DOI: 10.1542/peds.2007-1192 2008;122;8 Pediatrics Korpela, Tuija Poussa, Tuula Tuure and Mikael Kuitunen Kaarina Kukkonen, Erkki Savilahti, Tari Haahtela, Kaisu Juntunen-Backman, Riitta
Trang 1DOI: 10.1542/peds.2007-1192
2008;122;8
Pediatrics
Korpela, Tuija Poussa, Tuula Tuure and Mikael Kuitunen Kaarina Kukkonen, Erkki Savilahti, Tari Haahtela, Kaisu Juntunen-Backman, Riitta
Trial
Placebo-Controlled Prebiotic (Synbiotic) Treatment: Randomized, Double-Blind,
Long-Term Safety and Impact on Infection Rates of Postnatal Probiotic and
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located on the World Wide Web at:
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Boulevard, Elk Grove Village, Illinois, 60007 Copyright © 2008 by the American Academy published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
publication, it has been published continuously since 1948 PEDIATRICS is owned,
PEDIATRICS is the official journal of the American Academy of Pediatrics A monthly
Trang 2Long-Term Safety and Impact on Infection Rates of
Postnatal Probiotic and Prebiotic (Synbiotic)
Treatment: Randomized, Double-Blind,
Placebo-Controlled Trial
Kaarina Kukkonen, MD a , Erkki Savilahti, MD, PhD b , Tari Haahtela, MD, PhD a , Kaisu Juntunen-Backman, MD, PhD a , Riitta Korpela, PhD c , Tuija Poussa, MSc d , Tuula Tuure, PhD e , Mikael Kuitunen, MD, PhD a
a Department of Pediatrics, Skin and Allergy Hospital, b Department of Pediatrics, Hospital for Children and Adolescents, and c Department of Pharmacology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland; d STAT Consulting, Tampere, Finland; e Valio Research and Development, Helsinki, Finland
Financial Disclosure: Salaries Dr Kukkonen received and grants Dr Kuitunen received from the Clinical Research Institute of Helsinki University Central Hospital were funded by Valio Drs Korpela and Tuure were employed by Valio Research Centre Ms Poussa received consulting fees from Valio.
What’s Known on This Subject
Probiotics and prebiotics are known to modulate immune responses The accumulating
evidence of their health-promoting effects has led to increased consumption in infancy.
However, long-term follow-up and safety data for administration to newborn infants are
lacking.
What This Study Adds
This study documents safety and provides long-term follow-up data on probiotics and prebiotics administered to newborn infants The study suggests that feeding probiotics and prebiotics to allergy-prone infants may increase their resistance to respiratory infections.
ABSTRACT
OBJECTIVE.Live probiotic bacteria and dietary prebiotic oligosaccharides (together
termed synbiotics) increasingly are being used in infancy, but evidence of long-term
safety is lacking In a randomized, placebo-controlled, double-blind trial, we studied
the safety and long-term effects of feeding synbiotics to newborn infants
METHODS.Between November 2000 and March 2003, pregnant mothers carrying
in-fants at high risk for allergy were randomly assigned to receive a mixture of 4
probiotic species (Lactobacillus rhamnosus GG and LC705, Bifidobacterium breve Bb99,
and Propionibacterium freudenreichii ssp shermanii) or a placebo for 4 weeks before
delivery Their infants received the same probiotics with 0.8 g of
galactooligosaccha-rides, or a placebo, daily for 6 months after birth Safety data were obtained from
clinical examinations and interviews at follow-up visits at ages 3, 6, and 24 months
and from questionnaires at ages 3, 6, 12, and 24 months Growth data were collected
at each time point
RESULTS.Of the 1018 eligible infants, 925 completed the 2-year follow-up assessment
Infants in both groups grew normally We observed no difference in neonatal
morbidity, feeding-related behaviors (such as infantile colic), or serious adverse
events between the study groups During the 6-month intervention, antibiotics were
prescribed less often in the synbiotic group than in the placebo group (23% vs 28%)
Throughout the follow-up period, respiratory infections occurred less frequently in
the synbiotic group (geometric mean: 3.7 vs 4.2 infections)
CONCLUSION.Feeding synbiotics to newborn infants was safe and seemed to increase resistance to respiratory infections
during the first 2 years of life Pediatrics 2008;122:8–12
PROBIOTICS ARE LIVEmicrobes that, when ingested, may modulate systemic immune responses.1Their biological effects are strain specific, and prerequisites to their effects are viability and the ability to colonize.2Prebiotics are indigestible nutrients, such as galactooligosaccharides (GOSs) in human breast milk, that stimulate the growth and metabolic activity of beneficial bacteria in the gut flora but also may produce a direct immunologic effect.3,4 Long-term use of these immunomodulatory agents among infants has been beneficial in autoimmune and allergic disorders, such as inflammatory bowel diseases5 and atopic eczema.6 Their use is also associated with increased resistance to acute enteric and respiratory infections.7,8With the accumulating evidence of the benefits they produce, probiotics and prebiotics are added to dairy products, which results in long-term consumption9 among pregnant mothers and young infants
www.pediatrics.org/cgi/doi/10.1542/ peds.2007-1192
doi:10.1542/peds.2007-1192
This trial has been registered at www clinicaltrials.gov (identifier NCT00298337).
