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Position statement

CPS

Using probiotics in paediatric populations

Posted: Dec 9, 2022

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Principal author(s)

Rilla Schneider MD, Ana Sant’Anna MD; Canadian Paediatric Society, Nutrition and Gastroenterology Committee

Paediatr Child Health 2022 27(8):482–491.

Abstract

This statement defines probiotics and reviews the most recent literature on their use in paediatrics. Many studies have examined the potential benefit of probiotics, but significant variation in the strains and doses of probiotics used, the patient populations studied, and in study design, have led to heterogeneous results. Present evidence suggests that probiotics can decrease mortality and lower incidence of necrotizing enterocolitis in preterm and low birth weight neonates. Probiotics may also be beneficial in reducing feeding intolerance. In infants, probiotics may be considered to reduce symptoms of colic. In older children, probiotics can be considered to prevent antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea. Probiotic supplements used in conjunction with standard therapy can help with Helicobacter pylori eradication and decrease the side effects of treatment. Lactobacillus species can be considered to treat irritable bowel syndrome. Probiotics can also be considered to help prevent atopic dermatitis and eczema. To optimize paediatric policy and practice, large, quality studies are needed to determine what types and combinations of probiotics are most efficacious

Keywords: Irritable bowel syndrome (IBS); Neonates; Prevention; Probiotics

Probiotics are live micro-organisms that, when consumed in sufficient quantities, can have beneficial health effects [1]. This statement reviews the most recent literature on probiotics use in paediatric populations, with an aim to update guidance offered in a previous statement published by the Canadian Paediatric Society in 2012 [2].

A search of the literature was conducted on Ovid MEDLINE, in English and French, for the years 2012 to 2020. The Cochrane database was also searched for pertinent reviews. Search terms included ‘probiotic(s)’ combined with specific statement topics (e.g., sepsis, necrotizing enterocolitis (NEC), feeding and growth). Because of significant variability in study quality and design, only randomized control trials (RCTs) and quality meta-analyses have been included. Quality was assessed based on the impact factor of the publishing journal, and relevance was based both on condition prevalence and the availability of specific probiotics in Canada. Journal abstracts were screened for the type of probiotics used, mode of administration, and patient population.

Neonatal sepsis and mortality

Twenty-five studies [3]-[27] of the effects of probiotics on neonatal sepsis and infant mortality were included in this review. Six of the seven meta-analyses that focused on mortality found probiotics to be beneficial, whereas none of the RCTs did [18]-[20][22][23][26]. This discrepancy may be due to single probiotic strains, rather than combinations, being used in most RCTs. Two meta-analyses also found no benefit of use for single-strain probiotics, versus significant benefit when multi-strain combinations were used [22][26].

Overall, there is sufficient evidence to support the use of multi-strain probiotic combinations in preterm and low birth weight (LBW) infants with sepsis to lower mortality risk, if the treating care team feels that potential benefits outweigh the risks (also see the section Probiotic-related risks and concerns, below). 

Necrotizing enterocolitis

Seventeen studies [4]-[7][9][10][12][13][16]-[20][22][23][26][28] of the effects of probiotics on necrotizing enterocolitis (NEC) in neonates were included in this review. None of the RCTs found significant benefit of probiotics use for reducing NEC, surgical NEC, or mortality from NEC. Seven of the nine meta-analyses found a reduction in NEC in infants receiving probiotics, suggesting a beneficial effect that may not have been reflected in the RCTs due to smaller sample sizes [18]-[20][22][23][26][28].

While some studies found various individual probiotic strains to be beneficial, multiple meta-analyses found greater benefit for probiotic combinations, including a 2014 Cochrane review [20][22][26][28]. Three publications found that probiotics were beneficial in reducing NEC in very low birth weight (VLBW) infants (<1500 g), but not in extremely low birth weight (ELBW) infants (<1000 g) [20][22][28]. The Cochrane review was the only study to find a reduction in NEC mortality with probiotic use [20].

