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Probiotics Prevent Candida Colonization and Invasive Fungal Sepsis in Preterm Neonates: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
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
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
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
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
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.
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
To investigate whether probiotic supplementation could reduce the risk of fungal infection in preterm neonates in neonatal intensive care units (NICUs), we systematically searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials databases for randomized controlled trials (RCTs) focusing on the effect of probiotics on fungal infection in preterm neonates. The outcomes of interest were Candida colonization and invasive fungal sepsis. 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 = 329; relative risk (RR), 0.43; 95% confidence interval (CI), 0.27–0.67; p = 0.0002; I2 = 0%), and invasive fungal sepsis (7 RCTs, n = 1371; RR, 0.64; 95% CI, 0.46–0.88; p = 0.006; I2 = 13%). After excluding one study with a high baseline incidence (75%) of fungal sepsis, the effect of probiotics on invasive fungal sepsis became statistically insignificant (RR, 0.88; 95% CI, 0.44–1.78; p = 0.72; I2 = 15%). When using the random-effects model, the effect of probiotics remained favorable for Candida colonization (RR, 0.43; 95% CI 0.27–0.68; p = 0.0002; I2 = 0%) but not for fungal sepsis (RR, 0.64; 95% CI 0.38–1.08; p = 0.10; I2 = 13%). Current evidence indicates that probiotics can reduce the risk of Candida colonization in preterm neonates in NICUs. Limited data support that probiotic supplementation prevents invasive fungal sepsis in preterm neonates. High-quality and adequately powered RCTs are warranted.
Prevalence of Candida colonization in preterm newborns and VLBW in neonatal intensive care unit: role of maternal colonization as a risk factor in transmission of disease.
Neonatal IFIs are associated with an increased length of hospital stay, high morbidity and mortality, and neurodevelopmental impairment, which impact the survival of preterm infants.
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 procedures, administration of broad-spectrum antimicrobial drugs, and exposure to the hospital milieu which leads to gastrointestinal colonization with fungi.
Fungal colonization is associated with an increased risk of developing IFIs, and enteric colonization by Candida is the most important predictor of IFIs.
An association between anatomic site of Candida colonization and risk of invasive candidiasis exists also in preterm neonates in neonatal intensive care unit.
Clinical characteristics and response to prophylactic fluconazole of preterm VLBW neonates with baseline and acquired fungal colonisation in NICU: data from a multicentre RCT.
Despite the effective use of antifungal agents for prophylaxis, concerns 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.
Joint FAO-WHO Working Group Report on Drafting Guidelines for the Evaluation of Probiotics in Food. Guidelines for the evaluation of probiotics in food: report of a Joint FAO/WHO working group on drafting guidelines for the evaluation of probiotics in food, London, Ontario, Canada, April 30 and May 1, 2002. Available at ftp://ftp.fao.org/es/esn/food/wgreport2.pdf. [Accessed September 17, 2016].
However, studies of preterm neonates—the most vulnerable patient group cared for in NICUs—are surprisingly scant and controversial. 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 evidence, 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,
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
We searched PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases for 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 European 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”, “Lactococcus”, “LBW”, “low birth weight”, “preterm”, “premature”, “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 probiotics, studies in which patients were administered probiotics with prebiotics or other agents, and studies conducted on full-term infants or on children. Discrepancies 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 standardized 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 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 information, 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:
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 pertaining to each item was categorized as “low risk”, “high risk”, or “unclear risk”, based on the criteria specified in the Cochrane handbook.
To evaluate the effect of probiotics, we calculated the relative risks (RRs) for the incidence of Candida colonization 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.
The Mantel–Haenszel 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 trials. Publication bias was assessed by the Begg's test
A p value < 0.05 was statistically significant, 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 electronic 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 population
Oral supplementation with Lactobacillus casei subspecies rhamnosus prevents enteric colonization by Candida species in preterm neonates: a randomized study.
Role of probiotics in the prevention of the enteric colonization by Candida in preterm newborns: incidence of late-onset sepsis and neurological outcome.
Role of enteric supplementation of probiotics on late-onset sepsis by Candida species in preterm low birth weight neonates: a randomized, double blind, placebo-controlled trial.
Oral probiotics: Lactobacillus sporogenes for prevention of necrotizing enterocolitis in very low-birth weight infants: a randomized, controlled trial.
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.
Figure 1The selection process for the trials included in the meta-analysis.
Oral supplementation with Lactobacillus casei subspecies rhamnosus prevents enteric colonization by Candida species in preterm neonates: a randomized study.
Role of probiotics in the prevention of the enteric colonization by Candida in preterm newborns: incidence of late-onset sepsis and neurological outcome.
Role of enteric supplementation of probiotics on late-onset sepsis by Candida species in preterm low birth weight neonates: a randomized, double blind, placebo-controlled trial.
