Executive Summary
Evidence Report/Technology Assessment: Number 200
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Introduction / Methods / Results / Future Research / Conclusions / Full Report
Introduction
The Agency for Healthcare Research and Quality (AHRQ)
commissioned the Southern California Evidence-based Practice Center based at
RAND to carry out a systematic review on the safety of probiotics used in
research to reduce the risk of, prevent, or treat disease. The evidence report
was jointly sponsored by the National Institutes of Health (NIH) Office of
Dietary Supplements, the NIH National Center for Complementary and Alternative
Medicine, and the Food and Drug Administration Center for Food Safety and
Applied Nutrition.
Probiotics (literally, "for life") are bacteria or yeasts
considered to confer a health benefit on the host organism. The review
objective was to catalog what is known about the safety of interventions
containing organisms from six different genera used as probiotic agents (Lactobacillus,
Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and Bacillus),
alone or in combination, used to reduce the risk of, prevent, or treat disease
in research studies.
This evidence report
has a broad scope and was not restricted to specific interventions, specific
patient groups, or specific clinical outcomes. The large number of included
studies allowed unique analyses to explore adverse events reported to date in
research on probiotics.
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Methods
We searched 12 electronic databases (DARE, Cochrane Database
of Systematic Reviews, CENTRAL, PubMed®, Embase, CINAHL, AMED, MANTIS, TOXLINE,
ToxFile, NTIS, and AGRICOLA) and scanned the references of included studies and
pertinent reviews for studies addressing the safety of interventions using
products containing microorganisms purported to have probiotic properties (henceforth
called "probiotics") from database inception to August 2010 without language
restriction.
We systematically identified studies monitoring the
presence or absence of participants' adverse health outcomes, without
restriction due to study design, participant, or clinical field. Any studies
that assessed the effect of microorganisms used as probiotic agents and
reported on an adverse health outcome (its presence or absence) were included.
Two reviewers independently screened studies for inclusion, extracted data, and
assessed their quality. We differentiated studies that addressed a specific
adverse event from those with nonspecific safety statements.
We investigated the
quantity of adverse events (number of participants with adverse events per
treatment group, number of adverse event incidences per treatment group), the
quality of the adverse events (all adverse events, serious adverse events), and
the nature of adverse events (e.g., gastrointestinal events, infections). The
review aims to answer a large number of questions pertaining to product and
participant factors. Studies reporting direct comparisons (e.g., between two
different probiotic organisms) were primarily sought; in addition, indirect
evidence was analyzed in stratified analyses and meta-regressions.
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Results
The review demonstrates that there is a large volume of
literature on probiotics. However, the literature provided only limited evidence
to address the questions the review set out to answer.
The literature search identified 11,981 publications, of
which 2,189 were ordered as full-text publications after title and abstract
screening and 622 studies were included in the review. Of these, 235 studies
made only nonspecific safety statements (e.g., "the intervention was well
tolerated") without indicating what kind of adverse events were monitored. The
remaining 387 studies reported the presence or absence of one or more specific
adverse events; these studies were abstracted in detail and used to answer the Key
Questions. Across all included studies and treatment arms, 24,615 participants
used a probiotic product.
The review considered reports without study design
restrictions and included a large number of randomized controlled trials
(RCTs); however, the majority were not designed to address safety. The quality
of included studies varied greatly within study design categories. Adverse
events were poorly documented, and the parameters that were monitored were
often not stated. Interventions were poorly documented, lacking detail, for
example, on the specific probiotic strain administered. Very few of the
identified studies investigated Saccharomyces or Streptococcus,
and even fewer Enterococcus or Bacillus; the majority of
identified studies used Lactobacillus, alone or in combination with
other genera, most often Bifidobacterium.
To estimate the proportion of existing studies of probiotic
organisms found in the literature that are included in this safety review, we
noted all RCTs of probiotics that were found in our searches that reported on
patient outcomes. Of this pool of potentially relevant RCTs, 58 percent met
inclusion criteria for the review (i.e., made a nonspecific safety statement or
reported the presence or absence of a specific adverse event). The remaining
RCTs did not address the safety of probiotics as defined in this evidence
review.
