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Citation for the original published paper (version of record):

Hjern, A., Lindblom, K., Reuter, A., Silfverdal, S-A. (2020)A systematic review of prevention and treatment of infantile colicActa Paediatricahttps://doi.org/10.1111/apa.15247

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Acta Paediatrica. 2020;00:1–12.  |  1wileyonlinelibrary.com/journal/apa

1  | INTRODUC TION

Infant behaviours such as excessive crying, fussing and sleeping problems are found in approximately 20% of all children and are the most common complaints for which parents seek professional help. Infants referred for persistent crying problems and associated sleep-ing or feeding problems, so-called ‘infant regulation problems’, are at increased risk for developing more severe problems later in child-hood including ADHD, conduct problems, negative emotionality and academic difficulties.1

A varied amount of crying daily is considered normal in typically developing infants, with the duration increasing from birth and peak-ing at approximately 6 weeks.2 Infantile colic has been the subject of many investigations, and since 1954, it has been defined as ‘crying for at least three hours per day, for at least three days per week, for a period of three weeks or longer in otherwise healthy infants’; typ-ically known as Wessel ‘rule of threes’. Recently, the Wessel criteria have been further refined in the Rome classification of functional gastrointestinal disorders (Rome IV), with the replacement of the three weeks duration criterion with a 7-day duration criterion.3

Received: 8 September 2019  |  Revised: 14 January 2020  |  Accepted: 5 March 2020

DOI: 10.1111/apa.15247

R E V I E W A R T I C L E

A systematic review of prevention and treatment of infantile colic

Anders Hjern1,2,3  | Kristin Lindblom4 | Antonia Reuter5 | Sven-Arne Silfverdal6,7

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.© 2020 The authors. Acta Pædiatrica published by John Wiley & Sons Ltd on behalf of Foundation Acta Paediatrica

1Sachs’ Children and Youth hospital, Stockholm, Sweden2Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden3CHESS, Centre for Health Equity Studies, Stockholm University and Karolinska Institutet, Stockholm, Sweden4Child Health Services, Dalecarlia region, Falun, Sweden5Child and Youth Services, Primary Care, Västra Götaland region, Gothenburg, Sweden6Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden7Centre for Mother and Child Health Care, Region Västerbotten, Umeå, Sweden

CorrespondenceAnders Hjern, Centre for Health Equity Studies, Karolinska Institutet/Stockholm University, 106 91 Stockholm, Sweden.Email: [email protected]

Funding informationForskningsrådet om Hälsa, Arbetsliv och Välfärd, Grant/Award Number: 2015-01488

AbstractAim: The aim of this review was to evaluate the evidence for interventions for infan-tile colic.Methods: This was a systematic review based on a literature search in December 2017 for articles published during 2007–2017 about preventive and treatment inter-ventions for infantile colic in infants. The review included original randomised con-trolled trials (RCTs) and meta-analyses with at least 20 infants in each study group that were assessed according to GRADE criteria.Results: The review found moderately strong evidence that administration of Lactobacillus reuteri DSM 17938 shortened the crying duration, with positive evi-dence from three out of four national contexts. There were four RCTs of acupunc-ture, all with no or minimal effect on crying duration. All studies reviewed with a follow-up until or beyond three months of age show a quite steep decline over time in crying duration in both treatment and control groups.Conclusion: Lactobacillus reuteri DSM 17938 is a promising treatment for infantile colic with moderately strong evidence in this review, but studies in more populations are needed. Acupuncture is not an effective treatment for infantile colic. Systematic support strategies to parents with infantile colic are important knowledge gaps.

K E Y W O R D S

acupuncture, colic, excessive crying, infantile colic, infant, probiotics

Page 3

2  |     Hjern et al.

Infantile colic is a common disorder in the first months of life, affect-ing somewhere between 4% and 28% of infants worldwide, depending on geography and definitions used.2 Persistent infant colic can con-tribute to parental fatigue and distress and may result in strained pa-rental relationships and poor parental engagement with their infant.3

It has been assumed that the causes of excessive crying/infant colic are multifactorial, with maternal, paternal, infant and environ-mental factors being implicated.4 Maternal considerations include stress and postnatal depression, whereas infant factors may include the individual infant’s temperament, developmental milestones achieved, the infant’s sensory processing capacity and underlying organic causes. Organic causes are thought to include food protein allergy and/or food intolerances.2

The aim of this review was to evaluate the evidence for methods for prevention and treatment of excessive crying in infancy and to identify important knowledge gaps that need to be filled in future research.

2  | METHODS

We searched MEDLINE, Web of Science and PsycINFO in December 2017 for articles published during 2007–2017 about preventive and treatment interventions for sleep problems and crying/colic in in-fants. See Appendix S1 for search syntax. A total of 2070 unique records were found and screened through abstracts. When the retrieved articles indicated that the overlap in the literature of treatment of sleep disorders and infantile colic was minimal, it was decided to separate the review into two. The following criteria were used in the review of studies of infantile colic:

1. The article should describe an original randomised control trial (RCT) study. Quasi-randomised studies were also included.

2. Colic/ crying in infants below six months of age should be the target of the intervention.

3. Infant and parental outcomes were accepted.4. Intervention and control groups should consist of at least 20

infants.5. Systematic reviews were included only if the studies included ful-

filled the above search criteria.

The search flow is described in Figure 1.All articles were screened by two researchers with the GRADE

framework5 operationalised into a Swedish checklist by the Swedish Agency for Health Technology Assessment and Assessment of Social Services ( https://www.sbu.se/globa lasse ts/ebm/metod bok/mall_rando miser ade_studi er.pdf)

3  | RESULTS

There were 476 articles of original studies that were screened in full text. Ten articles that described original intervention studies and two

that described meta-analyses fulfilled the study criteria described above and were judged to be of moderate or high quality according to the GRADE criteria. These studies included interventions based on principles of education of parents, probiotics, food manipulation of the mother, pain relief and acupuncture. Table 1 provides a sum-mary of the studies included in the results.