These findings suggest that probiotics combinations may be of benefit in reducing the incidence of NEC in preterm neonates >1000 g, with no impact on NEC mortality. Large, quality trials are needed to provide evidence sufficient to inform policy and practice [29].

Neonatal feeding and growth

Twenty studies [3]-[7][9][10][12]-[14][17][20][22][30]-[36] focused on the effects of probiotics on neonatal feeding and growth were included in this review, and three potential benefits were considered: weight gain, feeding tolerance, and time to reach full enteral feeds.

Regarding weight gain, only two of the six RCTs found evidence of benefit from probiotics, and only for infants weighing 501 g to 750 g at birth [5][14]. None of the three meta-analyses found any benefit from probiotics use. 

Feeding intolerance was reduced in five of the seven RCTs examining this concern, with two of these studies finding beneficial effects only in VLBW or ELBW infants [3][6][7][10][30]. Only one meta-analysis looked at vomiting, and it found no beneficial effects with probiotics use [17]. 

Time to reach full enteral feeds was reduced in three of the eight RCTs and in all four of the meta-analyses with this focus, suggesting that probiotics may improve feeding patterns [10][12][14][20][22][35][36].

Overall, this evidence suggests a potential benefit of probiotics in helping neonates achieve enteral feeding. The major barrier to routinely implementing these findings in practice is that trials conducted to date have not reliably determined the optimal strains, combination, dosage, timing, or duration of use for routine prophylactic probiotics [29]. 

Infantile colic

Ten studies [30][37]-[45] looked at the effect of probiotics on preventing or treating infantile colic. All studies using Lactobacillus reuteri, except for one 2014 trial, showed a beneficial effect for relieving colic symptoms in infants [38]. Another study using Lactobacillus rhamnosus GG showed no benefit [41]. One Cochrane review including a total of six studies found no difference in the development of colic between the probiotic and placebo groups, but there was a significant decrease in crying times by the end of study periods in the probiotic groups [44].

Based on the evidence, L. reuteri supplementation can be considered for reducing colic symptoms.

Cow’s milk protein intolerance

Two RCTs and one meta-analysis have demonstrated benefits of probiotic use in young children (up to 13 months old) with a cow’s milk protein intolerance (CMPI). This condition was defined as being actively followed for signs and symptoms of intolerance during the RCTs or suspected or confirmed CMPI in the meta-analysis. Children developed tolerance to cow’s milk protein more quickly after receiving formula supplemented with L. rhamnosus GG compared to children receiving formula alone [46]-[48].

While there is not enough evidence at present to recommend probiotic use in CMPI, a few published studies have suggested a potential benefit.

Antibiotic-associated diarrhea (AAD)

Two studies found probiotics, specifically a combination probiotic (L. rhamnosus GG) and yogurt to be beneficial in preventing gastrointestinal (GI) symptoms, including diarrhea, following antibiotic courses [49][50]. Two other studies found no beneficial effect with probiotics use, but focused on Lactobacillus plantarum in the outpatient setting and L. reuteri DSM 17938 in hospitalized patients [51][52].

Seven meta-analyses, including two Cochrane reviews, showed a significant positive effect of probiotics use in preventing AAD [53]-[59]. Results from the most recent Cochrane review have suggested that higher dose probiotics (≥5 billion colony-forming units (CFUs) per day) may be of greater benefit and that L. rhamnosus or Saccharomyces boulardii are the most appropriate agents.

Therefore, L. rhamnosus and S. boulardii can be considered for the prevention of AAD.

Clostridium difficile and associated diarrhea

Only one RCT was included for this indication, and it found no benefit for L. reuteri DSM 17938 use in preventing C. difficile-associated diarrhea (CDAD) in hospitalized children, compared with placebo [52].  

All four meta-analyses focused on probiotics to reduce CDAD in children during antibiotic use and showed beneficial effect. Species showing the greatest benefit varied but included lactobacillus, saccharomyces, non-saccharomyces, and non-bifidobacterium [53][59][60]. One Cochrane review showed that probiotics reduced the incidence of CDAD, but risk reduction was based on baseline infection risk, with significance reached only in the high-risk groups (>5% baseline risk) [57].