Key Questions
Key
Question 1: What is the evidence that the active and lyophilized forms of
probiotics (Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and Bacillus) as single ingredients or in combination
with other probiotics or prebiotics in all delivery vehicles (and formulations)
when used to cure, treat, mitigate, or prevent a disease or reduce disease risk
are safe in the short term? In the long term?
Case studies indicated that fungemia, bacteremia, sepsis, and
other infections may be associated with administered probiotic organisms; the
ability to reliably determine whether administered strains match the clinical
isolate is now possible through DNA-based methods.
None of the identified case series, controlled clinical
trials, or parallel and crossover RCTs reported an infection caused by the
administered probiotic organisms. However, studies seldom reported that they
monitored for infections of the types identified in case reports. In fact, most
did not state what adverse events were monitored and did not systematically
address the safety of the probiotic products.
Across parallel RCTs there was no indication that the
quantity of reported adverse events was increased in short-term probiotic
intervention arms compared to control groups, based on the relative risk (RR)
of the number of participants with adverse events (RR 0.98; 95% confidence
interval [CI]: 0.93, 1.04, p = 0.537; 121 RCTs) as well as the number of adverse-event
incidences reported in each treatment group (RR 1.00; 95% CI: 0.93, 1.07,
p = 0.999; 208 RCTs). The current available evidence does not suggest a
widespread risk of adverse events associated with probiotics, but future
studies that explicitly monitor for the issues of concern are needed to
quantify the actual risk of specific adverse events in intervention studies.
Key
Question 2: What are characteristics and associations of the reported harms in
Question 1?
Across all included studies, the most commonly reported
adverse events were gastrointestinal in nature. This was followed by reported
infections and infestations. The third most common category was the "other" category
for symptoms that could not be assigned to a specific organ system or type of
adverse event.
Across identified RCTs, there was no indication that
participants using probiotic organisms experienced statistically significantly
more gastrointestinal (RR 1.03; 95% CI: 0.89, 1.18, p = 0.693; 126 RCTs), infections (RR 1.00; 95% CI: 0.87, 1.16, p = 0.967;
65 RCTs), or other adverse events (RR 1.01; 95% CI: 0.91 1.12, p = 0.923, 131
RCTs) compared to control group participants.
Studies rarely reported efforts to monitor adverse events
specific to probiotic products. Hence, safety evaluations may change with
future, more targeted assessment of adverse events in intervention studies.
Key
Question 3: What is the evidence that harms of Lactobacillus, Bifidobacterium,
Saccharomyces, Streptococcus, Enterococcus, and Bacillus
differ by product and delivery characteristics?
The lack of detail in the description of administered
probiotic organisms in most studies hindered evaluations of the safety. Many
studies did not specify which probiotic strains were investigated, nor was
there indication that intervention preparations were tested for identity of the
included organisms, quantity, viability, or contaminants.
Stratified analyses by probiotic genus showed no increased
risk of adverse events among the probiotic group compared to a control group in
RCTs using interventions reported to contain exclusively Lactobacillus
(RR 0.98; 95% CI: 0.87, 1.11; p = 0.785), Bifidobacterium (RR 0.92; 95% CI: 0.82, 1.03; p = 0.141), Saccharomyces(RR 1.00; 95% CI: 0.46, 2.18; p = 0.993), Streptococcus (0.99; 95% CI:
0.78, 1.25; p = 0.907), Enterococcus (RR 0.85; 95%
CI: 0.47, 1.54; p = 0.588), or Bacillus (0.99; 95% CI: 0.44, 2.22;
p = 0.973) strains. A meta-regression comparing the relative risk ratio
associated with the genera indicated a statistically significantly higher risk
for Streptococcus strains compared with the other genera; however, this
indirect comparison is based on a small number of studies that investigated Streptococcus, Enterococcus, or Bacillus interventions. Direct (head-to-head)
comparisons of genera, species, strains, or delivery vehicles are largely
absent in the literature.
