Pediatrics and Neonatology (2017) 58, 103e110

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REVIEW ARTICLE

Probiotics Prevent Candida Colonization and

Invasive Fungal Sepsis in Preterm Neonates:
A Systematic Review and Meta-Analysis of
Randomized Controlled Trials
Hua-Jian Hu, Guo-Qiang Zhang, Qiao Zhang, Shristi Shakya,
Zhong-Yue Li*

Department of Gastroenterology, Children’s Hospital of Chongqing Medical University, Ministry of

Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in
Chongqing, Chongqing International Science and Technology Cooperation Center for Child
Development and Disorders, Chongqing, China

Received Oct 9, 2015; received in revised form May 3, 2016; accepted Jun 27, 2016
Available online 14 September 2016

Key Words To investigate whether probiotic supplementation could reduce the risk of fungal infection in
Candida colonization; preterm neonates in neonatal intensive care units (NICUs), we systematically searched
invasive fungal sepsis; PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials databases for ran-
meta-analysis; domized controlled trials (RCTs) focusing on the effect of probiotics on fungal infection in pre-
preterm; term neonates. The outcomes of interest were Candida colonization and invasive fungal sepsis.
probiotics Seven trials involving 1371 preterm neonates were included. Meta-analysis (fixed-effects
model) showed that probiotic supplementation was significantly associated with a lower risk
of Candida colonization (2 RCTs, n Z 329; relative risk (RR), 0.43; 95% confidence interval
(CI), 0.27e0.67; p Z 0.0002; I2 Z 0%), and invasive fungal sepsis (7 RCTs, n Z 1371; RR,
0.64; 95% CI, 0.46e0.88; p Z 0.006; I2 Z 13%). After excluding one study with a high baseline
incidence (75%) of fungal sepsis, the effect of probiotics on invasive fungal sepsis became sta-
tistically insignificant (RR, 0.88; 95% CI, 0.44e1.78; p Z 0.72; I2 Z 15%). When using the
random-effects model, the effect of probiotics remained favorable for Candida colonization
(RR, 0.43; 95% CI 0.27e0.68; p Z 0.0002; I2 Z 0%) but not for fungal sepsis (RR, 0.64; 95%
CI 0.38e1.08; p Z 0.10; I2 Z 13%). Current evidence indicates that probiotics can reduce

* Corresponding author. Department of Gastroenterology, Children’s Hospital of Chongqing Medical University, Ministry of Education Key
Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology
Cooperation Center for Child Development and Disorders, No. 136, Zhongshan Second Road, Yuzhong District, 400014, Chongqing, China.
E-mail address: lizhongyue1001@hotmail.com (Z.-Y. Li).