3.1 | Education

In an intervention delivered by well-baby clinics in Melbourne, Australia, Hiscock et al6 mailed a 27-page booklet and 23-min DVD to randomised families. Control families received the routine sup-port and information provided by the well-baby clinic. The booklet contained information about normal infant sleep cycles, crying pat-terns, strategies to promote independent settling and self-care for parents. Intervention families were also offered an individual tel-ephone consultation at infant age 6–8 weeks (ie peak infant crying time) and a 1.5-h parent group session at approximately infant age 12 weeks. The intervention did not have any effect on crying dura-tion in the infants, but mothers in the intervention group had lower levels of clinical cases of depression according to the Edinburgh Parental Depression scale, with adjusted odds ratios (ORs) of 0.57 at the six-month follow-up.

3.2 | Probiotics

The developing gastrointestinal microbiota has been suggested to be involved in the causation of excessive crying in children in the age 2 week to 3 months, the typical period when excessive crying peaks and fades. This period is also the period when the previously sterile gut is colonised with bacteria, and it has been hypothesised that this process initially could cause uncomfort/pain in some infants.7

This hypothesis has been tested in a number of randomised controlled trials with different types of bacteria. The bacteria most consistently found to be linked with decreased crying time is Lactobacillus reuteri DSM 17938. In two population-based studies

Key notes

• One in five infants fulfil the criteria of infantile colic at the age of six weeks.

• There is moderately strong evidence that administration of the probiotic Lactobacillus reuteri DSM 17938 can shorten crying duration in infants with colic, while the available evidence does not support acupuncture for colic.

• There is a need for evidence-based parent support strat-egies for infantile colic. Such strategies should also in-clude the second parent.

Page 4

     |  3Hjern et al.

in Italy,8,9 this probiotic was evaluated as a preventive intervention for excessive crying in double-blind RCTs. Both studies favoured the intervention group, but one9 used indirect measures of exces-sive crying and thus should be interpreted cautiously. In a Finnish study, Kukkonen et al10 investigated the effects of a mix of probi-otic bacteria, not including Lactobacillus reuteri DSM 17938, on the development of allergic disorders, and also recorded the incidence of infantile colic. Very similar rates were found in control and inter-vention groups.

Harb et al11 performed a meta-analysis of six double-blind RCTs of the Lactobacillus reuteri DSM 17938 as treatment for infantile colic in infants with breastfeeding in populations from three European countries and Australia. Effects were estimated data at 21 days of treatment, because this was the common data collection point for these studies. Overall, Lactobacillus reuteri DSM 17938 reduced crying time in the infants studied (pooled MD _55.9 min/day, 95% CI _64.4 to _47.3, P < .001). It should be noted, however, that the largest study, a study from Australia

by Sung et al12, did not find any effect of the probiotic. In the GRADE terminology, the evidence was categorised as moderately strong rather than strong, because of this heterogeneity between populations.

Kianifar et al13, in Iran, examined the effects of a mixture of 6 species of microbiota, not including Lactobacillus reuteri DSM 17938, plus fructo-oligosaccharide on infants with infantile colic in a double-blind RCT, with a significant treatment effect on crying dura-tion on the seventh day of the intervention.

3.3 | Diet

In a French double-blind RCT of formula-fed infants, Dupont et al14 investigated the effects on crying duration in infants with infantile colic of an experimental formula enriched with probiotics (other than Lactobacillus reuteri DSM 17938) and reduced in protein and starch. No effect on crying duration was demonstrated.

F I G U R E 1   Search flow

Records iden�fied through database searching (n = 2760)

Scre

enin

gIn

clud

edEl

igib

ility

Iden

�fica

�on

Records a�er duplicates removed(n = 2070)

Records screened in abstracts

Records excluded(n = 1552)

Original ar�cles assessed for eligibility in full text

(n = 476)

Original studies included in synthesis

(n = 10)

Reviews (n = 42)

Reviews included in synthesis

(n =2)

Page 5

4  |     Hjern et al.

TAB

LE 1

 O

verv

iew

of a

rtic

les

incl

uded

in re

view

of p

reve

ntio

n an

d tr

eatm

ent f

or e

xces

sive

cry

ing/

infa

ntile

col

ic

Aut

hors

/yea

rSa

mpl

eSe

ttin

g an

d de

liver

yIn

terv

entio

n de

tails

Out

com

e

Was

the

prog

ram

me

effe

ctiv

e?

Info

rmat

ion/

educ

atio

n

His

cock

et

al (

2014

)In

terv

entio

n

N =

273

fam

ilies

Cont

rol

N =

274

fam

ilies

Mot

hers

and

thei

r chi

ld b

orn

at

32 w

eeks

’ ges

tatio

n or

late

r, w

ith

enou

gh E

nglis

h an

d no

kno

wn

chro

nic

diso

rder

Att

ritio

n: 5

5%

Des

ign

RCT

Sett

ing

42 w

ell-c

hild

cl

inic

s in

M

elbo

urne

, V

icto

ria,

Aus

tral

ia

Mot

hers

wer

e re

crui

ted

at th

e fir

st h

ome

visi

t by

thei

r Mat

erna

l and

Chi

ld H

ealth

(MC

H) n

urse

Inte

rven

tion

fam

ilies

wer

e m

aile

d a

27- p

age

book

let a

nd 2

3-m

in D

VD

. The

boo

klet

co

ntai

ned

info

rmat

ion

abou

t nor

mal

infa

nt s

leep

cy

cles

, cry

ing

patt

erns

, str

ateg

ies

to p

rom

ote

inde

pend

ent s

ettli

ng a

nd s

elf-

care

for p

aren

ts.

Inte

rven

tion

fam

ilies

wer

e al

so o

ffer

ed a

n in

divi

dual

tele

phon

e co

nsul

tatio

n at

infa

nt a

ge

6–8

wee

ks (i

e pe

ak in

fant

cry

ing

time

15) a

nd

a 1.

