PROBIOTIC SUPPLEMENTATION

HEALTH TECHNOLOGY ASSESSMENT SECTION

MEDICAL DEVELOPMENT DIVISION
MINISTRY OF HEALTH MALAYSIA
002/2012
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DISCLAIMER
Technology review is a brief report, prepared on an urgent basis, which draws on
restricted reviews from analysis of pertinent literature, on expert opinion and / or
regulatory status where appropriate. It has not been subjected to an external review
process. While effort has been made to do so, this document may not fully reflect all
scientific research available. Additionally, other relevant scientific findings may have
been reported since completion of this review.

Please contact: htamalaysia@moh.gov.my, if you would like further information.

Health Technology Assessment Section (MaHTAS),

Medical Development Division
Ministry of Health Malaysia
Level 4, Block E1, Precinct 1
Government Office Complex
62590 Putrajaya

Tel: 603 88831246

Fax: 603 88831230

Available at the following website: http://www.moh.gov.my

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Prepared by:

Ku Nurhasni binti Ku Abd Rahim

Senior Assistant Director
Health Technology Assessment Section (MaHTAS)
Ministry of Health Malaysia

Reviewed by:

Pn Noormah Mohd Darus

Senior Principal Assistant Director
Health Technology Assessment Section (MaHTAS)
Ministry of Health Malaysia

Datin Dr. Rugayah Bakri

Deputy Director
Health Technology Assessment Section (MaHTAS)
Ministry of Health Malaysia

External Reviewer:

Pn. Rokiah Don

Director
Nutrition Division
Ministry of Health

DISCLOSURE

The authors of this report have no competing interest in this subject and the
preparation of this report is totally funded by the Ministry of Health, Malaysia.

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EXECUTIVE SUMMARY

Introduction

The intestinal tract of a newborn is essentially sterile. During the birthing process and
during the first few days of life, bacterial colonization occurs rapidly. In most
breastfed infants, Bifidobacteria counts increase rapidly to constitute 80 -90% of the
total flora while for formula-fed infant, they tend to have mostly of coliforms and
Bacteroides.

Probiotics are supplements or foods that contain viable microorganisms that cause
alterations of the microflora of the host.1 According to The Food and Agriculture
Organization of the United Nations (FAO), probiotics defined as “live
microorganisms which when administered in adequate amounts confer a health
benefits on the host.”

Probiotic microorganisms are typically members of the genera Lactobacillus,

Bifidobacterium and Streptococcus which produce lactic acid. These bacteria are
fermentive, obligatory or facultative anaerobic organisms. Some yeasts such as
Saccharomyces Boulardii have also been studied and used as a probiotic agents.

This technology review was conducted upon a request by a medical officer from
Hospital Bentong to assess the available evidence on probiotic supplementation in
improving the weight gain and growth parameters and reducing incidence of
neonatal jaundice in term small for gestational age Orang Asli infants.

Objective/aim

To assess the safety, efficacy/effectiveness and cost-effectiveness of probiotic

supplementation in improving the weight gain and growth parameters and reducing
the incidence of neonatal jaundice in term small for gestational age Orang Asli
infants.

Results and conclusions

Safety

No scientific evidence was retrieved from the database on safety of probiotic

supplementation in term, small for gestational age Orang Asli or indigenous infants.
However, there was no reported adverse event that was related to the probiotic
supplementation in healthy term infants.

Efficacy /Effectiveness

No scientific evidence was retrieved from the scientific database on

efficacy/effectiveness of probiotic supplementation in improving the weight gain and
growth parameters and reducing the incidence of neonatal jaundice in term small for
gestational age Orang Asli or indigenous infants.

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However, only one abstract was retrieved on the use of probiotic in term small for
gestational age infant in the Philippines and suggested that probiotic may improved
the weight gain in term small for gestational age infants.

In healthy term infants, good level of evidence showed that there was no significant
difference in the mean weight gain and growth parameters (length and head
circumference).