http://dx.doi.org/10.1016/j.pedneo.2016.06.001
1875-9572/Copyright ª 2016, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-
NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
104
the risk of Candida colonization in preterm neonates in NICUs. Limited data support that pro-
biotic supplementation prevents invasive fungal sepsis in preterm neonates. High-quality and
adequately powered RCTs are warranted.
Copyright ª 2016, Taiwan Pediatric Association. Published by Elsevier Taiwan LLC. This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).
1. Introduction
Candida species are the third most common agent responsible
for late-onset sepsis in preterm neonates in neonatal intensive
care units (NICUs).1e3 In the past decade, the prevalence of
invasive fungal infections (IFIs) has increased dramatically.4,5
Rates range 1.6e9% in neonates of very low birth weight
(VLBW; < 1500 g) and 15% in neonates of extremely low birth
weight (ELBW; < 1000 g).6e9 Neonatal IFIs are associated with
an increased length of hospital stay, high morbidity and mor-
tality, and neurodevelopmental impairment, which impact
the survival of preterm infants.5,8,10
Preterm neonates in NICUs are highly prone to developing
IFIs because of immaturity of the skin/mucosal barrier and
immune response, invasive diagnostic and therapeutic pro-
cedures, administration of broad-spectrum antimicrobial
drugs, and exposure to the hospital milieu which leads to
gastrointestinal colonization with fungi.8 Fungal colonization
is associated with an increased risk of developing IFIs, and
enteric colonization by Candida is the most important pre-
dictor of IFIs.11e15 Reducing fungal colonization by using sys-
temic antifungal drugs effectively prevents IFIs.16e21 Despite
the effective use of antifungal agents for prophylaxis, con-
cerns remain with respect to cost, tolerability, long-term
safety, and emergence of resistant strains.
Probiotics, defined as live microorganisms, confer health
benefits to a host when administered at adequate doses.22
Substantial reports indicate that probiotics can reduce
Candida colonization and IFIs in mice models.23e26 However,
studies of preterm neonatesdthe most vulnerable patient
group cared for in NICUsdare surprisingly scant and contro-
versial. Furthermore, because such studies used small sample
sizes, they were inadequately powered to detect the effect of
probiotics on enteric colonization by Candida and fungal
sepsis. Thus, to provide the latest and most convincing evi-
dence, we systematically reviewed the currently available
literature to investigate whether probiotics reduced the risk
of Candida colonization and IFIs in preterm neonates in NICUs.
2. Methods
This systematic review and meta-analysis was conducted
and reported in adherence with the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses (PRISMA)
statement,27 and the guidelines of the Cochrane Handbook
for Systematic Reviews of Interventions.28
2.1. Literature search and selection criteria
We searched PubMed, EMBASE, and the Cochrane Central
Register of Controlled Trials (CENTRAL) databases for
H.-J. Hu et al
records that compared enteral probiotics with a placebo or
with no intervention in preterm neonates. We also searched
ClinicalTrials.gov (https://clinicaltrials.gov/) and the Eu-
ropean Union Clinical Trials Register (https://www.
clinicaltrialsregister.eu/). The keywords searched were as
follows: “acidophilus”, “Bifidobacterium”, “ELBW”,
“Enterococcus”, “Escherichia coli”, “extremely low birth
weight”, “lactic acid bacteria”, “Lactobacillus”, “Lacto-
coccus”, “LBW”, “low birth weight”, “preterm”, “prema-
ture”, “probiotic”, “probiotics”, “Saccharomyces”,
“Streptococcus”, “very low birth weight”, “VLBW”,
“yoghurt”, and “yogurt”. The last search was conducted on
August 20, 2015. No language restriction was imposed. All
citations were imported into a bibliographic database
(EndNote X7; Thomson Reuters, New York, NY, USA) for the
assessment of eligibility. Two authors (H-J H and G-Q Z)
independently conducted the initial search, removed
duplicate articles, screened the titles and abstracts for
relevance, and identified studies as excluded or requiring
further assessment. Full-text articles were then reviewed
for inclusion. The references of the retrieved articles and
relevant reviews were also manually checked to identify
any additional eligible trials.
Studies meeting the following criteria were included: (a)
the studied population comprised infants with a gestational
age < 37 weeks or birth weight < 2500 g or both; (b) the
intervention was the administration of any species, strains,
or doses of live probiotics for more than 7 days; (c) the
comparators were placebo or no probiotics; (d) the primary
outcomes were Candida colonization (monitored by
oropharyngeal, gastric aspirate, stool, or rectal specimen
cultures) and invasive fungal sepsis (confirmed by positive
blood, urine, or cerebrospinal fluid culture); and (e) the
study design was a randomized controlled trial (RCT). We
excluded studies using interventions other than live pro-
biotics, studies in which patients were administered pro-
biotics with prebiotics or other agents, and studies
conducted on full-term infants or on children. Discrep-
ancies between the two authors (H-J H and G-Q Z)
regarding study inclusion were resolved by consensus.
2.2. Data extraction and quality assessment
The two authors (H-J H and G-Q Z) independently extracted
relevant data from each included study by using a unified
data form. The extracted data were entered into a stan-
dardized Word file (Microsoft Corporation, Redmond, WA,
USA). The items in the data form were as follows: source
(first author, year of publication, country); number of
preterm neonates enrolled; strains, doses, and duration of
probiotics administered; type of milk (i.e., human milk or
formula); and outcomes of interest (Candida colonization
Probiotics on Fungal Infection in Preterms 105

