diarrhea prophylaxis in adult patients

American Journal of Gastroenterology 2010105(7)1636ndash41

Garrison 2000

Garrison MM Christakis DA A systematic review of

treatments for infant colic Pediatrics 2000106(1Pt 2)

184ndash90

Gavaghan 2000

Gavaghan DJ Moore AR McQay HJ An evaluation of

homogeneity tests in meta-analysis in pain using simulations

of patient data Pain 200085(3)415ndash24

Gill 2001

Gill HS Rutherford KJ Viability and dose-response

studies on the effects of the immunoenhancing lactic acid

bacterium Lactobacillus rhamnosus in mice British Journal

of Nutrition 200185(2)285ndash9

Guandalini 2000

Guandalini S Pensabene L Zikri MA Lactobacillus GG

administered in oral rehydration solution to children with

acute diarrhoea a multicenter European trial Journal of

Pediatric Gastroenterology and Nutrition 200030(1)54ndash60

Gupta 2002

Gupta SK Is colic a gastrointestinal disorder Current

Opinion in Pediatrics 200214(5)588ndash92

Ha 1999

Ha GY Yang CH Kim H Chong Y Case of sepsis caused

by Bifidobacterium longum Journal of Clinical Microbiology

199937(4)1227ndash8

He 2002

He F Morita H Hashimoto H Hosoda M Kurisaki J

Ouwehand AC et alIntestinal Bifidobacterium species

induce varying amounts of cytokine production Journal of

Allergy and Clinical Immunology 2002109(6)1035ndash6

Heine 2008

Heine RG Allergic gastrointestinal motility disorders

in infancy and early childhood Pediatric Allergy and

Immunology 200819(5)383ndash91

Hempel 2011

Hempel S Newberry S Ruelaz A Wang Z Miles JNV

Suttorp MJ et alSafety of probiotics to reduce risk and

prevent or treat disease wwwncbinlmnihgovbooks

NBK56091 2011 (accessed 20 November 2013)

Higgins 2002

Higgins JPT Thompson SG Quantifying heterogeneity in a

meta-analysis Statistics in Medicine 200221(11)1539ndash58

Higgins 2003

Higgins JPT Thompson SG Altman DG Measuring

inconsistency in meta-analyses BMJ 2003327557

Higgins 2008

Deeks JJ Higgins JPT Altman DG Chapter 9 Analysing

data and undertaking meta-analyses In Higgins JPT

Green S editor(s) Cochrane Handbook for Systematic Reviews

of Interventions Chichester John Wiley amp Sons 2008

243ndash96

Higgins 2011a

Higgins JPT Deeks JJ Chapter 7 Selecting studies

and collecting data In Higgins JPT Green S

(editors) Cochrane Handbook for Systematic Reviews

of Interventions Version 510 [updated March 2011]

The Cochrane Collaboration 2011 Available from

wwwcochrane-handbookorg

Higgins 2011b

Higgins JPT Altman DG Sterne JAC Chapter 8 Assessing

risk of bias in included studies In Higgins JPT Green

S (editors) Cochrane Handbook for Systematic Reviews




Higgins 2011c

Higgins JPT Deeks JJ Altman DG Chapter 16

Special topics in statistics In Higgins JPT Green S







Husni 1997

Husni RN Gordon SM Washington JA Longworth DL

Lactobacillus bacteremia and endocarditis review of 45

cases Clinical Infectious Diseases 199725(5)1048ndash55

Iacono 2005

Iacono G Merolla R DrsquoAmico D Bonci E Cavataio F

Di Prima L et alGastrointestinal symptoms in infancy a

population-based prospective study Digestive and Liver

Disease 200537432ndash8

Jenke 2012

Jenke A Ruf EM Hoppe T Heldmann M Wirth

S Bifidobacterium septicaemia in an extremely low-

birthweight infant under probiotic therapy Archives of

Disease in Childhood Fetal Neonatal Edition 201297(3)

217ndash8

Kalima 1996

Kalima P Masterton RG Roddie PH Thomas AE

Lactobacillus rhamnosus infection in a child following bone

marrow transplant Journal of Infection 199632(2)165ndash7

Kalliomaumlki 2001

Kalliomaumlki M Salminen S Arvilommi H Kero P Koskinen

P Isolauri E Probiotics in primary prevention of atopic

disease a randomised placebo-controlled trial Lancet 2001

357(9262)1076ndash9

Keefe 2006

Keefe MR Kajrisen KA Lobo ML Kotzer AM Dudley

WN Reducing parenting stress in families with irritable

infants Nursing Research 200655(3)198ndash205

Kirjavainen 1999

Kirjavainen PV ElNezami HS Salminen SJ Ahokas JT

Wright PF Effects of orally administered viable Lactobacillus

rhamnosus GG and Propionibacterium freudenreichii

subsp shermanii JS on mouse lymphocyte proliferation

Clinical and Diagnostic Laboratory Immunology 19996(6)

790ndash802

Kopp 2008

Kopp MV Hennemuth I Heinzmann A Urbanek R

Randomized double-blind placebo-controlled trial of

probiotics for primary prevention no clinical effects of

Lactobacillus GG supplementation Pediatrics 2008121(4)

e850ndash6

Kopp 2009

Kopp MV Salfeld P Probiotics and prevention of allergic

disease Current Opinion in Clinical Nutrition and Metabolic

Care 200912(3)298ndash303

Ku 2006

Ku WH Lau DC Huen KF Probiotics provoked D-lactic

acidosis in short bowel syndrome case report and literature

review Hong Kong Journal of Paediatrics 200611246ndash54

Kunz 2004

Kunz AN Noel JM Fairchok MP Two cases of Lactobacillus

bacteremia during probiotic treatment of short gut

syndrome Journal of Pediatric Gastroenterology and

Nutrition 200438(4)457ndash8

Kunze 2009

Kunze WA Mao YK Wang B Huizinga JD Ma X Forsythe

P et alLactobacillus reuteri enhances excitability of colonic

AH neurons by inhibiting calcium dependent potassium

channel opening Journal of Cellular and Molecular Medicine

200913(8B)2261ndash70

Larsen 2006

Larsen CN Nielsen S Kaeligstel P Brockmann E Bennedsen

M Christensen HR et alDose-response study of probiotic

bacteria Bifidobacterium animalis subsp lactis BB-12 and

Lactobacillus paracasei subsp paracasei CRL-341 in healthy

young adults European Journal of Clinical Nutrition 2006

60(11)1284ndash93

Lucassen 2000

Lucassen PL Assendelft WJ Gubbels JW Van Eijk JT

Douwes AC Infantile colic crying time reduction with a

whey hydrolysate a double-blind randomized placebo-

controlled trial Pediatrics 2000106(6)1349ndash54

Lucassen 2001

Lucassen PL Assendelft WJ Van Eijk JT Gubbels JW

Douwes AC Van Geldrop WJ Systematic review of the

occurrence of infantile colic in the community Archives of

Disease in Childhood 200184(5)398ndash403

Luyer 2005

Luyer MD Buurman WA Hadfoune M Strain-specific

effects of probiotics on gut barrier integrity following

hemorrhagic shock Infection and Immunity 200573(6)

