Probiotics, Prebiotics and Synbiotics use in Neonates: A critical appraisal of the evidence and ...

252 Pages·2014·5.55 MB·English

Probiotics, Prebiotics and Synbiotics use in
Neonates: A critical appraisal of the
evidence and evaluation of its application by
the food industry.

by
Mary Letizia Nkatha Mugambi
Dissertation presented for the degree of Doctor of
Philosophy in the Faculty of Medicine and Health Sciences
at Stellenbosch University
Supervisor: Prof Reneé Blaauw
Co-supervisor: Prof Taryn Young
April 2014
Stellenbosch University http://scholar.sun.ac.za
DECLARATION

By submitting this dissertation electronically, I declare that the entirety of the work contained therein is my
own, original work, that I am the sole author thereof (save to the extent explicitly otherwise stated), that
reproduction and publication thereof by Stellenbosch University will not infringe any third party rights and
that I have not previously in its entirety or in part submitted it for obtaining any qualification.

April 2014

Copyright © 2014 Stellenbosch University
All rights reserved
ii
Stellenbosch University http://scholar.sun.ac.za
Abstract
Background:

Synbiotics, probiotics and prebiotics are being added to infant formula. This study was an in-depth
evaluation of research on infants fed infant formula containing synbiotics, probiotics or prebiotics and was
carried out in two phases. Phase one included two systematic reviews that assessed if synbiotics, probiotics
or prebiotics led to improved growth and clinical outcomes in formula fed full term and preterm infants.
Phase two included two studies: A systematic review compared the methodological quality and outcomes of
industry and non-industry sponsored randomized controlled trials (RCTs) and a descriptive study evaluated
how the food industry applies the knowledge and evidence gained from probiotics, prebiotics or synbiotics
research in infants.

The research questions were: Does the consumption of probiotics, prebiotics or synbiotics supplemented
infant formula lead to improved clinical outcomes in infants? Is there an association between source of
funding and methodological quality, clinical outcomes and author’s conclusions in trials using probiotics,
prebiotics or synbiotics supplemented formula in infants? Does the food industry use the evidence gained
through probiotics, prebiotics and synbiotics research trials on infants for the benefit of the general paediatric
population?

The hypotheses were: Consumption of probiotics, prebiotics or synbiotics by infants leads to improved
clinical outcomes; The source of funding in research trials using probiotics, prebiotics or synbiotics
supplemented formula in infants is associated with outcomes in favour of the sponsor’s products and authors’
conclusions; Methodological qualities of non-industry sponsored trials are equivalent to industry sponsored
trials; Evidence gathered through probiotics, prebiotics and synbiotics research is implemented by the food
industry.

Methods:

Phase one:
Both systematic reviews on preterm and full term infants: Cochrane methodology was followed using RCTs
which compared preterm or full term formula containing probiotics, prebiotics or synbiotics to conventional
infant formula with / without placebo among healthy preterm or full term infants. The mean difference (MD)
and corresponding 95% confidence intervals (CI) were reported for continuous outcomes, risk ratio (RR) and
corresponding 95% CI for dichotomous outcomes.

iii
Stellenbosch University http://scholar.sun.ac.za
Phase two:
In the systematic review, Cochrane methodology was used to assess the risk of bias of included RCTs.
Association between source of funding and risk of bias, clinical outcomes and conclusions were assessed. In
the descriptive study, all listed companies that manufacture infant food products with added synbiotics,
probiotics or prebiotics for infants were identified and invited to participate. A letter of invitation was sent
and if they expressed willingness to take part in the study, a questionnaire with a written consent form was
sent. Descriptive statistics and associations between categorical variables were to be tested using a Chi-
square test.

Results:

Phase one:
Review on preterm infants: 8 studies were included. Probiotics increased stool frequency with no effect on
other clinical outcomes. Prebiotics increased stool frequency and bifidobacteria counts only.

Review on full term infants: 25 studies were included. Synbiotics improved stool frequency but had no effect
on other clinical outcomes. Probiotics did not have an effect on any clinical outcome. Prebiotics increased
weight gain and stool frequency with no effect on other outcomes.

Phase two:
Systematic review: 67 studies were included, majority were funded by food industry. There was no
significant association between the source of funding and four domains (sequence generation, allocation
concealment, blinding, selective reporting), majority of reported clinical outcomes or authors’ conclusions.
Source of funding was significantly associated with two domains (incomplete outcome data, free of other
bias), antibiotic use and conclusions on weight gain.

Descriptive study: 25 companies were identified and invited to participate. No company agreed to participate
in the survey for different reasons.

Conclusions
Phase one:
Review on preterm infants: There is not enough evidence to state that supplementation with probiotics or
prebiotics results in improved growth and clinical outcomes in exclusively formula fed preterm infants.

iv
Stellenbosch University http://scholar.sun.ac.za
Review on full term infants: There is not enough evidence to state that supplementation of term infant
formula with synbiotics, probiotics or prebiotics does result in improved growth or clinical outcomes in term
infants. There is no data available to establish if synbiotics are superior to probiotics or prebiotics.

