What do Cochrane systematic reviews say about probiotics as preventive interventions?

ABSTRACT BACKGROUND: Probiotics have been used for a range of clinical situations and their use is strongly encouraged by the media worldwide. This study identified and summarized all Cochrane systematic reviews about the preventive effects of probiotics in clinical practice. DESIGN AND SETTING: Review of systematic reviews, conducted in the Discipline of Evidence-Based Medicine, Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (Unifesp). METHODS: We included all Cochrane reviews on any probiotics when they were used as preventive interventions and compared with no intervention, placebo or any other pharmacological or non-pharmacological intervention. RESULTS: 17 Cochrane systematic reviews fulfilled our inclusion criteria and were summarized in this report. None of the reviews included in the present study provided high-quality evidence for any outcome. The benefits from use of probiotics included decreased incidence of antibiotic-associated diarrhea and Clostridium difficile-associated diarrhea; decreased incidence of upper respiratory tract infections and duration of episodes; decreased need for antibiotics and absences from school due to colds; and decreased incidence of ventilator-associated pneumonia. Probiotics seem to decrease the incidence of gestational diabetes mellitus, birthweight, risk of vaginal infection and incidence of eczema. CONCLUSION: Despite the marketing and the benefits associated with probiotics, there is little scientific evidence supporting the use of probiotics. None of the reviews provided any high-quality evidence for prevention of illnesses through use of probiotics. More trials are needed to gain better knowledge of probiotics and to confirm when their use is beneficial and cost-effective.


INTRODUCTION
More than 400 species of microorganisms dwell in the human gastrointestinal tract. 1,2Balance between them is vital for the host's health.Present-day high usage of antibiotics, together with environmental and physiological factors, can alter this ecosystem.This imbalance can cause illnesses such as diarrhea, which was responsible for 1.31 million deaths in 2015, including 499,000 among children under five. 3,4Some research has shown that use of probiotics can confer some health benefits, such as treatment for diarrheal disease, prevention of systemic infections and other effects. 2,5he 2001 definition from the World Health Organization (WHO) states that probiotics are "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host". 6They are currently presented by media sources as an attractive health promotion method that prevents or cures a range of clinical situations. 7Indeed, many trials assessing the effects of probiotics (including using different species of microorganisms) as preventive or therapeutic options for a range of diseases have been conducted and published. 2,5Consequently, a considerable amount of published data is currently available through MEDLINE.Corroborating this, a search in this database carried out on July 26, 2017, using the MeSH (medical subheading) term probiotics, retrieved 12,370 records, which corresponded to an increase of 278% in the number of records over the last ten years (from December 2007 to July 2017).
The questions that therefore arise are: Should probiotics be indicated for preventive purposes?And if so, for which patients?Which types of probiotics should be used, and at what dose and for how long?
In this review, we identified and summarized all Cochrane systematic reviews about the preventive effects of probiotics in clinical practice.

OBJECTIVE
To summarize the evidence from Cochrane systematic reviews focusing on probiotics for prevention of any disease or condition.

Design
Review of Cochrane systematic reviews.

Criteria for including reviews
• Types of studies We only included the latest version of completed Cochrane systematic reviews (SR).We excluded any published protocols or any SR marked as "withdrawn" in the Cochrane Database of Systematic Reviews (CDSR).

• Types of participants
We included healthy participants or those diagnosed with any clinical condition or disease.

• Types of intervention
This review included any probiotics that were used as preventive interventions and compared with no intervention, placebo or any other pharmacological or non-pharmacological intervention.

• Type of outcomes
We considered any clinical, social and laboratory outcomes, as evaluated in the systematic reviews that were included.

Search for reviews
We carried out a sensitive systematic search in the Cochrane Database of Systematic Reviews (via Wiley) on July 1, 2017.
The search strategy is presented in Table 1.