Oral probiotics: Lactobacillus sporogenes for prevention of necrotizing enterocolitis in very low-birth weight infants: a randomized, controlled trial.
Oral supplementation with Lactobacillus casei subspecies rhamnosus prevents enteric colonization by Candida species in preterm neonates: a randomized study.
Role of probiotics in the prevention of the enteric colonization by Candida in preterm newborns: incidence of late-onset sepsis and neurological outcome.
Role of enteric supplementation of probiotics on late-onset sepsis by Candida species in preterm low birth weight neonates: a randomized, double blind, placebo-controlled trial.
The incidence of fungal sepsis was calculated by subtracting the number of preterm neonates without fungal infection from the total number of infants enrolled.
Oral probiotics: Lactobacillus sporogenes for prevention of necrotizing enterocolitis in very low-birth weight infants: a randomized, controlled trial.
∗ The incidence of fungal sepsis was calculated by subtracting the number of preterm neonates without fungal infection from the total number of infants enrolled.
Oral supplementation with Lactobacillus casei subspecies rhamnosus prevents enteric colonization by Candida species in preterm neonates: a randomized study.
Role of probiotics in the prevention of the enteric colonization by Candida in preterm newborns: incidence of late-onset sepsis and neurological outcome.
Role of enteric supplementation of probiotics on late-onset sepsis by Candida species in preterm low birth weight neonates: a randomized, double blind, placebo-controlled trial.
Oral probiotics: Lactobacillus sporogenes for prevention of necrotizing enterocolitis in very low-birth weight infants: a randomized, controlled trial.
Oral supplementation with Lactobacillus casei subspecies rhamnosus prevents enteric colonization by Candida species in preterm neonates: a randomized study.
Role of probiotics in the prevention of the enteric colonization by Candida in preterm newborns: incidence of late-onset sepsis and neurological outcome.
Role of enteric supplementation of probiotics on late-onset sepsis by Candida species in preterm low birth weight neonates: a randomized, double blind, placebo-controlled trial.
reported stool fungal counts rather than the incidence of Candida colonization. Figure 2 shows the results from each trial and 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, 0.27–0.67; p = 0.0002; I2 = 0%) and the risk of developing invasive fungal sepsis (RR, 0.64; 95% CI, 0.46–0.88; p = 0.006; I2 = 13%). When excluding Roy et al
Role of enteric supplementation of probiotics on late-onset sepsis by Candida species in preterm low birth weight neonates: a randomized, double blind, placebo-controlled trial.
from the overall analysis, the effect of probiotics on invasive fungal sepsis became statistically insignificant (RR, 0.88; 95% CI, 0.44–1.78; p = 0.72; I2 = 15%). When using the random-effects model, the protective effect of probiotics remained for Candida colonization (RR, 0.43; 95% CI, 0.27–0.68; p = 0.0002; I2 = 0%), but not for fungal sepsis (RR, 0.64; 95% CI, 0.38–1.08; p = 0.10; I2 = 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 = 0.445; Begg's test: p = 0.260). None of the included studies reported any systemic infection caused by the supplemented probiotic organisms.
Figure 2The effect of probiotic supplementation on Candida colonization and invasive fungal sepsis in preterm neonates in neonatal intensive care units. CI, confidence interval; M-H = Mantel–Haenszel method.
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 incidence of Candida colonization in preterm neonates in NICUs. There are limited data to support probiotic supplementation 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 probiotics in reducing the risk of enteric fungal colonization and systemic fungal infections.
Two recent trials reported that prophylactic supplementation of Saccharomyces boulardii or Lactobacillus reuteri was as effective as nystatin in preventing fungal colonization and IFIs in preterm neonates in NICUs.
The efficacy of a mixture of species of probiotics in preventing rectal colonization by Candida was also investigated and confirmed in critically ill children in a pediatric intensive care unit.
Can Lactobacillus fermentum LF10 and Lactobacillus acidophilus LA02 in a slow-release vaginal product be useful for prevention of recurrent vulvovaginal candidiasis?: a clinical study.
Lactic acid bacteria colonization and clinical outcome after probiotic supplementation in conventionally treated bacterial vaginosis and vulvovaginal candidiasis.
In general, current evidence indicates that colonization by probiotics can afford protection against the fungal proliferation in the gastrointestinal tract and prevent subsequent IFIs. The plausible biological mechanisms by which probiotics might prevent IFIs include competitively colonizing the gut, competitive exclusion of fungi,
A fermented formula in preterm infants: clinical tolerance, gut microbiota, down-regulation of faecal calprotectin and up-regulation of faecal secretory IgA.
Importance of intestinal colonisation in the maturation of humoral immunity in early infancy: a prospective follow up study of healthy infants aged 0–6 months.