One meta-analysis involving adults and children demonstrated that multi-species probiotic preparations reduced the odds of C. difficile infections, with reduced risk persisting when adjusted for age [61].

Based on the evidence, consideration of probiotics to reduce the incidence of CDAD in children on antibiotics is recommended, especially when they are at high risk (>5% baseline risk) of infection. Use of probiotics to treat established CDAD is not recommended.

Infectious diarrhea

Two North American RCTs were included in this review. One found no benefit of L. rhamnosus GG supplementation in pre-school aged children presenting to emergency departments with acute gastroenteritis [62], while the other showed that combined L. rhamnosus and Lactobacillus helveticus had no beneficial effects on symptoms, compared with placebo, regardless of the infectious etiology [63].

Six meta-analyses found probiotics to be beneficial for the treatment of infectious diarrhea in children [64]-[69], however. Although probiotic type and duration of treatment differed among studies, they were associated with a shorter duration of symptoms (i.e., by about one day). Importantly, many of the included studies took place in the developing world, where both the etiologies of infectious diarrhea and strategies to prevent and treat them differ from those in Canada. Divergent contexts likely explain these discrepant results. One Cochrane review did not find that probiotics reduced the duration of diarrhea or the risk of diarrhea lasting at least 48 h [70]. Duration of hospital stays were found to be shorter in the review, but this measure of severity was not included in the other studies [64]-[66][70][71].

Based on North American evidence, use of probiotics to shorten the duration of infectious diarrhea is not recommended in Canada.

Persistent diarrhea 

One 2013 Cochrane review evaluated probiotics use for treating persistent diarrhea in children, defined as diarrhea that starts acutely and persists for at least 14 days. Meta-analysis of only two studies demonstrated that probiotics reduced the duration of symptoms by 4.02 days. One included trial also reported shorter hospital stays in the intervention group [72].

Present evidence is insufficient to recommend probiotics use to treat persistent diarrhea at this time.

Helicobacter pylori (H. pylori)

One RCT compared standard triple therapy with standard therapy plus probiotics (Lactobacillus acidophilus and Bifidobacterium bifidum) to treat H. pylori infections in children for a total of 6 weeks. The H. pylori eradication rate was significantly higher in the group receiving probiotics, with no difference in side effects between groups [73]. Two meta-analyses associated probiotics with better eradication rates of H. pylori and fewer side effects [74][75]. Probiotic supplementation concurrent with standard therapy (both started earlier and extending throughout treatment, and started at the same time and ending post-treatment) were found to be beneficial. However, supplementing beyond standard therapy had a smaller and less significant effect size overall [75].

Considering probiotics in conjunction with standard therapy to increase H. pylori eradication and decrease the side effects of treatment is recommended.

Infection prevention

Probiotics have emerged as a preventive strategy against infection, both in otherwise healthy and in hospitalized children. Explanations for benefit include immune system stimulation and improved gut permeability, although supporting evidence for either theory remains limited. Eleven studies [50][76]-[80][81]-[85] conducted in otherwise healthy children were included in this review. Two of the three RCTs looking at nosocomial infections showed a beneficial effect for probiotics use, specifically in preventing ventilator-associated pneumonia and other respiratory tract infections [86]-[88].

However, there is not yet enough evidence to recommend probiotic use to prevent infections, even in otherwise healthy children.

Functional gastrointestinal disorders (FGIDs)

Six RCTs [30][89]-[93] and four meta-analyses, including one Cochrane review [94]-[97] analyzed the potential benefits of probiotics in the management of various FGIDs. Doses ranged in these studies from 1 x 107 CFU, twice daily, to 3 x 1010 CFU, twice daily. Results have suggested a positive response to probiotics use, with the strongest evidence being for Lactobacillus sp. to treat abdominal pain-related to FGIDs, especially IBS.

Lactobacillus sp. can be considered to treat abdominal pain related to FGIDs, especially IBS.

Atopic diseases

Prevention

Eighteen studies [46][98]-[114] included in this review looked at the potential benefit of probiotics use for preventing atopic diseases. The heterogeneity among studies, regarding supplement timing (prenatal or postnatal), strains, and duration of treatment was significant. 