5-h

pare

nt g

roup

ses

sion

at a

ppro

xim

atel

y in

fant

age

12

wee

ks

Cont

rol g

roup

—Th

e co

ntro

l gro

up re

ceiv

ed u

sual

w

ell-c

hild

car

e

Infa

nt o

utco

mes

wer

e m

easu

red

by p

osta

l su

rvey

at a

ppro

xim

atel

y 4

and

6 m

onth

s of

age

. Car

egiv

ers

wer

e as

ked

if th

ey h

ad

expe

rienc

ed a

pro

blem

(yes

/no)

with

infa

nt

day

slee

p, c

ryin

g or

feed

ing,

and

if th

ey

resp

onde

d in

the

affir

mat

ive,

to ra

te th

e se

verit

y of

eac

h pr

oble

m o

n a

7-po

int L

iker

t sc

ale,

from

1=

‘har

dly

any

prob

lem

” to

7 =

“a

seve

re p

robl

em’

Ther

e w

ere

no d

iffer

ence

s be

twee

n gr

oups

in

car

egiv

er re

port

of i

nfan

t sle

ep, c

ryin

g,

or fe

edin

g pr

oble

ms

at fo

llow

-up

at 4

and

6

mon

ths

of a

ge

Leve

ls o

f mat

erna

l dep

ress

ion,

how

ever

, w

ere

low

er in

the

inte

rven

tion

grou

p at

the

6-m

onth

, but

not

4-m

onth

follo

w-u

p

No

on in

fant

cr

ying

In

conc

lusi

ve,

on m

ater

nal

men

tal

heal

th

Prob

iotic

sPr

even

tion

Indr

io e

t al (

2014

)In

terv

entio

n N

= 4

68 fa

mili

es

Cont

rol

N =

471

fam

ilies

Incl

usio

n cr

iteria

wer

e (1

) ges

tatio

nal

age

mor

e th

an 3

7 to

less

than

41

wee

ks, (

2) a

ge le

ss th

an 1

wee

k on

en

try

into

the

stud

y, (3

) birt

hwei

ght

adeq

uate

for g

esta

tiona

l age

, (4)

A

pgar

sco

re o

f mor

e th

an 8

at 1

0 m

in, (

5) n

o co

ngen

ital d

isor

ders

and

/or

clin

ical

or p

hysi

cal a

ltera

tions

at

clin

ical

exa

min

atio

n an

d (6

) no

antib

iotic

or p

robi

otic

adm

inis

trat

ion

befo

re in

clus

ion

Att

ritio

n:

20%

Des

ign

RCT

Sett

ing

9 Pa

edia

tric

cl

inic

s in

Ital

y

Recr

uitm

ent a

t nin

e pa

edia

tric

clin

ics.

Age

at

recr

uitm

ent o

r rea

sons

for a

tten

ding

the

clin

ic

are

not d

ocum

ente

d in

the

artic

le. I

nfan

ts

wer

e ra

ndom

ly a

lloca

ted

to re

ceiv

e ei

ther

L

reut

eri D

SM 1

7938

or p

lace

bo. F

ive

drop

s of

th

e fo

rmul

atio

n, d

eliv

erin

g a

dose

of 1

× 1

08

colo

ny-f

orm

ing

units

of L

reut

eri D

SM17

938,

w

ere

adm

inis

tere

d to

the

new

born

s ea

ch d

ay fo

r 90

day

s

Pare

nts

wer

e as

ked

to re

cord

min

utes

per

day

of

inco

nsol

able

cry

ing

from

recr

uitm

ent u

p to

ag

e 3

mon

ths

At 3

mon

ths

of a

ge, t

he m

ean

dura

tion

of

cryi

ng ti

me

(38

vs 7

1 m

in; P

< .0

1) fo

r the

L

reut

eri D

SM17

938

and

plac

ebo

grou

ps,

resp

ectiv

ely,

was

sig

nific

antly

diff

eren

t

Com

men

t: O

utco

mes

wer

e no

t ana

lyse

d se

para

tely

for f

orm

ula

and

brea

stfe

d ch

ildre

n

Yes (C

ontin

ues)

Page 6

     |  5Hjern et al.

Aut

hors

/yea

rSa

mpl

eSe

ttin

g an

d de

liver

yIn

terv

entio

n de

tails

Out

com

e

Was

the

prog

ram

me

effe

ctiv

e?

Kukk

onen

et

al (

2014

)In

terv

entio

n N

=46

1 fa

mili

es

Cont

rol

N =

464

fam

ilies

Att

ritio

n:

8%

Des

ign

RCT

Sett

ing

42 w

ell-c

hild

cl

inic

s in

M

elbo

urne

, V

icto

ria,

Aus

tral

ia

Mot

hers

took

cap

sule

s co

ntai

ning

a m

ixtu

re

of L

acto

baci

llus r

ham

nosu

s GG

and

LC

705,

Bi

fidob

acte

rium

bre

ve B

b99

and

Prop

ioni

bact

eriu

m

freu

denr

eich

ii ss

p sh

erm

anii

JS (8

–9 _

109

col

ony-

form

ing

units

in e

ach

caps

ule)

or a

pla

cebo

twic

e da

ily fo

r 4 w

eeks

bef

ore

deliv

ery.

For

6 m

onth

s af

ter b

irth,

the

infa

nts

rece

ived

dai

ly 1

ope

ned

caps

ule

of th

e sa

me

prob

iotic

s an

d 0.

8 g

of

GO

Ss (o

f bov

ine

orig

in) i

n liq

uid

form

or p

lace

bo

(mic

rocr

ysta

lline

cel

lulo

se p

lus

suga

r syr

up)

Que

stio

nnai

re a

t 3 m

onth

s

Infa

ntile

col

ic, d

efin

ed a

s cr

ying

at l

east

4 h

pe

r day

for a

t lea

st 3

day

s pe

r wee

k oc

curr

ed

in 4

% a

nd s

imila

r but

less

freq

uent

cry

ing

(onc

e or

twic

e pe

r wee

k) o

ccur

red

in 1

0% o

f ea

ch g

roup

Com

men

t: Re

cord

ing

of c

olic

not

ver

y de

taile

d, m

ain

purp

ose

of s

tudy

is p

reve

ntio

n of

alle

rgie

s

No

Savi

no e

t al (

2015

)In

terv

entio

n N

=51

chi

ldre

n

Cont

rol

N =

54 c

hild

ren

Incl

usio

n cr

iteria

: H

ealth

y te

rm in

fant

s <

10 d

ays

Att

ritio

n:

7%

Des

ign

RCT

Sett

ing

3 G

P of

fices

an

d on

e pa

edia

tric

cl

inic

in

Gen

ova

and

Turin

, Ita

ly

Patie

nts

wer

e ra

ndom

ly a

ssig

ned

to re

ceiv

e fiv

e dr

ops

cont

aini

ng th

e pr

obio

tic L

. reu

teri

DSM

17

938

(108

cfu

) with

400

UI o

f vita

min

D3

or o

nly

400

UI o

f vita

min

D3

daily

(vita

min

D is

rout

inel

y ad

min

iste

red

to a

ll ne

wbo

rns)

. The

trea

tmen

t gr

oup

rece

ived

a s

uspe

nsio

n of

free

ze-d

ried

L.

reut

eri D

SM 1

7938

in a

mix

ture

of s

unflo

wer

oi

l and

med

ium

-cha

in tr

igly

cerid

e oi

l sup

plie

d w

ith a

dded

vita

min

D3,

in a

5-m

L da

rk b

ottle

fit

ted

with

a d

ropp

er c

ap. T

he c

ontr

ol p

rodu

ct

was

a s

uspe

nsio

n of

oliv

e oi

l with

cho

leca

lcife

rol

(vita

min

D) 2

.5 m

g (1

00,0

00 U

I/m

L), i

n a

10-m

L da

rk b

ottle

with

a d

ropp

er c

ap. T

he tw

o liq

uids

lo

oked

and

sm

elle

d si

mila

r

The

use

of p

ain-

relie

ving

age

nts

(sim

ethi

cone

, ci

met

ropi

um b

rom

ide)

was

repo

rted

eac

h da

y by

par

ents

dur

ing

the

inte

rven

tion

perio

d in

to th

e ‘d

iary

’ and

was

ass

esse

d an

d re

port

ed in

the

tabl

e da

ta b

y a

stud

y te

am

mem

ber.

The

paed

iatr

icia

n no

ted

the

num

ber

of p

hone

cal

ls a

nd v

isits

due

to in

fant

ile c

olic

. A

ll ou

tcom

es fa

vour

ed th

e in

terv

entio

n gr

oup

Com

men

t: In

dire

ct m

easu

res

of c

ryin

g

Yes

Trea

tmen

t

Har

b 20

16M

eta-

anal

ysis

bas

ed o

n (N

in

terv

entio

n/N

con

trol

): C

hau

2015

(52/

52) i

n O

ntar

io, C

anad

aM

i 201

5 (3

9/39

) in

Zhen

gzho

u, C

hina

Savi

no 2

010

(46/

46) i

n N

orth

-Wes

t It

aly

Savi

no 2

007

(83/

83) i

n N

orth

-Wes

t It

aly

Sung

201

4 (1

27/6

8) in

Mel

bour

ne,

Aus

tral

ia

Szaj

ewsk

a (8

0/69

) in

War

saw

, Pol

and

Des

ign

RCT

Sett

ing

All

stud

ies

are

doub

le-b

lind

RCTs

of t

he p

robi

otic

L

reut

eri.

The

stud

ies

incl

ude

infa

nts

with

exc

lusi

ve a

nd

part

ial b

reas

tfee

ding

but

exc

lude

stu

dies

with

fo

rmul

a-fe

d in

fant

s

Cry

ing

time

reco

rded

in d

iarie

s in

all

incl

uded

st

udie

s

Five

of t

he s

ix s

tudi

es fa

vour

ed th

e in

terv

entio

n. T

he s

umm

aris

ed e

ffec

t was

a

redu

ctio

n of

54

min

cry

ing

time

per d

ay

Com

men

t: Th

e la

rges

t stu

dy, b

y Su

ng

et a

l in

Aus

tral

ia s

how

ed n

o ef

fect

of t

he

inte

rven

tion

Yes

TAB

LE 1

 (C

ontin

ued)

(Con

tinue

s)

Page 7

6  |     Hjern et al.

Aut

hors

/yea

rSa

mpl

eSe

ttin

g an

d de

liver

yIn

terv

entio

n de

tails

Out

com

e

Was

the

prog

ram

me

effe

ctiv

e?

Kia

nfar

201

4In

terv

entio

n N

=25

chi

ldre

n

Cont

rol

N =

20 c

hild

ren

Incl

usio

n cr

iteria

: Te

rm in

fant

s, ag

ed 3

wee

ks to

3

mon

ths,

wea

ned

(form

ula-

fed)

, w

ith n

orm

al g

row

th a

nd w

ith m

ore

than

3 w

eeks

of c

ryin

g pe

riods

, at

leas

t 3h

per d

ay, 3

day

s pe

r wee

k (W

esse

l et a

l., 1

954)

Att

ritio

n:

10%

Des

ign

RCT

Sett

ing

Teac

hing

ho

spita

l in

Iran

Inte

rven

tion

infa

nts

rece

ived

a s

ymbi

otic

sac

het

cont

aini

ng 1

bill

ion

CFU

of L

. cas

ei, L

. rha

mno

sus,

St

rept

ococ

cus

ther

mop

hilu

s, B

ifido

bact

eriu

m

brev

e, L

. aci

doph

ilus,

B. i

nfan

tis, L

. bul

garic

us a

nd

FOS

(Pro

texi

n H

ealth

care

, Som

erse

t, U

K).

The

cont

rol g

roup

rece

ived

pla

cebo

that

was

mat

ched

fo

r siz

e, v

olum

e, s

hape

and

man

ufac

ture

d by

the

sam

e co

mpa

ny. B

oth

synb

iotic

s an

d pl

aceb

o w

ere

disp

ense

d by

hos

pita

l pha

rmac

ist

Inte

rven

tion

was

con

ceal

ed fr

om s

tudy

in

vest

igat

ors,

pha

rmac

ist a

nd p

aren

ts to

min

imis

e tr

eatm

ent b

ias

Out

com

e m

easu

res

wer

e (1

) red

uctio

n in

the

daily

cry

ing

time

> 50

%, y

es/n

o), (

2) re

duct

ion

in th

e da

ily c

ryin

g tim

e >

90%

(yes

/no)

and

(3)

Mea

n da

ily c

ryin

g tim

e

All

thre

e ou

tcom

es fa

vour

ed th

e in

terv

entio

n at

day

7

Yes

Oth

er n

utrit

iona

l

Dup

ont 2

010

Inte

rven

tion

N =

30 c

hild

ren

Cont

rol

N =

32 c

hild

ren

Incl

usio

n cr

iteria

: he

alth

y br

east

fed

infa

nts

aged

2

wee

ks to

4 m

onth

s w

ith in

fant

col

ic

defin

ed a

s pe

r Wes

sel’s

crit

eria

Att

ritio

n:

26%

Des

ign

RCT

Sett

ing

?