Key Words
probiotic, prebiotic, synbiotic, safety, growth, respiratory infections, antibiotics
Abbreviations
GOS— galactooligosaccharide OR— odds ratio
CI— confidence interval
Accepted for publication Nov 6, 2007 Address correspondence to Kaarina Kukkonen,
MD, Helsinki University Central Hospital, Skin and Allergy Hospital, Meilahdentie 2, PO Box
160, 00029 HUCH Helsinki, Finland E-mail: kaarina.kukkonen@hus.fi
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275) Copyright © 2008 by the American Academy of Pediatrics
Trang 3Gut microbiota affect nutrient uptake and thereby
host energy metabolism.10 In view of that, probiotics
may have an impact on weight gain and growth
Probiotics and prebiotics are regulated mostly within the
context of food, not drugs Although they are generally
considered safe,11reporting on the long-term safety of
bac-terial strains proven to colonize and to induce a clinical
effect is warranted In this placebo-controlled study, we
document safety and provide long-term follow-up data
The synbiotics consisted of 4 probiotic strains and prebiotic
GOSs They were given in a double-blinded manner to
pregnant mothers and to their allergy-prone infants from
birth to the age of 6 months.12
METHODS
A detailed description of the study design appears
else-where.12 In brief, we enrolled 1223 pregnant mothers
carrying infants at high risk for allergy in an
allergy-prevention trial in Helsinki, Finland, between November
2000 and March 2003 Mothers took capsules containing
a mixture of Lactobacillus rhamnosus GG and LC705,
Bi-fidobacterium breve Bb99, and Propionibacterium
freuden-reichii ssp shermanii JS (8 –9⫻ 109colony-forming units
in each capsule) or a placebo twice daily for 4 weeks
before delivery For 6 months after birth, the infants
received daily 1 opened capsule of the same probiotics
and 0.8 g of GOSs (of bovine origin) in liquid form or
placebo (microcrystalline cellulose plus sugar syrup)
Parents received illustrated instructions to mix the
pro-biotic powder with liquid (water, breast milk, or
for-mula) in a teaspoon and to feed it to the infants with the
spoon Exclusion criteria included birth at⬍37 weeks of
gestation, being a B twin, and having a major
malfor-mation Mothers provided their written informed
con-sent, and the ethics committee at the local hospital
ap-proved the study protocol
The study pediatrician, blinded to group allocation,
examined the infants and interviewed the parents at
ages 3, 6, and 24 months At 3, 6, 12, and 24 months, the
parents completed questionnaires covering 0 to 3, 3 to 6,
6 to 12, and 12 to 24 months, respectively We inquired
about neonatal morbidity, feeding-related behaviors,
nutrition, the environment, and numbers of infections,
antibiotics, and other diseases The questionnaires were
delivered by mail except for the 3- to 6-month
question-naire, which was given in person at the 3-month visit
The questionnaires were returned during the study visits
(at 3, 6, and 24 months) or by mail (at 12 months) The
parents were advised to contact the study pediatrician in
the event of adverse reactions The infants’
anthropo-metric measures were obtained from primary health
care charts Growth measurements were converted to
SD scores with Pediator software (Tilator Ltd, S ¨akyl ¨a,
Finland), by using data for Finnish children as reference
data.13
All analyses used an intention-to-treat approach The
sample size calculations are presented elsewhere.12