The results across studies were inconsistent. However, many showed a significant reduction in the occurrence of atopic dermatitis and eczema with probiotic supplementation. Meta-analyses have suggested that the effect of probiotics may be protective only when supplementation is started during the antenatal period, and when a combination of probiotics is used [104][106][107][109][111][113].

Evidence that probiotics are beneficial for reducing other atopic diseases, including asthma, wheezing, food allergies, and rhinoconjunctivitis, remains limited.

Despite the early benefits that have been observed, follow-up studies appear to show that most positive effects are short-lived [115]-[119]. Longer term benefit in the reduced occurrence of atopic disease was demonstrated with L. rhmanosus HN001. The cumulative prevalence of eczema was reduced in the probiotic group at 4, 6, and 11 years of age [120]-[122]. 

Treatment

Six RCTs looked at probiotic treatments in children with atopic dermatitis or eczema [98][123]-[127]. The Scoring Atopic Dermatitis (SCORAD) numbers were lower in the probiotic group in three trials [123][124][126]. The three studies that did not find a significant reduction in SCORAD numbers were in children younger than 30 months old [98][125][127].

Three meta-analyses assessed probiotics for treating atopic dermatitis or eczema in children older than 12 months [111][128][129]. All found a significant decrease in SCORAD numbers for children in the probiotic groups, but study parameters were heterogeneous and their results are not clinically significant [129]. 

For treatment of asthma, one RCT showed that both Lactobacillus paracasei and Lactobacillus fermentum, used alone or in combination, decreased asthma severity and improved asthma control after 3 months [130]. Pooled results of three studies in the meta-analysis showed fewer episodes of asthma in the probiotics group. However, none of the other analyses demonstrated a statistically significant difference between groups for daytime or night-time symptom relief or symptom-free days [131].

For the treatment of allergic rhinitis, one meta-analysis associated a significant improvement in the Rhinitis Quality of Life scores with the use of probiotics, but no significant benefit on Rhinitis Total Symptoms scoring [132].

Consideration of probiotics to help prevent atopic dermatitis and eczema is recommended, but further research is needed to confirm optimal strains and timing of administration. Probiotics are not recommended for the prevention of other atopic diseases. Current evidence remains insufficient to support a recommendation for the use of probiotics to treat atopic diseases.

Inflammatory bowel disease (IBD)

Crohn’s disease

One RCT showed no benefit for adjunctive use of L. rhamnosus GG with standard Crohn’s disease therapy in children [133]. Also, because the paediatric literature is limited, the results from one recent Cochrane review of two adult trials, which showed no benefit of probiotics use for inducing remission in patients with Crohn’s disease, compared with placebo, should be noted [134].

Ulcerative colitis (UC)

One RCT has shown that adding a VSL#3 probiotic combination to standard steroid induction and mesalamine maintenance in newly diagnosed paediatric UC patients led to greater remission rates, fewer relapses at one year, and lower endoscopy and histology scores on follow-up endoscopy, compared with placebo [135]. Another RCT demonstrated that in children with mild to moderate distal UC, the addition of rectal L. reuteri enemas lowered the Mayo Score/Disease Activity Index and also improved histological scores [136].

Three meta-analyses assessed the benefit of probiotics for inducing UC remission. One study showed greater remission rates in patients treated with aminosalicylic acid (ASA) and probiotics, compared with ASA alone [137], but another showed no overall benefit [138]. Neither study had a paediatric sub-analysis. A recent Cochrane review showed only a low certainty of evidence that probiotics are superior at inducing clinical remission overall, when compared to placebo. This finding held in the paediatric sub-analysis, which included two RCTs [139].

Based on present evidence, the use of probiotics to treat IBD is not recommended.

Cystic fibrosis (CF)

Multiple studies have suggested that probiotics may reduce intestinal inflammation in children and youth with CF, as evidenced by reduced fecal calprotectin levels [140]-[143] and normalization of gut permeability [144].        