Cost/Cost-effectiveness

The cost/cost-effectiveness of probiotic supplementation in term small for gestational

age Orang Asli or indigenous infants in improving the weight gain and growth
parameters and reducing the incidence of neonatal jaundice cannot be determined as
there was no evidence retrieved from the scientific database.

Methods

Scientific electronic databases were searched through OVID interface which include
OVID MEDLINE (R) In process & Other Non-Indexed Citations and OVID MEDLINE
(R) 1946 to present, Cochrane Central Register of Controlled Trials May 2012,
Cochrane Database of Systematic Reviews 2005 to April 2012, EBM Reviews-
Database of Abstracts of Reviews of Effects 2nd Quarter 2012, EBM Reviews- Health
Technology Assessment 2nd Quarter 2012, EBM Reviews- NHS Economic Evaluation
Database 2nd Quarter 2012, Pubmed and National Horizon Scanning Centre.

Last search was done on 24th May 2012 and there was no limitation during the
search. Relevant articles were critically appraised using Critical Appraisal Skills
Programme (CASP) and evidence graded according to the US / Canadian Preventive
Services Task Force.

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 PROBIOTIC SUPPLEMENTATION

1. INTRODUCTION

The intestinal tract of a newborn is essentially sterile. During the birthing process
and during the first few days of life, bacterial colonization occurs rapidly.1 The
newborn infants’ microflora is markedly dependant on infant’s gestational age,
mode of delivery (vaginal versus caesarean section), type of feeding and early
environmental surroundings.1,2 Neonates born by caesarean section, born
preterm, and /or exposed to perinatal or postnatal antibiotics have a delay in
intestinal commensal probiotic bacterial colonization. 1 In contrast, neonates
delivered vaginally, either breastfed infants or formula fed, have similar pattern of
bacterial colonization at 48 hours of age. In most breastfed infants, bifidobacteria
counts increase rapidly to constitute 80 -90% of the total flora while for formula-
fed infant, they tend to have mostly of coliforms and Bacteroides.2

The infants’ early diet and intestinal microflora environment are thought to serve
pivotal factors in overall health of the infants.2 Postbiotics bacterial byproducts,
probiotics bacteria and dietary prebiotics are believed to exert positive effects on
development of the mucosal immune system.2

By definitions, probiotics are supplements or foods that contain viable

microorganisms that cause alterations of the microflora of the host.1 According to
The Food and Agriculture Organization of the United Nations (FAO), probiotics
defined as “live microorganisms which when administered in adequate amounts
confer a health benefits on the host.” 3,4,5 Probiotic microorganisms can be
delivered and ingested separately as supplements or medicinal. They can also
be added to or naturally exist in functional foods.1

This technology review was conducted upon a request by a medical officer from
Hospital Bentong to assess the available evidence on probiotic supplementation
in improving the weight gain and growth parameters and reducing incidence of
neonatal jaundice in term small for gestational age Orang Asli infants.

2. OBJECTIVE/AIM

The objective of the technology review was to assess the safety,

efficacy/effectiveness and cost-effectiveness of probiotic supplementation in
improving the weight gain and growth parameters and reducing the incidence of
neonatal jaundice in term small for gestational age Orang Asli infants.
3. TECHNICAL FEATURES

There are several kinds of probiotics and they were capable of conferring a
health benefits by modifying the gut microbial ecology. Probiotic microorganisms

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are typically members of the genera Lactobacillus, Bifidobacterium and
Streptococcus which produce lactic acid and are most widely used in the food
supply.1,2 These bacteria are fermentive, obligatory or facultative anaerobic
organisms.