3686ndash92

Ma 2009

Ma X Mao YK Wang B Huizinga JD Bienenstock J Kunze

W Lactobacillus reuteri ingestion prevents hyperexcitability

of colonic DRG neurons induced by noxious stimuli

American Journal of Physiology Gastrointestinal and Liver

Physiology 2009296(4)G868ndash75

Martiacuten-Muntildeoz 2012

Martiacuten-Muntildeoz MF Fortuni M Caminoa M Belver T

Quirce S Caballero T Anaphylactic reaction to probiotics

Cowrsquos milk and henrsquos egg allergens in probiotic compounds

Pediatric Allergy Immunology 201223(8)778ndash84

Munakata 2010

Munakata S Arakawa C Kohira R Fujita Y Fuchigami

T Mugishima H A case of D-lactic acid encephalopathy

associated with use of probiotics Brain and Development

201032(8)691ndash4

Ohishi 2010

Ohishi A Takahashi S Ito Y Ohishi Y Tsukamoto K

Nanba Y et alBifidobacterium septicemia associated

with postoperative probiotic therapy in a neonate with

omphalocele Journal of Pediatrics 2010156(4)679ndash81

Pedone 1999

Pedone CA Bernabeu AO Postaire ER Bouley CF Reinert

P The effect of supplementation with milk fermented by

Lactobacillus casei (strain DN-114 001) on acute diarrhoea



in children attending day care centres International Journal

of Clinical Practice 199953(3)179ndash84

Perapoch 2000

Perapoch J Planes AM Querol A Loacutepez V Martiacutenez-

Bendayaacuten I Tormo R et alFungemia with Saccharomyces

cerevisiae in two newborns only one of whom had been

treated with ultra-levura European Journal of Clinical

Microbiology and Infectious Diseases 200019(6)468ndash70

Perry 2011

Perry R Hunt K Ernst E Nutritional supplements

and other complementary medicines for infantile colic a

systematic review Pediatrics 2011127(4)720ndash33

Petschow 2005

Petschow BW Figueroa R Harris CL Beck LB Ziegler E

Goldin B Effects of feeding an infant formula containing

Lactobacillus GG on the colonization of the intestine a

dose-response study in healthy infants Journal of Clinical

Gastroenterology 200539(9)786ndash90

Prescott 2008

Prescott SL Wiltschut J Taylor A Westcott L Jung W

Currie H et alEarly markers of allergic disease in a primary

prevention study using probiotics 25-year follow-up

phase Allergy 200863(11)1481ndash90

Rautio 1999

Rautio M Jousimies-Somer H Kauma H Pietarinen

I Saxelin M Tynkkynen S et alLiver abscess due to a

Lactobacillus rhamnosus strain indistinguishable from L

rhamnosus strain GG Clinical Infectious Diseases 199928

(5)1159ndash60

Reddy 2013

Reddy VS Patole SK Rao S Role of probiotics in short

bowel syndrome in infants and children - a systematic

review Nutrients 20135(3)679ndash99

Review Manager 2011

The Nordic Cochrane Centre The Cochrane Collaboration

Review Manager (RevMan) 51 Copenhagen The Nordic

Cochrane Centre The Cochrane Collaboration 2011

Rhoads 2009

Rhoads JM Fatheree NY Norori J Liu Y Lucke JF

Tyson JE et alAltered fecal microflora and increased fecal

calprotectin in infants with colic Journal of Pediatrics 2009

155(6)823ndash8

Roberfroid 2007

Roberfroid M Prebiotics the concept revisited Journal of

Nutrition 2007137(3 Suppl 2)830ndash7S

Roberts 2004

Roberts DM Ostapchuk M OrsquoBrien JG Infant colic

American Family Physician 200470(4)735ndash40

Rosander 2008

Rosander A Connolly E Roos S Removal of antibiotic

resistance plasmids from Lactobacillus reuteri ATCC

55 730 and characterization of the resulting daughter

strain L reuteri DSM 17 938 Applied and Environmental


Saavedra 1999

Saavedra JM Probiotics plus antibiotics regulating our

bacterial environment Journal of Pediatrics 1999135(5)

535ndash7

Salminen 2002

Salminen MK Tynkkynen S Rautelin H Saxelin M Vaara

M Ruutu P et alLactobacillus bacteremia during a rapid

increase in probiotic use of Lactobacillus rhamnosus GG in

Finland Clinical Infectious Diseases 200235(10)1155ndash60

Salminen 2004

Salminen MK Rautelin H Tynkkynen S Poussa T Saxelin

M Valtonen V et alLactobacillus bacteremia clinical

significance and patient outcome with special focus on

probiotic L rhamnosus GG Clinical Infectious Diseases

200438(1)62ndash9

Savino 2004

Savino F Cresi F Pautasso S Palumeri E Tullio V Roana

J et alIntestinal microflora in breastfed colicky and non-

colicky infants Acta Paediatrica 200493(6)825ndash9

Savino 2005

Savino F Bailo E Oggero R Tullio V Roana J Carlone N

et alBacterial counts of intestinal Lactobacillus species in

infants with colic Pediatric Allergy and Immunology 2005

18(1)72ndash5

Savino 2006

Savino F Grassino EC Guidi C Oggero R Silvestro L

Miniero R Ghrelin and motilin concentration in colicky

infants Acta Paediatrica 200695(6)738ndash41

Savino 2007a

Savino F Focus on infantile colic Acta Paediatrica 200796

(9)1259ndash64

Savino 2007b

Savino F Pelle E Castagno E Palumeri E Oggero R Must

infants with colic really be hospitalized Acta Paediatrica

200796(7)1109

Savino 2009

Savino F Cordisco L Tarasco V Calabrese R Palumeri E

Matteuzzi D Molecular identification of coliform bacteria

from colicky breast-fed infants Acta Paediatrica 200998

(10)1582ndash8

Savino 2010

Savino F Cordisco L Tarasco V Palumeri E Calabrese R

Oggero R et alLactobacillus reuteri DSM 17938 in infant

colic a randomized double-blind placebo controlled trial

Pediatrics 2010126(3)e526ndash33

Savino 2012a

Savino F Tarasco V Lingua C Moja L Ricceri F Pain-

relieving agents for infant colic Cochrane Database

of Systematic Reviews 2012 Issue 7 [DOI 101002

14651858CD009999]

Savino 2012b

Savino F Tarasco V Sorrenti M Lingua C Moja L Gordon

M et alDietary modifications for infantile colic Cochrane

Database of Systematic Reviews In press



Soleman 2003

Soleman N Laferl H Kneifel W Tucek G Budschedl E

Weber H et alHow safe is safe A case of Lactobacillus

paracasei ssp paracasei endocarditis and discussion of

the safety of lactic acid bacteria Scandinavian Journal of

Infectious Diseases 200335(10)759ndash62

Sterne 2008

Sterne JAC Egger M Moher D Chapter 10 Addressing

reporting biases In Higgins JPT Green S editor(s)

Cochrane Handbook for Systematic Reviews of Interventions

Chichester John Wiley amp Sons 2008297ndash333

Stifter 1998

Stifter CA Bono MA Effect of infant colic on maternal

self-perceptions and mother-infant bonding Child Care

Health and Development 199824(5)339ndash51

Taylor 2007

Taylor AL Dunstan JA Prescott SL Probiotic

supplementation for the first 6 months of life fails to reduce

the risk of atopic dermatitis and increases the risk of allergen

sensitization in high-risk children a randomized controlled

trial Journal of Allergy and Clinical Immunology 2007119

(1)184ndash91

Thomas 2010

Thomas DW Greer FR Committee on Nutrition

Probiotics and prebiotics in pediatrics Pediatrics 2010126

(6)1217ndash31

Thompson 2001

Thompson C McCarter YS Krause PJ Herson VC

Lactobacillus acidophilus sepsis in a neonate Journal of

Perinatology 200121(4)258ndash60

Tynkkynen 1998

Tynkkynen S Singh KV Varmanen P Vancomycin

resistance factor of Lactobacillus rhamnosus GG in

relation to enterococcal vancomycin resistance (van) genes

International Journal of Food Microbiology 199841(3)