Selection of systematic reviews
Two of the three researchers (VLB, LPDSR and DDB) independently and randomly selected and evaluated all references that were retrieved through the systematic search, to confirm their eligibility in accordance with the inclusion criteria.Any disagreements were resolved by consulting a more experienced author (RR).

Presentation of the results
We presented all the reviews included in this synthesis in a narrative manner (qualitative synthesis).The key points considered were their relevance, methods, results, quality of the body of the evidence for each outcome, and applicability.

Search results
The initial search resulted in 39 reviews and 13 protocols.
First, we excluded all protocols.After full-text assessment, we excluded 23 reviews since they either considered use of probiotics to be therapeutic interventions rather than preventive interventions or did not analyze probiotics alone.Thus, 16 Cochrane systematic reviews fulfilled our inclusion criteria and were summarized in this report.

Antibiotic-associated diarrhea among children
The review 13 assessed the efficacy and safety of probiotics for pre-

Acute upper respiratory tract infections
The review 15 evaluated the effectiveness and safety of probiotics for prevention of acute upper respiratory tract infections (URTIs) and included 13 RCTs (3,780 participants) that compared probiotics with placebo.Probiotics presented benefits through reducing the following outcomes: • the number of people who had one or more URTIs (odds ratio, OR 0.53; 95% confidence interval, CI 0.37 to 0.76; 7 RCTs; 1,927 participants; low quality of evidence); • the number of people who had three or more URTIs (OR 0.53; 95% CI 0.36 to 0.80; three RCTs; 650 participants; low quality of evidence); • the duration of the event (mean difference [MD] -1.89; 95% CI -2.03 to -1.75; 3 RCTs; 831 participants; low quality of evidence); • the need for antibiotics (OR 0.65; 95% CI 0.45 to 0.94; 4 RCTs; 1,184 participants; moderate quality of evidence); and • missing school due to colds (OR 0.10; 95% CI 0.02 to 0.47; 1 RCT; 80 children; very low quality of evidence).
No difference between the groups was found regarding adverse events (OR 0.88; 95% CI 0.65 to 1.19; 4 RCTs; 1,234 participants; low quality of evidence).The authors concluded that, based on very low to low quality of evidence due to the heterogeneity between studies, use of probiotics may be associated with reductions in the numbers of URTIs, duration of the event, need for antibiotics and missing school due to URTIs.For further details, and to check the form of probiotics used in each study, refer to the original abstract, available at: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006895.pub3/full.

Bacterial sepsis and wound complications after liver transplantation
The review 16 assessed the effects of different interventions for prevention of bacterial sepsis and wound complications in patients undergoing liver transplantation.Seven RCTs were included in this review, but only two (161 participants) assessed preventive effects of probiotics.There was no difference between probiotics plus prebiotics and selective bowel decontamination regarding the risk of needing retransplantation (OR 2.91; 95% CI 0.12 to 68.81; 1 RCT; 63 participants) or the risk of graft rejection requiring medical treatment (OR 1.94; 95% CI 0.38 to 9.83; 1 RCT; 63 participants).In comparing probiotics plus prebiotics with prebiotics, there was no difference regarding the risk of retransplantation (OR 0.33; 95% CI 0.01 to 7.90; 2 RCTs; 129 participants) or the risk of graft rejection requiring medical treatment (OR 0.69; 95% CI 0.12 to 3.84; 1 RCT; 63 participants).The authors' conclusion was that there was no evidence to support use of probiotics for reducing wound complications and bacterial sepsis in patients with previous liver transplantation.For further details, and to check the probiotics used in each study, refer to the original abstract, available at: http://

Quality of evidence (GRADE approach)
Pediatric patients receiving antibiotics 13 Probiotics versus placebo Benefits: decreased incidence of antibiotic-associated diarrhea Moderate Risk of some adverse effects in immunocompromised, severely debilitated and other patients Adults and children receiving antibiotics 17 Probiotics versus placebo or no treatment Benefit: decreased incidence of adverse events relating to Clostridium difficile-associated diarrhea Moderate No benefit regarding incidence of Clostridium difficile infection Adults, children and the elderly 15 Probiotics versus placebo