The probiotics microorganisms’ details and their possible health benefits are as
follows:

Lactobacillus

The probiotics agent in this spesies including L.rhamnosus (GG),

L. acidophilus, L. casei, L. johnsonii and L,reuteri , L.plantarium, L. salivarius
and L.gasseri.2,3 Studies have shown that Lactobacillus can be linked to
beneficial effect in treating and/or preventing yeast infections, urinary tract
infection, antibiotic related diarrhea,traveler’s diarrhea, irritable bowel syndrome,
skin disorders and treating lactose tolerance.3

Figure 1: Lactobacillus Acidophillus6

Bifidobacteria

It was estimated that approximately 90% of the healthy bacteria in the colon
consist of bifidobacteria. They will appear in the intestinal tract within days of
birth, especially in those breastfed infants. 3 Among bifidobacteria, the most
commonly studied are B.breve, B.infantis, B.lactis (also called B.bifidum,
B.animalis or Bifidobacterium strain Bb12), and B.Longum.2

Figure 2: Bifidobacterium animalis7

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Other types of probiotic bacteria are Streptococcus thermophilus
which produces large quantities of the enzyme lactase, making it effective as
shown in some report in the prevention of lactose tolerance and Enterococcus
faecium which has been used extensively in food processing.3 Some yeasts
such as Saccharomyces Boulardii have also been studied and used as a
probiotic agents.1

MECHANISM OF ACTION

Probiotics have multiple influences on the host with different mechanism of action
as follow; 8

1) Antimicrobial activity
2) Enhancement of barrier function
3) Immunomodulation.

Different organisms may influence the intestinal luminal environment, ephitelial

and mucosal barrier function and also the mucosal immune system. Probiotic
microorganism particularly bacteria can inhibit the growth of potential pathogenic
bacteria by reducing luminal pH, inhibiting bacterial adherence and translocation
or producing antibacterial substances.8

Other mechanism of probiotic is by the enhancement of the intestinal barrier

function through modulation of cytoskeletal and tight junctional protein
phorylation and increasing mucus production. It may be beneficial in disease
such as inflammatory bowel disease (IBD) and enteric infections whereby the
disruption of epithelial barrier function is seen in this diseases.8

The mechanisms of immunomodulation are through the effects on epithelial cells,

dendritic cells, monocytes/macrophage and effects on lymphocytes including B
lymphocytes, NK cells, T cells and T cell redistribution. 8 Rijkers GT et al.
illustrated the 3 levels of action of a probiotic as shown in figure 3. 9

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 Figure 3: The 3 levels of action of a probiotic. Probiotic bacteria can
interfere with growth or survival of pathogenic microorganisms in the gut
lumen (level 1). Probiotic bacteria can improve the mucosal barrier
function and mucosal immune system (level 2) and, beyond the gut, have
an effect on the systemic immune system as well as other cell and organ
systems such as liver and brain
(level 3).

4. METHODS

4.1. Searching

Electronic databases searched through the Ovid interface;

OVID MEDLINE (R) In process &Other Non-Indexed Citations and OVID
MEDLINE (R) 1946 to present.
EBM Reviews - Cochrane Central Register of Controlled Trials- May 2012.
EBM Reviews – Database of Abstracts of Review of Effects 2nd Quarter 2012.
EBM Reviews - Cochrane database of systematic reviews – 2005-April 2012.
EBM Reviews - Health Technology Assessment – 2nd Quarter 2012.
NHS economic evaluation database – 2nd Quarter 2012.

Other databases

PubMed
Horizon Scanning database (National Horizon Scanning Centre)

In addition, other search engine such as Google was used to search for

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 additional web based-materials and information. Additional articles such as from
reviewing the bibliographies of retrieved articles were also included.

4.2. Selection

A reviewer screened the titles and abstracts against the inclusion and exclusion
criteria and then evaluated the selected full-text articles for final article selection.

The inclusion and exclusion criteria were:

Inclusion criteria

Population Term, small for gestational age, Orang Asli infants, Aboriginal
infants, Indigenous infants
Interventions Probiotic Supplementation
Comparators None
Outcomes 1) Weight gain and growth parameters
2) Reduction in incidence of neonatal jaundice
Study design Systematic Review, Randomized Controlled Trial (RCT),
Health technology Assessment (HTA)
Type of Full text English language article
publication

Exclusion criteria

Study design Observational studies

Type of Non- English language full text article
publication
Population Study conducted among pre-term infants

Relevant articles were critically appraised using Critical Appraisal Skills

Programme (CASP) and evidence graded according to the US / Canadian
Preventive Services Task Force.