and/or fungal sepsis). To minimize the possibility of errors,

all data were compared by the same two authors, and
disagreements were resolved after further checking the
original articles. For studies containing inadequate infor-
mation, the article’s authors were contacted to obtain the
relevant data.
To measure study quality, two authors independently
assessed the following criteria using the Cochrane Risk of
Bias Tool:29 adequate sequence generation, allocation
concealment, blinding of participants and personnel,
blinding of outcome assessment, incomplete outcome data,
selective reporting, and other bias. Judgment of bias per-
taining to each item was categorized as “low risk”, “high
risk”, or “unclear risk”, based on the criteria specified in
the Cochrane handbook.29

2.3. Statistical analysis

To evaluate the effect of probiotics, we calculated the

relative risks (RRs) for the incidence of Candida coloniza-
tion and invasive fungal sepsis between the intervention
and control groups. When trials investigated two separate
probiotic groups versus a control group, data on the two
probiotic groups were combined into a single RR value,
which we included in the meta-analysis.
Heterogeneity across studies was tested by using the I2
statistic. Studies with an I2 value greater than 50% were
considered to have a significant heterogeneity.30 The Man-
teleHaenszel method with the fixed-effects or random-
effects model was used to calculate the pooled RRs and
95% confidence intervals (CIs). A sensitivity analysis was
conducted to assess the influence of individual studies on
the pooled result by excluding each study one by one, and
then recalculating the combined RRs on the remaining tri-
als. Publication bias was assessed by the Begg’s test31 and
the Egger’s tests.32 A p value < 0.05 was statistically sig-
nificant, except where otherwise specified. All statistical
analyses were performed by statistical software Stata 12.0
(Stata Corporation, College Station, TX, USA) and RevMan
5.3 (Nordic Cochrane Center, Copenhagen, Denmark).
3. Results
A total of 637 records were identified by the initial elec-
tronic literature search. One hundred and twenty-eight
records were excluded for duplication, and 478 records
were excluded based on their titles and abstracts. The
remaining 31 full-text articles were assessed for eligibility;
of these, 21 studies were excluded because the incidence
of fungal sepsis was not reported. Three trials were further
excluded owing to ineligible population33 or ineligible
intervention.34,35 Seven trials were ultimately included in
our review.36e42 The selection process is shown in Figure 1.
The characteristics of the seven trials are summarized in
Table 1. The outcome data of each included study are
presented in Table 2. The quality of the trials as assessed by
the Cochrane Risk of Bias Tool is summarized in Table 3.
The incidence of enteric colonization by Candida was
reported in two trials.37,39 The trial by Roy et al40 reported
stool fungal counts rather than the incidence of Candida
colonization. Figure 2 shows the results from each trial and
Figure 1 The selection process for the trials included in the
meta-analysis.
the overall results, using a fixed-effects model, for probiotics
in preventing Candida colonization and fungal sepsis. Our
analysis indicated that prophylactic probiotics significantly
reduced the incidence of Candida colonization (RR, 0.43;
95% CI, 0.27e0.67; p Z 0.0002; I2 Z 0%) and the risk of
developing invasive fungal sepsis (RR, 0.64; 95% CI,
0.46e0.88; p Z 0.006; I2 Z 13%). When excluding Roy et al40
from the overall analysis, the effect of probiotics on invasive
fungal sepsis became statistically insignificant (RR, 0.88; 95%
CI, 0.44e1.78; p Z 0.72; I2 Z 15%). When using the random-
effects model, the protective effect of probiotics remained
for Candida colonization (RR, 0.43; 95% CI, 0.27e0.68;
p Z 0.0002; I2 Z 0%), but not for fungal sepsis (RR, 0.64; 95%
CI, 0.38e1.08; p Z 0.10; I2 Z 13%). The meta-analysis of
probiotics on fungal sepsis showed no evidence of significant
publication bias, based on formal statistical tests (Egger’s
test: p Z 0.445; Begg’s test: p Z 0.260). None of the
included studies reported any systemic infection caused by
the supplemented probiotic organisms.
4. Discussion
Seven RCTs with 1371 preterm neonates were included in
our review. With the limited evidence available, our results
indicated that the use of probiotics could reduce the inci-
dence of Candida colonization in preterm neonates in
NICUs. There are limited data to support probiotic supple-
mentation to prevent invasive fungal sepsis in preterm
neonates. None of the included trials reported any systemic
infection caused by the supplemented probiotic organisms.
Studies in mice models have shown the efficacy of pro-
biotics in reducing the risk of enteric fungal colonization
106 H.-J. Hu et al