By contrast, however, one multicentre double-blinded RCT showed that L. rhamnosus GG had no effect on respiratory or nutritional outcomes compared with placebo after 12 months of therapy [145].

The data appear to indicate a promising future for probiotic use in the setting of CF, to reduce exacerbations and intestinal inflammation, but further studies are required to standardize interventions and therapy [146].

The evidence remains insufficient to recommend probiotics use to treat CF at this time.

Autism spectrum disorder (ASD)

Interest in the potential benefits of probiotics use in the setting of ASD has grown in recent years. Two RCTs [147][148] focused on L. plantarum, with similar doses. One study found mild improvement in the probiotics group after 4 weeks, as evaluated by the Swanson, Nolan, and Pelham (SNAP)-IV questionnaire, compared with the placebo group, but minimal improvement based on the Social Responsiveness Scale [147]. Results of the other study were weakened by dropout rates and poor compliance but found no significant differences in GI symptoms or psychological assessments between groups [148].

There is insufficient evidence to recommend probiotic use to treat or reduce symptoms of ASD.

Dentistry

Four RCTs looking at short-term risk in this review found that various Lactobacilli and Streptococci species decreased caries prevalence in children [149]-[152], while Streptococcus salivarius improved halitosis in patients, 10 to 30 years old, with orthodontic braces [153]. Long-term results are less consistent [154]-[156], however.

Present evidence is insufficient to recommend probiotics use to prevent dental carries in children.

Probiotics-related risks and concerns

Probiotics are generally considered safe to use in paediatrics. However, in at-risk individuals, four potential safety concerns are worth noting: sepsis, metabolic effects, immunological effects, and transfer of antimicrobial resistance [157][158].

Multiple cases of sepsis associated with Saccharomyces and Lactobacilli species have been reported in susceptible children, particularly those who are immunocompromised, have an active malignancy, or are born prematurely [157][158]. Other risk factors for sepsis include central venous catheter access, impaired intestinal barrier, critical illness, short gut, administration via jejunostomy, high mucosal adhesion, and cardiac valvular disease [158].

Negative metabolic effects include the production of D-lactate and lactic acidosis from certain lactic acid bacterial strains and deconjugation of bile salts [157][158].

The effect of probiotics on the developing immune system is being investigated, with their long-term effects still not fully known [157][158].

Finally, the potential for transfer of antimicrobial resistance exists for certain species, such as Lactobacillus, which is naturally resistant to vancomycin. By contrast, however, L. rhamnosus GG, a commonly used Lactobacillus probiotic, has no plasmids that contain transferable resistance [158].

Health care settings that use probiotics in at-risk populations must be aware that they are anaerobic organisms (do not require molecular oxygen for growth), and that they need specialized media and techniques for identification. Assurance that microbiological labs can identify these organisms appropriately is imperative [159][160]. Doctors and pharmacists should know the strains and sensitivity patterns of probiotics used within their institution to ensure that appropriate antimicrobial coverage is provided in suspected sepsis cases [159].

A universally agreed-upon framework for probiotics regulation does not exist. Therefore, probiotics are not subject to the same stringent standards and processes as pharmaceuticals [159], and product quality is known to vary widely [161]. In Canada, probiotics are considered a natural health product, and they are regulated along similar lines with vitamins, minerals, and herbal remedies [162].

Health care providers (HCPs) should discuss the considerable costs of probiotics with families before recommending regular use. Recommendations for probiotics use in paediatrics must be individualized, made in consultation with families, and based on optimal, accessible, and affordable strains.

Recommendations

The use of probiotics in paediatric populations remains a challenge, as evidenced by contradictory recommendations in current published guidelines [157][158][163]. Based on the literature reviewed for this statement, the following recommendations can be made (listed here, and in Table 1, from strongest to weakest).