5. RESULTS AND DISCUSSION

There was no retrievable scientific evidence addressing the

efficacy/effectiveness, safety and cost/cost effectiveness of probiotic
supplementation in improving the weight gain and growth parameters and
reducing the incidence of neonatal jaundice in term small for gestational age
Orang Asli or indigenous infants.

However, our search strategy also identified studies conducted in other term
infants. One randomized controlled trial was retrieved on effects of probiotic

10
 supplementation on growth parameters in term small for gestational age infants
in the Philippines.

In addition, there were seven randomized controlled trial and one pooled analysis
trial retrieved from the scientific database on safety and efficacy/effectiveness of
probiotic supplementation in improving the weight gain and growth parameters in
healthy term infants.

One technology assessment report also reported on safety of probiotics to

reduce risk and prevent or treat disease in all age groups.

5.1. SAFETY

Seven studies related to the safety of probiotic used in term infants and not
specific to Orang Asli or indigenous infants were included in this review.

A Technology Assessment report was produced by Agency for Healthcare

Research and Quality on safety of probiotics to reduce risk and prevent or treat
disease in all age groups. Among the adverse events reported in this review
were diarrhea, constipation, vomiting, abdominal pain, headache, infectious and
parasitic diseases, feeding problem and dermatitis. The pooled result of 27 trials
showed that the risk to experience an adverse event was not statistically
significant for children (under 24 months of age) who received probiotic or
synbiotic agent when compared to control group. The relative risk was 0.96 (95%
CI: 0.88-1.05) 5 Level I

Campos MG et al. conducted a randomized double - blinded controlled study on

137 healthy infants aged 1 month old fed with formula containing L.fermentum
and reported that no adverse effects associated to probiotic supplementation
were detected during the study. 11 Level I

Vlieger AM et al. reported a randomized controlled trial of 133 term infants whom
were randomized to receive a prebiotic-containing starter formula supplemented
with Lactobacillus .paracasei ssp. paracasei and Bifidobacterium.animalis
ssp.lactis or the same formula without the probiotics for the first three months of
life. The findings of the trial reported that five infants in the probiotics group
developed rash compared with 12 infants in control group (p <0.05). However, no
serious adverse events reported could be related to the study formula. No
differences were seen in other adverse effects between the two groups in both
the first and second trimester. 12 Level I

A prospective, randomized double- blind controlled trial conducted in 5 centres in

France by Chouraqui JP. et al. in 284 healthy, full term infants showed that there
were no significant differences in the frequency of either serious adverse events
or adverse events between the different groups of infants receiving study formula

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 Bifidobacterium longum BL999+ Lactobacillus rhamnosus(LPR), BL999
+LPR+4g/L 90%galactooligosaccharides/10% short chain fructooligosaccharides
(GOS/SCFOS), BL999 + Lactobacillus paracasei ST11 +4g/L GOS/SCFOS or
control formula. 13 Level I

Another prospective randomized, reference-controlled, double blinded trial by

Puccio G. et al. were conducted at single centre in Palermo Italy. The trial
involved 138 healthy full-term infants who were randomized to receive either
experimental formula supplemented with B.longum BL999 and 4g/L of a mixture
of a GOS and FOS (90% and 10%) or control formula without the supplement. It
was reported that frequencies of adverse events, whether serious or not were not
significantly different between groups. (chi square test; P >0.4). None of the
adverse events were assessed as related to study formula.14 Level I

