Long-Term Safety and Impact on Infection Rates of Postnatal Probiotic and Prebiotic (Synbiotic) Treatment: Randomized, Double-Blind, Placebo-Controlled Trial Kaarina Kukkonen, Erkki Savilahti, Tari Haahtela, Kaisu Juntunen-Backman, Riitta Korpela, Tuija Poussa, Tuula Tuure and Mikael Kuitunen Pediatrics 2008;122;8 DOI: 10.1542/peds.2007-1192 The online version of this article, along with updated information and services, is located on the World Wide Web at: http://pediatrics.aappublications.org/content/122/1/8.full.html PEDIATRICS is the official journal of the American Academy of Pediatrics A monthly publication, it has been published continuously since 1948 PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007 Copyright © 2008 by the American Academy of Pediatrics All rights reserved Print ISSN: 0031-4005 Online ISSN: 1098-4275 Downloaded from pediatrics.aappublications.org at Viet Nam:AAP Sponsored on March 2, 2013 ARTICLE Long-Term Safety and Impact on Infection Rates of Postnatal Probiotic and Prebiotic (Synbiotic) Treatment: Randomized, Double-Blind, Placebo-Controlled Trial Kaarina Kukkonen, MDa, Erkki Savilahti, MD, PhDb, Tari Haahtela, MD, PhDa, Kaisu Juntunen-Backman, MD, PhDa, Riitta Korpela, PhDc, Tuija Poussa, MScd, Tuula Tuure, PhDe, Mikael Kuitunen, MD, PhDa aDepartment of Pediatrics, Skin and Allergy Hospital, bDepartment of Pediatrics, Hospital for Children and Adolescents, and cDepartment of Pharmacology, Institute of Biomedicine, University of Helsinki, Helsinki, Finland; dSTAT Consulting, Tampere, Finland; eValio 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 What This Study Adds 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 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 www.pediatrics.org/cgi/doi/10.1542/ peds.2007-1192 doi:10.1542/peds.2007-1192 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 probiotic species (Lactobacillus rhamnosus GG and LC705, Bifidobacterium breve Bb99, and Propionibacterium freudenreichii ssp shermanii) or a placebo for weeks before delivery Their infants received the same probiotics with 0.8 g of galactooligosaccharides, or a placebo, daily for 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) 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 CONCLUSION Feeding synbiotics to newborn infants was safe and seemed to increase resistance to respiratory infections during the first years of life Pediatrics 2008;122:8–12 P ROBIOTICS 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 KUKKONEN et al Downloaded from pediatrics.aappublications.org at Viet Nam:AAP Sponsored on March 2, 2013 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 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 months.12 METHODS 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 allergyprevention 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 ϫ 109 colony-forming units in each capsule) or a placebo twice daily for weeks before delivery For months after birth, the infants received daily 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 Ͻ37 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 to 3, to 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, Sakyl ¨ 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 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) TABLE Baseline Demographic and Clinical Characteristics of the Infants in the Intention-to-Treat Synbiotic and Placebo Groups Male gender, % Birth weight, mean Ϯ SD, g Birth length, mean Ϯ SD, cm Vaginal delivery, % Maternal smoking, % Daily exposure to tobacco smoke, % Partially breastfed for Ն6 mo, % Total duration of breastfeeding, mean Ϯ SD, mo Attending day care before y of age, % Firstborn child in the family, %a Maternal allergy, % Both parents allergic, % Synbiotic (n ϭ 506) Placebo (n ϭ 512) 50 3595 Ϯ 483 50.5 Ϯ 2.0 83 16 32 71 8.6 Ϯ 5.4 50 58 81 38 49 3593 Ϯ 484 50.6 Ϯ 1.9 83 13 29 68 8.2 Ϯ 5.0 51 52 81 38 a P Ͻ 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 Ն3 months) No significant differences in other baseline variables were observed 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) 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, infants in the synbiotic group and 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 ϭ 468; placebo, n ϭ 471) completed the 6-month follow-up evaluation, and 925 (synbiotic, n ϭ 461; placebo, n ϭ 464) completed the 2-year follow-up evaluation 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) Infantile Colic and Defecation Infantile colic, defined as crying Ն4 hours per day for Ն3 days per week,14 occurred in 4% and similar but lessfrequent crying (once or twice per week) occurred in 10% of each group Defecating Ն3 times per day was less frequent in the synbiotic group (18% vs 29%; P Ͻ 001) Tolerance and Adverse Events Feeding-related behaviors (vomiting, constipation, excessive crying, and abdominal discomfort) occurred simPEDIATRICS Volume 122, Number 1, July 2008 Downloaded from pediatrics.aappublications.org at Viet Nam:AAP Sponsored on March 2, 2013 TABLE Neonatal Morbidity and Reasons for Discontinuation of the 6-Month Intervention in the Study Groups No of Infants Neonatal morbidity Jaundice Hypoglycemia Infection Oxygen supplementation Other (meconium plug obstruction, patent ductus arteriosus, or neonatal hepatitis) Reasons for discontinuing the intervention Abdominal discomfort Vomiting Crying Difficulty in swallowing the product Noncompliance Reasons for hospitalization at 0–2 y Respiratory infection Septic infection Seizures Malignancy Other Synbiotic (n ϭ 506) Placebo (n ϭ 512) 11 14 11 11 11 24 18 26 2 22 28 16 6 15 13 ilarly in the study groups (data shown elsewhere).12 Symptoms that caused discontinuation of the intervention are presented in Table One of the 