195ndash204

Vanderhoof 1998

Vanderhoof JA Young RJ Murray N Kaufman SS

Treatment strategies for small bowel bacterial overgrowth in

short bowel syndrome Journal of Pediatric Gastroenterology

and Nutrition 199827(2)155ndash60

Walter 2011

Walter J Britton RA Roos S Host-microbial symbiosis in

the vertebrate gastrointestinal tract and the Lactobacillus

reuteri paradigm Proceedings of the National Academy of

Sciences of the United States of America 2011108(Suppl 1)

4645ndash52

Wang 2010

Wang B Mao YK Diorio C Wang L Huizinga JD

Bienenstock J et alLactobacillus reuteri ingestion and IK

(Ca) channel blockade have similar effects on rat colon

motility and myenteric neurones Neurogastroenterology and

Motility 201022(1)98ndash107

Wessel 1954

Wessel MA Cobb JC Jackson EB Harris GS Jr Detwiler

AC Paroxysmal fussing in infancy sometimes called ldquocolicrdquo

Pediatrics 195414(5)421ndash35lowast Indicates the major publication for the study

C O N T R I B U T I O N S O F A U T H O R S

Vijayakumar Praveen Shama Praveen - prepared the initial draft of the protocol

Sanjay K Patole Girish Deshpande - reviewed the protocol

Vijayakumar Praveen Sanjay K Patole - reviewed search results

D E C L A R A T I O N S O F I N T E R E S T

Vijayakumar Praveen - none known

Sanjay K Patole - none known

Shama Praveen - none known

Girish Deshpande - I am the principal investigator for the project Probiotics for Preterm Neonates which is conducted at the Nepean

Neonatal Intensive Care Unit Sydney Australia This project is partly funded by the Nepean Neonatal Parents Support Group ($5000

for year 2011 to 2012)



T A B L E O F C O N T E N T S

1HEADER

1ABSTRACT

1BACKGROUND

4OBJECTIVES

4METHODS

10ACKNOWLEDGEMENTS

10REFERENCES

14CONTRIBUTIONS OF AUTHORS

14DECLARATIONS OF INTEREST

iOral probiotics for infantile colic (Protocol)








Australia








A B S T R A C T



B A C K G R O U N D








































































2010 FAO 2010)




CAST 2010 FAO 2010)





2010 FAO 2010)



2005 Falony 2006)













route in infants









































































































infants with colic











































































O B J E C T I V E S



M E T H O D S


Types of studies

RCTs and quasi RCTs
























Primary outcomes





Secondary outcomes























Electronic searches



(CENTRAL)

2 Ovid MEDLINE


Citations

4 Embase

5 CINAHL

6 PsycINFO







Humanities



ndltdorg)






anzctrorgau)







1 colic

2 colic$tw


or cramp$))tw


5 crying


7 or1-6

8 probiotics

9 probiotic$tw





14 lactobacill$tw


16 Bifidobacter$tw

17 Bifidus$tw


19 Saccharomyces$tw

20 Streptococcus

21 streptococc$tw




3)tw



Little Tummy$)tw

25 or8-24

26 exp infant


neonat$)tw

28 26 or 27

29 7 and 25 and 28
















Handsearching






Adverse effects







Language


















































Sequence generation





















































randomisation









Selective reporting



























intervals (CI)





























Cross-over trials



























viduals

































































































Data synthesis


















proach





(Higgins 2008)





















strategies






and outcome


infant formula


























analyses
















R E F E R E N C E S


Alfaleh 2011




[DOI 10100214651858CD005496pub3]

Andresen 2006



1073ndash88

Baldassarre 2010






Bongaerts 1997





Borriello 2003




200336(3)775ndash80

Boyle 2006




Broughton 1983



19832(5)382ndash4

Bruni 2009




321ndash3

CAST 2010






Cohen 2012





Commane 2005





102ndash9





Suppl)S22ndash5

DerSimonian 1986



Deshpande 2010




Deshpande 2011



201127(1)13ndash8

Dobson 2012




[DOI 10100214651858CD004796pub2]

Donner 1980





Egger 1997



1997315(7109)629ndash34

Elbourne 2002





Falony 2006






FAO 2010






Freedman 2009




Freeman 1989




Furukawa 2005





Gao 2010







Garrison 2000



184ndash90

Gavaghan 2000




Gill 2001





Guandalini 2000





Gupta 2002



Ha 1999



199937(4)1227ndash8

He 2002





Heine 2008




Hempel 2011





Higgins 2002



Higgins 2003



Higgins 2008





243ndash96

Higgins 2011a







Higgins 2011b







Higgins 2011c









Husni 1997




Iacono 2005





Jenke 2012





217ndash8

Kalima 1996




Kalliomaumlki 2001




357(9262)1076ndash9

Keefe 2006




Kirjavainen 1999






790ndash802

Kopp 2008





e850ndash6

Kopp 2009



Care 200912(3)298ndash303

Ku 2006




Kunz 2004





Kunze 2009





200913(8B)2261ndash70

Larsen 2006






60(11)1284ndash93

Lucassen 2000





Lucassen 2001





Luyer 2005




3686ndash92

Ma 2009











Munakata 2010




201032(8)691ndash4

Ohishi 2010





Pedone 1999








Perapoch 2000






Perry 2011




Petschow 2005






Prescott 2008





Rautio 1999





(5)1159ndash60

Reddy 2013




Review Manager 2011




Rhoads 2009




155(6)823ndash8

Roberfroid 2007



Roberts 2004



Rosander 2008






Saavedra 1999



535ndash7

Salminen 2002





Salminen 2004





200438(1)62ndash9

Savino 2004




Savino 2005




18(1)72ndash5

Savino 2006




Savino 2007a


(9)1259ndash64

Savino 2007b



200796(7)1109

Savino 2009




(10)1582ndash8

Savino 2010





Savino 2012a




14651858CD009999]

Savino 2012b






Soleman 2003






Sterne 2008





Stifter 1998




Taylor 2007






(1)184ndash91

Thomas 2010



(6)1217ndash31

Thompson 2001




Tynkkynen 1998





195ndash204

Vanderhoof 1998





Walter 2011





4645ndash52

Wang 2010






Wessel 1954























Australia








A B S T R A C T



B A C K G R O U N D








































































2010 FAO 2010)




CAST 2010 FAO 2010)





2010 FAO 2010)



2005 Falony 2006)













route in infants









































































































infants with colic











































































O B J E C T I V E S



M E T H O D S


Types of studies

RCTs and quasi RCTs
























Primary outcomes





Secondary outcomes























Electronic searches



(CENTRAL)

2 Ovid MEDLINE


Citations

4 Embase

5 CINAHL

6 PsycINFO







Humanities



ndltdorg)






anzctrorgau)







1 colic

2 colic$tw


or cramp$))tw


5 crying


7 or1-6

8 probiotics

9 probiotic$tw





14 lactobacill$tw


16 Bifidobacter$tw

17 Bifidus$tw


19 Saccharomyces$tw

20 Streptococcus

21 streptococc$tw




3)tw



Little Tummy$)tw

25 or8-24

26 exp infant


neonat$)tw

28 26 or 27

29 7 and 25 and 28
















Handsearching






Adverse effects







Language


















































Sequence generation





















































randomisation









Selective reporting



























intervals (CI)





