Gibson RA. et al. performed a single centre, randomized double-blind, controlled,

parallel-group trial perform in Women’s and Children Hospital, Children, Youth
and Women’s Health Service (CYWHS) Adelaide Australia in 142 healthy term
infant and found out that the frequency of feeding problems was significantly
lower in the B.Lactis, fish oil DHA and arachidonic acid supplemented group
compared to control group (p=0.03). No deaths were reported despite 40 serious
adverse events (SAE) which were similarly distributed among the two groups
observed in the trial. 20 of the (SAE) were considered to be unrelated and 17
cases of (SAE) were unlikely to be related to the formula. Three (SAE)
considered to be probably related to the formula were gastrointestinal problems
(one in each group) and respiratory problem in control group.15 Level I

The most frequent gastrointestinal disorders included in a pooled analysis of

randomized controlled studies by Steenhout PG et al. were gastroenteritis,
diarrhea, gatroesphageal reflux and vomiting. From the pooled analysis, 24% of
the infants in the probiotic group had experienced the gastrointestinal disorders
compared with 29% in the non-probiotic group (RR = 0.89, 95% CI 0.7-1.13,
p=0.3513). 16 Level I

Currently, probiotics are often regulated as dietary supplements rather than

biological or pharmaceutical products which do not require premarket review and
approval by the United Stated Food and Drug Administration (US FDA).4
However, probiotics products that are marketed specifically for the treatment or
prevention of a disease are classified as biological product. Hence, the US FDA
requires the product to be reviewed and approved before being marketed. 1

5.2. EFFICACY/ EFFECTIVENESS

5.2.1 Term small for gestational age Orang Asli or indigenous infants

There was no retrievable evidence on the use of probiotic supplementation in

improving the weight gain and growth parameters and reducing the incidence of

12
neonatal jaundice in term small for gestational age Orang Asli or indigenous
infants.

5.2.2 Term small for gestational age infants

One abstract was retrieved on effects of probiotic supplementation on growth

parameters in small for gestational age term infants in Philippines.

N. de Vera MG conducted a double-blind randomized placebo-controlled trial in

fifty term, small for gestational age infants and found that the probiotics
significantly improved the weight gain of term small for gestational age infants (p
<0.05).The author also reported that the head growth and length gain was not
statistically significant with p value of 0.506 and 0.3011. However, the result was
extracted from an abstract and the article was not retrievable from scientific
database.10

5.2.3 Healthy term infants

Seven randomized controlled trials and one pooled analysis were retrieved on
the use of probiotic supplementation in improving the weight gain and growth
parameters in healthy term infants.

Campos MG et al. reported that intervention formula effect was not significant for
the weight for age (p = 0.061) and neither for the head circumference (p = 0.453)
However, the intervention formula effect was significant (p = 0.021) for the length
for age indicating that those infants in the intervention group had higher length for
age compared to the control group. The standards of weight, length and head
circumference for age were calculated based on the WHO Child Growth
Standards. No significant differences were observed for weight and weight gain
at 4 months and 6 months. The mean weight of infants at 4 months and 6 months
were 6.9±0.7 and 8.0±0.9 in intervention group and 6.8±0.8 and 7.9±1.0 in
control group while the mean weight gain were 24.8±5.1 and 25.3±6.0
respectively. Similar findings were observed for head circumference and head
circumference gain with mean gain/day of 0.43±0.1 in intervention group and
0.421±0.1 in control group. Even though no significant differences were observed
between groups in the length at 4 months of age, it was reported that at 6 months
of age, infants in the intervention group were significantly taller than infants in
control group with mean length of 68.1±3.4 versus 66.6±2.5 (p = 0.038). No
significant differences were observed for length gain (cm/day) with mean length
gain of 0.96±0.3 in intervention group and 0.90±0.2 in controlled group. 11 Level I

Vlieger AM et al. presents the standard deviation scores for weight, length and
head circumference at birth and the age of 3 months for the intention- to-treat-
group and at 6 months of age for per protocol group. No statistical differences
were detected in SD change scores for weight gain and length during the first 3
months with 2507g and 10.3cm in probiotics group and 2661g and 10.6cm in

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control group (p= 0.64 and p=0.85 respectively). The weight gain and length
gain after 6 months were 4152g and 17.7cm in probiotics group and 4282g and
17.3cm in the control group (p=0.60 and p=0.30).12 Level I

