Use of Probiotics in Preterm Infants

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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 PEDIATRICS
a 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 PEDIATRICS
administration 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                                                                                               3
a 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 PEDIATRICS
outcomes, 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                                                                                                     7
Use of Probiotics in Preterm Infants
       Brenda Poindexter and COMMITTEE ON FETUS AND NEWBORN
              Pediatrics originally published online May 24, 2021;

Updated Information &          including high resolution figures, can be found at:
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Use 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
has been published continuously since 1948. Pediatrics is owned, published, and trademarked by
the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2021
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