Phase two:
Systematic review: In RCTs on infants fed infant formula containing probiotics, prebiotics or synbiotics, the
source of funding does not influence majority of outcomes in favour of the sponsors’ products. More non-
industry funded research is needed to further assess the impact of funding on reported clinical outcomes and
authors’ conclusions.

Descriptive study: Due to companies refusing to participate in this study, no conclusion could be drawn on
how the food industry applies evidence gained through probiotics, prebiotics or synbiotics research on
infants. More transparency is needed from the infant formula manufactures on how they apply the evidence
gained from probiotic, prebiotic or synbiotic research on infants.
v
Stellenbosch University http://scholar.sun.ac.za
Abstrakt

Agtergrond

Synbiotika, probiotika en prebiotika word gereeld by baba formule gevoeg. Hierdie studie was 'n in-diepte
evaluering van navorsing oor babas gevoed met formule melk wat synbiotika, probiotika of prebiotika bevat
en is uitgevoer in twee fases. Fase een het twee sistematiese oorsigte ingesluit wat die rol van synbiotika,
probiotika en prebiotika op verbeterde groei en kliniese uitkomste van formule gevoede volterm babas en
vroeg gebore babas evalueer het. Fase twee het bestaan uit twee studies: 'n sistematiese oorsig wat die
metodologiese kwaliteit en uitkomste van die bedryf en nie-bedryf geborgde ewekansige gekontroleerde
proewe (RCTs) evalueer het, asook 'n beskrywende studie wat die kennis en toepassing van bewyse oor die
effektiewiteit van probiotika, prebiotika of synbiotika in die voedsel industrie bestudeer het.

Die hipotese stellings was: verbruik van probiotika, prebiotika of synbiotika by babas lei tot verbeterde
kliniese uitkomste; die bron van befondsing vir synbiotics, probiotika of prebiotika navorsing beïnvloed
uitkomste ten gunste van die borg se produkte; bewyse ingesamel deur middel van probiotika, prebiotika en
synbiotika navorsing word geïmplementeer deur die voedselindustrie.

Metodes

Fase een:
Beide sistematiese oorsigte op volterm en premature babas: Cochrane metodes is gevolg deur ewekansige,
gekontroleerde studies wat vol termyn of premature formule met probiotika, prebiotika of synbiotika met
konvensionele baba formule met / sonder plasebo onder gesonde volterm of premature babas bestudeer. Die
gemiddelde verskil (MD) en die ooreenstemmende 95% vertrouensintervalle is gebruik vir deurlopende
uitkomste, risiko verhouding (RR) en die ooreenstemmende 95% CI vir tweeledige uitkomste.

Fase twee:
In die sistematiese oorsig is Cochrane metodiek gebruik om die risiko van vooroordeel van ingesluite
ewekansige, gekontroleerde studies te evalueer. Assosiasie tussen bron van befondsing en die risiko van
vooroordeel, asook kliniese uitkomste en gevolgtrekkings was beoordeel. In die beskrywende studie, is alle
genoteerde maatskappye wat babavoeding produkte vervaardig met bygevoegde synbiotika, probiotika of
prebiotika vir babas geïdentifiseer en uitgenooi om deel te neem. 'n Uitnodigingsbrief is vir die relevante
maatskappye gestuur om hul bereidwilligheid om deel te neem te bevestig. Indien hulle wel bereid was om
vi
Stellenbosch University http://scholar.sun.ac.za
deel te neem was 'n vraelys met 'n skriftelike toestemming vorm gestuur. Beskrywende statistiek en
assosiasies tussen kategoriese veranderlikes was getoets met behulp van 'n Chi-kwadraat toets.

Resultate

Fase een:
Oorsig oor premature babas: 8 studies was ingesluit. Probiotika verhoog stoelgang frekwensie met geen effek
op ander kliniese uitkomste. Prebiotika verhoog ook stoelgang frekwensie en slegs bifidobakteriële tellings.
Oorsig oor die vol termyn babas: 25 studies was ingesluit. Synbiotika verbeter stoelgang frekwensie, maar
het geen effek op ander kliniese uitkomste gehad nie. Probiotika het nie 'n effek op enige kliniese uitkoms
gehad nie. Prebiotika verhoog gewigstoename en stoelgang frekwensie met geen effek op ander uitkomste.

Fase twee:
Sistematiese oorsig: 67 studies was ingesluit, en die meerderheid was befonds deur die voedsel bedryf. Daar
was geen beduidende assosiasie tussen die bron van befondsing en vier gebiede (toekenningsvolgorde,
toekenningsverberging, studie verblinding, selektiewe verslaggewing), en die meerderheid van
gerapporteerde kliniese uitkomste of skrywers se gevolgtrekkings. Die bron van befondsing was beduidend
verbind met twee gebiede (onvolledige uitslag data, vry van ander vooroordeel), antibiotika gebruik en
gevolgtrekkings op gewigstoename.