  • There is sufficient evidence to support the use of multi-strain probiotic combinations to lower mortality risk in preterm and low birth weight (LBW) infants with sepsis.
  • Probiotics combinations may be of benefit in reducing the incidence of necrotizing enterocolitis (NEC) in preterm neonates >1000 g, but appears to have no impact on NEC mortality.
  • Lactobacillus sp. can be considered to treat abdominal pain related to functional gastrointestinal disorders, especially irritable bowel syndrome.
  • Lactobacillus rhamnosus and Saccharomyces boulardii can be considered for the prevention of antibiotics-associated diarrhea.
  • Consideration of probiotics to reduce the incidence of Clostridium difficile-associated diarrhea (CDAD) in children on antibiotics is recommended, especially when they are at high risk (>5% baseline risk) of infection. Use of probiotics to treat established CDAD is not recommended.
  • Consideration of probiotics in conjunction with standard therapy to increase Helciobacter pylori eradication and decrease the side effects of treatment is recommended.
  • Lactobacillus reuteri supplementation can be considered for reducing colic symptoms.
  • Consideration of probiotics to help prevent atopic dermatitis and eczema is recommended, but further research is needed to confirm optimal strains and timing of administration. Probiotics are not recommended for the prevention of other atopic diseases

Table 1. Recommendations for probiotics by category and number of studies
Category Recommendation RCT MA
Neonatal sepsis and mortality Multi-strain probiotic combinations in preterm and low birth weight (LBW) infants with sepsis to lower mortality risk if the treating care team feels the potential benefits outweigh the risks 18 7
NEC Multi-strain probiotics could be beneficial in newborns weighing >1000 g if the treating care team feels the potential benefits outweigh the risks 8 9
Neonatal feeding/Growth Probiotics could be beneficial to reach full enteral feeds, but there is insufficient evidence to make a recommendation at this time   13 7
CMPI Insufficient evidence to support probiotics use 2 1
Infantile colic Consider Lactobacillus reuteri  to reduce colic symptoms 6 4
AAD Consider use of Lactobacillus rhamnosus and Saccharomyces boulardii to help prevent AAD 4 7
CDAD Consider use to prevent CDAD in high-risk patients 1 5
Infectious diarrhea Not recommended 5 8
Persistent diarrhea Insufficient evidence 0 1
Heliobacter pylori infections Consider use in conjunction with standard therapy 1 2
Infection prevention Insufficient evidence 6 5
FGIDs Considering Lactobacillus species in abdominal pain-related FGIDs, specifically IBS 6 4
Atopic diseases Consider for prevention of atopic dermatitis and eczema 21 17
IBD Not recommended 3 5
CF Insufficient evidence 5 1
ASD Insufficient evidence 2 0
Dentistry Insufficient evidence 8 1
Legend: AAD, antibiotic-associated diarrhea; ASD, autism spectrum disorder; CF, cystic fibrosis; CDAD, Clostridium difficile-associated diarrhea; CMPI = cow’s milk protein intolerance; FGIDs, functional gastrointestinal disorders; IBD, inflammatory bowel disease; IBS, irritable bowel disease; MA, meta-analysis; NEC, necrotizing enterocolitis; RCT, randomized control trial

Acknowledgements

This position statement has been reviewed by the Community Paediatrics, Fetus and Newborn, Infectious Diseases and Immunization, and Mental Health and Developmental Disabilities Committees of the Canadian Paediatric Society (CPS), as well as by the CPS Developmental Paediatrics and Paediatric Oral Health Section Executives.

CANADIAN PAEDIATRIC SOCIETY NUTRITION AND GASTROENTEROLOGY COMMITTEE (2020-2021)

Members: Belal Alshaikh MD, Linda Casey MD, Eddy Lau MD (Board Representative), Catherine Pound

MD (Chair), Gina Rempel MD, Ana Sant'Anna MD, Pushpa Sathya MD, Rilla Schneider MD (Resident

Member), Christopher Tomlinson MD

Liaisons: Sanjukta Basak MD (Canadian Pediatric Endocrine Group), Subhadeep Chakrabarti (Health Canada), Patricia D'Onghia (Health Canada), Tanis Fenton (Dietitians of Canada), Laura Haiek (Breastfeeding Committee for Canada)

Principal authors: Rilla Schneider MD, Ana Sant’Anna MD

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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.

Last updated: Feb 8, 2024

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