Cross-over trials



























viduals

































































































Data synthesis


















proach





(Higgins 2008)





















strategies






and outcome


infant formula


























analyses
















R E F E R E N C E S


Alfaleh 2011




[DOI 10100214651858CD005496pub3]

Andresen 2006



1073ndash88

Baldassarre 2010






Bongaerts 1997





Borriello 2003




200336(3)775ndash80

Boyle 2006




Broughton 1983



19832(5)382ndash4

Bruni 2009




321ndash3

CAST 2010






Cohen 2012





Commane 2005





102ndash9





Suppl)S22ndash5

DerSimonian 1986



Deshpande 2010




Deshpande 2011



201127(1)13ndash8

Dobson 2012




[DOI 10100214651858CD004796pub2]

Donner 1980





Egger 1997



1997315(7109)629ndash34

Elbourne 2002





Falony 2006






FAO 2010






Freedman 2009




Freeman 1989




Furukawa 2005





Gao 2010







Garrison 2000



184ndash90

Gavaghan 2000




Gill 2001





Guandalini 2000





Gupta 2002



Ha 1999



199937(4)1227ndash8

He 2002





Heine 2008




Hempel 2011





Higgins 2002



Higgins 2003



Higgins 2008





243ndash96

Higgins 2011a







Higgins 2011b







Higgins 2011c









Husni 1997




Iacono 2005





Jenke 2012





217ndash8

Kalima 1996




Kalliomaumlki 2001




357(9262)1076ndash9

Keefe 2006




Kirjavainen 1999






790ndash802

Kopp 2008





e850ndash6

Kopp 2009



Care 200912(3)298ndash303

Ku 2006




Kunz 2004





Kunze 2009





200913(8B)2261ndash70

Larsen 2006






60(11)1284ndash93

Lucassen 2000





Lucassen 2001





Luyer 2005




3686ndash92

Ma 2009











Munakata 2010




201032(8)691ndash4

Ohishi 2010





Pedone 1999








Perapoch 2000






Perry 2011




Petschow 2005






Prescott 2008





Rautio 1999





(5)1159ndash60

Reddy 2013




Review Manager 2011




Rhoads 2009




155(6)823ndash8

Roberfroid 2007



Roberts 2004



Rosander 2008






Saavedra 1999



535ndash7

Salminen 2002





Salminen 2004





200438(1)62ndash9

Savino 2004




Savino 2005




18(1)72ndash5

Savino 2006




Savino 2007a


(9)1259ndash64

Savino 2007b



200796(7)1109

Savino 2009




(10)1582ndash8

Savino 2010





Savino 2012a




14651858CD009999]

Savino 2012b






Soleman 2003






Sterne 2008





Stifter 1998




Taylor 2007






(1)184ndash91

Thomas 2010



(6)1217ndash31

Thompson 2001




Tynkkynen 1998





195ndash204

Vanderhoof 1998





Walter 2011





4645ndash52

Wang 2010






Wessel 1954



















































2010 FAO 2010)




CAST 2010 FAO 2010)





2010 FAO 2010)



2005 Falony 2006)













route in infants









































































































infants with colic











































































O B J E C T I V E S



M E T H O D S


Types of studies

RCTs and quasi RCTs
























Primary outcomes





Secondary outcomes























Electronic searches



(CENTRAL)

2 Ovid MEDLINE


Citations

4 Embase

5 CINAHL

6 PsycINFO







Humanities



ndltdorg)






anzctrorgau)







1 colic

2 colic$tw


or cramp$))tw


5 crying


7 or1-6

8 probiotics

9 probiotic$tw





14 lactobacill$tw


16 Bifidobacter$tw

17 Bifidus$tw


19 Saccharomyces$tw

20 Streptococcus

21 streptococc$tw




3)tw



Little Tummy$)tw

25 or8-24

26 exp infant


neonat$)tw

28 26 or 27

29 7 and 25 and 28
















Handsearching






Adverse effects







Language


















































Sequence generation





















































randomisation









Selective reporting



























intervals (CI)





























Cross-over trials



























viduals

































































































Data synthesis


















proach





(Higgins 2008)





















strategies






and outcome


infant formula


























analyses
















R E F E R E N C E S


Alfaleh 2011




[DOI 10100214651858CD005496pub3]

Andresen 2006



1073ndash88

Baldassarre 2010






Bongaerts 1997





Borriello 2003




200336(3)775ndash80

Boyle 2006




Broughton 1983



19832(5)382ndash4

Bruni 2009




321ndash3

CAST 2010






Cohen 2012





Commane 2005





102ndash9





Suppl)S22ndash5

DerSimonian 1986



Deshpande 2010




Deshpande 2011



201127(1)13ndash8

Dobson 2012




[DOI 10100214651858CD004796pub2]

Donner 1980





Egger 1997



1997315(7109)629ndash34

Elbourne 2002





Falony 2006






FAO 2010






Freedman 2009




Freeman 1989




Furukawa 2005





Gao 2010







Garrison 2000



184ndash90

Gavaghan 2000




Gill 2001





Guandalini 2000





Gupta 2002



Ha 1999



199937(4)1227ndash8

He 2002





Heine 2008




Hempel 2011





Higgins 2002



Higgins 2003



Higgins 2008





243ndash96

Higgins 2011a







Higgins 2011b







Higgins 2011c









Husni 1997




Iacono 2005





Jenke 2012





217ndash8

Kalima 1996




Kalliomaumlki 2001




357(9262)1076ndash9

Keefe 2006




Kirjavainen 1999






790ndash802

Kopp 2008





e850ndash6

Kopp 2009



Care 200912(3)298ndash303

Ku 2006




Kunz 2004





Kunze 2009





200913(8B)2261ndash70

Larsen 2006






60(11)1284ndash93

Lucassen 2000





Lucassen 2001





Luyer 2005




3686ndash92

Ma 2009











Munakata 2010




201032(8)691ndash4

Ohishi 2010





Pedone 1999








Perapoch 2000






Perry 2011




Petschow 2005






Prescott 2008





Rautio 1999





(5)1159ndash60

Reddy 2013




Review Manager 2011




Rhoads 2009




155(6)823ndash8

Roberfroid 2007



Roberts 2004



Rosander 2008






Saavedra 1999



535ndash7

Salminen 2002





Salminen 2004





200438(1)62ndash9

Savino 2004




Savino 2005




18(1)72ndash5

Savino 2006




Savino 2007a


(9)1259ndash64

Savino 2007b



200796(7)1109

Savino 2009




(10)1582ndash8

Savino 2010





Savino 2012a




14651858CD009999]

Savino 2012b






Soleman 2003






Sterne 2008





Stifter 1998




Taylor 2007






(1)184ndash91

Thomas 2010



(6)1217ndash31

Thompson 2001




Tynkkynen 1998





195ndash204

Vanderhoof 1998





Walter 2011





4645ndash52

Wang 2010






Wessel 1954















































































infants with colic











































































O B J E C T I V E S



M E T H O D S


Types of studies

RCTs and quasi RCTs
























Primary outcomes





Secondary outcomes























Electronic searches



(CENTRAL)

2 Ovid MEDLINE


Citations

4 Embase

5 CINAHL

6 PsycINFO







Humanities



ndltdorg)






anzctrorgau)







1 colic

2 colic$tw


or cramp$))tw


5 crying


7 or1-6

8 probiotics

9 probiotic$tw





14 lactobacill$tw


16 Bifidobacter$tw

17 Bifidus$tw


19 Saccharomyces$tw

20 Streptococcus

21 streptococc$tw




3)tw



Little Tummy$)tw

25 or8-24

26 exp infant


neonat$)tw

28 26 or 27

29 7 and 25 and 28
















Handsearching






Adverse effects







Language


















































Sequence generation





















































randomisation









Selective reporting



























intervals (CI)





