A pr

ospe

ctiv

e, m

ultic

entr

e ra

ndom

ised

, dou

ble-

blin

d, p

lace

bo-c

ontr

olle

d st

udy

com

pare

d tw

o In

fant

For

mul

as, d

urin

g 1

mon

th, i

n co

licky

fo

rmul

a-fe

d ch

ildre

n. T

he e

xper

imen

tal f

orm

ula

(EF,

M

odila

c D

iges

t 1) w

as a

-lact

albu

min

-enr

iche

d an

d pr

obio

tics s

uppl

emen

ted

(Lac

toba

cillu

s rha

mno

sus,

Bifid

obac

teriu

m in

fant

is), r

educ

ed in

pro

tein

and

la

ctos

e co

nten

t, an

d th

icke

ned

with

cor

n st

arch

. Th

e co

ntro

l for

mul

a (C

F) w

as n

ot e

nric

hed

in

a-la

ctal

bum

in, h

ad a

hig

her q

uant

ity o

f pro

tein

s and

la

ctos

e, a

nd n

eith

er p

robi

otic

s nor

sta

rch

The

cryi

ng d

urat

ion

decr

ease

d si

mila

rly w

ith

time

in c

ontr

ol a

nd in

terv

entio

n gr

oup

No

Hill

201

5In

terv

entio

n N

=47

chi

ldre

n

Con

trol

N

=43

chi

ldre

n

Mat

erna

l ato

py w

as p

rese

nt in

aro

und

50%

in b

oth

inte

rven

tion

and

cont

rol

grou

ps In

clus

ion

crite

ria:

Hea

lthy

brea

stfe

d in

fant

s w

ith in

fant

co

lic d

efin

ed a

s pe

r Wes

sel’s

crit

eria

.

Mea

n ag

e at

sta

rt o

f int

erve

ntio

n; 5

.5

wee

ks

Att

ritio

n:

11%

in in

terv

entio

n gr

oup

and

20%

in

cont

rol g

roup

Des

ign

RCT

Sett

ing

Wel

l-bab

y cl

inic

s in

M

elbo

urne

, A

ustr

alia

The

effe

cts

of 2

mat

erna

l die

t pro

gram

mes

, tha

t is

a lo

w-a

llerg

en d

iet t

hat e

xclu

ded

maj

or fo

od

alle

rgen

s an

d a

cont

rol d

iet t

hat i

nclu

ded

thes

e fo

ods,

wer

e co

mpa

red.

Bot

h di

ets

avoi

ded

food

pr

eser

vativ

es, c

olou

rs a

nd a

dditi

ves.

Inte

rven

tion

mot

hers

wer

e in

stru

cted

to e

xclu

de a

ll fo

ods

cont

aini

ng d

airy

pro

duct

s, s

oy, w

heat

, egg

s,

pean

uts,

tree

nut

s an

d fis

h fr

om th

eir d

iet.

Thei

r di

et in

clud

ed a

rice

milk

drin

k, m

eats

, veg

etab

les,

fr

uits

and

cer

eals

(cor

n an

d ric

e). A

cal

cium

su

pple

men

t (1.

2 g/

day)

was

pre

scrib

ed

Redu

ctio

n in

cry

ing

time

afte

r one

wee

k w

as

mor

e pr

omin

ent i

n ch

ildre

n w

ith m

othe

rs o

n th

e el

imin

atio

n di

et, p

artic

ular

ly fo

r mod

erat

e re

duct

ion

Com

men

t: N

ot b

linde

d, v

ery

high

leve

l of

atop

y in

mot

hers

, red

uctio

n by

ato

py w

as

not r

epor

ted,

adh

eren

ce to

die

t was

poo

r in

cont

rol g

roup

Yes

TAB

LE 1

 (C

ontin

ued)

(Con

tinue

s)

Page 8

     |  7Hjern et al.

Aut

hors

/yea

rSa

mpl

eSe

ttin

g an

d de

liver

yIn

terv

entio

n de

tails

Out

com

e

Was

the

prog

ram

me

effe

ctiv

e?

Pain

relie

f

Biag

ioli

2016

Coch

rane

Rev

iew

of r

ando

mis

ed

cont

rolle

d tr

ials

(RC

Ts) a

nd q

uasi

-RC

Ts e

valu

atin

g th

e ef

fect

s of

pa

in-r

elie

ving

age

nts

give

n to

infa

nts

with

col

ic, s

atis

fyin

g th

e W

esse

l cr

iteria

. The

revi

ew in

clud

ed 1

8 RC

Ts

invo

lvin

g 10

14 in

fant

s

Des

ign

RCTs

and

qu

asi-R

CTs

Sett

ing

Thre

e st

udie

s co

mpa

red

sim

ethi

cone

with

pla

cebo

, an

d on

e w

ith M

enth

a pi

perit

a; fo

ur s

tudi

es

com

pare

d he

rbal

age

nts

with

pla

cebo

; tw

o co

mpa

red

sucr

ose

or g

luco

se w

ith p

lace

bo; f

ive

com

pare

d di

cycl

omin

e w

ith p

lace

bo; a

nd tw

o co

mpa

red

cim

etro

pium

—on

e ag

ains

t pla

cebo

and

th

e ot

her a

t tw

o di

ffer

ent d

osag

es. O

ne m

ultip

le-

arm

stu

dy c

ompa

red

sucr

ose

and

herb

al te

a vs

no

trea

tmen

t

Sim

ethi

cone

. Com

paris

on w

ith p

lace

bo

reve

aled

no

diff

eren

ces

with

pla

cebo

H

erba

l age

nts.

Low

and

mod

erat

e qu

ality

ev

iden

ce s

ugge

stin

g th

at h

erba

l age

nts

redu

ced

the

dura

tion

of c

ryin

g co

mpa

red

with

pl

aceb

o

Sucr

ose.

