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CLINICAL REPORT Guidance for the Clinician in Rendering Pediatric Care
Use of Probiotics in Preterm Infants
Brenda Poindexter, MD, MS, FAAP, COMMITTEE ON FETUS AND NEWBORN
Probiotic products in the United States are available for use in the general abstract
category of dietary supplements, bypassing the rigor of the US Food and Drug
Children’s Healthcare of Atlanta and School of Medicine, Emory
Administration (FDA) approval process in safety, efficacy, and manufacturing University, Atlanta, Georgia
standards. As a result, currently available probiotics lack FDA-approved drug
Clinical reports from the American Academy of Pediatrics benefit from
labeling and cannot be marketed to treat or prevent disease in preterm expertise and resources of liaisons and internal (AAP) and external
reviewers. However, clinical reports from the American Academy of
infants, including necrotizing enterocolitis and late-onset sepsis. Despite lack Pediatrics may not reflect the views of the liaisons or the
of availability of a pharmaceutical-grade product, the number of preterm organizations or government agencies that they represent.
infants receiving probiotics in the United States and Canada is steadily Dr Poindexter was responsible for conceptualizing, writing, and
revising the manuscript and considering input from all reviewers and
increasing. According to recent reports from large collaborative databases in the board of directors; the author approved of the final manuscript as
the United States, approximately 10% of extremely low gestational age submitted.
neonates receive a probiotic preparation during their stay in the NICU, with The guidance in this clinical report does not indicate an exclusive
course of treatment or serve as a standard of medical care.
wide variation in practice among units. In sum, more than 10 000 preterm Variations, taking into account individual circumstances, may be
infants have been enrolled in randomized clinical trials of probiotic appropriate.
supplementation worldwide. Methodologic differences among study protocols All clinical reports from the American Academy of Pediatrics
automatically expire 5 years after publication unless reaffirmed,
included different strains and combinations of therapy, masking of trials, and revised, or retired at or before that time.
a priori definitions of the primary outcome measure. Large meta-analyses of
The findings and conclusions in this article are those of the authors
these trials have demonstrated the efficacy of multiple-strain probiotics in and do not necessarily represent the official position of the Centers for
Disease Control and Prevention.
reducing necrotizing enterocolitis and all-cause mortality, whereas the efficacy
of single-strain probiotic preparations is less certain. In the absence of an This document is copyrighted and is property of the American
Academy of Pediatrics and its Board of Directors. All authors have filed
appropriate medical-grade product in the United States, dietary conflict of interest statements with the American Academy of
Pediatrics. Any conflicts have been resolved through a process
supplement–grade probiotics, some of which have been the subject of recent approved by the Board of Directors. The American Academy of
recalls for contamination, are being prescribed. Given the lack of FDA- Pediatrics has neither solicited nor accepted any commercial
involvement in the development of the content of this publication.
regulated pharmaceutical-grade products in the United States, conflicting data
DOI: https://doi.org/10.1542/peds.2021-051485
on safety and efficacy, and potential for harm in a highly vulnerable
population, current evidence does not support the routine, universal Address correspondence to Brenda Poindexter, MD. E-mail:
brenda.poindexter@emory.edu
administration of probiotics to preterm infants, particularly those with a birth
weight of ,1000 g. PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2021 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: The author has indicated she has no financial
relationships relevant to this article to disclose.
INTRODUCTION FUNDING: No external funding.
There is a rapidly growing body of literature related to the developing
intestinal microbiome and the use of probiotics and prebiotics in the To cite: Poindexter B, AAP COMMITTEE ON FETUS AND
NEWBORN. Use of Probiotics in Preterm Infants. Pediatrics.