There was some indication across studies that safety
findings may differ by delivery vehicle. Intervention participants in studies
in which yogurt or other dairy products were administered were more likely to
experience adverse events compared with control group participants (RR 1.37; 95%
CI: 1.05, 1.79; p = 0.022) based on the number of adverse event incidences
reported across groups in a subgroup analysis. However, studies directly
comparing delivery vehicles are missing.
We did not find conclusive evidence in the existing
literature that interventions with a mixture of different organisms reported more
adverse events than studies using one probiotic strain only or evidence that
synbiotics (mixtures of prebiotics and probiotics) differ from probiotics;
however, there is a lack of direct comparisons.
Key Question 4: How do the harms of Lactobacillus,
Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus, and Bacillus vary based on (a) dose; (b) timing; (c) mode of
administration; (d) age, gender, ethnicity, disease or immunologic status; (e)
relationship to efficacy?
Very few studies overall explored the effect of intervention
or participant characteristics on safety. To
summarize, in the
few studies that reported on the time of onset of gastrointestinal effects,
most effects were observed in the first 3 days of treatment. The onset of
infections tended to occur 1 week to several weeks after initiation of
probiotics use; however, this information is primarily derived from case
studies and was not systematically reported.
In indirect comparisons across studies, we found no evidence
that a particular mechanism or route of administration of probiotic organisms
was associated with an increased risk of an adverse event in intervention
participants relative to control group participants. Stratified analyses and meta-regressions showed no
increased risk of adverse events for children (RR 0.96; 95% CI: 0.88, 1.04;
p = 0.296, 35 RCTs), adults (RR 0.97; 95% CI:
0.79, 1.19; p = 0.745, 40 RCTs),
or elderly (RR 0.94; 95% CI: 0.82, 1.08; p = 0.367,
4 RCTs) participants
compared with adverse events observed in corresponding control groups; however,
it has to be noted that only very few studies were identified that reported on
elderly participants.
There
was some indication that health status is associated with the experience of an
adverse event when using probiotics. Case studies reporting serious adverse
events described health-compromised, not generally healthy participants who
contracted (most often) a serious infection potentially caused by probiotic
organisms. However, subgroup analyses of RCTs in medium health-compromised
participants (RR 1.03; 95% CI: 0.94, 1.13; p = 0.491) and critically ill patients (RR 0.79; 95% CI: 0.51, 1.22; p = 0.286) did not
show a statistically significantly increased risk of experiencing adverse
events for intervention participants compared with control group participants
with similar patient characteristics.
Key
Question 5: How often does harm associated with Lactobacillus, Bifidobacterium,
Saccharomyces, Streptococcus, Enterococcus, and Bacillus
lead to hospital admission or lengthened hospitalization?
While
several case studies reported hospitalizations associated with the consumption
of a product including Saccharomyces, Lactobacillus, or Bacillus strains, none
of the case series or controlled trials reported that a probiotics intervention
led to a hospitalization in the intervention participants. However, the
number of hospitalizations due to adverse events was only explicitly reported
on in a few of the included studies, and older publications may not have
associated a hospitalization with probiotics intake.
RCTs reporting on the presence or absence of serious adverse
events showed that differences across probiotic and control group participants
were not statistically significant (RR 1.06; 95% CI: 0.97,
1.16; p = 0.201, 66 RCTs). However, this result is primarily based on Lactobacillus interventions,
and a few studies investigating Saccharomyces and Bifidobacterium;
there was a lack of studies reporting on the presence or absence of serious
adverse events for other genera.
Key
Question 6: How does harm associated with Lactobacillus, Bifidobacterium,
Saccharomyces, Streptococcus, Enterococcus, and Bacillus
relate to use of concomitant antibiotics, confounding diet therapies,
corticosteroid use, immune suppressants, or other potential confounders?
We did
not identify studies that addressed possible interactions or confounders of
probiotics interventions. Although the risk of adverse events in general might
be higher in individuals taking multiple medications, subgroup analyses of studies
in which the intervention participants as well as the control group
participants received antibiotics (RR 1.07; 95% CI: 0.94, 1.23; p = 0.271) or
corticosteroids (RR
1.04; 95% CI: 0.88, 1.22; p = 0.650) found no statistically
significant increased risk of adverse effects among intervention participants. There
were too few studies to explore interactions with concomitant diet therapies,
and studies in participants using immune suppressants were also largely absent from
the existing literature.