Chouraqui JP et al. did an equivalent study and reported a comparison of the

mean weight gain per day of infants fed each of the study formulas and the
control formula (Per protocol analysis (PP) population) that showed a treatment
effect of 1.41 (90% CI:-0.77 to 3.590 in the BLL999+LPR group; 0.82(90% CI: -
1.40 to 3.05) in the BL999 +LPR +GOS/SCFOS group; and 1.64(90% CI:-0.53 to
3.81) in the BL999 +ST11+GOS/SCFOS group. In all groups, the two sided 90%
CI interval lay between -3.9 and +3.9 indicating equivalent weight gain in infants
fed with study and control formula. The author also reported that similar results
obtained from analysis of the intention to treat (ITT) data set. The mean changes
in length,(boys; 31.9±6.0, 31.5±5.9, 32.1±5.9, 30.9±6.1 and girls; 27.9±6.0,
27.5±6.0, 28.1±6.0, 26.9±6.0), head circumference (boys; 18.7±2.4, 17.9±2.3,
18.3±2.3, 18.4±2.3 and girls; 17.0±2.4, 16.2±2.3, 16.6±2.4, 16.7±2.4) and BMI
measurements (boys; 1.2±0.4, 1.2±0.4, 1.2±0.4, 1.1±0.4 and girls; 1.0±0.4,
1.0±0.4, 1.0±0.4, 0.9±0.4) during the treatment period were not different between
the study groups and the control group (P> 0.05 for all comparison). The z-
scores were not different from the WHO growth reference for all groups in PP
population followed through the treatment period of 0-4 months and no significant
differences observed between control and study groups.12 LEVEL I Hence, the
study showed that the study formula is equivalent to the unsupplemented infant
formula.13 Level I

A report by Puccio G et al. showed that based on the predefined equivalence

boundaries of -3.9 - +3.9 g/d, the mean weight gain in the two groups was
equivalent ( ITT: +0.50, 90% CI -1.48 to +2.8; PP: +1.09, 90% CI -0.98 to +3.15).
The mean changes in recumbent length showed no statistically significant
differences (35.1± 4.4 versus 35.1 ±4.2 for boys and 32.2±4.6 versus 32.2±4.3
for girls, P >0.1) and the head circumference
(17.4±2.9 versus 17.9±2.7 for boys and 15.5±3.0 versus 16.0±2.8 for girls) also
showed no significant differences between the two groups (P > 0.1) 14 Level I

According to Gibson RA et al., there were no significant differences in weight

between the two groups throughout the study data. Mean weight gain between
(day 14 - day 119) was 1.5 and 2.0 g/d for the ITT and PP populations. The 90%
CI (ITT:-0.08-3.1g/d, and PP:0.1-3.8g/d) lay within the -3.9-+3.9g/d interval which
indicating equivalent growth among the infants in both groups. The mean
changes between experimental and control group in length (boys; 35±3.7 versus
37.3±4.9 and girls; 32.8±4 versus 32±4.6), head circumference (boys; 18±2.4
versus 17.5±3.4 and girls; 16.1±2.7 versus 16±3) and BMI (boys; 1.1±0.6 versus
1±0.5 and girls; 0.9±0.5 versus 0.8±0.4) were not significantly different between
both groups. It was reported that a comparison of weight-for age, length-for age
and head circumference -for-age with the Centre for Disease Control and