maintenance of health and in the prevention and treatment of a number of
2021;147(6):e2021051485
disease states. In preterm infants, probiotics have been evaluated in
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PEDIATRICS Volume 147, number 6, June 2021:e2021051485 FROM THE AMERICAN ACADEMY OF PEDIATRICSa number of randomized clinical trials In addition, a number of factors are required to meet higher regulatory
for the prevention of severe known to alter the microbiota in standards. Indeed, the International
necrotizing enterocolitis (NEC), late- preterm infants, including mode of Scientific Association for Probiotics
onset sepsis, and all-cause mortality.1 delivery, exposure to antibiotics, use and Prebiotics expert panel noted
Despite significant differences in the of histamine antagonists, and diet distinctive criteria for a “probiotic
combination of probiotic preparations (especially human milk, promoting drug” with a specific indication for
used in these trials and the lack of prevalence of Bifidobacterium treatment or prevention of disease to
availability of a pharmaceutical-grade species).3,4 Numerous studies have require a defined strain(s) of live
probiotic product in the United States, described intestinal dysbiosis microbe, proof of delivery of viable
the number of preterm infants preceding the onset of NEC in probiotic at efficacious dose at end of
receiving probiotics is steadily preterm infants, most commonly shelf-life, and a risk/benefit
increasing. According to recent characterized by increased assessment to justify use based on
reports from large collaborative Proteobacteria and decreased relative appropriate trials to meet regulatory
databases in the United States, abundancies of Firmicutes and standards for drugs.8 It is important
approximately 10% of extremely low Bacteroidetes species.5 Proposed to note that none of the probiotic
gestational age neonates receive benefits of probiotics include trials published to date in preterm
some type of probiotic during their preventing intestinal dysbiosis and infants for the prevention of NEC
stay in the NICU, with wide variation assisting in metabolism of dietary meet these criteria or level of
in practice among units.2 Although nutrients, leading to byproducts evidence. In the United States,
some infant formulas for term infants essential for intestinal health. For probiotic products are typically
available in the United States now example, Bifidobacterium longum manufactured as a dietary
contain probiotics, formulas for subspecies infantis consumes human supplement. If a probiotic is going to
preterm infants do not. milk oligosaccharides, promoting be marketed as a drug for treatment
The purpose of this clinical report is a healthy intestinal microbiota.6 of a disease or disorder, it has to meet
to (1) highlight differences among stricter requirements, including proof
commercially available probiotic of safety and efficacy for its intended
PROBIOTIC PREPARATIONS use through clinical trials and
preparations and the current (lack of)
regulatory standards in the United An expert panel convened by the approval by the US Food and Drug
States; (2) outline potential risks International Scientific Association Administration before it can be
associated with the use of probiotics, for Probiotics and Prebiotics defined sold.9,10
supporting a cautionary approach probiotics as “live microorganisms
Probiotic preparations may include
with their routine use in preterm that, when administered in adequate
a single bacterial strain or
infants; (3) review the current amounts, confer a health benefit to
a combination of multiple strains. In
evidence evaluating the use of the host.”7 In contrast, a prebiotic is
addition to the particular bacterial
probiotics in both prevention and a nutrient (oligosaccharides, for
species on the probiotic product label,
treatment of NEC, late-onset sepsis, example) that can modify the gut
the preparations are highly variable
and mortality; and (4) highlight the microbiota. Importantly, this
in terms of the number of viable
need for pharmaceutical-grade consensus panel proposed
microorganisms both at the time of
probiotics that have been rigorously benchmark standards, recognizing
manufacturing and after shelf storage.
evaluated for safety and efficacy. differences in regulatory approaches
for probiotics in different countries. Studies evaluating the efficacy of oral
Such differences have significant probiotics for the prevention of NEC
INTESTINAL MICROBIOME OF THE implications for interpretation of have included single bacterial strains
PRETERM INFANT studies of probiotic supplementation and mixtures of probiotics, often
Over the past decade, the role of the and for recommendations for clinical including Lactobacillus,
intestinal microbiome as a marker of use of probiotics in the NICU, Bifidobacterium, and/or
health and disease in preterm infants including but not limited to the Saccharomyces species. Despite the
has been increasingly recognized. number of colony-forming units observation that infants receiving
Differences in the intestinal (CFUs) in the product, claims of human milk are colonized with
microbiota among infants born at benefit that are not strain specific, Bifidobacterium breve and
term and those born preterm have and the intent to support a healthy Bifidobacterium infantis,6 not all
been demonstrated, with fewer gut microbiota versus to prevent probiotic preparations contain these
bacterial species, less diversity, and disease. Unlike products used as bacteria. It is also important to note
increased proportions of potentially dietary supplements, probiotics that the duration of colonization of
pathogenic strains in preterm infants. labeled with the intent to treat are the gastrointestinal tract after
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2 FROM THE AMERICAN ACADEMY OF PEDIATRICSadministration of products containing and Penicillium species. Three of the earliest randomized trials
Bifidobacterium organisms is Gastrointestinal mucormycosis has of probiotics in preterm infants
discontinued may only persist for been reported in a preterm infant suggesting benefit were conducted
a few months.11 In a recent study, 16 receiving contaminated ABC Dophilus outside the United States. Bin-Nun
different commercially available Powder.17 et al23 (Israel) evaluated the mixture of
probiotic products were evaluated to B infantis, Streptococcus thermophilus,
The Agency for Healthcare Research
determine if the bacteria species and Bifidobacteria bifidus; Dani et al24
and Quality recently issued a report
listed on the label matched that (Italy) evaluated L rhamnosus GG; and
on the safety of probiotics to reduce
obtained by culture and polymerase Lin et al25 (Taiwan) evaluated
risk and prevent or treat disease
chain reaction in the laboratory. Lactobacillus acidophilus and B infantis.