Cross-over trials



























viduals

































































































Data synthesis


















proach





(Higgins 2008)





















strategies






and outcome


infant formula


























analyses
















R E F E R E N C E S


Alfaleh 2011




[DOI 10100214651858CD005496pub3]

Andresen 2006



1073ndash88

Baldassarre 2010






Bongaerts 1997





Borriello 2003




200336(3)775ndash80

Boyle 2006




Broughton 1983



19832(5)382ndash4

Bruni 2009




321ndash3

CAST 2010






Cohen 2012





Commane 2005





102ndash9





Suppl)S22ndash5

DerSimonian 1986



Deshpande 2010




Deshpande 2011



201127(1)13ndash8

Dobson 2012




[DOI 10100214651858CD004796pub2]

Donner 1980





Egger 1997



1997315(7109)629ndash34

Elbourne 2002





Falony 2006






FAO 2010






Freedman 2009




Freeman 1989




Furukawa 2005





Gao 2010







Garrison 2000



184ndash90

Gavaghan 2000




Gill 2001





Guandalini 2000





Gupta 2002



Ha 1999



199937(4)1227ndash8

He 2002





Heine 2008




Hempel 2011





Higgins 2002



Higgins 2003



Higgins 2008





243ndash96

Higgins 2011a







Higgins 2011b







Higgins 2011c









Husni 1997




Iacono 2005





Jenke 2012





217ndash8

Kalima 1996




Kalliomaumlki 2001




357(9262)1076ndash9

Keefe 2006




Kirjavainen 1999






790ndash802

Kopp 2008





e850ndash6

Kopp 2009



Care 200912(3)298ndash303

Ku 2006




Kunz 2004





Kunze 2009





200913(8B)2261ndash70

Larsen 2006






60(11)1284ndash93

Lucassen 2000





Lucassen 2001





Luyer 2005




3686ndash92

Ma 2009











Munakata 2010




201032(8)691ndash4

Ohishi 2010





Pedone 1999








Perapoch 2000






Perry 2011




Petschow 2005






Prescott 2008





Rautio 1999





(5)1159ndash60

Reddy 2013




Review Manager 2011




Rhoads 2009




155(6)823ndash8

Roberfroid 2007



Roberts 2004



Rosander 2008






Saavedra 1999



535ndash7

Salminen 2002





Salminen 2004





200438(1)62ndash9

Savino 2004




Savino 2005




18(1)72ndash5

Savino 2006




Savino 2007a


(9)1259ndash64

Savino 2007b



200796(7)1109

Savino 2009




(10)1582ndash8

Savino 2010





Savino 2012a




14651858CD009999]

Savino 2012b






Soleman 2003






Sterne 2008





Stifter 1998




Taylor 2007






(1)184ndash91

Thomas 2010



(6)1217ndash31

Thompson 2001




Tynkkynen 1998





195ndash204

Vanderhoof 1998





Walter 2011





4645ndash52

Wang 2010






Wessel 1954


















































O B J E C T I V E S



M E T H O D S


Types of studies

RCTs and quasi RCTs
























Primary outcomes





Secondary outcomes























Electronic searches



(CENTRAL)

2 Ovid MEDLINE


Citations

4 Embase

5 CINAHL

6 PsycINFO







Humanities



ndltdorg)






anzctrorgau)







1 colic

2 colic$tw


or cramp$))tw


5 crying


7 or1-6

8 probiotics

9 probiotic$tw





14 lactobacill$tw


16 Bifidobacter$tw

17 Bifidus$tw


19 Saccharomyces$tw

20 Streptococcus

21 streptococc$tw




3)tw



Little Tummy$)tw

25 or8-24

26 exp infant


neonat$)tw

28 26 or 27

29 7 and 25 and 28
















Handsearching






Adverse effects







Language


















































Sequence generation





















































randomisation









Selective reporting



























intervals (CI)





























Cross-over trials



























viduals

































































































Data synthesis


















proach





(Higgins 2008)





















strategies






and outcome


infant formula


























analyses
















R E F E R E N C E S


Alfaleh 2011




[DOI 10100214651858CD005496pub3]

Andresen 2006



1073ndash88

Baldassarre 2010






Bongaerts 1997





Borriello 2003




200336(3)775ndash80

Boyle 2006




Broughton 1983



19832(5)382ndash4

Bruni 2009




321ndash3

CAST 2010






Cohen 2012





Commane 2005





102ndash9





Suppl)S22ndash5

DerSimonian 1986



Deshpande 2010




Deshpande 2011



201127(1)13ndash8

Dobson 2012




[DOI 10100214651858CD004796pub2]

Donner 1980





Egger 1997



1997315(7109)629ndash34

Elbourne 2002





Falony 2006






FAO 2010






Freedman 2009




Freeman 1989




Furukawa 2005





Gao 2010







Garrison 2000



184ndash90

Gavaghan 2000




Gill 2001





Guandalini 2000





Gupta 2002



Ha 1999



199937(4)1227ndash8

He 2002





Heine 2008




Hempel 2011





Higgins 2002



Higgins 2003



Higgins 2008





243ndash96

Higgins 2011a







Higgins 2011b







Higgins 2011c









Husni 1997




Iacono 2005





Jenke 2012





217ndash8

Kalima 1996




Kalliomaumlki 2001




357(9262)1076ndash9

Keefe 2006




Kirjavainen 1999






790ndash802

Kopp 2008





e850ndash6

Kopp 2009



Care 200912(3)298ndash303

Ku 2006




Kunz 2004





Kunze 2009





200913(8B)2261ndash70

Larsen 2006






60(11)1284ndash93

Lucassen 2000





Lucassen 2001





Luyer 2005




3686ndash92

Ma 2009











Munakata 2010




201032(8)691ndash4

Ohishi 2010





Pedone 1999








Perapoch 2000






Perry 2011




Petschow 2005






Prescott 2008





Rautio 1999





(5)1159ndash60

Reddy 2013




Review Manager 2011




Rhoads 2009




155(6)823ndash8

Roberfroid 2007



Roberts 2004



Rosander 2008






Saavedra 1999



535ndash7

Salminen 2002





Salminen 2004





200438(1)62ndash9

Savino 2004




Savino 2005




18(1)72ndash5

Savino 2006




Savino 2007a


(9)1259ndash64

Savino 2007b



200796(7)1109

Savino 2009




(10)1582ndash8

Savino 2010





Savino 2012a




14651858CD009999]

Savino 2012b






Soleman 2003






Sterne 2008





Stifter 1998




Taylor 2007






(1)184ndash91

Thomas 2010



(6)1217ndash31

Thompson 2001




Tynkkynen 1998





195ndash204

Vanderhoof 1998





Walter 2011





4645ndash52

Wang 2010






Wessel 1954

























Electronic searches



(CENTRAL)

2 Ovid MEDLINE


Citations

4 Embase

5 CINAHL

6 PsycINFO







Humanities



ndltdorg)






anzctrorgau)







1 colic

2 colic$tw


or cramp$))tw


5 crying


7 or1-6

8 probiotics

9 probiotic$tw





14 lactobacill$tw


16 Bifidobacter$tw

17 Bifidus$tw


19 Saccharomyces$tw

20 Streptococcus

21 streptococc$tw




3)tw



Little Tummy$)tw

25 or8-24

26 exp infant


neonat$)tw

28 26 or 27

29 7 and 25 and 28
















Handsearching






Adverse effects







Language


















































Sequence generation





















































randomisation









Selective reporting



























intervals (CI)





