Beskrywende studie: 25 maatskappye is geïdentifiseer en genooi om deel te neem. Geen maatskappy het
ingestem om deel te neem aan die studie om verskillende redes.

Gevolgtrekkings

Fase een:
Oorsig oor premature babas: Daar is nie genoeg bewyse dat die aanvulling met probiotika of prebiotika
resultate in verbeterde groei en kliniese uitkomste in uitsluitlik formule gevoede premature babas tot gevolg
het nie.
Oorsig oor die volle termyn babas: Daar is nie genoeg bewyse om te sê dat die aanvulling van term baba
formule met synbiotika, probiotika of prebiotika lei tot verbeterde groei of kliniese uitkomste in termyn
babas. Daar is geen inligting beskikbaar om te stel of synbiotika beter is as probiotika of prebiotika nie.

Fase twee:
Sistematiese oorsig: In studies op babas gevoed met formule melk wat probiotika, prebiotika of synbiotika
bevat het, het die bron van befondsing nie meerderheid van die uitkomste in die guns van die borge se
vii
Stellenbosch University http://scholar.sun.ac.za
produkte beïnvloed nie. Meer nie-industrie befondsde navorsing is nodig om verder die impak van
befondsing op kliniese uitkomste en skrywers se gevolgtrekkings te evalueer.

Beskrywende studie: Aangesien al die maatskappy deelname geweier het, kon geen gevolgtrekking gemaak
word of die voedsel bedryf bewyse oor die gebruik van probiotika, prebiotika of synbiotika toepas nie. Meer
deursigtigheid is nodig van die formule vervaardigers oor hoe hulle die bewyse oor die gebruik van
probiotika, prebiotika of synbiotika toepas.

viii
Stellenbosch University http://scholar.sun.ac.za
ACKNOWLEGMENTS

My heartfelt appreciation, love and gratitude to:
My parents, †Johnson Kiraithi Mugambi and Martha Karwitha Mugambi, for the gift of education, you
always believed in me and never once doubted,
My husband Bernard Kyalo Musau for dropping everything, following me everywhere and supporting me no
matter what, thank you for letting me lean heavily on your shoulders,
My daughter Martha Mwikali for teaching me what is important in life,
My son Victor Muriuki Muange, for saving my life, keeping me grounded,
My sisters and brother, Grace Kaome, Martin Mugathia, Sheila Kathambi, Patricia Kaweria who pressed me
to get up every morning even when I did not want to, you taught me that it is darkest just before dawn,
My mentor and idol, Reverend Ida Mitchel who burned the midnight candles in prayer for me, you are
everything I want to be,
My supervisors, Prof Reneé Blaauw, Dr Taryn Young, it was a great privilege to learn, work with you; you
pointed the way forward and let me go at my own pace,
To my colleagues Alfred Musekiwa for statistical guidance, Martani Lombard for many hours spent combing
through mountains of paper, thank you,
The librarians who answered my endless questions with smiles on their faces, always pointing out where I
needed to find information, you are simply the best,
God, who always knew the strength I had, even when my faith was low, you convinced me to just take
another step and keep going.

Because of you all, I am. On your shoulders I stand. I salute your greatness.

Mary Letizia Nkatha Mugambi

ix
Stellenbosch University http://scholar.sun.ac.za
TABLE OF CONTENTS

Abstract .......................................................................................................................................... iii
Abstrakt ......................................................................................................................................... vi
List of Abbreviations ................................................................................................................... xiv
Definition of terms ...................................................................................................................... xvi
Chapter 1. Introduction ....................................................................................................................... 1
1.0 Introduction ................................................................................................................................... 2
1.0.1 Overview of study .................................................................................................................. 2
1.1 Background ................................................................................................................................... 3
1.1.1 Growth .................................................................................................................................... 3
1.2 Infant feeding ............................................................................................................................. 4
1.3 Intervention ................................................................................................................................ 7
1.4 Probiotics ................................................................................................................................... 8
1.5 Prebiotics ................................................................................................................................. 11
1.6 Evidence of probiotics, prebiotics and synbiotics effects on gastrointestinal tract in infants . 13
1.7 Rationale for study .................................................................................................................. 26
1.8 Ethics ....................................................................................................................................... 28
1.9 Research questions, objectives, hypotheses. ........................................................................... 29
1.10 Scope of work: ....................................................................................................................... 31
1.11 Chapter overviews ................................................................................................................. 36
1.12 References ............................................................................................................................. 43
Chapter 2: Probiotics, prebiotics infant formula use in preterm or low birth weight infants: A
systematic review .............................................................................................................................. 50
Objective .......................................................................................................................................... 53
Methods ............................................................................................................................................ 53
Results .............................................................................................................................................. 55
Effects of interventions ................................................................................................................... 58
Discussion ........................................................................................................................................ 64
x