Elbert Aldrin Harijanto – 102016109

Tutor : Dr.Josef Setia Budi, Sp.A

Abstract
 Objective
 Investigate the effectiveness of Lactobacillus reuteri DSM
17938 for the treatment of infantile colic in breastfed
Canadian infants, compared with placebo
 Study design
 Randomized, double-blind, pacebo-controlled trial was
conducted involving 52 infants with colic, according to
modified Wessel criteria, who were assigned at random to
receive Lactobacillus reuteri DSM 17938 (108 colony-forming
units)(n=24) or placebo (n=28) for 21 days. Daily crying and
fussing times were recorded in a structured diary, and
maternal questionnaries were completed to monitor changes
in infant colic symptoms and adverse events
Abstract
 Result
 Total average crying and fussing times throghout the study (from
baseline to day 21) were significantly shorter among infants with
colic in the probiotic group compared with infants in the placebo
group (1719 ±750 minutes [29 ±13 hours] vs 2195 ± 765 minutes
[37±13 hours];P = 0.28)(relative risk, 0.78; 95% CI, 0.58-0.98).
Infants given Lactobacillus reuteri DSM 17938 showed a significant
reduction in daily crying and fussing times at the end of treatment
period compared with those receiving placebo (median, 60
minutes/day [IQR, 64 minutes/day] vs 102 minutes/day [IQR, 87
minutes/day]; P=0,45). On day 21, a significanty higher proprtion of
infants in the Lactobacillus reuteri DSM 17938 group responded to
treatment with a ≥50% crying time reduction compared with
infants given placebo (17 vs 6, P=0.35; relative risk, 3.3; 95% CI, 1.55-
7.03).
Abstract
 Conclusion
 Administration of Lactobacillus reuteri DSM 17938
significantly improved colic symptoms by reducing
crying and fussing times in breastfed Canadian infants
with colic
Introduction
 Crying, normal during infancy serving as the infant’s
means of survival to alert and elicit help to their
physiological needs
 Wessel et al – infantile colic
 Fussy infant with colic as “one who is otherwise healthy
and well-fed, had paroxysms of irritability, fussy or
crying, lasting for a total of 3 hours a day, occurring on
more than 3 days in any one week for a period of 3
weeks”
 Fussing
 “behavior that is not quite crying but not content either.”
Introduction
 Manifest as early as 2 weeks of age
 Peak between 6 and 8 weeks of age
 Diminishing between 3 and 4 months of age
 Sudden crying and fussy/gassy periods can commence
and subside without an obvious trigger or cause.
Introduction
 Unclear etiology
 Various theories :
 Overproduction of intestinal gas
 Forceful intestinal contraction
 Cow’s milk protein hypersensitivity
 Transient lactase deficiency
 Negative or inadequate maternal-infant bonding or parental
overstimulation
 Difficult infant temperament
 Insecure parental attachment
 Intestinal microbiota
Introduction
 Infants with colic
 Lack of lactobacilli in early infancy
 More frequently colonized with gas-forming Clostridium
difficile, Escherichia sp, and Klebsiella sp.
 Infantile colic not only related to atypical microbacterial
colonization pattern, but also the lack of microbial
diversity of the intestinal microbiota in early days of life
Introduction
 Probiotics
 “live microorganisms that, when administered in
adequate amounts, confer health benefits on the host”
 Supplementation with probiotics can modulate
intestinal bacterial patterns by aiding the colonization
of beneficial bacteria, which surpress intestinal
inflammation by preventing the overgrowth of
inflammation-inducing microbes and gas-forming
coliforms
Methods
 Conducted between February 2012 and April 2014
 The Hospital for Sick Children and in pediatric care
practices in Toronto, Ontario, Canada
 Before study initiation, approval was obtained from
The Hospital for Sick Children’s Research Ethics Board
and Health Canada
 Eligible infants were included in the study ater written
informed constent was obtained from a
parent/guardian.
Methods
 Inclusion Criteria :
 Diagnosis of infantile colic (ie, crying or fussy/gassy episodes
≥3 hours/day for ≥3 days/7 days, as defined by a modified
definition of Wessel criteria) at study commencement
 Age 3 weeks to 6 months at study commencement (although
infantile colic typically manifests between age 2 weeks and 3-
4 months, to capture infants with delayed onset of colic,
infants with colic up to 6 months were eligible)
 Exclusively breastfed
 ≥37 weeks gestation at birth
 5-minute Apgar score ≥7
 Birth weight ≥2500 g
Methods
 Exclusion Criteria
 A major medical problem or acute illness, including
gastroesophageal reflux, as determined by a pediatrician
 History of antibiotic treatment before or during the study
 History of probiotic or L reuteri supplementation
 History of any allergies to any of the ingredients in the
probiotic L reuteri DSM 17938 (freeze-dried, 1 x108 per 5
drops; sunflower oil, medium-chain triglyceride oil, and
silicon dioxide) or placebo (sunflower oil, medium-chain
triglyceride oil, and silicon dioxide)
 Concurrent participation in another clinical trial
Methods
 Primary Outcome
 Reduction in duration of average crying and fussing
times, from baseline to end of treatment, to <3 hours per
day
 Secondary Outcome
 Number of participants who responded to treatment on
days 7, 14, and 21
 Defined as infants who experienced a reduction in daily
average crying and/or fussing time of ≥50% from
baseline.
Methods
 Parents were instructed to record any adverse events
daily, along with weekly measurements of weight,
changes in bowel movements and stool characteristics
(frequency and consistency), and frequency of
digestive discomfort and/or intolerance (regurgitation
or vomiting). These data were collected for the
duration of the treatment period.
