and well-being of children and youth
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As more is learned about the importance of the intestinal microbiome to human health there is increasing interest in the potential benefits of probiotics. Probiotics are live micro-organisms which, when consumed in adequate amounts, confer a health effect on the host by altering its microflora. Probiotics have been administered both prophylactically and therapeutically for various conditions. This statement definines the development and role of intestinal microflora, and examines the evidence supporting the use of different probiotics to treat common paediatric conditions, such as diarrhea, atopy, functional intestinal disorders and necrotizing enterocolitis. Recommendations to guide physicians in the judicious use of these products are offered.
Key Words: Bifidobacteria; Diarrhea; Lactobacilli; Microflora; Probiotics; Saccharomyces
This statement defines what probiotics and prebiotics are, reviews the development and role of intestinal microflora and examines evidence supporting the use of different probiotics for various childhood conditions. A literature review was conducted in English and French using Medline (1966 to 2011), the Cochrane database and relevant websites. PubMed was used to identify relevant randomized controlled trials (RCTs) and meta-analyses involving the use of probiotics in paediatrics. Physician guidance for the judicious use of these products in paediatric patients is offered.
Probiotics (eg, lactobacilli, bifidobacteria, saccharomyces) are live micro-organisms which can confer a health effect on the host when consumed in adequate amounts. They are nonpathogenic in the normal host, resist processing and are able to survive in the digestive tract. Prebiotics (eg, fructo- and galacto-oligosaccharides) are nonviable food components which can confer a health benefit on the host by modulating intestinal microflora.
Colonization of an infant’s intestine begins immediately after birth. Type of delivery, the infant diet (breast milk versus formula) and other factors, such as environment, gestational age and the presence of antibiotics, influence the composition of gut microflora. Because bifidobacteria and galacto-oligosaccharides are components of breast milk, the flora of breastfed infants contain more lactobacilli and bifidobacteria than the flora of formula-fed infants. Once solid food is introduced into the diet, the composition of a child’s intestinal microflora begins to resemble the adult flora.
The gut microflora is a complex ecosystem supporting the structure and function of the intestinal mucosa. Intestinal bacteria contribute to the gut’s barrier function by competing with pathogenic bacteria, increasing mucin secretion, decreasing gut permeability and modulating the gut’s immune function.[1][3]Colonic bacteria metabolize malabsorbed carbohydrates into short-chain fatty acids (SCFA). SCFA are a preferential fuel for the enterocyte; they also acidify colonic content and increase water absorption.
Probiotics modify the gut microflora by lowering colonic pH through production of SCFA, by producing antimicrobial compounds and antitoxins, and by competing with other bacteria for nutrients and adhesion receptors. They also enhance gut barrier function and have a role in immunomodulation. Different strains of probiotics have different biological activities.
Antibiotic-associated diarrhea (AAD) is usually defined as ≥3 loose stools/day for ≥2 days occurring up to two weeks after the initiation of antibiotics. AAD occurs in about 30% of patients.
A 2002 meta-analysis which included two paediatric and seven adult studies favoured the use of probiotics, with an OR of 0.37.[4] Several paediatric RCTs using different strains of probiotics were also published [5][12](Table 1), as well as two specifically paediatric meta-analyses, which showed a significant reduction of AAD using various probiotics (RR 0.47 and 0.44). The most consistently effective were Lactobacillus rhamnosus GG (LGG) and Saccharomyces boulardii. However, the number needed to treat to prevent one case of diarrhea was 10 in one meta-analysis and seven in the other.[13][14] Consuming yogurt containing probiotics did not prevent AAD in another study.[15]
While per protocol results seem to indicate that probiotics such as S boulardii and LGG decrease the incidence of AAD, the intention to treat analysis showed less impressive results, suggesting that lack of compliance may be an issue.
