PEDIATRICS Vol. 122 No. 1 July 2008, pp. 8-12 (doi:10.1542/peds.2007-1192)
ARTICLE |
Long-Term Safety and Impact on Infection Rates of Postnatal Probiotic and Prebiotic (Synbiotic) Treatment: Randomized, Double-Blind, Placebo-Controlled Trial
a Department of Pediatrics, Skin and Allergy Hospital
b Department of Pediatrics, Hospital for Children and Adolescents
c Department of Pharmacology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland
d STAT Consulting, Tampere, Finland
e Valio Research and Development, Helsinki, Finland
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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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 infants 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 galactooligosaccharides, 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.
Key Words: probiotic • prebiotic • synbiotic • safety • growth • respiratory infections • antibiotics
Abbreviations: GOS—galactooligosaccharide • OR—odds ratio • CI—confidence interval
Probiotics are live microbes that, when ingested, may modulate systemic immune responses.1 Their biological effects are strain specific, and prerequisites to their effects are viability and the ability to colonize.2 Prebiotics 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.7,8 With 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.
Gut 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,11 reporting on the long-term safety of bacterial 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
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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A detailed description of the study design appears elsewhere.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, Bifidobacterium breve Bb99, and Propionibacterium freudenreichii ssp shermanii JS (8–9 x 109 colony-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 probiotic powder with liquid (water, breast milk, or formula) 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 malformation. Mothers provided their written informed consent, and the ethics committee at the local hospital approved 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 questionnaire, 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’ anthropometric measures were obtained from primary health care charts. Growth measurements were converted to SD scores with Pediator software (Tilator Ltd, Skyl, 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 Anthropometric measures were analyzed by using the t test for independent samples. The 
2 test was used to compare 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 comparisons, and the results are presented as synbiotic/placebo ratios with 95% CIs. The data were analyzed with SPSS 14.0 (SPSS, Chicago, IL).
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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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.
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Neonatal Morbidity
We observed no significant differences in parent-reported neonatal morbidity of any cause for infants in the synbiotic group, compared with those in the placebo group (Table 2).
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Infantile Colic and Defecation
Infantile colic, defined as crying
4 hours per day for 3 days per week,14 occurred in 4% and similar but less-frequent crying (once or twice per week) occurred in 10% of each group. Defecating 3 times per day was less frequent in the synbiotic group (18% vs 29%; P < .001).
Tolerance and Adverse Events
Feeding-related behaviors (vomiting, constipation, excessive crying, and abdominal discomfort) occurred similarly in the study groups (data shown elsewhere).12 Symptoms that caused discontinuation of the intervention are presented in Table 2. One of the 6 infants with difficulties swallowing the powder experienced a choking event associated with ingestion of the powder but recovered completely. Any other reason for hospitalization after discharge from the maternity hospital to 2 years of age (Table 2) was likely unrelated to the intervention.
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.
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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 frequently in the synbiotic group (93%) than in the placebo group (97%; OR: 0.49; 95% CI: 0.27–0.92; P = .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; 95% CI: 0.92–1.12; P = .736). During the follow-up period (6–24 months), most infants received antibiotics, with no significant difference between the synbiotic group (80%) and the placebo group (83%); the geometric mean number of antibiotic courses was 2.2 vs 2.4 (ratio: 0.92; 95% CI: 0.81–1.05; P = .206).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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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 synbiotics occurred. In fact, the synbiotics seemed to improve 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 experienced fewer respiratory infections.
This is the largest randomized, clinical trial on probiotics and prebiotics given to pregnant mothers and their newborn infants. Probiotics and prebiotics have generally 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 probiotic bacterial colonization was initiated when the use of probiotics and prebiotics in infant foods was still uncommon.12
Vaginal flora is crucial to the initial colonization of the newborn gut after normal delivery,15 and treating pregnant mothers with probiotics promotes newborn colonization with the same bacteria.16 Perinatal exposure may be vital to the probiotic effect, because postnatal administration of Lactobacillus acidophilus showed no preventive effect on atopy.17 In addition, the diversity of gut microbiota is important for maturation of the immune system.18 Among these infants, total counts of bifidobacteria and lactobacilli were significantly higher in the active group, which indicates the effectiveness of our intervention.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 administered 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 information available on the duration and severity of infectious diseases but allowed us to compare incidences of infections.
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 noteworthy when our results are compared with the benefits of GOSs for bottle-fed infants.19,20 More than simethicone, Lactobacillus reuteri has ameliorated infantile colic in breastfed infants.21 We observed no such effect, however. The overall incidence of infantile colic (4%) was lower than that in the aforementioned trials20,21 and less than the 9% incidence of infantile colic in a community-based trial.22 Parents of colicky infants in our study received counseling from our trained nurses and thus might have felt more confident in handling such symptoms.
Gut microbiota contribute to the host's energy metabolism.10 Probiotic bacteria may enhance the uptake of nutrients and thereby increase nutritional status (ie, improve 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.24 In the United States, growth was similar in 3- to 24-month-old infants who received Bifidobacterium lactis and Streptococcus thermophilus or a placebo.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 randomized trial in which L rhamnosus GG improved resistance to respiratory infections in infants attending day care.8 In 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 contrast, newborn Australian infants who received L acidophilus postnatally for 6 months received no protection from atopy or respiratory infections but were more likely to be given antibiotics.17 The lower frequency of antibiotic 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 synbiotics promotes maturation of the immune system, which results in 13% risk reduction for respiratory infections 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 because they exhibit weaker antibody responses to vaccines27 and their resistance to respiratory infections is compromised.28 Our results support the idea that probiotics and prebiotics may enhance immune maturation and protect infants against respiratory pathogens.1
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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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.
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ACKNOWLEDGMENTS |
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This study was supported by the Helsinki University Central Hospital Research Funds and Valio (Helsinki, Finland).
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FOOTNOTES |
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Accepted 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{at}hus.fi
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.
This trial has been registered at www.clinicaltrials.gov (identifier NCT00298337).
| 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.
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| 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.
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics
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