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Future Research
Future studies need to characterize the intervention
preparations in more detail. As identification methods progress, the reporting
should include verification with DNA-based methods to identify the individual
strains included in preparation, their potency and viability, and any potential
confounders. The majority of existing studies report on Lactobacillus,
alone or in combination with other genera, most commonly Bifidobacterium
strains, and more studies are needed to explore potential adverse events
associated with interventions that include the genera Enterococcus and
Bacillus, in addition to studies on Streptococcus species selected
for their probiotic properties, as well as studies on the use of Saccharomyces in some patient groups.
Studies should describe which adverse events were
monitored to allow a clearer understanding of the presence and absence of
adverse events in probiotics intervention studies. The reporting of adverse
events should follow reporting guidelines such as the extension of the CONSORT
statement for harms. In addition, there are comprehensive systems for
cataloging adverse events, such as the Common Terminology Criteria for Adverse
Events system. Monitored harms should include infections with probiotics
organisms as well as treatment failures in order to be able to quantify the
risk for participants in intervention studies. Critical outcomes, such as
all-cause mortality, should be assessed and reported in primary studies, and
reviews should consider all studies measuring the outcome regardless of whether
the study was conducted to evaluate the efficacy of the intervention or the
occurrence of adverse events.
Long-term effects of probiotic interventions are largely
unknown, and there is a need to evaluate long-term interventions. In addition,
large cohort studies following self-selected use of probiotic organisms are
needed to fully understand the efficacy and safety of probiotics among
representative populations.
Currently, few studies address complex questions about
probiotic safety, such as interactions of participant or intervention characteristics
with the use of probiotic products. The effect of product, intervention, or
participant characteristics should be addressed with appropriate multivariate
analyses. There is also indication that participants with compromised health should
be monitored closely for potential adverse events associated with the use of
probiotic products. Studies evaluating effects on elderly participants are largely
absent from the literature, and the effects of delivery vehicles should be
investigated systematically.
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Conclusions
There is a lack of assessment and systematic reporting of
adverse events in probiotic intervention studies, and interventions are poorly
documented. RCTs and case studies diverge in the
outcomes they report. The available evidence in RCTs does not indicate
an increased risk; however, rare adverse events are
difficult to assess, and despite the substantial number of publications, the
current literature is not well equipped to answer specific questions on the
safety of probiotic interventions with confidence.
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Full Report
The executive summary is part of the following document:
Hempel S, Newberry S, Ruelaz A, Wang Z, Miles JNV, Suttorp MJ, Johnsen B,
Shanman R, Slusser W, Fu N, Smith A, Roth E, Polak J, Motala A, Perry T,
Shekelle PG. Safety of Probiotics to Reduce Risk and Prevent or Treat Disease.
Evidence Report/Technology Assessment No. 200. (Prepared by the Southern
California Evidence-based Practice Center under Contract No. 290-2007-10062-I.)
AHRQ Publication No. 11-E007. Rockville, MD: Agency for Healthcare Research and
Quality. April 2011. Available at: http://www.ahrq.gov/clinic/tp/probiotictp.htm.
For More Copies
For more copies of Safety of Probiotics to Reduce Risk
and Prevent or Treat Disease: Executive Summary No. 200 (AHRQ Pub. No.
11-E007-1), please call the AHRQ Clearinghouse at 1-800-358-9295 or E-mail ahrqpubs@ahrq.hhs.gov.
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AHRQ Publication Number 11-E007-1
Current as of April 2011
Internet Citation:
Hempel S, Newberry S, Ruelaz A, et al. Safety of Probiotics Used to Reduce Risk and Prevent or Treat Disease, Executive Summary, Evidence Report/Technology Assessment: Number 200. AHRQ Publication Number 11-E007-1, April 2011. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/probiotsum.htm
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