Cross-over trials



























viduals

































































































Data synthesis


















proach





(Higgins 2008)





















strategies






and outcome


infant formula


























analyses
















R E F E R E N C E S


Alfaleh 2011




[DOI 10100214651858CD005496pub3]

Andresen 2006



1073ndash88

Baldassarre 2010






Bongaerts 1997





Borriello 2003




200336(3)775ndash80

Boyle 2006




Broughton 1983



19832(5)382ndash4

Bruni 2009




321ndash3

CAST 2010






Cohen 2012





Commane 2005





102ndash9





Suppl)S22ndash5

DerSimonian 1986



Deshpande 2010




Deshpande 2011



201127(1)13ndash8

Dobson 2012




[DOI 10100214651858CD004796pub2]

Donner 1980





Egger 1997



1997315(7109)629ndash34

Elbourne 2002





Falony 2006






FAO 2010






Freedman 2009




Freeman 1989




Furukawa 2005





Gao 2010







Garrison 2000



184ndash90

Gavaghan 2000




Gill 2001





Guandalini 2000





Gupta 2002



Ha 1999



199937(4)1227ndash8

He 2002





Heine 2008




Hempel 2011





Higgins 2002



Higgins 2003



Higgins 2008





243ndash96

Higgins 2011a







Higgins 2011b







Higgins 2011c









Husni 1997




Iacono 2005





Jenke 2012





217ndash8

Kalima 1996




Kalliomaumlki 2001




357(9262)1076ndash9

Keefe 2006




Kirjavainen 1999






790ndash802

Kopp 2008





e850ndash6

Kopp 2009



Care 200912(3)298ndash303

Ku 2006




Kunz 2004





Kunze 2009





200913(8B)2261ndash70

Larsen 2006






60(11)1284ndash93

Lucassen 2000





Lucassen 2001





Luyer 2005




3686ndash92

Ma 2009











Munakata 2010




201032(8)691ndash4

Ohishi 2010





Pedone 1999








Perapoch 2000






Perry 2011




Petschow 2005






Prescott 2008





Rautio 1999





(5)1159ndash60

Reddy 2013




Review Manager 2011




Rhoads 2009




155(6)823ndash8

Roberfroid 2007



Roberts 2004



Rosander 2008






Saavedra 1999



535ndash7

Salminen 2002





Salminen 2004





200438(1)62ndash9

Savino 2004




Savino 2005




18(1)72ndash5

Savino 2006




Savino 2007a


(9)1259ndash64

Savino 2007b



200796(7)1109

Savino 2009




(10)1582ndash8

Savino 2010





Savino 2012a




14651858CD009999]

Savino 2012b






Soleman 2003






Sterne 2008





Stifter 1998




Taylor 2007






(1)184ndash91

Thomas 2010



(6)1217ndash31

Thompson 2001




Tynkkynen 1998





195ndash204

Vanderhoof 1998





Walter 2011





4645ndash52

Wang 2010






Wessel 1954




















Adverse effects







Language


















































Sequence generation





















































randomisation









Selective reporting



























intervals (CI)





























Cross-over trials



























viduals

































































































Data synthesis


















proach





(Higgins 2008)





















strategies






and outcome


infant formula


























analyses
















R E F E R E N C E S


Alfaleh 2011




[DOI 10100214651858CD005496pub3]

Andresen 2006



1073ndash88

Baldassarre 2010






Bongaerts 1997





Borriello 2003




200336(3)775ndash80

Boyle 2006




Broughton 1983



19832(5)382ndash4

Bruni 2009




321ndash3

CAST 2010






Cohen 2012





Commane 2005





102ndash9





Suppl)S22ndash5

DerSimonian 1986



Deshpande 2010




Deshpande 2011



201127(1)13ndash8

Dobson 2012




[DOI 10100214651858CD004796pub2]

Donner 1980





Egger 1997



1997315(7109)629ndash34

Elbourne 2002





Falony 2006






FAO 2010






Freedman 2009




Freeman 1989




Furukawa 2005





Gao 2010







Garrison 2000



184ndash90

Gavaghan 2000




Gill 2001





Guandalini 2000





Gupta 2002



Ha 1999



199937(4)1227ndash8

He 2002





Heine 2008




Hempel 2011





Higgins 2002



Higgins 2003



Higgins 2008





243ndash96

Higgins 2011a







Higgins 2011b







Higgins 2011c









Husni 1997




Iacono 2005





Jenke 2012





217ndash8

Kalima 1996




Kalliomaumlki 2001




357(9262)1076ndash9

Keefe 2006




Kirjavainen 1999






790ndash802

Kopp 2008





e850ndash6

Kopp 2009



Care 200912(3)298ndash303

Ku 2006




Kunz 2004





Kunze 2009





200913(8B)2261ndash70

Larsen 2006






60(11)1284ndash93

Lucassen 2000





Lucassen 2001





Luyer 2005




3686ndash92

Ma 2009











Munakata 2010




201032(8)691ndash4

Ohishi 2010





Pedone 1999








Perapoch 2000






Perry 2011




Petschow 2005






Prescott 2008





Rautio 1999





(5)1159ndash60

Reddy 2013




Review Manager 2011




Rhoads 2009




155(6)823ndash8

Roberfroid 2007



Roberts 2004



Rosander 2008






Saavedra 1999



535ndash7

Salminen 2002





Salminen 2004





200438(1)62ndash9

Savino 2004




Savino 2005




18(1)72ndash5

Savino 2006




Savino 2007a


(9)1259ndash64

Savino 2007b



200796(7)1109

Savino 2009




(10)1582ndash8

Savino 2010





Savino 2012a




14651858CD009999]

Savino 2012b






Soleman 2003






Sterne 2008





Stifter 1998




Taylor 2007






(1)184ndash91

Thomas 2010



(6)1217ndash31

Thompson 2001




Tynkkynen 1998





195ndash204

Vanderhoof 1998





Walter 2011





4645ndash52

Wang 2010






Wessel 1954




































randomisation









Selective reporting



























intervals (CI)





























Cross-over trials



























viduals

































































































Data synthesis


















proach





(Higgins 2008)





















strategies






and outcome


infant formula


























analyses
















R E F E R E N C E S


Alfaleh 2011




[DOI 10100214651858CD005496pub3]

Andresen 2006



1073ndash88

Baldassarre 2010






Bongaerts 1997





Borriello 2003




200336(3)775ndash80

Boyle 2006




Broughton 1983



19832(5)382ndash4

Bruni 2009




321ndash3

CAST 2010






Cohen 2012





Commane 2005





102ndash9





Suppl)S22ndash5

DerSimonian 1986



Deshpande 2010




Deshpande 2011



201127(1)13ndash8

Dobson 2012




[DOI 10100214651858CD004796pub2]