One

ver

y lo

w-q

ualit

y st

udy

invo

lvin

g 35

infa

nts

repo

rted

that

suc

rose

redu

ced

hour

s sp

ent c

ryin

g co

mpa

red

with

pla

cebo

(M

D 1

.72,

95%

CI 1

.38

to 2

.06)

Dic

yclo

min

e. O

ne s

tudy

met

qua

lity

crite

ria,

show

ing

an e

ffec

t of R

R 2.

50, 9

5% C

I 1.1

7 to

5.3

4, c

ompa

red

with

pla

cebo

. Tw

o of

five

st

udie

s re

port

ed re

leva

nt a

dver

se e

ffec

ts

(long

er s

leep

4%

, wid

e-ey

ed s

tate

4%

, dr

owsi

ness

13%

)

Cim

etro

pium

bro

mid

e. O

ne v

ery

low

-qua

lity

stud

y sh

owed

redu

ced

cryi

ng d

urat

ion

com

pare

d w

ith p

lace

bo

No

Inco

nclu

sive

In

conc

lusi

ve

Serio

us

adve

rse

effe

cts

Inco

nclu

sive

Acu

punc

ture

Rein

thal

et a

l (20

8)In

terv

entio

n N

= 2

0 ch

ildre

n

Cont

rol

N =

20

Att

ritio

n:

0% re

port

ed

Des

ign

RCT

Sett

ing

Priv

ate

acup

unct

ure

clin

ic

A p

rosp

ectiv

e qu

asi-r

ando

mis

ed s

ingl

e-bl

ind

cont

rol s

tudy

The

stru

ctur

ed p

rogr

amm

e of

four

trea

tmen

ts

over

a p

erio

d of

two

wee

ks w

as d

eliv

ered

in a

pr

ivat

e ac

upun

ctur

e cl

inic

, with

refe

rral

from

21

child

hea

lth c

linic

s. T

he in

fant

s al

loca

ted

to h

ave

acup

unct

ure

subs

eque

ntly

rece

ived

ligh

t nee

dlin

g at

poi

nt L

I4 o

f the

han

d’s

first

dor

sal i

nter

ossa

l m

uscl

e

Pain

dia

ry d

ivid

ed in

to 4

–6 h

per

iods

. For

eac

h pe

riod

a ra

ting

betw

een

0 an

d 10

was

mad

e.

Freq

uenc

y an

d cr

ying

dur

atio

n w

ere

also

re

cord

ed

No

diff

eren

ce in

redu

ctio

n of

cry

ing

dura

tion

betw

een

inte

rven

tion

and

cont

rol g

roup

s C

omm

ent:

This

is a

sm

all s

tudy

with

mul

tiple

ou

tcom

es

No

TAB

LE 1

 (C

ontin

ued)

(Con

tinue

s)

Page 9

8  |     Hjern et al.

Aut

hors

/yea

rSa

mpl

eSe

ttin

g an

d de

liver

yIn

terv

entio

n de

tails

Out

com

e

Was

the

prog

ram

me

effe

ctiv

e?

Land

gren

et

al (

2010

)In

terv

entio

n N

= 4

3 ch

ildre

n

Cont

rol

N =

38

Incl

usio

n cr

iteria

: hea

lthy

infa

nts,

bor

n af

ter g

esta

tiona

l wee

k 36

, not

trea

ted

with

dic

yclo

min

e an

d fu

lfilli

ng th

e m

odifi

ed W

esse

l crit

eria

for c

olic

: ‘c

ryin

g/fu

ssin

g fo

r at l

east

3 h

a d

ay,

occu

rrin

g 3

days

or m

ore

in th

e sa

me

wee

k’

Att

ritio

n:

10%

Des

ign

RCT

Sett

ing

Priv

ate

acup

unct

ure

clin

ic

The

rand

omis

atio

n pr

oced

ure

divi

ded

the

infa

nts

into

an

inte

rven

tion

grou

p w

ith a

str

uctu

red

prog

ram

me

incl

udin

g ac

upun

ctur

e (a

cupu

nctu

re

grou

p) o

r to

the

sam

e st

ruct

ured

pro

gram

me

not

incl

udin

g ac

upun

ctur

e (c

ontr

ol g

roup

)

The

stud

y w

as d

oubl

e-bl

ind

as n

eith

er th

e pa

rent

s w

ho re

gist

ered

the

infa

nts

cryi

ng n

or th

e nu

rse

who

met

the

pare

nts

knew

to w

hich

gro

up th

e in

fant

bel

onge

d. T

wo

clos

ed d

oors

sep

arat

ed th

e pa

rent

s fr

om th

e tr

eatm

ent r

oom

and

mus

ic w

as

alw

ays

play

ed. P

aren

ts w

ere

info

rmed

that

the

need

le w

as v

ery

thin

, usu

ally

cau

sed

no b

leed

ing

or v

isib

le m

arks

and

that

acu

punc

ture

doe

s no

t ne

cess

arily

pro

voke

cry

ing

The

stru

ctur

ed p

rogr

amm

e w

as d

eliv

ered

in a

pr

ivat

e ac

upun

ctur

e cl

inic

and

con

sist

ed o

f a

tota

l of s

ix b

iwee

kly

visi

ts to

the

acup

unct

ure

clin

ic. T

he in

fant

s al

loca

ted

to h

ave

acup

unct

ure

subs

eque

ntly

rece

ived

min

imal

, sta

ndar

dise

d ac

upun

ctur

e w

ith a

ste

rilis

ed, d

ispo

sabl

e ac

upun

ctur

e ne

edle

, Vin

co M

icro

Cle

an, 0

.20

× 13

m

m. T

he n

eedl

e w

as in

sert

ed u

nila

tera

lly a

nd le

ft

in p

lace

for 2

s a

t an

appr

oxim

ate

dept

h of

2 m

m

at p

oint

LI4

of t

he h

and’

s fir

st d

orsa

l int

eros

sal

mus

cle

Pare

nts

repo

rted

infa

nts’

fuss

ing,

cry

ing

and

colic

ky c

ryin

g in

a s

tand

ardi

sed

diar

y fo

rm

Inte

rven

tion

and

cont

rol g

roup

s ha

d si

mila

r im

prov

emen

t ove

r tim

e w

ith re

gard

to

cryi

ng ti

me.