Table 1 Characteristics of the randomized controlled trials included in our meta-analysis.

First author, N Participants Probiotics group Type of Outcomes of
year, country Strains, doses, duration milk interest
36
Al-Hosni 101 BW 501e1000 g A mixture of L. rhamnosus FM Fungal sepsis
2012 GG and B. infantis, 1
109 (blood culture-proven)
United States CFU/d, from first enteral
feed until discharge or 34
wk corrected age
Manzoni37 80 BW <1500 g L. rhamnosus GG, 6
109 HM Candida colonization*,
2006 CFU/d, from 3rd day of life fungal sepsis (blood
Italy for 6 wk or until discharge culture-proven)
Oncel38 424 GA 32 wk and L. reuteri, 1
108 CFU/d, HM or FM Fungal sepsis (blood
2014 BW  1500 g from 1st feed until discharge culture-proven)
Turkey
Romeo39 249 GA <37 wk and L. reuteri, 1
108 CFU/d, or HM or FM Candida colonizationy,
2011 BW < 2500 g L. rhamnosus, 6
109 CFU/d, fungal sepsis (blood/urine/
Italy from first 48 h for 6 wk or until CSF culture-proven)
discharge
Roy40 112 GA <37 wk and A mixture of B. longum, B. lactis, HM Candida colonizationz,
2014 BW < 2500 g B. bifidum, and L. acidophilus, fungal sepsis (blood/urine/
India 1.5-3
109 CFU/d, from first 72 CSF culture-proven)
h for 6 wk or until discharge
Sari41 242 GA <33 wk or L. sporogenes, 3.5
108 CFU/d, HM or FM Fungal sepsis (blood
2011 BW <1500 g from first feed until discharge culture-proven)
Turkey
Hikaru42 208 BW < 1500 g B. breve, 1
109 CFU/d, from HM or FM Fungal sepsis (blood
2010 the first several hours after birth culture-proven)
Japan until discharge
B. bifidum Z Bifidobacterium bifidum; B. breve Z Bifidobacterium breve; B. infantis Z Bifidobacterium infantis; B.
lactis Z Bifidobacterium lactis; B. longum Z Bifidobacterium longum; BW Z birth weight; CFU Z colony-forming unit;
CSF Z cerebrospinal fluid; FM Z formula milk; GA Z gestational age; HM Z human milk (i.e., mother’s milk and/or donor milk); L.
acidophilus Z Lactobacillus acidophilus; L. reuteri Z Lactobacillus reuteri; L. rhamnosus Z Lactobacillus rhamnosus; L.
sporogenes Z Lactobacillus sporogenes.
* Confirmed by oropharyngeal/gastric aspirate/stool/rectal specimen cultures.
y
Confirmed by oropharyngeal/gastric aspirate/stool specimen cultures.
z
Confirmed by gastric aspirate/stool specimen cultures.