An-thropometric measures were analyzed by using the t test
for independent samples The2test was used to
com-pare categorized or dichotomized conditions between
the groups The results are given as odds ratios (ORs)
with 95% confidence intervals (CIs) The numbers of infections and antibiotic courses were skewed to the
right and were logarithmically transformed The t test for
independent samples was then used for group compar-isons, and the results are presented as synbiotic/placebo ratios with 95% CIs The data were analyzed with SPSS 14.0 (SPSS, Chicago, IL)
RESULTS Study Groups
Of the 1223 randomly assigned mothers, 156 refused to participate, and 49 of their infants (plus 14 B twins) were ineligible Of these, 8 infants in the synbiotic group and 7 in the placebo group were born prematurely to mothers who had started the intervention The baseline characteristics of the 1018 intention-to-treat infants were comparable between the study groups (Table 1) A
total of 939 infants (synbiotic, n ⫽ 468; placebo, n ⫽
471) completed the 6-month follow-up evaluation, and
925 (synbiotic, n ⫽ 461; placebo, n ⫽ 464) completed
the 2-year follow-up evaluation
Neonatal Morbidity
We observed no significant differences in parent-re-ported neonatal morbidity of any cause for infants in the synbiotic group, compared with those in the placebo group (Table 2)
Infantile Colic and Defecation
Infantile colic, defined as cryingⱖ4 hours per day for ⱖ3 days per week,14 occurred in 4% and similar but less-frequent crying (once or twice per week) occurred in 10% of each group Defecatingⱖ3 times per day was less
frequent in the synbiotic group (18% vs 29%; P⬍ 001)
Tolerance and Adverse Events
Feeding-related behaviors (vomiting, constipation, ex-cessive crying, and abdominal discomfort) occurred
sim-TABLE 1 Baseline Demographic and Clinical Characteristics of the
Infants in the Intention-to-Treat Synbiotic and Placebo Groups
Synbiotic
(n⫽ 506)
Placebo
(n⫽ 512)
Birth weight, mean ⫾ SD, g 3595 ⫾ 483 3593 ⫾ 484 Birth length, mean ⫾ SD, cm 50.5 ⫾ 2.0 50.6 ⫾ 1.9
Daily exposure to tobacco smoke, % 32 29 Partially breastfed for ⱖ6 mo, % 71 68 Total duration of breastfeeding, mean ⫾ SD, mo 8.6 ⫾ 5.4 8.2 ⫾ 5.0 Attending day care before 2 y of age, % 50 51 Firstborn child in the family, % a 58 52
aP⬍ 05 between the intention-to-treat groups, but no difference occurred between the study groups included in this safety analysis (at follow-up times of ⱖ3 months) No significant differ-ences in other baseline variables were observed.
Trang 4ilarly in the study groups (data shown elsewhere).12
Symptoms that caused discontinuation of the
interven-tion are presented in Table 2 One of the 6 infants with
difficulties swallowing the powder experienced a
chok-ing event associated with chok-ingestion of the powder but
recovered completely Any other reason for
hospitaliza-tion after discharge from the maternity hospital to 2
years of age (Table 2) was likely unrelated to the
inter-vention
Growth
The anthropometric measures at the ages of 6 months
and 2 years, showing similar normal growth in the 2
groups, are presented in Table 3
Infections and Antibiotics
During the intervention (0 – 6 months), we observed no
significant difference between the synbiotic and placebo
groups in the occurrence (at least once) of respiratory
infections (66% vs 68%), middle ear infections (15% vs
19%), or gastroenteritis (13% vs 14%) However, fewer
infants received antibiotics in the synbiotic group than in