Donner 1980





Egger 1997



1997315(7109)629ndash34

Elbourne 2002





Falony 2006






FAO 2010






Freedman 2009




Freeman 1989




Furukawa 2005





Gao 2010







Garrison 2000



184ndash90

Gavaghan 2000




Gill 2001





Guandalini 2000





Gupta 2002



Ha 1999



199937(4)1227ndash8

He 2002





Heine 2008




Hempel 2011





Higgins 2002



Higgins 2003



Higgins 2008





243ndash96

Higgins 2011a







Higgins 2011b







Higgins 2011c









Husni 1997




Iacono 2005





Jenke 2012





217ndash8

Kalima 1996




Kalliomaumlki 2001




357(9262)1076ndash9

Keefe 2006




Kirjavainen 1999






790ndash802

Kopp 2008





e850ndash6

Kopp 2009



Care 200912(3)298ndash303

Ku 2006




Kunz 2004





Kunze 2009





200913(8B)2261ndash70

Larsen 2006






60(11)1284ndash93

Lucassen 2000





Lucassen 2001





Luyer 2005




3686ndash92

Ma 2009











Munakata 2010




201032(8)691ndash4

Ohishi 2010





Pedone 1999








Perapoch 2000






Perry 2011




Petschow 2005






Prescott 2008





Rautio 1999





(5)1159ndash60

Reddy 2013




Review Manager 2011




Rhoads 2009




155(6)823ndash8

Roberfroid 2007



Roberts 2004



Rosander 2008






Saavedra 1999



535ndash7

Salminen 2002





Salminen 2004





200438(1)62ndash9

Savino 2004




Savino 2005




18(1)72ndash5

Savino 2006




Savino 2007a


(9)1259ndash64

Savino 2007b



200796(7)1109

Savino 2009




(10)1582ndash8

Savino 2010





Savino 2012a




14651858CD009999]

Savino 2012b






Soleman 2003






Sterne 2008





Stifter 1998




Taylor 2007






(1)184ndash91

Thomas 2010



(6)1217ndash31

Thompson 2001




Tynkkynen 1998





195ndash204

Vanderhoof 1998





Walter 2011





4645ndash52

Wang 2010






Wessel 1954






























viduals

































































































Data synthesis


















proach





(Higgins 2008)





















strategies






and outcome


infant formula


























analyses
















R E F E R E N C E S


Alfaleh 2011




[DOI 10100214651858CD005496pub3]

Andresen 2006



1073ndash88

Baldassarre 2010






Bongaerts 1997





Borriello 2003




200336(3)775ndash80

Boyle 2006




Broughton 1983



19832(5)382ndash4

Bruni 2009




321ndash3

CAST 2010






Cohen 2012





Commane 2005





102ndash9





Suppl)S22ndash5

DerSimonian 1986



Deshpande 2010




Deshpande 2011



201127(1)13ndash8

Dobson 2012




[DOI 10100214651858CD004796pub2]

Donner 1980





Egger 1997



1997315(7109)629ndash34

Elbourne 2002





Falony 2006






FAO 2010






Freedman 2009




Freeman 1989




Furukawa 2005





Gao 2010







Garrison 2000



184ndash90

Gavaghan 2000




Gill 2001





Guandalini 2000





Gupta 2002



Ha 1999



199937(4)1227ndash8

He 2002





Heine 2008




Hempel 2011





Higgins 2002



Higgins 2003



Higgins 2008





243ndash96

Higgins 2011a







Higgins 2011b







Higgins 2011c









Husni 1997




Iacono 2005





Jenke 2012





217ndash8

Kalima 1996




Kalliomaumlki 2001




357(9262)1076ndash9

Keefe 2006




Kirjavainen 1999






790ndash802

Kopp 2008





e850ndash6

Kopp 2009



Care 200912(3)298ndash303

Ku 2006




Kunz 2004





Kunze 2009





200913(8B)2261ndash70

Larsen 2006






60(11)1284ndash93

Lucassen 2000





Lucassen 2001





Luyer 2005




3686ndash92

Ma 2009











Munakata 2010




201032(8)691ndash4

Ohishi 2010





Pedone 1999








Perapoch 2000






Perry 2011




Petschow 2005






Prescott 2008





Rautio 1999





(5)1159ndash60

Reddy 2013




Review Manager 2011




Rhoads 2009




155(6)823ndash8

Roberfroid 2007



Roberts 2004



Rosander 2008






Saavedra 1999



535ndash7

Salminen 2002





Salminen 2004





200438(1)62ndash9

Savino 2004




Savino 2005




18(1)72ndash5

Savino 2006




Savino 2007a


(9)1259ndash64

Savino 2007b



200796(7)1109

Savino 2009




(10)1582ndash8

Savino 2010





Savino 2012a




14651858CD009999]

Savino 2012b






Soleman 2003






Sterne 2008





Stifter 1998




Taylor 2007






(1)184ndash91

Thomas 2010



(6)1217ndash31

Thompson 2001




Tynkkynen 1998





195ndash204

Vanderhoof 1998





Walter 2011





4645ndash52

Wang 2010






Wessel 1954




























Data synthesis


















proach





(Higgins 2008)





















strategies






and outcome


infant formula


























analyses
















R E F E R E N C E S


Alfaleh 2011




[DOI 10100214651858CD005496pub3]

Andresen 2006



1073ndash88

Baldassarre 2010






Bongaerts 1997





Borriello 2003




200336(3)775ndash80

Boyle 2006




Broughton 1983



19832(5)382ndash4

Bruni 2009




321ndash3

CAST 2010






Cohen 2012





Commane 2005





102ndash9





Suppl)S22ndash5

DerSimonian 1986



Deshpande 2010




Deshpande 2011



201127(1)13ndash8

Dobson 2012




[DOI 10100214651858CD004796pub2]

Donner 1980





Egger 1997



1997315(7109)629ndash34

Elbourne 2002





Falony 2006






FAO 2010






Freedman 2009




Freeman 1989




Furukawa 2005





Gao 2010







Garrison 2000



184ndash90

Gavaghan 2000




Gill 2001





Guandalini 2000





Gupta 2002



Ha 1999



199937(4)1227ndash8

He 2002





Heine 2008




Hempel 2011





Higgins 2002



Higgins 2003



Higgins 2008





243ndash96

Higgins 2011a







Higgins 2011b







Higgins 2011c









Husni 1997




Iacono 2005





Jenke 2012





217ndash8

Kalima 1996




Kalliomaumlki 2001




357(9262)1076ndash9

Keefe 2006




Kirjavainen 1999






790ndash802

Kopp 2008





e850ndash6

Kopp 2009



Care 200912(3)298ndash303

Ku 2006




Kunz 2004





Kunze 2009





200913(8B)2261ndash70

Larsen 2006






60(11)1284ndash93

Lucassen 2000





Lucassen 2001





Luyer 2005




3686ndash92

Ma 2009











Munakata 2010




201032(8)691ndash4

Ohishi 2010





Pedone 1999








Perapoch 2000






Perry 2011




Petschow 2005






Prescott 2008





Rautio 1999





(5)1159ndash60

Reddy 2013




Review Manager 2011




Rhoads 2009




155(6)823ndash8

Roberfroid 2007



Roberts 2004



Rosander 2008






Saavedra 1999



535ndash7

Salminen 2002





Salminen 2004





200438(1)62ndash9

Savino 2004




Savino 2005




18(1)72ndash5

Savino 2006




Savino 2007a


(9)1259ndash64

Savino 2007b



200796(7)1109

Savino 2009




(10)1582ndash8

Savino 2010





Savino 2012a




14651858CD009999]

Savino 2012b






Soleman 2003






Sterne 2008





Stifter 1998




Taylor 2007






(1)184ndash91

Thomas 2010



(6)1217ndash31

Thompson 2001




Tynkkynen 1998





195ndash204

Vanderhoof 1998





Walter 2011





4645ndash52

Wang 2010






Wessel 1954























R E F E R E N C E S


Alfaleh 2011




[DOI 10100214651858CD005496pub3]