The results of our review provided preliminary evidence that probiotics may be useful in reducing enteric Candida colonization and further preventing invasive fungal sepsis in 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 probiotics with nystatin regarding their effects on fungal infection in preterm infants. Oncel et al
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 efficacy and safety of probiotics in preventing necrotizing enterocolitis and late-onset sepsis in preterm neonates.
Probiotics for preventing late-onset sepsis in preterm neonates: a PRISMA-compliant systematic review and meta-analysis of randomized controlled trials.
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 prevention strategy to prevent fungal infection in preterm infants. Manzoni et al
Oral supplementation with Lactobacillus casei subspecies rhamnosus prevents enteric colonization by Candida species in preterm neonates: a randomized study.
also recommended using combinations of antifungal drugs and probiotics in all VLBW neonates, with greater reliance on probiotics in larger neonates 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 unknown. Several cases of systemic infections caused by supplemented probiotics have been reported and reviewed elsewhere.
Probiotics for preventing late-onset sepsis in preterm neonates: a PRISMA-compliant systematic review and meta-analysis of randomized controlled trials.
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.
Hence, further clinical and experimental 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 outcomes.
Oral probiotics: Lactobacillus sporogenes for prevention of necrotizing enterocolitis in very low-birth weight infants: a randomized, controlled trial.
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 population characteristics, probiotic regimens (i.e., various organisms, 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 al
Role of enteric supplementation of probiotics on late-onset sepsis by Candida species in preterm low birth weight neonates: a randomized, double blind, placebo-controlled trial.
Role of enteric supplementation of probiotics on late-onset sepsis by Candida species in preterm low birth weight neonates: a randomized, double blind, placebo-controlled trial.
trial from the overall analysis, the pooled incidence of fungal sepsis was 1.9% and 2.2% in the probiotics group and placebo group, respectively. 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 al
Role of enteric supplementation of probiotics on late-onset sepsis by Candida species in preterm low birth weight neonates: a randomized, double blind, placebo-controlled trial.
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 trial
Role of enteric supplementation of probiotics on late-onset sepsis by Candida species in preterm low birth weight neonates: a randomized, double blind, placebo-controlled trial.
is because of the high incidence of fungal sepsis, which resulted in sufficient power to detect beneficial effects. However, this result needs to be confirmed by further adequately powered RCTs. Fourth, the methodological quality of the included trials varied and was poor overall with an unclear risk of selection bias and performance 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.
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 prevents 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 warranted, 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).
References
Manzoni P.
Use of Lactobacillus casei subspecies rhamnosus GG and gastrointestinal colonization by Candida species in preterm neonates.
Prevalence of Candida colonization in preterm newborns and VLBW in neonatal intensive care unit: role of maternal colonization as a risk factor in transmission of disease.
An association between anatomic site of Candida colonization and risk of invasive candidiasis exists also in preterm neonates in neonatal intensive care unit.
Clinical characteristics and response to prophylactic fluconazole of preterm VLBW neonates with baseline and acquired fungal colonisation in NICU: data from a multicentre RCT.
Joint FAO-WHO Working Group Report on Drafting Guidelines for the Evaluation of Probiotics in Food. Guidelines for the evaluation of probiotics in food: report of a Joint FAO/WHO working group on drafting guidelines for the evaluation of probiotics in food, London, Ontario, Canada, April 30 and May 1, 2002. Available at ftp://ftp.fao.org/es/esn/food/wgreport2.pdf. [Accessed September 17, 2016].
The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
Oral supplementation with Lactobacillus casei subspecies rhamnosus prevents enteric colonization by Candida species in preterm neonates: a randomized study.
Role of probiotics in the prevention of the enteric colonization by Candida in preterm newborns: incidence of late-onset sepsis and neurological outcome.
Role of enteric supplementation of probiotics on late-onset sepsis by Candida species in preterm low birth weight neonates: a randomized, double blind, placebo-controlled trial.
Oral probiotics: Lactobacillus sporogenes for prevention of necrotizing enterocolitis in very low-birth weight infants: a randomized, controlled trial.
Can Lactobacillus fermentum LF10 and Lactobacillus acidophilus LA02 in a slow-release vaginal product be useful for prevention of recurrent vulvovaginal candidiasis?: a clinical study.
Lactic acid bacteria colonization and clinical outcome after probiotic supplementation in conventionally treated bacterial vaginosis and vulvovaginal candidiasis.
A fermented formula in preterm infants: clinical tolerance, gut microbiota, down-regulation of faecal calprotectin and up-regulation of faecal secretory IgA.
Importance of intestinal colonisation in the maturation of humoral immunity in early infancy: a prospective follow up study of healthy infants aged 0–6 months.
Probiotics for preventing late-onset sepsis in preterm neonates: a PRISMA-compliant systematic review and meta-analysis of randomized controlled trials.
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