Methods
 All participants were randomized into 1 of 2 treatment arms, the
L reuteri DSM 17938 group or placebo group. Independent
Research Support Pharmacy personnel, not participating in the
study at The Hospital for Sick Children, prepared a computer-
generated 2-treatment randomization schedule with a random
block of varying size to ensure balance in the allocation of
participants between treatment arms. In addition, a Research
Support Pharmacy pharmacist prepared the treatment and
placebo study products in identical packaging, to ensure that the
drops were indistinguishable to all study investigators and
participants. All study investigators and participants remained
blinded to treatment allocation at each phase of the trial,
including the final data analysis. The randomization code was
revealed only on completion of all outcome analyses.
Methods
 Enrollment day (day 0)
 Gestational age
 Type of delivery
 Personal medical history
 Smoking status
 History of gastrointestinal disease
 Infant birth weight
 Description of colic symptoms
 The referring pediatrician performed a medical
examination on day 0, and infant growth parameters were
recorded on day 0 and all subsequent follow-up visits (days
7, 14, and 21)
Methods
 Caregivers were instructed to administer 5 drops orally,
once daily for 21 days, preferably at the same time each day.
 Parents and/or legal guardians were instructed to refrain
from other modes of therapy or methods to console their
infant with colic.
 The active study product
 1x108 CFU/5 drops of L reuteri DSM 17938 suspended in
sunflower oil, medium-chain triglyceride oil, and silicon
dioxide.
 The placebo contained the same excipient ingredients but
without the live bacteria.
 All study products were kept refrigerated until use.
Methods
 Parents were instructed to complete a structured 21-day
maternal diary, modified from Barr et al, to record:
 the frequency of colic episodes and the daily crying and
fussing time (in minutes)
 feeding schedule
 stool frequency and characteristics
 adverse events experienced (eg, con-stipation, vomiting,
erythema), along with the frequency and duration of each
adverse event
 At all phases of the trial, parents and caregivers were
encouraged to contact the referring pediatrician and study
team investigators as necessary
Methods
 To monitor the progress of study participants, follow-
up visits were conducted on study days 7, 14, and 21 by
the same referring pediatrician and a study
investigator. During each study visit, the following
data were collected :
 change in infant colic symptoms (ie, no change, mild
improvement, or significant improvement)
 infant weight
 study-associated adverse events
Methods
 Day 21, a medical examination was again performed by
the same referring pediatrician, and a study
investigator collected the remainder of unused study
product and the completed maternal diary.
 The diaries were reviewed for completion
independently by the pediatrician and 2 study team
investigators.
 Data entry was preformed independently by 2 study
team investigators, and was reviewed by a third
investigator to ensure accuracy of data transferred
from the diaries.
Statistical Analyses
 A minimum of 22 participants per study arm was needed to
provide 80% power to detect an effect size of 0.5 and a
detectable difference between groups in mean crying and
fussing times of 50 minutes. Statistical analyses were
performed using SPSS version 20 (IBM, Armonk, New
York) using an intention-to-treat approach. The Student t
test was used to compare mean values of continuous
variables approximating a normal distribution, and the
Mann-Whitney U test was used for nonnormally
distributed variables. Proportions were compared using the
χ2 test or Fisher exact test, as appropriate. All reported
statistical tests were 2-sided.
Results
Results
Results
Results
Results
 Safety and Tolerance
 Both the probiotic and the placebo were generally well
tolerated, with no reported adverse events associated
with the administration of either study product. There
were no differences between the L reuteri and placebo
groups in terms of change in mean weight (45.3 ±0.7 g vs
56.7 ±0.3 g; P = .28), height (3.8 ±0.5 cm vs 3.7±0.2 cm; P
= .99), and head circumference (3.2±0.8 cm vs 2.9±0.7
cm; P = .86) from baseline to the end of the study.
Discussion
 Administration of L reuteri DSM 17938 to exclusively
breastfed infants diagnosed with infantile colic
proved superior to placebo in reducing daily crying
and fussing times. The difference was statistically
significant as early as 7 days after initiation of the probiotic
therapy. Analysis of the number of responders to treatment
revealed a similar trend by day 21 of treatment
 A few minor differences notwithstanding, writer’s results
are consistent with other previously reported studies from
Italy and Poland, which used similar definitions of infantile
colic and primary outcome measures
Discussion
 In the trial reported by Savino et al, breastfeeding
mothers were instructed to refrain from consuming
dairy products containing cow’s milk protein.
 Similar to the trial of Szajewska et al, writers did not
request breastfeeding mothers to adhere to a cow’s
milk protein elimination diet, and, despite that,
writers observed comparable improvements in daily
crying and fussing times in the L reuteri–treated
group. This demonstrates that merely eliminating
cow’s milk protein is not effective in reducing
daily crying times of infants with colic
Discussion
 The need for a placebo group is essential in this type
of self-limiting condition, which tends to improve
over time. In this study, 6 of 28 infants (21%) given
placebo showed a significant reduction in crying and
fussing times from baseline (day 0) to the end of the study
(day 21), compared with 15 of 24 infants (63%) in the L
reuteri group. The placebo effect was also reported by
Savino et al, Szajewska et al, and Sung et al, but at far
higher levels (71%, 37.5%, and not reported, respectively).
In contrast to the previously mentioned studies and the
present study, Sung et al reported no difference in
improvement in colic symptoms between the probiotic and
placebo groups
Discussion
 Potential limitation of this study is that the measure
to assess the duration of crying and fussing times
in infants with colic relied solely on the mothers’
report of the duration of crying and fussing episodes
in the maternal diaries
 Objective measures of compliance with the study
products were not assessed. A potential approach to
assessing compliance is to weigh the study bottles
both before and after dispensing, however, this
method reportedly produces highly variable results
Conclusion
 Supplementation of probiotics in early infancy is
effective in managing colic symptoms