the placebo group (23% vs 28%; OR: 0.74; 95% CI:
0.55–1.00; P⫽ 049)
After the intervention, during the follow-up period
(6 –24 months), respiratory infections occurred less
fre-quently in the synbiotic group (93%) than in the
.023) The total number of respiratory infections was
significantly lower in the synbiotic group (geometric
mean: 3.7 vs 4.2 infections; ratio: 0.87; 95% CI: 0.79 –
0.97; P⫽ 009) In these respective groups, middle ear
infections occurred in 72% vs 76% (ratio: 0.83; 95% CI:
0.62–1.11; P ⫽ 204) The total number of middle ear
infections tended to be lower in the synbiotic group
(geometric mean: 1.7 vs 1.9 infections; ratio: 0.89; 95%
CI: 0.78 –1.01; P ⫽ 068) Gastroenteritis was equally common in the synbiotic and placebo groups (74% vs 71%; geometric mean: 1.3 vs 1.2 episodes; ratio: 1.02;
period (6 –24 months), most infants received antibiotics, with no significant difference between the synbiotic group (80%) and the placebo group (83%); the geomet-ric mean number of antibiotic courses was 2.2 vs 2.4
(ratio: 0.92; 95% CI: 0.81–1.05; P⫽ 206)
DISCUSSION
We showed that treatment of mothers with probiotics during late pregnancy and treatment of their healthy, allergy-prone infants with synbiotics for 6 months after birth were safe Infants in both treatment groups grew normally, and no difference in morbidity related to syn-biotics occurred In fact, the synsyn-biotics seemed to im-prove the infants’ resistance to respiratory infections; during their first 6 months of life, they were prescribed antibiotics less frequently than were infants receiving placebo and, thereafter to the age of 2 years, they expe-rienced fewer respiratory infections
This is the largest randomized, clinical trial on probi-otics and prebiprobi-otics given to pregnant mothers and their newborn infants Probiotics and prebiotics have gener-ally been well tolerated, but we documented the safety
of their prenatal use with respect to neonatal morbidity Our trial with baseline-comparable treatment groups, good adherence to the treatment, and successful probi-otic bacterial colonization was initiated when the use of probiotics and prebiotics in infant foods was still uncom-mon.12
Vaginal flora is crucial to the initial colonization of the newborn gut after normal delivery,15and treating preg-nant mothers with probiotics promotes newborn coloni-zation with the same bacteria.16Perinatal exposure may
be vital to the probiotic effect, because postnatal
admin-istration of Lactobacillus acidophilus showed no preventive
effect on atopy.17In addition, the diversity of gut
micro-TABLE 3 Anthropometric Measurements at 6 and 24 Months of Age
for Infants Who Received Synbiotics or Placebo During the First 6 Months of Life
Visit Synbiotic Group
(n⫽ 446) a
Placebo Group
(n⫽ 456) b Age, mean ⫾ SD, d 6 mo 183 ⫾ 10 184 ⫾ 11
24 mo 736 ⫾ 17 735 ⫾ 20 Length, mean ⫾ SD, cm 6 mo 68.4 ⫾ 2.4 68.4 ⫾ 2.4
24 mo 88.4 ⫾ 3.2 88.6 ⫾ 3.1 Length SD scores, mean ⫾ SD 6 mo 0.00 ⫾ 0.97 ⫺0.04 ⫾ 0.98
24 mo 0.28 ⫾ 1.01 0.34 ⫾ 0.96 Weight, mean ⫾ SD, kg 6 mo 8.16 ⫾ 0.98 8.09 ⫾ 0.95
24 mo 12.8 ⫾ 1.5 12.8 ⫾ 1.4 Head circumference, mean ⫾ 6 mo 43.9 ⫾ 1.3 43.9 ⫾ 1.3
SD, cm 24 mo 49.4 ⫾ 1.5 49.5 ⫾ 1.7 Growth measurements were converted to SD scores by using data on Finnish children as reference data 13
a Growth data were available for 442 infants at the age of 24 months.
b Growth data were available for 449 infants at the age of 24 months.