and systemic fungal infections.23e26,43,44 Two recent trials preterm neonates in NICUs.45,46 The efficacy of a mixture of
reported that prophylactic supplementation of Saccharo- species of probiotics in preventing rectal colonization by
myces boulardii or Lactobacillus reuteri was as effective as Candida was also investigated and confirmed in critically ill
nystatin in preventing fungal colonization and IFIs in children in a pediatric intensive care unit.33 Moreover,
several trials have reported that probiotics are effective in
preventing and treating vulvovaginal candidiasis.47e49 In
Table 2 The outcome data of the included studies. general, current evidence indicates that colonization by
Study (y) Candida Fungal sepsis probiotics can afford protection against the fungal prolif-
colonization eration in the gastrointestinal tract and prevent subsequent
IFIs. The plausible biological mechanisms by which pro-
Probiotics Control Probiotics Control biotics might prevent IFIs include competitively colonizing
Al-Hosni36 (2012) NR NR 2/50 0/51 the gut, competitive exclusion of fungi,25,26 augmentation
Manzoni37 (2006) 9/39 20/41 4/39 5/41 of immunoglobulin A mucosal responses,50,51 modulation of
Oncel38 (2014) NR NR 1/200 3/200 the gut barrier function and permeability,52 production of
Romeo39 (2011) 15/166 19/83 2/166 4/83 antimicrobial peptides,53 and upregulation of immune
Roy40,* (2014) NR NR 23/56 42/56 responses.54
Sari41 (2011) NR NR 3/110 1/111
Hikaru42 (2010) NR NR 1/108 0/100
4.1. Implications for practice
NR Z not reported.
* The incidence of fungal sepsis was calculated by subtracting
The results of our review provided preliminary evidence
the number of preterm neonates without fungal infection from
that probiotics may be useful in reducing enteric Candida
the total number of infants enrolled.
colonization and further preventing invasive fungal sepsis in
Probiotics on Fungal Infection in Preterms 107

Table 3 The risk of bias assessment of the included randomized controlled trials.*
Study (y) Adequate Allocation Blinding of Blinding of Incomplete Selective Other Overall risk
sequence concealment participants and outcome outcome data reporting bias of bias
generation personnel assessment
Al-Hosni36 (2012) Unclear Unclear Yes Yes No No No Unclear
Manzoni37 (2006) Yes Unclear Unclear Unclear No No No Unclear
Oncel38 (2014) Yes Yes Yes Yes No No No Low
Romeo39 (2011) Yes Unclear Unclear Unclear No No No Unclear
Roy40 (2014) Yes Unclear Yes Unclear No No No Unclear
Sari41 (2011) Yes Unclear Unclear Yes No No No Unclear
Hikaru42 (2010) Unclear Yes Yes Unclear No No No Unclear
* Risk of bias was assessed by using the Cochrane Risk of Bias Tool.

preterm neonates in NICUs. However, in clinical practice,
the common strategy of preventing fungal infection in
preterm infants is by using intravenous fluconazole or oral
nystatin. To our knowledge, only two trials compared pro-
biotics with nystatin regarding their effects on fungal
infection in preterm infants. Oncel et al45 and Demirel
et al46 consistently concluded that supplementation of
Lactobacillus reuteri or Saccharomyces boulardii was as
effective as nystatin with respect to fungal colonization
and IFIs, and more effectively reduced the incidence of
sepsis, duration of hospitalization, and feeding intolerance.
Moreover, updated meta-analyses have confirmed the effi-
cacy and safety of probiotics in preventing necrotizing
enterocolitis and late-onset sepsis in preterm neo-
nates.55,56 Because of concerns about medical costs,
tolerability, long-term safety, and emergence of resistant
strains with the use of antifungal agents, prophylactic
probiotics merit further consideration as a potential pre-
vention strategy to prevent fungal infection in preterm in-
fants. Manzoni et al37 also recommended using
combinations of antifungal drugs and probiotics in all VLBW
neonates, with greater reliance on probiotics in larger ne-
onates and less reliance in smaller neonates. Hence, this
prophylactic option could be discussed with patients or
caregivers in clinical practice. However, because of the
paucity of data comparing probiotics with fluconazole or
nystatin, head-to-head comparative studies are required to
assess the most effective preparations.
It is noteworthy that the beneficial effects of probiotics
seem to be strain-specific and the exact mechanism by which
probiotic organisms prevent fungal infection remains un-
known. Several cases of systemic infections caused by