TABLE 1 | |||
Study | Patient number, age range | Probiotic | Results |
Tankanow, 1990[12] | 38 | L acidophilus L bulgaricus | RR 0.96 (NS) |
Arvola, 1999[8] | 167 (119)† | LGG | Probiotic 5% |
Vanderhoof, 1999[7] | 202 (188) | LGG | Probiotic 8% Placebo 26% RR 0.29 * |
Jirapinyo, 2002[11] | 18 | L acidophilus B infantis | Probiotic 37% |
Kotowska, 2004[5] | 269 (246) | S boulardii | Probiotic 7.5% |
Erdeve, 2004[6] | 466 | S boulardii | Probiotics 5.7% |
Correa 2005[10] | 169 (157) | B lactis| S thermophilus | Probiotics 16% |
Ruszczynski, 2008[9] | 240 | L rhamnosus (strains E/N, Oxy and Pen) | Probiotic 2.5% |
NS: non-significant, * : p < 0.05 CFU Colony forming unit, † Brackets indicate final study population | |||
One adult study showed a 50% decrease in the relapse rate in patients with recurrent C difficile when treated with S boulardii in conjunction with antibiotics, but no benefit for those with an initial episode.[16] An adult meta-analysis found no evidence to support the use of probiotics in the treatment of C difficile.[17] To date there have been no paediatric RCTs.
While there is currently no evidence to support using probiotics either to prevent or treat C difficile in children or adults, there might be a role for probiotics in preventing relapse in patients with recurrent C difficile infection.
Probiotics have been used to treat acute viral diarrhea in children. Five paediatric meta-analyses showed reduced durations of diarrhea, ranging between -16.8 h and -30.0 h.[18][22] The subgroup with rotaviral diarrhea seemed to be more responsive to probiotics[19] and LGG appeared to be the most effective probiotic [5][12](Table 2).
While probiotics are useful in reducing the duration of acute infectious viral diarrhea, efficacy is strain- and dose-dependant. The beneficial effects of probiotics seem to be more evident when treatment is initiated early (<48 h). Probiotics are not useful for treating bacterial diarrhea.
TABLE 2 | |||
Meta-analysis | Trials (patients) | Probiotics | Results |
Szajewska, 2001[26] | 8 (731) (incidence) 8 (773) (duration) | LGG (3) | Diarrhea >3 days Duration of diarrhea |
Van Niel, 2002[22] | 3 (122) (no. stools) 7 (675) (duration) | LGG (4) | No. stools on day 2 Duration of diarrhea |
Huang, 2002[21] | 18 (1917) | LGG (9) | Duration of diarrhea |
Allen, 2004[19] | 15 (1341) (diarrhea >3 day) 12 (duration) | LGG (2) | Diarrhea >3 days Duration of diarrhea |
Allen 2010[18] | 63 (8014) | various | Duration of diarrhea |
NS: non-significant, * : p < 0.05 | |||
The efficacy of probiotics in preventing infectious diarrhea has been studied in multiple settings (with hospitalized patients, in child care settings and in the community) using various strains of probiotics. LGG reduced the incidence of acute diarrhea, particularly in non-breastfed infants [23]-[26] as did S boulardii, Bifidobacterium bifidum, Lactobacillus casei, Bifidobacterium lactis, and Lactobacillus reuteri in other individual studies.[27]-[31] A combination of Bifidobacterium breve and Streptococcus thermophilus decreased the incidence of dehydration.[32] Other studies did not show a significant decrease in the incidence of acute diarrhea [33]-[34](Table 3).
There seems to be a modest effect for some probiotic strains in preventing acute diarrhea, particularly in children who are not breastfed. Probiotic use may be considered in long-term facilities or for patients attending child care who have recurrent infections.
TABLE 3 | |||
Study | Patients (pts), age, setting, study duration | Probiotic | Results |
Saavedra, 1994[28] | 55 | B bifidum S thermophilus | Incidence of diarrhea |
Oberhelman, 1999[25] | 204 | LGG 3.7x1010 CFU daily, | Diarrhea episodes (all pts) |
Pedone, 2000[29] | 928 (779)† | L casei | Incidence of diarrhea |
Hatakka, 2001[23] | 571 (513) | LGG 5 – 10x105 CFU/mL of formula, | Days with gastrointestinal symptoms |
Szajewska, 2001[26] | 81 | LGG 6x109 CFU twice daily | Nosocomial diarrhea |
Mastretta, 2002[24] | 269 (220) | LGG 1x1010 CFU daily | Nosocomial rotavirus (27.7%) |
Chouraqui, 2004[33] | 90 | B lactis (Bb 12) 1x106 CFU/g of powder (formula) | Incidence of diarrhea |
Thibault, 2004[32] | 971 (913) | B breve (C50) S thermophilus 065 | Incidence of diarrhea |
Weizman, 2005[30] | 201 (194) | B lactis (Bb12) L reuteri | Episodes of diarrhea |
Billoo, 2006[27] | 100 | S boulardii | Episodes of diarrhea |
Binns, 2007[31] | 496 (315) | B lactis and prebiotics | RR 0.8 * |
Chouraqui, 2008[34] | 284 (227) | B longum (BL999) L rhamnosus (LPR) L paracasei (ST11) | BL999 + LPR 6% |
| NS: non-significant, * : p < 0.05 CFU Colony forming unit, † Brackets indicate final study population NTT number needed to treat | |||
Alteration of the gut microflora may be implicated in the pathogenesis of irritable bowel syndrome (IBS). It is a common problem in children and treatment options are limited.