including 622 studies. Unfortunately,
Disturbingly, only 1 of the 16 In each of these early studies,
one-third of the studies reported only
products containing Bifidobacterium researchers found a reduction in the
nonspecific safety statements (such
organisms matched the label exactly, incidence of NEC in infants who were
as “well-tolerated”), and the authors
and there was substantial variability randomly assigned to receive
noted that adverse events were not
in the composition of probiotics by lot probiotics when compared with those
well documented in the majority of
and pill. One of the products tested in the control group. These 3 studies
studies. The conclusions of this report
did not contain any of the species and those that have followed have had
were as follows: “There is a lack of
listed.12 wide heterogeneity of subjects and
assessment and systematic reporting
interventions and are also limited by
of adverse events in probiotic
the small number of infants with
SAFETY intervention studies, and
a birth weight less than 1000 g, the
interventions are poorly documented.
The potential infectious risk population at highest risk for NEC.
The available evidence in
associated with probiotic
[randomized controlled trials] does The studies are hindered by
supplementation may be related to
not indicate an increased risk; methodologic differences among
the risk of sepsis associated with the
however, rare adverse events are study protocols, including different
bacterial strain in the probiotic
difficult to assess, and despite the strains and combinations of therapy,
product that colonizes the infant or
substantial number of publications, masking of trials, and having an
from contamination of the product
the current literature is not well a priori definition of the primary
with a pathogen during the
equipped to answer questions on the outcome measure. It is not clear
manufacturing process.
safety of probiotic interventions with whether it is appropriate to pool data
Although there have been a few cases confidence.”18 Other systematic from trials by using different strains
of probiotic-associated sepsis reviews have similarly reported of probiotics, leading many
reported in neonates receiving inadequate reporting of adverse and investigators to urge caution in
Lactobacillus rhamnosus GG,13 a meta- serious adverse events in studies interpretation of meta-analyses of
analysis including more than 5000 evaluating probiotics in high-risk probiotics for the prevention of
infants in randomized trials reported patients.19,20 morbidity in preterm infants.26
no systemic infection with the
supplemental probiotic organism.14 The PiPS trial, conducted in the
CURRENT EVIDENCE United Kingdom, was a large,
Although the risk appears to be low,
the potential of bacterial cross- Probiotics for the Prevention of NEC multicenter, randomized controlled
colonization among infants within trial of B breve supplementation in
Several recent meta-analyses have
a unit is also a potential risk.15 In the 1315 very preterm infants. In
evaluated the effects of probiotics to contrast to some of the earlier trials
Probiotics in Very Preterm Infants
prevent NEC (Bell stage 2 or 3), late- conducted in low-resource settings, in
(PiPS) trial, B breve was identified as
onset sepsis, and death in preterm the PiPS trial, researchers found no
a cross contaminant in 37% of infants
infants (typically very low birth difference in the primary outcomes of
randomly assigned to the placebo
weight infants). In the past 5 years,
control group.16 However, it may be NEC (RR, 0.93; 95% confidence
there have been numerous published interval [CI], 0.68–1.27), sepsis (RR,
difficult to distinguish the change in
systematic reviews.21,22 Despite great 0.97; 95% CI, 0.73–1.29), or death
the infant from the change in the
heterogeneity among studies, the
resident flora of the NICU. (RR, 0.93; 95% CI, 0.67–1.30) before
cumulative pooled risk ratio (RR) for hospital discharge.16
There have been several recent NEC (including more than 10 000
recalls of dietary supplement–grade infants) is strongly in favor of The ProPrems trial, conducted in 10
probiotics for contamination, treatment with probiotics for the perinatal centers in Australia and
including with Salmonella, Rhizopus, prevention of NEC.22 New Zealand, evaluated the effect of
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PEDIATRICS Volume 147, number 6, June 2021 3a probiotic combination (B infantis, advocating for caution with regard to Evaluation approach.33 Similar to the
Streptococcus thermophiles, and routine use of probiotics in preterm ESPGHAN, the American
Bifidobacterium lactis) in 1099 very infants. In 2010, an American Academy Gastroenterological Association made
low birth weight (,1500 g) infants of Pediatrics clinical report cautioned a conditional recommendation for use
with high exposure to human milk. that “the combinations of probiotics of a certain probiotic strain or strain
Although no difference in the primary most convincing for NEC prevention combination for the prevention of NEC
outcome of late-onset sepsis was are not available in the United States… in preterm infants but did not address
found in this trial, the incidence of not all probiotics have been studied; the lack of a pharmaceutical-grade
NEC (Bell stage 2 or greater) was therefore, all probiotics cannot be product for this population.