Andresen 2006



1073ndash88

Baldassarre 2010






Bongaerts 1997





Borriello 2003




200336(3)775ndash80

Boyle 2006




Broughton 1983



19832(5)382ndash4

Bruni 2009




321ndash3

CAST 2010






Cohen 2012





Commane 2005





102ndash9





Suppl)S22ndash5

DerSimonian 1986



Deshpande 2010




Deshpande 2011



201127(1)13ndash8

Dobson 2012




[DOI 10100214651858CD004796pub2]

Donner 1980





Egger 1997



1997315(7109)629ndash34

Elbourne 2002





Falony 2006






FAO 2010






Freedman 2009




Freeman 1989




Furukawa 2005





Gao 2010







Garrison 2000



184ndash90

Gavaghan 2000




Gill 2001





Guandalini 2000





Gupta 2002



Ha 1999



199937(4)1227ndash8

He 2002





Heine 2008




Hempel 2011





Higgins 2002



Higgins 2003



Higgins 2008





243ndash96

Higgins 2011a







Higgins 2011b







Higgins 2011c









Husni 1997




Iacono 2005





Jenke 2012





217ndash8

Kalima 1996




Kalliomaumlki 2001




357(9262)1076ndash9

Keefe 2006




Kirjavainen 1999






790ndash802

Kopp 2008





e850ndash6

Kopp 2009



Care 200912(3)298ndash303

Ku 2006




Kunz 2004





Kunze 2009





200913(8B)2261ndash70

Larsen 2006






60(11)1284ndash93

Lucassen 2000





Lucassen 2001





Luyer 2005




3686ndash92

Ma 2009











Munakata 2010




201032(8)691ndash4

Ohishi 2010





Pedone 1999








Perapoch 2000






Perry 2011




Petschow 2005






Prescott 2008





Rautio 1999





(5)1159ndash60

Reddy 2013




Review Manager 2011




Rhoads 2009




155(6)823ndash8

Roberfroid 2007



Roberts 2004



Rosander 2008






Saavedra 1999



535ndash7

Salminen 2002





Salminen 2004





200438(1)62ndash9

Savino 2004




Savino 2005




18(1)72ndash5

Savino 2006




Savino 2007a


(9)1259ndash64

Savino 2007b



200796(7)1109

Savino 2009




(10)1582ndash8

Savino 2010





Savino 2012a




14651858CD009999]

Savino 2012b






Soleman 2003






Sterne 2008





Stifter 1998




Taylor 2007






(1)184ndash91

Thomas 2010



(6)1217ndash31

Thompson 2001




Tynkkynen 1998





195ndash204

Vanderhoof 1998





Walter 2011





4645ndash52

Wang 2010






Wessel 1954

















Egger 1997



1997315(7109)629ndash34

Elbourne 2002





Falony 2006






FAO 2010






Freedman 2009




Freeman 1989




Furukawa 2005





Gao 2010







Garrison 2000



184ndash90

Gavaghan 2000




Gill 2001





Guandalini 2000





Gupta 2002



Ha 1999



199937(4)1227ndash8

He 2002





Heine 2008




Hempel 2011





Higgins 2002



Higgins 2003



Higgins 2008





243ndash96

Higgins 2011a







Higgins 2011b







Higgins 2011c









Husni 1997




Iacono 2005





Jenke 2012





217ndash8

Kalima 1996




Kalliomaumlki 2001




357(9262)1076ndash9

Keefe 2006




Kirjavainen 1999






790ndash802

Kopp 2008





e850ndash6

Kopp 2009



Care 200912(3)298ndash303

Ku 2006




Kunz 2004





Kunze 2009





200913(8B)2261ndash70

Larsen 2006






60(11)1284ndash93

Lucassen 2000





Lucassen 2001





Luyer 2005




3686ndash92

Ma 2009











Munakata 2010




201032(8)691ndash4

Ohishi 2010





Pedone 1999








Perapoch 2000






Perry 2011




Petschow 2005






Prescott 2008





Rautio 1999





(5)1159ndash60

Reddy 2013




Review Manager 2011




Rhoads 2009




155(6)823ndash8

Roberfroid 2007



Roberts 2004



Rosander 2008






Saavedra 1999



535ndash7

Salminen 2002





Salminen 2004





200438(1)62ndash9

Savino 2004




Savino 2005




18(1)72ndash5

Savino 2006




Savino 2007a


(9)1259ndash64

Savino 2007b



200796(7)1109

Savino 2009




(10)1582ndash8

Savino 2010





Savino 2012a




14651858CD009999]

Savino 2012b






Soleman 2003






Sterne 2008





Stifter 1998




Taylor 2007






(1)184ndash91

Thomas 2010



(6)1217ndash31

Thompson 2001




Tynkkynen 1998





195ndash204

Vanderhoof 1998





Walter 2011





4645ndash52

Wang 2010






Wessel 1954





















Husni 1997




Iacono 2005





Jenke 2012





217ndash8

Kalima 1996




Kalliomaumlki 2001




357(9262)1076ndash9

Keefe 2006




Kirjavainen 1999






790ndash802

Kopp 2008





e850ndash6

Kopp 2009



Care 200912(3)298ndash303

Ku 2006




Kunz 2004





Kunze 2009





200913(8B)2261ndash70

Larsen 2006






60(11)1284ndash93

Lucassen 2000





Lucassen 2001





Luyer 2005




3686ndash92

Ma 2009











Munakata 2010




201032(8)691ndash4

Ohishi 2010





Pedone 1999








Perapoch 2000






Perry 2011




Petschow 2005






Prescott 2008





Rautio 1999





(5)1159ndash60

Reddy 2013




Review Manager 2011




Rhoads 2009




155(6)823ndash8

Roberfroid 2007



Roberts 2004



Rosander 2008






Saavedra 1999



535ndash7

Salminen 2002





Salminen 2004





200438(1)62ndash9

Savino 2004




Savino 2005




18(1)72ndash5

Savino 2006




Savino 2007a


(9)1259ndash64

Savino 2007b



200796(7)1109

Savino 2009




(10)1582ndash8

Savino 2010





Savino 2012a




14651858CD009999]

Savino 2012b






Soleman 2003






Sterne 2008





Stifter 1998




Taylor 2007






(1)184ndash91

Thomas 2010



(6)1217ndash31

Thompson 2001




Tynkkynen 1998





195ndash204

Vanderhoof 1998





Walter 2011





4645ndash52

Wang 2010






Wessel 1954



















Perapoch 2000






Perry 2011




Petschow 2005






Prescott 2008





Rautio 1999





(5)1159ndash60

Reddy 2013




Review Manager 2011




Rhoads 2009




155(6)823ndash8

Roberfroid 2007



Roberts 2004



Rosander 2008






Saavedra 1999



535ndash7

Salminen 2002





Salminen 2004





200438(1)62ndash9

Savino 2004




Savino 2005




18(1)72ndash5

Savino 2006




Savino 2007a


(9)1259ndash64

Savino 2007b



200796(7)1109

Savino 2009




(10)1582ndash8

Savino 2010





Savino 2012a




14651858CD009999]

Savino 2012b






Soleman 2003






Sterne 2008





Stifter 1998




Taylor 2007






(1)184ndash91

Thomas 2010



(6)1217ndash31

Thompson 2001




Tynkkynen 1998





195ndash204

Vanderhoof 1998





Walter 2011





4645ndash52

Wang 2010






Wessel 1954

















Soleman 2003






Sterne 2008





Stifter 1998




Taylor 2007






(1)184ndash91

Thomas 2010



(6)1217ndash31

Thompson 2001




Tynkkynen 1998





195ndash204

Vanderhoof 1998





Walter 2011





4645ndash52

Wang 2010






Wessel 1954

















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