TABLE 2 Neonatal Morbidity and Reasons for Discontinuation of
the 6-Month Intervention in the Study Groups
No of Infants Synbiotic
(n⫽ 506)
Placebo
(n⫽ 512) Neonatal morbidity
Other (meconium plug obstruction, patent
ductus arteriosus, or neonatal hepatitis)
Reasons for discontinuing the intervention
Difficulty in swallowing the product 2 2
Reasons for hospitalization at 0–2 y
Trang 5biota is important for maturation of the immune
sys-tem.18Among these infants, total counts of bifidobacteria
and lactobacilli were significantly higher in the active
group, which indicates the effectiveness of our
interven-tion.12
Some parents encountered problems in administering
the powder to their newborn infants Although parents
had received illustrated instructions to mix the powder
with liquid, the powder caused a choking event in one
infant Therefore, if the preparation is administered as a
powder, parents should receive personal instruction to
mix the powder with adequate quantities of breast milk
or formula The GOS syrup alone was easily
adminis-tered and had no such disadvantage
We chose structured questionnaires and interviews
rather than diaries, to enhance compliance during the
long follow-up period This limited the detailed
informa-tion available on the durainforma-tion and severity of infectious
diseases but allowed us to compare incidences of
infec-tions
We observed no benefit of the synbiotics in
feeding-related behaviors During our intervention, the majority
of infants (70%) were breastfed Breast milk contains
large quantities of GOSs (0.8 g/100 mL), which is
note-worthy when our results are compared with the benefits
of GOSs for bottle-fed infants.19,20 More than
simethi-cone, Lactobacillus reuteri has ameliorated infantile colic
in breastfed infants.21We observed no such effect,
how-ever The overall incidence of infantile colic (4%) was
lower than that in the aforementioned trials20,21and less
than the 9% incidence of infantile colic in a
community-based trial.22 Parents of colicky infants in our study
re-ceived counseling from our trained nurses and thus
might have felt more confident in handling such
symp-toms
Gut microbiota contribute to the host’s energy
me-tabolism.10Probiotic bacteria may enhance the uptake of
nutrients and thereby increase nutritional status (ie,
im-prove growth and iron status).23 In Estonia, bottle-fed
infants who received L rhamnosus GG-enriched formula
for 6 months grew better than did those who received
regular formula.24In the United States, growth was
sim-ilar in 3- to 24-month-old infants who received
Bi-fidobacterium lactis and Streptococcus thermophilus or a
pla-cebo.11 Consistently, the normal growth observed in
both our study groups did not support improved growth
with probiotics in otherwise well-nourished infants
The occurrence of fewer respiratory infections with
our synbiotics is in line with the results of a large
ran-domized trial in which L rhamnosus GG improved
resis-tance to respiratory infections in infants attending day
care.8In an Israeli multicenter trial, L reuteri and B lactis
provided no protection against respiratory infections
among children in day care, but the use of L reuteri was
associated with fewer prescribed antibiotics.25 In
con-trast, newborn Australian infants who received L
aci-dophilus postnatally for 6 months received no protection
from atopy or respiratory infections but were more likely
to be given antibiotics.17The lower frequency of
antibi-otic use among infants in day care who received formula
containing S thermophilus plus B lactis11 agrees with the
results of our study, indicating fewer antibiotic courses throughout the intervention We infer that feeding syn-biotics promotes maturation of the immune system, which results in 13% risk reduction for respiratory in-fections from 6 to 24 months of age
Our synbiotics failed to prevent episodes of diarrhea, which were rare (14%) during the intervention In the
Finnish study among children in day care, L rhamnosus
GG in milk failed to reduce the already low incidence of gastroenteritis.8
Our cohort consisted of infants who were genetically
at risk for atopy Some researchers have proposed that immune maturation in atopic infants is delayed,26 be-cause they exhibit weaker antibody responses to vac-cines27 and their resistance to respiratory infections is compromised.28Our results support the idea that probi-otics and prebiprobi-otics may enhance immune maturation and protect infants against respiratory pathogens.1
CONCLUSIONS
This study indicates that the use of live probiotic bacteria and prebiotic nutrients, even when administered to newborn infants over the long term, carries no risks Feeding probiotic bacteria to urban westernized infants genetically prone to atopy may increase their resistance
to infection Additional in vivo studies are warranted to identify the immunologic mechanisms that produce these benefits
ACKNOWLEDGMENTS
This study was supported by the Helsinki University Central Hospital Research Funds and Valio (Helsinki, Finland)
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STUDY: MOM’S MARKET VALUE AT $117,000
“Boston—If a stay-at-home mom could be compensated in dollars rather than personal satisfaction and unconditional love, she’d rake in a nifty sum of nearly $117,000 a year That’s according to a pre-Mother’s Day study released Thursday by Salary.com, a Waltham, Mass.-based firm that studies workplace compensation The eighth annual survey calculated a mom’s market value by studying pay levels for 10 job titles with duties that a typical mom performs, ranging from housekeeper and day care center teacher to van driver, psy-chologist and chief executive officer One stay-at-home mom said the six-figure salary sounds a little low.”
Burlington Free Press May 9, 2008
Noted by JFL, MD
Trang 7DOI: 10.1542/peds.2007-1192
2008;122;8
Pediatrics
Korpela, Tuija Poussa, Tuula Tuure and Mikael Kuitunen Kaarina Kukkonen, Erkki Savilahti, Tari Haahtela, Kaisu Juntunen-Backman, Riitta
Trial
Placebo-Controlled Prebiotic (Synbiotic) Treatment: Randomized, Double-Blind,
Long-Term Safety and Impact on Infection Rates of Postnatal Probiotic and
Services
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