Probiotic, Calcium and Acute Diarrhea in Indonesian children

178 Pages·2012·4.54 MB·English

by  Rina Agustina

Probiotics, calcium and
acute diarrhea
A randomized trial in Indonesian children

Rina Agustina
Thesis committee
Thesis supervisors
Prof. dr. ir. F.J. Kok
Professor of Nutrition and Health
Wageningen University

Prof. dr. A. Firmansyah, MD
Professor of Pediatric Gastroenterology
University of Indonesia
Thesis co-supervisor
Dr. ir. I.M.J. Bovee-Oudenhoven
Project Leader, Top Institute Food and Nutrition (TIFN), Wageningen
Senior Scientist, NIZO food research, Ede

Other members
Prof. dr. E. Isolauri, University of Turku/Turku University Central Hospital, Finland
Prof. dr. E.G. Schouten, Wageningen University
Dr. ir. J.C.M. Verhoef, London School of Hygiene and Tropical Medicine, UK/Wageningen University

Dr. J. Steijns, FrieslandCampina, Amersfoort

This research was conducted under the auspices of the Graduate School VLAG (Advanced studies in
Food Technology, Agrobiotechnology, Nutrition and Health Sciences).
Probiotics, calcium and
acute diarrhea
A randomized trial in Indonesian children

Rina Agustina

Thesis
submitted in fulfillment of the requirements for the degree of doctor
at Wageningen University
by the authority of the Rector Magnificus
Prof. dr. M.J. Kropff,
in the presence of the
Thesis Committee appointed by the Academic Board
to be defended in public
on Friday, 21 September 2012
at 11 a.m. in the Aula.
Rina Agustina

Probiotics, calcium and acute diarrhea – A randomized trial in Indonesian children
176 pages

Thesis, Wageningen University, Wageningen, The Netherlands (2012)
With references, with summaries in English, Dutch and Indonesian
ISBN 978-94-6173-372-6
Especially dedicated to

The health of children in Indonesia and other developing world

My beloved family

my late Ibu, Aslamiah binti Abdul Kohar
who motivated me to become a physician who can help people reach their good
health and wellbeing, especially to those socio-economically marginalized

my ayah, Sanusi Ardidja Ranadipradja
my mamah, Siti Ulyah
my husband, Ahmad Sadariskar
my beautiful daughters, Arini Ayatika Sadariskar
and Dinaka Tatsbita Sadariskar
my brothers and sisters

Abstract
Background
Acute diarrhea and acute respiratory tract infections (ARTIs) continue to lead the infectious
cause of morbidity and mortality among children <5 years of age in developing countries,
including Indonesia. Efforts to prevent diarrheal disease by probiotics and milk calcium
supplementation as alternative strategy are promising. We investigated the efficacy of
calcium with or without two probiotic strains, tested independently, on incidence and
duration of acute diarrhea and ARTIs among Indonesian children. In addition, cumulative
duration and severity of diarrhea due to rotavirus or other causes, growth, and iron and zinc
status were tested. The associations of food-hygiene practices with diarrhea prevalence in
children were also determined.
Methods
We conducted a 6-month, double-blind, placebo-controlled trial. A total of 494 Indonesian
healthy children aged 1 to 6 years randomly received low-lactose milk with low calcium
content (LC; ∼50 mg/day; n = 124), regular calcium content (RC; ∼440 mg/day; n = 126),
RC with 5.108 colony-forming units per day of Lactobacillus casei CRL 431 (casei; n = 120),
or RC with 5.108 colony-forming units per day of Lactobacillus reuteri DSM 17938 (reuteri;
n = 124). Incidence and duration of diarrhea were the primary outcomes. Secondary
outcomes were incidence and duration of ARTIs, severity of diarrhea (modified Vesikari
score and fecal osmolarity, calprotection and mucin), growth, and iron and zinc status. The
cross-sectional association between food-hygiene practices and 7-day record period of
diarrhea prevalence was assessed among 274 randomly selected children aged 12-59 months
in a low socioeconomic urban area of Jatinegara sub-district of East Jakarta, Indonesia.
Results
Incidence of World Health Organization-defined diarrhea (≥3 loose/liquid stools in 24
hours) was not significantly different between RC and LC (relative risk 0.99; 95% confidence
interval (CI): 0.62-1.58), between casei and RC (relative risk 1.21; 95% CI: 0.76-1.92), or
between reuteri and RC (relative risk 0.76; 95% CI: 0.46-1.25) groups. Incidence of all
reported diarrhea (≥2 loose/liquid stools in 24 hours) was significantly lower in the reuteri
versus RC group (relative risk 0.68; 95% CI: 0.46-0.99). Irrespective of the definition used,
reuteri significantly reduced diarrhea incidence in children with lower nutritional status
(below-median height-and-weight-for-age z score). None of the interventions affected
ARTIs. The mean total duration (131 children, 190 diarrheal episodes) was 1.35 days shorter
in the reuteri group (relative risk 0.60; 95% CI: 0.36-0.99) in a 6-month period, likely by
mainly affecting rotavirus-positive diarrhea. Rotavirus prevalence in diarrheal cases (30%)
was not significantly different across the groups. None of the supplements affected diarrhea
severity based on Vesikari score and fecal markers, except for a higher fecal mucin
concentration in the casei group (P = .006). The increase in weight gain, weight-for-age z
score (WAZ) changes and monthly weight and height velocities were significantly higher in
the reuteri compared with RC group over 6 months period, whereas. L. casei, although giving
less benefit, modestly improved weight velocity. Changes in underweight and stunting
prevalence, anemia prevalence and iron and zinc status were similar among groups. No
serious adverse events related to the interventions were reported. Children living in a house
with clean sewage had a significantly lower diarrhea prevalence compared to those who did
not have one or had dirty sewage (adjusted odds ratio 0.16; 95% CI: 0.03-0.73). The overall
food-hygiene practice score was not significantly associated with diarrhea in the total group,
but it was in children aged <2 years (adjusted odds ratio 4.55; 95% CI: 1.08-19.1).
Conclusion
L. reuteri may prevent diarrhea especially in children with lower nutritional status, reduce
total duration of diarrheal episodes, and modestly improve growth over 6 months, but does
not affect diarrhea severity. L. casei modestly improves monthly weight velocity, but does
not reduce diarrhea incidence, duration or severity. However, it seems too early to
recommend probiotics (e.g. L. reuteri) for routine use or for follow-up in public health
programs to prevent diarrhea in children in developing countries. Milk calcium alone does
not affect any of the outcomes. Moreover, none of the dietary treatments affect incidence and
duration of ARTIs, and iron and zinc status in Indonesian children. In addition to other
major determinants, poor mother’s food-hygiene practices contributes to the occurrence of
diarrhea in Indonesian children <2 years.
Contents

Chapter 1. General introduction 11

Chapter 2. Randomized trial of probiotics and calcium on diarrhea 27
and respiratory tract infections in Indonesian children

Published in Pediatrics 2012;129(5):e1155-1164

Chapter 3. Randomized trial of Lactobacillus reuteri DSM 17938, 45
Lactobacillus casei CRL 431 and calcium on diarrhea
duration and severity in Indonesian children

Submitted for publication

Chapter 4. Effect of milk calcium with or without probiotics on 63
growth, iron and zinc status of Indonesian children

Submitted for publication

Chapter 5. Association of food-hygiene practices and diarrhea 85
prevalence among Indonesian young children from low
socioeconomic urban areas

Submitted for publication

Chapter 6. General discussion 101

Summary 143

Samenvatting 149

Ringkasan 155

Acknowledgements 161

About the author 169