Probiotics Control Risk ratio Risk ratio

Study or subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI

Manzoni (2006)37
Romeo (2011)39

p
p

AI-Hosni (2012)36
Manzoni (2006)37
Oncel (2014)38
Romeo (2011)39
Roy (2014)40
Sari (2011)41
Hikaru (2010)42

Figure 2 The effect of probiotic supplementation on Candida colonization and invasive fungal sepsis in preterm neonates in
neonatal intensive care units. CI, confidence interval; M-H Z ManteleHaenszel method.
108
supplemented probiotics have been reported and reviewed
elsewhere.55,56 Hence, probiotics should be prescribed with
caution. The uncertain efficacy and safety of probiotics have
restricted the clinical use of probiotics in intensive care units
(ICUs), and most ICU pharmacists would not currently
recommend probiotics for the prevention of ventilator-
associated pneumonia.57 Hence, further clinical and exper-
imental studies are strongly needed to accurately determine
suitable probiotic organisms, optimal dose, timing of
administration, duration of treatment, and safety.
4.2. Quality of evidence
A strength of our study is the completeness of the search
strategy, which reviewed multiple citation databases and
trial registries. By omitting outcome-related search terms,
we identified trials that were not primarily focused on
fungal infection, but nevertheless reported relevant out-
comes.36,38,41,42 Moreover, low heterogeneity and lack of
publication bias added robustness to our main findings.
Several limitations should be taken into consideration
when interpreting the results. First, there was no statistical
heterogeneity for the primary outcomes, although popula-
tion characteristics, probiotic regimens (i.e., various or-
ganisms, daily doses, time of initiation, and length of
intervention), and type of milk differed across the included
studies. We adopted the random-effects model to try to
account for this variability. Second, only a limited number
of trials, most of which included small sample sizes, were
available for this meta-analysis, which could lead to a
spurious result. However, one reason we conducted this
review was to increase power. Third, seven trials were
included for the outcome of invasive fungal sepsis, of which
only the trial by Roy et al40 was primarily designed to
evaluate the effect of probiotics on invasive fungal sepsis.
When excluding the Roy et al40 trial from the overall
analysis, the pooled incidence of fungal sepsis was 1.9% and
2.2% in the probiotics group and placebo group, respec-
tively. Because of the low incidence of fungal sepsis and
relatively small sample sizes, the six trials were not
adequately powered to detect the effect of probiotics on
fungal sepsis, and therefore the effect of probiotics on
fungal sepsis became statistically insignificant. The trial by
Roy et al40 had a very high incidence of fungal sepsis in their
center: 41% in the probiotics group and 75% in the placebo
group. We speculate that the reason that the effect of
probiotics on fungal sepsis reached statistical significance
in the Roy trial40 is because of the high incidence of fungal
sepsis, which resulted in sufficient power to detect bene-
ficial effects. However, this result needs to be confirmed by
further adequately powered RCTs. Fourth, the methodo-
logical quality of the included trials varied and was poor
overall with an unclear risk of selection bias and perfor-
mance bias. Both types of bias significantly increase the
likelihood that the intervention may be effective. Hence,
high-quality RCTs are warranted. Fifth, only one of the
included RCTs enrolled ELBW infants as study participants.
Our study was unable to define the effects of probiotics in
ELBW infants, who are at the greatest risk of developing
sepsis and necrotizing enterocolitis. Studies in ELBW infants
are therefore greatly needed.
H.-J. Hu et al
4.3. Conclusions
Current evidence indicates that probiotics can reduce risk
of Candida colonization in preterm neonates in NICUs.
Limited data support that probiotic supplementation pre-
vents invasive fungal sepsis in preterm neonates. This
finding largely relies on several trials of low methodological
quality (i.e., unclear risk of selection bias and performance
bias). High-quality and adequately powered RCTs are war-
ranted, especially in ELBW infants. It is too soon to
recommend its routine use in clinical practice; however,
the prophylactic option could be discussed with patients or
caregivers.
Conflicts of interest
None of the authors has any conflicts of interest to disclose
relevant to this article.
Acknowledgments
This study was supported by the Health Department of
Chongqing City Foundation (Chongqing, China; Grant No.,
2013-1-023).
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