Dur

ing

the

seco

nd w

eek

fuss

ing

and

colic

ky c

ryin

g w

as s

light

ly lo

wer

in th

e in

terv

entio

n gr

oup

Com

men

t: So

lely

bre

astf

eedi

ng ra

tes

wer

e sl

ight

ly lo

wer

in c

ontr

ol g

roup

, 66%

vs

74%

No

TAB

LE 1

 (C

ontin

ued)

(Con

tinue

s)

Page 10

     |  9Hjern et al.

Aut

hors

/yea

rSa

mpl

eSe

ttin

g an

d de

liver

yIn

terv

entio

n de

tails

Out

com

e

Was

the

prog

ram

me

effe

ctiv

e?

Land

gren

et

al (

2017

)In

terv

entio

n G

roup

A =

47

child

ren

Gro

up B

= 4

9 ch

ildre

n

Cont

rol

48 c

hild

ren

Incl

usio

n cr

iteria

: Elig

ible

infa

nts

wer

e be

twee

n 2

and

8 w

eeks

of a

ge w

ho,

acco

rdin

g to

thei

r par

ents

’ rec

ords

in

a d

iary

, crie

d an

d/or

fuss

ed >

3 h

/da

y fo

r > 3

day

s du

ring

the

base

line

wee

k (B

L). B

efor

e in

clus

ion

they

als

o ne

eded

to h

ave

trie

d a

diet

exc

ludi

ng

cow

’s m

ilk p

rote

in fr

om b

reas

tfee

ding

m

othe

rs a

nd/o

r app

ropr

iate

form

ula

for a

t lea

st 5

day

s. T

he e

xclu

sion

cr

iteria

incl

uded

bei

ng b

orn

befo

re

37 w

eeks

’ ges

tatio

n, ta

king

any

kin

d of

pre

scrib

ed m

edic

atio

n or

hav

ing

prev

ious

ly tr

ied

acup

unct

ure

Att

ritio

n:

2%

Des

ign

RC

T

Sett

ing

Fo

ur w

ell-

baby

clin

ics

in S

wed

en

A m

ultic

entr

e th

ree-

arm

ed R

CT

cond

ucte

d.

Infa

nts

wer

e ra

ndom

ly a

lloca

ted

to e

ither

A.

stan

dard

ised

min

imal

acu

punc

ture

at p

oint

LI4

of

the

hand

’s fir

st d

orsa

l int

eros

sal m

uscl

e; B

. sem

i-st

anda

rdis

ed in

divi

dual

ised

acu

punc

ture

insp

ired

by tr

aditi

onal

Chi

nese

; or C

. reg

ular

sup

port

from

C

HC

Pare

nts

repo

rted

infa

nts’

fuss

ing

and

cryi

ng

in a

sta

ndar

dise

d di

ary

form

Inte

rven

tion

and

cont

rol g

roup

s ha

d si

mila

r im

prov

emen

t ov

er ti

me

with

rega

rd to

cry

ing

time.

Col

icky

cr

ying

was

slig

htly

low

er in

inte

rven

tions

gr

oups

at f

ollo

w-u

p

Com

men

t: A

naly

sis

of s

ucce

ss o

f blin

ding

sh

owed

that

72%

of i

nter

vent

ion

pare

nts

but

only

21%

had

und

erst

ood

whi

ch g

roup

thei

r ch

ild w

as in

clud

ed in

No

Skej

ie e

t al (

2013

)In

terv

entio

n N

= 3

8 ch

ildre

n w

ith d

iarie

s N

= 4

4 ch

ildre

n w

ith p

aren

tal i

nter

view

s M

ean

age

6 w

eeks

at t

he s

tart

of t

he

inte

rven

tion

Cont

rol

N =

41

with

dia

ries

Mea

n ag

e 6

wee

ks

at th

e st

art o

f the

dia

ries

Incl

usio

n cr

iteria

: Ter

m in

fant

who

fu

lfille

d th

e W

esse

l crit

eria

for c

olic

: ‘c

ryin

g/fu

ssin

g fo

r at l

east

3h

a da

y,

occu

rrin

g 3

days

or m

ore

in th

e sa

me

wee

k’

Att

ritio

n:

10%

Des

ign

RCT

Sett

ing

13 G

P’s

offic

es in

N

orw

ay

The

rand

omis

atio

n pr

oced

ure

divi

ded

the

infa

nts

into

an

inte

rven

tion

grou

p w

ith a

str

uctu

red

prog

ram

me

incl

udin

g ac

upun

ctur

e (a

cupu

nctu

re

grou

p) a

nd a

con

trol

gro

up w

ith n

o tr

eatm

ent.

Both

gro

ups

visi

ted

the

GP

offic

e on

the

day

of

the

incl

usio

n an

d da

y 4

and

day

5

The

GP

was

alo

ne in

the

trea

tmen

t roo

m w

ith

the

infa

nt d

urin

g th

e in

terv

entio

n. Id

entic

al

proc

edur

e, e

xcep

t for

the

need

le in

sert

ions

, was

pe

rfor

med

on

each

infa

nt in

the

trea

tmen

t and

no

-tre

atm

ent c

ontr

ol g

roup

The

prim

ary

outc

ome

was

diff

eren

ce in

ch

ange

s in

cry

ing

time

in th

e re

gist

ratio

n pe

riod

Inte

rven

tion

and

cont

rol g

roup

s ha

d si

mila

r im

prov

emen

t ove

r tim

e w

ith re

gard

to c

ryin

g tim

e. T

he b

lindi

ng w

as e

valu

ated

and

foun

d to

be

succ

essf

ul

No

TAB

LE 1

 (C

ontin

ued)

Page 11

10  |     Hjern et al.

3.4 | Pain relief

In a Cochrane review by Biagoli et al15, a number of pain relief medications and herbal agents, that had been studied in RCTs and quasi-RCTs of infants with infant colic, were analysed. Three studies examined simethicone and found no effect compared with a control group. No conclusive evidence for treatment effects was found for herbal agents, sucrose nor cimetropium bromide. Biagoli et al15 also reports one RCT of moderate quality of Dicyclomine. In this study, more of the infants given dicyclomine responded with less crying than those given placebo. Major adverse effects of the drug, however, were reported, with longer sleep 4%, wide-eyed state 4% and drowsi-ness 13%.