Infections after liver resection
The review 9 assessed the benefits and harm of different interventions for prevention of infectious complications and improving the outcomes after liver resection.Seven RCTs were included, but only two RCTs (125 participants) evaluated probiotics as preventive interventions.One of these compared use of prebiotics and probiotics versus placebo and found that there was no difference in mortality (RR 0.36; 95% CI 0.10 to 1.35; 44 participants).The other RCT, with 81 participants, compared use of preoperative and postoperative prebiotics and probiotics versus use of postoperative prebiotics and probiotics and found that there was no significant difference in mortality (RR 0.39; 95% CI 0.15 to 1.00).Both of these studies presented low quality of evidence.
The authors' conclusion was that there was no evidence to support or refute the use of any type of treatment to decrease the frequency of infectious complications after liver resection.

Maintenance of remission in ulcerative colitis
The review 20 assessed the efficacy and safety of probiotics for prevention of relapses in cases of ulcerative colitis.Four RCTs (587 participants) were included and these showed the following: probiotics versus mesalazine: no difference between the groups regarding the risk of relapse (OR 1.33; 95% CI 0.94 to 1.90; 3 RCTs; 555 participants; low quality of evidence) or the incidence of adverse events (OR 1.21; 95% CI 0.80 to 1.84; 2 RCTs; 430 participants; moderate quality of evidence); probiotics versus placebo: no difference between the groups regarding the risk of relapse (OR 0.27; 95% CI 0.03 to 2.68; 1 RCT; 32 participants; moderate quality of evidence).The authors concluded that there was insufficient evidence to support use of probiotics for preventing relapses in cases of ulcerative colitis.
For further details, and to check the form of probiotics used in each study, refer to the original abstract, available at: http:// onlinelibrary.wiley.com/doi/10.1002/14651858.CD007443.pub2/full.

Pouchitis after ileal pouch-anal anastomosis for ulcerative colitis
The review 10 assessed the effectiveness of different interventions for prevention of pouchitis after ileal pouch-anal anastomosis in cases of chronic ulcerative colitis.Thirteen RCTs were included in this review, but only two studies were about the use of probiotics.One RCT assessed prevention of pouchitis in patients with ileal pouch-anal anastomosis and showed that there were no benefits from using Bifidobacterium longum, in comparison with placebo (RR 1.43; 95% CI 0.66 to 3.11; 1 RCT; 12 participants; very low quality of evidence).
Another outcome assessed related to treatment of acute pouchitis.One RCT with 20 participants compared the use of Lactobacillus GG with placebo and there was no difference in clinical improvement (RR 3.95%; CI 0.14 to 65.9), with very low quality of evidence.
The authors' conclusions, based on the very low quality of evidence, was that probiotics did not seem to prevent pouchitis after ileal pouch-anal anastomosis in cases of chronic ulcerative colitis or to have any effect in treatments for patients with acute pouchitis.For more information about the other types of treatment in this study, refer to this link: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001176.pub3/full.

Urinary tract infections
The review 19 evaluated the effects of probiotics for prevention of urinary tract infections in susceptible or healthy adults and children.Nine RCTs (735 participants) were included and these showed that there was no difference in the risk of symptomatic bacterial urinary tract infection, in comparisons of use of probiotics versus placebo (OR 0.82; 95% CI 0.60 to 1.12; 6 RCTs; 352 participants) or use of probiotics versus antibiotics (OR 1.12; 95% CI 0.95 to 1.33; 1 RCT; 158 women).
The authors concluded that, based on the few studies available, which were of small size (low quality of evidence), there was no benefit from using probiotics, in comparison with placebo or no treatment.For further details, and to check the probiotics used in each study, refer to the original abstract, available at: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008772.pub2/full.