14
 Prevention (CDC) growth references showed that z-scores were within the
normal ranges for the two groups.15 Level I

Steenhout P.G et al. conducted a pooled analysis of data from 5 randomized

controlled clinical trials that included infants fed formula containing probiotics
Bifidobacterium lactis. A new formula is considered to be as good as
reference if the lower margin of the 95% CI of mean weight gain is not lower than
-3g/day. Analysis of the data pooled from the 5 RCTs showed the difference in
mean weight gain from enrolment up to 120 days between both groups was
+1.5g/day (95% CI 0.09-2.93,p=0.0368) and mean gain in BMI was +3.44g/day
(95%CI 0.13-6.75,P=0.0418). A sub analysis of vulnerable infants born to
mothers with HIV fed with infants formulas containing B. Lactis, led to significant
difference in the mean weight gain +3.1306g/day (95% CI 0.4477 - 5.8135,
p=0.00226) and mean gain in BMI + 6.3838g/m2 /d (95% CI 0.2956 - 12.4720,
p=0.04) Among the infants with HIV-negative mothers, there were no significant
differences in any of these growth parameters between the two groups. The
difference in the mean weight gain in the infants fed with infant formulas
containing B.Lactis was +0.5242g/day (95% CI -1.0855-2.1339, p=0.5212) and
the mean gain in BMI was +1.7376 g/m2 /d (95%CI -2.1613-5.6365, p=0.3806)16
Level I

Saavedra J.M et al reported a prospective double-blind randomized placebo

controlled study of healthy infants aged 3-24 months to evaluate the tolerance to
formulas containing 2 levels of Bifidobacterium lactis and Streptococcus
thermophilus and effects on growth, general clinical status and intestinal health in
free living healthy infants. It was shown that the difference in weight/age in all
groups showed positive z scores (0.09±0.64 in high-supplement formula group,
0.06±0.72 in low-supplement formula group and 0.16±0.69 in placebo group) with
no significant differences between the groups.17 Level I

A prospective, randomized, double-blind placebo controlled clinical study was

performed by Vendt et al found that their changes in length and weight (standard
deviation scores-SDS) of infants in the intervention group of Lactobacillus
rhamnosus GG (LGG) at the end of the study were significantly higher than the
regular group. The results were:
Changes in length (standard deviation scores-SDS) = (0.44±0.37 vs 0.07±
0.06, P< 0.01).
Changes in weight (standard deviation scores-SDS) = 0.44± 0.19 vs 0.00
± 0.01, P<0.005).18 Level I

5.3 COST/COST-EFFECTIVENESS

There was no retrievable scientific evidence addressing the cost/cost-

effectiveness of probiotic supplementation in improving the weight gain, growth
parameters and incidence of neonatal jaundice in term small for gestational age
Orang Asli or indigenous infants included in this review.

15
5.4 LIMITATIONS

Selection of studies was done by one reviewer and reviewed by another

reviewer.
Although there was no restriction in language during the search, only English
language full text articles were included in this report
Although all effort has been made to retrieve all the full text articles, we were
unable to retrieve the full text article for one study. Hence, the quality of the
study cannot be determined.
Due to our inclusion and exclusion criteria, only articles on term infants were
included in this report.

6. CONCLUSION

6.1. SAFETY

No scientific evidence was retrieved from the database on safety of probiotic

supplementation in term small for gestational age Orang Asli or indigenous
infants. However, there was no reported adverse event that was related to the
probiotic supplementation in healthy term infants.

6.2. EFFICACY/EFFECTIVENESS

No scientific evidence was retrieved from the scientific database on

efficacy/effectiveness of probiotic supplementation in improving the weight gain
and growth parameters and reducing the incidence of neonatal jaundice in term
small for gestational age Orang Asli or indigenous infants. Hence, the use of
probiotic supplementation in improving the weight gain and growth parameters
and reducing the incidence of neonatal jaundice in term small for gestational age
Orang Asli infants cannot be determined.

However, only one abstract was retrieved on the use of probiotic in term, small
for gestational age infant in the Philippines and suggested that probiotic may
improved the weight gain in term small for gestational age infants.

In healthy term infants, good level of evidence showed that there was no
significant difference in the mean weight gain and growth parameters (length and
head circumference).

16
6.3. COST/COST-EFFECTIVENESS

The cost/cost-effectiveness of probiotic supplementation in term small for

gestational age Orang Asli or indigenous infants in improving the weight gain and
growth parameters and reducing the incidence of neonatal jaundice cannot be
determined as there was no evidence retrieved from the scientific database.