Two adult meta-analyses using various strains of probiotics found a modest improvement in symptoms.[35][36] There have been four published paediatric trials. LGG decreased abdominal distension [37] and was more likely to improve symptoms of patients with IBS than a placebo.[38] Escherichia coli decreased gassiness and bloating, and one product, VSL#3 (Seaford Pharmaceuticals, Ontario), improved IBS scores [39][40](Table 4).
The data on IBS and probiotics are preliminary but there seems to be an effect in improving some symptoms.
Patients, study duration | Probiotic | Results | |
64 (50)† | LGG 1x1010 CFU twice daily | Improved abdominal pain Improved abdominal distension | |
112 (104) | LGG 3x109 CFU twice daily | Treatment success (no pain) | |
203 | E coli 1.5-4.5 x 107 CFU | Improvement of gassiness and bloating* | |
59 | VSL # 3 | Improvement of the IBS score (SGAR) at 6 wks | |
NS: non-significant, * : p < 0.05, † Brackets indicate final study population | |||
The intestinal microflora may play a role in pathogenesis of colic. Lower counts of lactobacilli have been found in the intestinal flora of colicky infants.[41][42] Two trials showed a significant reduction of crying in infants receiving L reuteri [43][44](Table 5).
While there may be a role for probiotics in treating infantile colic, there is insufficient evidence to recommend for or against using probiotics to manage this condition. A recent CPS practice point on infantile colic reached the same conclusion.
Study | Patients, age, study duration | Probiotic | Results |
Savino, 2010[44] | 50 (46)† | L reuteri | Daily crying time on day 21 Probiotics 35 min Placebo 90 min* |
Savino, 2007[43] | 90 (83) | L reuteri 1x108 CFU daily versus simethicone | Daily crying time on day 28 Probiotic 51 min Simethicone 145 min* |
NS: non-significant, * : p < 0.05, † Brackets indicate final study population | |||
Altered intestinal permeability and intestinal bacteria may be involved in the pathogenesis of necrotizing enterocolitis (NEC). One recent study showed that a bifidobacteria-supplemented formula decreased intestinal permeability in preterm infants.[45] Studies with NEC prevention as their primary outcome are listed in Table 6. In the first published study, LGG did not decrease the incidence of NEC significantly.[46] Subsequent studies showed that infants fed breast milk supplemented with lactobacillus and bifidobacteria had a significantly lower incidence of NEC and deaths than infants receiving unsupplemented breast milk.[47]-[49] The severity and incidence of NEC was lower in infants given a mixture of Bifidobacterium infantis, B bifidus and S thermophilus.[50]
In three recent meta-analyses, enteral probiotic supplementation significantly reduced the incidence of severe NEC (RR 0.32 to 0.36) and mortality (RR 0.40 to 0.47) without systemic infection with the bacteria used as probiotics.[51]-[53]
Probiotics may help to prevent NEC. Administering live microorganisms to preterm newborns should be approached with caution. Along with breastfeeding promotion, probiotics can be considered for the prevention of NEC in preterm infants >1 kg who are at risk for NEC. There is currently no data for infants weighing <1000 g.
Study | Patients, age / weight, feeding | Probiotic | Results |
Dani, 2002[46] | 585 | LGG 6x109 CFU daily | NEC Sepsis |
Lin, 2005[47] | 367 | L acidophilus 125 mg/kg twice daily | NEC stage 2 or 3 Deaths Sepsis |
Bin-Nun, 2005[50] | 155 (145) | B infantis 1x109 CFU daily | NEC |
Lin, 2008[48] | 434 | B bifidus | NEC |
Braga, 2011[49] | 258 (231) | B breve | NEC |
NS: non-significant, * : p < 0.05 CFU Colony forming unit | |||
There are no paediatric studies of probiotics in preventing traveller’s diarrhea. A meta-analysis of adult trials showed a statistically significant protective effect for various probiotics (RR 0.85),[54] but most of these studies had significant limitations. No conclusions can be drawn from the literature at this time and further trials are needed.