Ventilator-associated pneumonia
The review 11

Vulvovaginal candidiasis in HIV-infected women
The review 23

Allergic disease and food hypersensitivity among children
The review 12 assessed the effect of probiotics for prevention of allergic disease relating to food hypersensitivity among infants.It included 12 RCTs that compared use of probiotics with placebo or use of probiotics plus prebiotics with placebo.The overall results from the pooled data showed that the incidence of infant eczema was reduced in the probiotics group (RR 0.82; 95% CI 0.70 to 0.95; 5 RCTs; 1,477 participants; I 2 = 63.6%).However, these studies were heterogeneous and there was no statistical difference when the analysis was limited to atopic eczema (RR 0.80; 95% CI 0.62 to 1.02).There was also no significant difference regarding the other outcomes evaluated.The authors concluded that there was insufficient evidence to support use of probiotics for preventing allergies or food hypersensitivity among infants, given that the findings were inconsistent and there were many follow-up losses.For further details, and to check the form of probiotics used in each study, refer to the original abstract, available at: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006475.pub2/full.

Gestational diabetes in women without metabolic or chronic diseases
The review 8 evaluated the effects of probiotics for prevention of gestational diabetes mellitus (GDM).One RCT (256 pregnant women) was included and it found that there were benefits from use of probiotics (compared with placebo or diet) for reducing the rate of GDM (RR 0.38; 95% CI 0.20 to 0.70; 225 women) and for reducing the birthweight (MD -127.71g; 95% CI -251.37 to -4.06; 256 women).No difference between the groups was found for the following outcomes: • death (OR 2.00; 95% CI 0.35 to 11.35; 256 women); • risk of premature birth (RR 3.27; 95% CI 0.44 to 24.43; 238 women); • cesarean delivery (RR 1.23; 95% CI 0.65 to 2.32; 218 women).
All the infants included in this study were within the normal range for birthweight.The authors concluded that use of probiotics seemed to be associated with reduction in GDM.However, they considered that further studies would be required to confirm these results.For more details, and to check the form of probiotics used in each study, refer to the original abstract, available at: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009951.pub2/full.
Regarding the risk of relapse among children, there was no difference between Lactobacillus GG and placebo (RR 1.85; 95% CI 0.77 to 4.40; 1 RCT; 75 participants).
Regarding the risk of adverse events, Lactobacillus GG was associated with a risk of adverse events in comparison with maintenance therapy using aminosalicylates or azathioprine (no numerical data provided).A small RCT found that, at the end of the study, there was no difference in use of Saccharomyces boulardii plus conventional maintenance therapy versus placebo plus conventional maintenance therapy for relapses, according to the clinical disease activity index (CDAI) (RR 0.17; 95% CI 0.02 to 1.23).
The authors concluded that there was no evidence that probiotics were beneficial for maintenance of remission in cases of Crohn's disease.For further details, and to check the probiotics used in each study, refer to the original abstract, available at: http://onlinelibrary. wiley.com/doi/10.1002/14651858.CD004826.pub2/full.

Necrotizing enterocolitis in premature newborns
The review 14

Postoperative recurrence of Crohn's disease
The objective of the review 21 was to evaluate the medical therapies for prevention of postoperative recurrence of Crohn's disease.It included 23 RCTs, but only 4 RCTs were about probiotics.These RCTs found that there was no difference between probiotics and placebo regarding the risk of clinical recurrence (RR