reduced (2.0% vs 4.4%) in infants generally recommended.”30 In 2019,
randomly assigned to receive the the Canadian Pediatric Society
PROS AND CONS OF ADMINISTRATION
probiotic combination (RR, 0.46; 95% reaffirmed the lack of safety and
OF CURRENTLY AVAILABLE PROBIOTIC
CI, 0.23–0.93). However, in efficacy data for infants with a birth PRODUCTS
a prespecified subgroup analysis of weight of ,1000 g as follows:
infants born at ,28 weeks’ “Probiotics may help to prevent NEC. NEC remains a devastating disease in
gestational age and with a birth Administering live microorganisms to preterm infants, with high mortality and
weight of ,1000 g, there was no preterm newborns should be morbidity.34 Given the number of
difference in the rate of NEC.27 approached with caution. Along with publications in favor of using probiotics
breastfeeding promotion, probiotics for the prevention of NEC, it is not at all
Not All Probiotics Are Equal: Single can be considered for the prevention of surprising that the use of probiotics is
Versus Multiple Strain NEC in preterm infants .1 kg who are increasing, even with the inherent
at risk for NEC. There is currently no limitations of dietary supplement–grade
Multiple-strain probiotics were
data for infants weighing ,1000 g.”31 products that are currently available in
associated with a significant reduction
The ESPGHAN recently published the United States. A recent series of
in NEC (pooled odds ratio, 0.36; 95%
consensus-based guidance for the articles has eloquently outlined the pros
CI, 0.24–0.53) and mortality (pooled
potential use of probiotics in preterm and cons of routine usage of currently
odds ratio, 0.58; 95% CI, 0.43–0.79),
infants.32 With regard to the safety of available probiotic products,35,36 and
whereas interventions using single-
administration of probiotics to preterm other groups have also urged caution
strain probiotic (usually Lactobacillus)
infants, the panel stipulated that local before implementation of routine use of
had only a borderline effect in
laboratories should have the ability to probiotics.37
reducing NEC and no effect on
mortality.28 The European Society for detect probiotic bacteremia, that only Some of the products currently
Paediatric Gastroenterology, products manufactured according to available in the United States include
Hepatology and Nutrition (ESPGHAN) current good manufacturing practices Culturelle (L rhamnosus GG), Similac
recently published a strain-specific should be used, and that the potential Probiotic Tri-Blend (B infantis, S
systematic review of the efficacy of risks and benefits are provided to thermophilus, and B lactis), and Evivo
probiotics for prevention of NEC, parents of preterm infants. The panel (B infantis). Each of these
highlighting important differences conditionally recommended use of L preparations are categorized as
among various bacterial strains.29 rhamnosus GG (dose from 1 3 109 dietary supplements and are not
CFUs to 6 3 109 CFUs) or labeled with the number of CFUs for
Probiotics for the Prevention of a combination of B infantis, B lactis, and the probiotic strain(s).