17
8. REFERENCES

1. Thomas DW, Greer FR; American Academy of Pediatrics Committee on

Nutrition; American Academy of Pediatrics Section on Gastroenterology,
Hepatology, and Nutrition Probiotics and prebiotics in pediatrics. Pediatrics.2010
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2. Saavedra.JM. Use of probiotics in Pediatrics: Rationale,Mechanisms of Action,

and Practical Aspects.Nutr Clin Pract.2007June;22(3):351-365.

3. Probiotics. Available at: http://www.medicinenet.com/probiotics/article.htm.

Accessed on 8th May 2012.

4. Boyle RJ, Robins-Browne RM et al. Probiotic use in clinical practice: what are the
risk?Am J Clin Nutr.2006;83:1256-64.

5. Hempel S, Newberry S.et al. Safety of Probiotics to Reduce Risk and Prevent or
treat Disease. Evidence Report / Technology Assessment No.200. (Prepared by
the Southern California Evidence-based Practice Center under Contract No.290-
2007-10062-I.) AHRQ Publication No.11-E007. Rockville,MD:Agency for
Healthcare Research and Quality. April 2011. Available
at:www.ahrq.gov/clinic/tp/probiotictp.htm.

6. Lactobacillus Acidophillus Probiotics: A Human Friendly Bacteria. Available at:

http://buyprobiotics.net/education/probiotics_lactobacillus_acidophilus Accessed
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7. Bifidus bacteria against toxic. http://www.scienceknowledge. org/2011/02/01/

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9. Rijkers GT, Bengmark S, Enck P et al. Guidance for Substantiating the Evidence
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10. N.de Vera MG. Effects of Probiotics Supplementation On Growth Parameters in

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9. APPENDIX

9.1. Appendix 1: LITERATURE SEARCH STRATEGY

Ovid MEDLINE® In-process & other Non-Indexed citations and OvidMEDLINE®

1948 to present

1. ((Term birth.tw.or infant or infant.tw.or infant newborn or infant newborn.tw.) and

(infant, small for gestational age) and (Orang asli.tw.or Aboriginal.tw.or
Indigenous.mp.)) and ((Probiotics or probiotics.tw.or probiotic or probiotic.tw.or
Lactobacillus or Lactobacillus.mp.or Bifidobacterium or Bifidobacterium.mp. or
Saccharomyces or Saccharomyces.mp. or Streptococcus or Streptococcus.mp.
or Enterococcus or Enterococcus.mp. or Bacillus or Bacillus.mp.)) and ((Weight
gain or weight gain.tw.or jaundice or jaundice.tw. or jaundice neonatal or growth
parameters or growth parameters.tw.or growth parameter or growth
parameter.tw.))

OTHER DATABASES
EBM Reviews - Cochrane Same MeSH, keywords, limits used as per

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Central Register of MEDLINE search
Controlled Trials
EBM Reviews - Database
of Abstracts of Review of
Effects
EBM Reviews - Cochrane
database of systematic
reviews
EBM Reviews - Health
Technology Assessment
PubMed

NHS economic
evaluation database
National Horizon
Scanning Centre

9.2. Appendix 2

HIERARCHY OF EVIDENCE FOR EFFECTIVENESS STUDIES

DESIGNATION OF LEVELS OF EVIDENCE

I Evidence obtained from at least one properly designed randomized controlled

trial.

II-I Evidence obtained from well-designed controlled trials without

randomization.

II-2 Evidence obtained from well-designed cohort or case-control analytic studies,

preferably from more than one centre or research group.

II-3 Evidence obtained from multiple time series with or without the intervention.
Dramatic results in uncontrolled experiments (such as the results of the
introduction of penicillin treatment in the 1940s) could also be regarded as this
type of evidence.

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III Opinions or respected authorities, based on clinical experience; descriptive
studies and case reports; or reports of expert committees.

SOURCE: US/CANADIAN PREVENTIVE SERVICES TASK FORCE (Harris 2001)

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