Probiotics may be useful in preventing infections, both by decreasing intestinal permeability and stimulating the immune system. In one Finnish study, children in day care centres who drank milk supplemented with LGG experienced fewer days with respiratory and gastrointestinal symptoms, but the only outcome to reach statistical significance was the number of days of absence due to illness.[23] B lactis and S thermophilus decreased antibiotic use significantly in children attending daycare.[55] Infant formulas supplemented with B lactis and L reuteri reduced the number of episodes of fever and diarrhea, the number of medical visits, the number of days absent from child care and antibiotic use[30] in one Israeli study. Finally, infants in one community who required formula feeding under two months of age were given LGG and B lactis Bb-12. These infants had a lower incidence of otitis media and recurrent respiratory infections, and were prescribed fewer antibiotics than others who received placebo[56](Table 7).
Probiotics might help to reduce childhood respiratory illnesses, antibiotic use and absences from child care due to illness. However, more trials are needed before any definitive conclusions can be made.
Study | Patients, setting, duration | Probiotic | Results |
Hatakka, 2001[23] | 571 (513)† | LGG | Days of absence due to illness Days with respiratory symptoms Antibiotic treatments |
Saavedra, 2004[55] | 131 (118) | B lactis Low dose (LD): High dose (HD): | Days of absence due to illness Antibiotic treatments |
Weizman, 2005[30] | 201 (194) | B lactis (Bb12) L reuteri 1x107 CFU/g powder (formula) | Days of absence from daycare Antibiotic treatments Days with respiratory illness |
Rautava, 2009[56] | 81(72) | LGG B lactis (Bb12) 1x1010 CFU daily | Acute otitis media Antibiotic treatment Recurrent infections |
NS: non-significant, * : p < 0.05, † Brackets indicate final study population | |||
Atopic diseases are often related to food allergies, which are more likely to develop when intestinal permeability is altered. Probiotics decrease intestinal permeability and the absorption of large molecules. This effect may help to prevent expression of an atopic constitution by diminishing allergen uptake. Lower counts of lactobacilli and bifidobacteria are found in children with atopic dermatitis compared with healthy controls.[57] In studies of children with atopic dermatitis treated with lactobacilli, a significant decrease in measures of intestinal permeability was observed, suggesting that impairments of gut barrier function in these patients can be improved with probiotics.[2] Also, gut microflora interact with gut-associated lymphoid tissue. Probiotics may influence the balance between the TH1 and TH2 responses and prevent the development of allergic disease.
Two RTCs suggested that LGG supplementation before delivery for pregnant mothers with a family history of atopy, and subsequent supplementation while breastfeeding or formula feeding later, reduced the risk of developing atopic dermatitis in their infants.[58]-[60] However, subsequent studies did not show such an effect.[61]-[64] A recent meta-analysis concluded that there was insufficient evidence to recommend adding probiotics to infant feeds to prevent allergic disease or food hypersensitivity [65] (Table 8).
Despite initially encouraging results, recent studies have failed to demonstrate a beneficial effect, and further research is required.
Study | Patients | Probiotic | Results |
| Kalliomaki, 2001[58] Kalliomaki, 2003[59] | 134 mother-infant pairs (at 2 yrs) 107 mother-infant pairs (at 4 yrs) 2 to 4 wks prenatally 24 wks postnatally | LGG 1x1010 twice daily | Atopic dermatitis at 2 yrs Atopic dermatitis at 4 yrs |
Rautava, 2002[60] | 62 mother-infant pairs (57)† | LGG 2x1010 CFU daily | Atopic dermatitis in the first 2 yrs |
Kukkonen, 2007[63] | 1223 mother-infant pairs (925) 2 to 4 wks prenatally | Mixture of four strains of probiotics and one prebiotic | No effect on allergic diseases |
Taylor, 2007[61] | 231 newborns of mothers with allergies (178) 6 mos postnatally | L acidophilus 3x109 CFU daily | Atopic dermatitis at 6 mos Atopic dermatitis at 1 yr |
Abrahamsson, 2007[62] | 232 mother-infant pairs with history of allergies (188) 4 wks prenatally 1 yr postnatally | L reuteri 1x108 CFU daily | Atopic dermatitis Positive skin prick test |
Kopp, 2008 [64] | 105 pregnant mothers with history of atopic disease (94) 4 to 6 wks prenatally 6 mos postnatally | LGG 5x109 CFU twice daily | Atopic dermatitis at 2 yrs |
NS: non-significant, * : p < 0.05, † Brackets indicate final study population | |||
Two early probiotics studies showed promising results for the treatment of atopic dermatitis. LGG and L reuterii were used for six weeks in children with moderate to severe eczema. While there was no significant improvement in objective disease measurements, subjects on probiotics perceived significantly more improvement than those on placebo.[66] L fermentum also diminished atopic dermatitis scores.[67] However, three subsequent meta-analyses concluded that reductions in eczema severity from probiotic treatment were modest and unlikely to be clinically significant.[68]-[70]
Using LGG as an adjunct to maternal hypoallergenic diet in breastfed infants with rectal bleeding caused by allergic colitis did not significantly affect the duration of rectal bleeding.[71] One recent study suggested that there was a greater decrease in fecal calprotectin (a marker of intestinal inflammation) and that rectal bleeding disappeared more quickly in infants treated with extensively hydrolysed formula with probiotics than with extensively hydrolysed formula alone.[72]
Further studies are needed to draw conclusions at this point.