DISCUSSION
This overview found that despite increasing marketing of probiotics, there are still few systematic reviews on the preventive use of probiotics and there is a scarcity of high-quality randomized trials.None of the reviews included in the present study provided high-quality evidence for any outcome.
Many clinical trials assessed in this study showed very low or low quality of evidence.Another point that needs to be noted is the huge variety of probiotics that have been considered in RCTs.
This made it difficult to identify the individual effect of each probiotic agent, and also precluded meta-analyses.
Most of the studies focused on gastrointestinal diseases.
We found that there were some benefits from use of probiotics, with moderate quality of evidence, regarding their use for decreasing the incidence of antibiotic-associated diarrhea among children 13 and the incidence of Clostridium difficile-associated diarrhea among adults and children. 17Other benefits that were observed with very low or low quality of evidence were that use of probiotics decreased the incidence of infections and the number of infectious episodes in patients undergoing liver transplantation. 16The benefit of decreased incidence of severe necrotizing enterocolitis and mortality among preterm infants was noted in another review, but the quality of its evidence could not be assessed. 14 relation to respiratory diseases, probiotics showed some benefits regarding decreased incidence of upper respiratory tract infections and duration of episodes, the need for antibiotics and missing school due to colds, 15 and regarding the incidence of ventilator-associated pneumonia in patients receiving mechanical ventilation. 11These studies were classified as presenting very low or low quality of evidence, using the GRADE approach.
In three systematic reviews about gynecological and obstetric diseases, we found that there were some benefits in relation to decreasing the rate of gestational diabetes mellitus, decreasing both the birthweight 8 and the risk of vaginal infection, 22 although the quality of evidence could not be assessed.One RCT found that there was a benefit in relation to reducing the incidence of eczema among infants with a family history of allergy or food hypersensitivity and among healthy infants. 12spite the potential benefits of probiotics, we did not find any high-quality evidence that could change clinical practice or recommendations for their use.Furthermore, some probiotics may be harmful in groups of patients such as those presenting immunosuppression, severe debilitation and other such conditions.On the other hand, it is important to examine the number needed to treat (NNT) and to analyze the cost-effectiveness of use of probiotics.
Goldenberg et al. concluded that the NNT to prevent one case of diarrhea was ten.Thus, in this example, probiotics reduced the number of cases of diarrhea even with only a few patients treated. 13 prevent Clostridium difficile-associated diarrhea, 29 patients would need to be treated. 17r systematic review has the advantage of the number of studies included, given that the topic of probiotics is currently a matter of debate and that there are uncertainties regarding their effectiveness.Another advantage is that it summarizes the evidence relating to probiotics and their use that has been gathered in the Cochrane Library, which is recognized as the largest database of systematic reviews, given that the information about probiotics is distributed among many studies.
This overview has some limitations.Our search was conducted in a single database, even though the Cochrane Library is recognized as the most important database of systematic reviews.The limited data available is a consequence of the small number of papers, and the low quality of evidence is related to the small sample sizes and bias of the RCTs.Another point that should be noted is the huge variety of prebiotics that have been considered in RCTs, which led to difficulty in identifying the individual effect of each probiotic agent, and also precluded meta-analyses.The NNT was not determined in some reviews, which made it more challenging to analyze cost-effectiveness.
Regarding the implications for practice, our study summarizes the use of probiotics as a preventive intervention for some clinical settings and shows the situations in which there is a real benefit.From this, healthcare professionals can decide when to indicate probiotics for patients and can improve outcomes in their hospitals.For example, probiotics can be used to reduce the incidence of vaginal infection during pregnancy and to decrease the incidence of VAP.On the other hand, probiotics should not be recommended when there is uncertainty about their benefits and harm.
Here, we make it clear that much needs to be done in relation to studying probiotics.Firstly, basic research is needed in order to elucidate the pathophysiological links between different diseases and use of probiotics.Secondly, RCTs with high-quality evidence are needed, with larger sample sizes and better control over variables.Thirdly, research on the cost-effectiveness of use of probiotics needs to be stimulated, because their use must be analyzed in terms of their consequences for health and economic repercussions.

CONCLUSION
This overview included 16 Cochrane systematic reviews about the use of probiotics as preventive measures within clinical practice.There was little scientific evidence to support the use of probiotics.None of the reviews provided high-quality evidence for preventive action achieved through use of probiotics and each review analyzed only a few randomized controlled trials.

Table 2 .
Characteristics, main findings and quality of evidence from systematic reviews focusing on patient-directed interventions with probiotics onlinelibrary.wiley.com/doi/10.1002/14651858.CD006660.