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 years of age (Table 2) was likely unrelated to the intervention Growth The anthropometric measures at the ages of months and years, showing similar normal growth in the groups, are presented in Table Infections and Antibiotics During the intervention (0 – 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 ϭ 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 ϭ 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 ϭ 009) In these respective groups, middle ear infections occurred in 72% vs 76% (ratio: 0.83; 95% CI: 0.62–1.11; P ϭ 204) The total number of middle ear infections tended to be lower in the synbiotic group 10 KUKKONEN et al TABLE Anthropometric Measurements at and 24 Months of Age for Infants Who Received Synbiotics or Placebo During the First Months of Life Age, mean Ϯ SD, d Length, mean Ϯ SD, cm Length SD scores, mean Ϯ SD Weight, mean Ϯ SD, kg Head circumference, mean Ϯ SD, cm Visit Synbiotic Group (n ϭ 446)a Placebo Group (n ϭ 456)b mo 24 mo mo 24 mo mo 24 mo mo 24 mo mo 24 mo 183 Ϯ 10 736 Ϯ 17 68.4 Ϯ 2.4 88.4 Ϯ 3.2 0.00 Ϯ 0.97 0.28 Ϯ 1.01 8.16 Ϯ 0.98 12.8 Ϯ 1.5 43.9 Ϯ 1.3 49.4 Ϯ 1.5 184 Ϯ 11 735 Ϯ 20 68.4 Ϯ 2.4 88.6 Ϯ 3.1 Ϫ0.04 Ϯ 0.98 0.34 Ϯ 0.96 8.09 Ϯ 0.95 12.8 Ϯ 1.4 43.9 Ϯ 1.3 49.5 Ϯ 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 (geometric mean: 1.7 vs 1.9 infections; ratio: 0.89; 95% CI: 0.78 –1.01; P ϭ 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 ϭ 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 ϭ 206) DISCUSSION We showed that treatment of mothers with probiotics during late pregnancy and treatment of their healthy, allergy-prone infants with synbiotics for 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 months of life, they were prescribed antibiotics less frequently than were infants receiving placebo and, thereafter to the age of 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 micro- Downloaded from pediatrics.aappublications.org at Viet Nam:AAP Sponsored on March 2, 2013 biota 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 feedingrelated 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 communitybased 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 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 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 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 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) REFERENCES Cross ML Microbes versus microbes: immune signals generated by probiotic lactobacilli and their role in protection against microbial pathogens FEMS Immunol Med Microbiol 2002;34(4): 245–253 Viljanen M, Savilahti E, Haahtela T, et al Probiotics in the treatment of atopic eczema/dermatitis syndrome in infants: a double-blind placebo-controlled trial Allergy 2005;60(4): 494 –500 Boehm G, Stahl B Oligosaccharides from milk J 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during the first months of life in infants using formula enriched with Lactobacillus rhamnosus GG: double-blind, randomized trial J Hum Nutr Diet 2006;19(1):51–58 Weizman Z, Asli G, Alsheikh A Effect of a probiotic infant formula on infections in child care centers: comparison of two probiotic agents Pediatrics 2005;115(1):5–9 Jung T, Lack G, Schauer U, et al Decreased frequency of interferon-␥- and interleukin-2-producing cells in patients with atopic diseases measured at the single cell level J Allergy Clin Immunol 1995;96(4):515–527 Prescott SL, Sly PD, Holt PG Raised serum IgE associated with reduced responsiveness to DPT vaccination during infancy Lancet 1998;351(9114):1489 Paunio M, Peltola H, Virtanen M, Leinikki P, Ma¨kela¨ A, Heinonen OP Acute infections, infection pressure, and atopy Clin Exp Allergy 2006;36(5):634 – 639 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, psychologist and chief executive officer One stay-at-home mom said the sixfigure salary sounds a little low.” Burlington Free Press May 9, 2008 Noted by JFL, MD 12 KUKKONEN et al Downloaded from pediatrics.aappublications.org at Viet Nam:AAP Sponsored on March 2, 2013 Long-Term Safety and Impact on Infection Rates of Postnatal Probiotic and Prebiotic (Synbiotic) Treatment: Randomized, Double-Blind, Placebo-Controlled Trial Kaarina Kukkonen, Erkki Savilahti, Tari Haahtela, Kaisu Juntunen-Backman, Riitta Korpela, Tuija Poussa, Tuula Tuure and Mikael Kuitunen Pediatrics 2008;122;8 DOI: 10.1542/peds.2007-1192 Updated Information & Services including high resolution figures, can be found at: http://pediatrics.aappublications.org/content/122/1/8.full.html References This article cites 27 articles, of which can be accessed free at: http://pediatrics.aappublications.org/content/122/1/8.full.html #ref-list-1 Citations This article has been cited by 13 HighWire-hosted articles: http://pediatrics.aappublications.org/content/122/1/8.full.html #related-urls Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): Infectious Disease & Immunity http://pediatrics.aappublications.org/cgi/collection/infectious_ disease Permissions & Licensing Information about reproducing this article in parts (figures, tables) or in its entirety can be found online at: http://pediatrics.aappublications.org/site/misc/Permissions.xht ml Reprints Information about ordering reprints can be found online: http://pediatrics.aappublications.org/site/misc/reprints.xhtml PEDIATRICS is the official journal of the American Academy of Pediatrics A monthly publication, it has been published continuously since 1948 PEDIATRICS is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007 Copyright © 2008 by the American Academy of Pediatrics All rights reserved Print ISSN: 0031-4005 Online ISSN: 1098-4275 Downloaded from pediatrics.aappublications.org at Viet Nam:AAP Sponsored on March 2, 2013