Culture-Proven Sepsis in Preterm S thermophilus (dose of 3.0 to 3.5 3
Infants 108 CFUs of each strain) for the
reduction of stage 2 or 3 NEC but noted LONG-TERM CONSIDERATIONS
In a 2014 Cochrane review that
included 19 randomized or quasi- low certainty of evidence. In addition, The long-term implications of giving
randomized trials of probiotic the panel recommended against the probiotics to preterm infants and how
supplementation in 5338 preterm use of certain probiotic preparations on administration of microorganisms may
infants, there was no evidence of the basis of safety concerns and permanently alter the microbiome is
significant reduction of nosocomial uncertainty of evidence. Finally, the currently unknown. Jacobs et al38
sepsis (RR, 0.91; 95% CI, 0.80–1.03).14 panel noted the lack of evidence related found comparable rates of survival
to the optimal start and length of without major neurodevelopmental
treatment. Most recently, the American impairment among subjects enrolled in
CURRENT PRACTICE GUIDELINES Gastroenterological Association the ProPrems trial. Although reassuring
The American Academy of Pediatrics, published recommendations using the that administration of the probiotic
Canadian Pediatric Society, and Grading of Recommendations preparation was not associated with
ESPGHAN have all issued statements Assessment, Development and adverse neurodevelopmental
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4 FROM THE AMERICAN ACADEMY OF PEDIATRICSoutcomes, future studies are needed to these reasons, current evidence Ivan Hand, MD
more rigorously assess the effects of does not support the routine, Ira Adams-Chapman, MD, MD
Susan W. Aucott, MD
probiotics on longer-term outcomes. universal administration of
Karen M. Puopolo, MD
probiotics to preterm infants, Jay P. Goldsmith, MD
ONGOING CLINICAL TRIALS particularly those with a birth David Kaufman, MD
weight of ,1000 g. Camilia Martin, MD
Although many trials involving Meredith Mowitz, MD
• Centers making the decision to
probiotics use of a dietary
administer probiotics to select
supplement–grade product, a phase
preterm infants should discuss the FORMER COMMITTEE MEMBER
Ib study evaluating the safety and
potential risks and benefits of this Brenda Poindexter, MD, MS, FAAP
tolerability of 2 doses of
therapy with parents and should
a pharmaceutical-grade probiotic
strongly consider a formalized LIAISONS
(STP206; NCT01954017) in preterm
informed consent process. Such
infants was recently completed. In Timothy Jancelewicz, MD – American
centers should develop local
addition, a phase III randomized Academy of Pediatrics Section on Surgery
guidelines addressing probiotic use Michael Narvey, MD – Canadian Paediatric
clinical trial to evaluate the safety and
and conduct surveillance to assess Society
efficacy of Lactobacillus reuteri (IBP-
local impacts because the Russell Miller, MD – American College of
9414; NCT03978000) to prevent NEC Obstetricians and Gynecologists
introduction of probiotics has been
in preterm infants is currently RADM Wanda Barfield, MD, MPH – Centers
shown to alter the center’s flora
ongoing. Proponents for routine for Disease Control and Prevention
and potentially affect all infants Lisa Grisham, APRN, NNP-BC – National
administration of probiotics for NEC
cared for in the center. Association of Neonatal Nurses
prevention agree that future research
should compare high-quality • Clinicians must be aware of the lack
probiotic products (both purity and of regulatory standards for STAFF
viability of microbes) and doses.36 commercially available probiotic Jim Couto, MA
preparations manufactured as
dietary supplements and the
SUMMARY
potential for contamination with ABBREVIATIONS
• In studies supporting the use of pathogenic species.
probiotics to decrease the risk of CFU: colony-forming unit
• Centers choosing to administer
NEC and late-onset infection, CI: confidence interval
probiotics should carefully
researchers have used multiple ESPGHAN: European Society for
document outcomes, adverse
different products in diverse Paediatric Gastroenter-
events, and safety.
settings and in diverse preterm ology, Hepatology and
target populations. The most recent Nutrition
modern trials have not LEAD AUTHOR NEC: necrotizing enterocolitis
demonstrated a reduction in NEC in PiPS: Probiotics in Very Preterm
Brenda Poindexter, MD, MS, FAAP
infants at the highest risk for this Infants
morbidity. A pharmaceutical-grade RR: risk ratio
probiotic product is not currently COMMITTEE ON FETUS AND NEWBORN,
available in the United States. Long- 2019–2020
term safety remains unknown. For James Cummings, MD, Chairperson
POTENTIAL CONFLICT OF INTEREST: The author has indicated she has no potential conflicts of interest to disclose.
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PEDIATRICS Volume 147, number 6, June 2021 7Use of Probiotics in Preterm Infants
Brenda Poindexter and COMMITTEE ON FETUS AND NEWBORN
Pediatrics originally published online May 24, 2021;
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Downloaded from www.aappublications.org/news by guest on May 27, 2021Use of Probiotics in Preterm Infants
Brenda Poindexter and COMMITTEE ON FETUS AND NEWBORN
Pediatrics originally published online May 24, 2021;
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/early/2021/05/21/peds.2021-051485
Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
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