Some probiotics may cause systemic or local infections. LGG and saccharomyces sepsis have been described in critically ill or immunocompromised patients, in some immunocompetent patients, and in patients with a central venous catheter.[73]-[79] There have been no reports of bifidobacterial systemic infection, and there was no increase in the incidence of lactobacilli sepsis in Finland following their introduction of lactobacilli in dairy products. [80]
The literature suggests there are benefits to using probiotics for treating some diseases, such as AAD and acute infectious viral diarrhea, and to help prevent NEC. There might also be a beneficial effect in patients with colic and IBS. The role of probiotics remains unproven in preventing or treating atopic diseases. Caution should be exercised in giving probiotics to patients with an immunodeficiency. The efficacy of probiotics is both strain- and disease-specific, and any probiotic must be provided in adequate amount. Physicians need to be more aware of the differences among probiotic preparations, and government agencies should be involved in regulating the viability and composition of probiotic products.
Table 9 lists some probiotic products. No preparation of LGG is currently available in this country. A list of products licensed in Canada is available at: www.hc-sc.gc.ca/dhp-mps/prodnatur/applications/licen-prod/lnhpd-bdpsnh-eng.php
Name | Probiotics | Concentration |
Bio K + milk-based | L acidophilus | 50 billion/container |
Bio K + capsules | L acidophilus | 50 billion/capsule |
Probaclac children | B bifidum, B longum, | 3 billion/capsule |
Florastor Kids | S boulardi | 250 mg/packet |
VSL # 3 | B breve, B longum, B infantis, | 450 billion/packet |
| Lactibiane Kids (not available in Canada) | LGG | 4 billion/packet |
| Culturelle Kids (not available in Canada) | LGG | I billion/packet |
BioGaia | L reuteri | Drops, straw, lozenge, ORS, chewable tablets, lifetop cap |
ORS Oral rehydration solution | ||
1. Keeping in mind that the effect of probiotics is both strain- and disease-specific, physicians should consider recommending probiotics to:
2. Based on current evidence, the use of probiotics cannot yet be recommended for the treatment or prevention of atopic diseases.
3. Physicians should be aware of the small risks of invasive infections with using some strains of probiotics in immunocompromised patients, and more rarely in the healthy child.
4. Physicians should advocate for further research to define which strains and dose of probiotics should be used in specific conditions.
The federal government should require manufacturers of probiotics and products containing probiotics to provide high quality products with precise and informative labelling.
This statement was reviewed by the Fetus and Newborn, and Infectious Diseases and Immunization Committees of the Canadian Paediatric Society.
CPS NUTRITION AND GASTROENTEROLOGY COMMITTEE
Members: Dana L Boctor MD; Jeffrey N Critch MD(Chair); Manjula Gowrishankar MD; Daniel Roth MD; Sharon L Unger MD; Robin C Williams MD (Board Representative)
Liaisons: Jatinder Bhatia MD, American Academy of Pediatrics; Genevieve Courant NP, MSc, Breastfeeding Committee for Canada; A George F Davidson MD, Human Milk Banking Association; Tanis Fenton, Dietitians of Canada; Jennifer McCrea, Health Canada; Jae Hong Kim MD (Past member); Lynne Underhill MSc, Bureau of Nutritional Sciences, Health Canada
Principal author: Valérie Marchand MD (past Chair)
Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.