3.5 | Acupuncture

Four Scandinavian studies investigated acupuncture as treatment for infantile colic (according to the Wessel criteria); three RCTs and one quasi-RCT. Three Swedish studies used light needling at the hand’s first dorsal interossal muscle. Two of these studies were made in private acupuncture clinics16,17, while Landgren et al18 investigated acupuncture as an intervention in well-baby clinics in Malmö, with nurses delivering the acupuncture. The decrease in crying duration over time was similar in control and study groups in all of these three intervention studies. The intention in all these three studies was to blind whether the infant had received acu-puncture or not, but in the one study that investigated the quality of the blinding, it was found that many parents in the acupuncture group had understood that their infant was in the treatment group. In a Norwegian study, Skeije et al19 applied acupuncture below the patella in the office of GPs in a blinded RCT. The blinding was found to be successful, but no positive treatment effect was identified.

4  | DISCUSSION

In this study, we have reviewed original studies and meta-analyses published during 2007–2017 of prevention and treatment interven-tions for infantile colic. We found several different strategies for in-terventions with an infant-centred focus; probiotics, acupuncture, pain relief and herbal medicines. A few studies had a parent-focused approach based on dietary manipulation of breastfeeding mothers or education of parents.

The review showed moderately strong evidence that the admin-istration of Lactobacillus reuteri DSM 17938 can shorten the crying duration in infants with infantile colic. RCTs conducted in three dif-ferent countries in south and east Europe have shown significant re-ductions in crying time in infants with infantile colic. This conclusion is further supported by a also supported by two recent meta-anal-yses by Sung et al20 and Gutiérrez-Castrellón et al21. There is less evidence for a positive effect in formula-fed infants, as concluded in the meta-analysis by Sung et al20, and no evidence of an effect

in infants with colic in Australia. It has been suggested that the ef-fect of Lactobacillus reuteri DSM 17938 is dependent on the infant gut microbiota and that differences between the effect on crying duration in breastfed and formula-fed infants are explained by dif-ferences in microbiota7,22. It is possible that infant gut microbiota also differs between national populations and that results of effects of Lactobacillus reuteri DSM 17938 from one population therefore may not be transferrable to other national contexts.23 This could potentially explain the lack of effect of Lactobacillus reuteri DSM 17938 on infants with colic in Australia. Lactobacillus reuteri DSM 17938 has also been investigated as a preventive measure on the population level, but here solid evidence is lacking, as concluded in a recent Cochrane review by Ong et al.24 More preventive studies are needed in sufficiently large study population to enable detection of the low-grade effects that can be expected in such trials.

With regard to pain relief, simeticone has been investigated in several RCTs, but without any clinically relevant treatment ef-fects.15 There is some, albeit limited, evidence for dicyclomine as a pain relief for colicky infants, but the reported adverse effects were so severe that the drug was retrieved from the market in the early 1990s.25

Building on experimental evidence from a Swedish study on the association of maternal intake of cow milk to crying in colicky in-fants,26 breastfeeding mothers with colicky infants are often given the advice to eliminate cow milk from their diet.27 Unfortunately, there was no RCT in this review that tested this hypothesis. It should be remembered, however, that cow milk allergy is a fairly common organic cause of infant colic that should always be considered in the medical examination of a colicky infant.3

Acupuncture as treatment for infant colic had been investigated in four controlled studies in Scandinavia, where three were RCTs and at least one was successfully blinded. The effects were minimal at the most. Further presentation of data from these studies also shows considerable pain associated with the treatment sessions.28 Acupuncture can thus not be recommended as a treatment for infant colic.

4.1 | Limitations

This study used a limited time window from 2007 to 2017, thus not taking into account studies published before or after that date. Publication bias should always be considered in evaluation of treat-ment studies and particularly when economic incentives are in-volved. Lactobacillus reuteri DSM 17938 is a commercial product, and the possibility of such bias thus cannot be excluded for this treatment.

5  | FUTURE STUDIES

The lack of evidence for interventions for infantile colic in formula-fed infants makes such studies a high priority in this field. As has

Page 12

     |  11Hjern et al.

been mentioned above, there is also a need for further studies of this probiotic as a preventive intervention for colic. Manipulation of maternal diets are often suggested as interventions for colic in breastfed infants in clinical practice, but evidence for this from more than single RCT is lacking.21

All studies reviewed with a follow-up until or beyond three months showed a quite steep decline over time in crying duration in both treatment and control groups. A review by Wolke et al29 found a mean population prevalence of around 20% for infantile colic during the first 6 weeks of life, 11% at 8–9 weeks of age and less than one per cent at 10–12 weeks of age. The primary challenge is thus not to cure infants with excessive crying during their first months, but to alleviate stress during these months to prevent secondary ef-fects in the family. There was only one study in this review6 that explored this line of thought in a study with an educational strategy with positive effects on maternal depression. A recent Cochrane re-view by Gordon et al in 201930 on parent training programmes for infantile colic, with broader inclusion criteria than this review, simi-larly found limited evidence for positive effects. Further studies are needed to develop and evaluate such strategies of support, with the inclusion also of the second parent.

ACKNOWLEDG EMENTSWe are grateful for the valuable comments on the first draft of this manuscript provided professor emeritus Ian St James Roberts, University College, London, and the assistance in the literature search provided by Gun Brit Knutssön at the Karolinska University Library.

FUNDING INFORMATIONThis review was supported by a network grant from the Swedish Research Council for Health, Working Life and Welfare.

CONFLIC T OF INTERE S TThe authors have no conflicts of interest to report.

ORCIDAnders Hjern https://orcid.org/0000-0002-1645-2058 Sven-Arne Silfverdal https://orcid.org/0000-0002-3606-3797

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SUPPORTING INFORMATIONAdditional supporting information may be found online in the Supporting Information section.

How to cite this article: Hjern A, Lindblom K, Reuter A, Silfverdal S-A. A systematic review of prevention and treatment of infantile colic. Acta Paediatr. 2020;00:1–12. https://doi.org/10.1111/apa.15247