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Pediatrics
March 2016, VOLUME 137 / ISSUE 3
Review Article

Probiotic Supplementation and Late-Onset Sepsis in Preterm Infants: A Meta-analysis

Shripada C. Rao, Gayatri K. Athalye-Jape, Girish C. Deshpande, Karen N Simmer, Sanjay K. Patole
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Abstract

CONTEXT: Late-onset sepsis (LOS) is a major cause of mortality and morbidity in preterm infants. Despite various preventive measures, its incidence continues to remain high, hence the urgent need for additional approaches. One such potential strategy is supplementation with probiotics. The updated Cochrane Review (2014) did not find benefits of probiotics in reducing the risk of LOS in preterm infants (19 studies, N = 5338). Currently there are >30 randomized controlled trials (RCTs) of probiotics in preterm infants that have reported on LOS.

OBJECTIVES: To conduct a systematic review including all relevant RCTs.

DATA SOURCES: PubMed, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature, and E-abstracts from the Pediatric Academic Society meetings and other pediatric and neonatal conference proceedings were searched in June and August 2015.

STUDY SELECTION: RCTs comparing probiotics versus placebo/no probiotic were included.

DATA EXTRACTION: Relevant data were extracted independently by 3 reviewers.

RESULTS: Pooled results from 37 RCTs (N = 9416) using fixed effects model meta analysis showed that probiotics significantly decreased the risk of LOS (675/4852 [13.9%] vs 744/4564 [16.3%]; relative risk, 0.86; 95% confidence interval, 0.78–0.94; P = .0007; I2 = 35%; number needed to treat, 44). The results were significant even after excluding studies with high risk of bias.

CONCLUSIONS: Probiotic supplementation reduces the risk of LOS in preterm infants.

  • Abbreviations:
    CFU —
    colony-forming unit
    CI —
    confidence interval
    FEM —
    fixed-effects model
    GRADE —
    Grades of Recommendation, Assessment, Development and Evaluation
    LOS —
    late-onset sepsis
    NEC —
    necrotizing enterocolitis
    RCT —
    randomized controlled trial
    REM —
    random effects model
    ROB —
    risk of bias
    RR —
    relative risk

    • Late-onset sepsis (LOS) is a major cause of mortality and morbidity, including adverse long-term neurodevelopmental outcomes in preterm infants.1–8 The burden of LOS is significant in developed2,8,9 and developing nations of the world.10–13 The incidence of LOS varies inversely with gestational age and birth weight.4 The important risk factors for LOS in preterm infants are intravascular catheters, delayed commencement of enteral feeds, prolonged use of parenteral nutrition, prolonged ventilation, and surgery.1 Although the predominant organism causing LOS is coagulase-negative staphylococci, other organisms such as Staphylococcus aureus, Gram-negative bacteria, and fungi also are important.3,9,14–17 The cost-effective strategies for preventing LOS include antimicrobial stewardship, limited steroid use, early enteral feeding, limited use of invasive devices, standardization of catheter care practices, and meticulous hand hygiene.18,19 Despite these preventive measures, the incidence of LOS remains high in preterm infants.2,3,20 Therefore, additional approaches to reduce LOS are needed urgently.8,21 One such potential strategy that might reduce LOS is supplementation with probiotics.22

    Probiotics are defined as live microorganisms that when administered in adequate amounts may confer health benefits on people with specific illnesses.23 Animal research and in vitro studies24 have shown that probiotics improve gut barrier function,25,26 inhibit gut colonization with pathogenic bacteria,27 improve colonization with healthy commensals,28,29 protect from enteropathogenic infection through production of acetate,30 enhance innate immunity,31 and increase maturation of the enteric nervous system,32 all of which have the potential to decrease the risk of LOS in preterm infants. However, the recent Cochrane Review33 (2014) concluded that probiotic supplementation did not result in statistically significant reduction of LOS in preterm infants (relative risk [RR] 0.91; 95% confidence interval [CI], 0.80–1.03; 19 studies, N = 5338). Another meta-analysis34 (2015) also reported similar results on LOS (RR, 0.919; 95% CI, 0.823–1.027; P = .137; 17 randomized controlled trials [RCTs], N = 5215).

    The meta-analyses done so far have included a maximum of 19 RCTs, whereas currently there are >30 RCTs of probiotic supplementation that have reported on LOS. Therefore, we decided to conduct a systematic review and meta-analysis to evaluate the role of probiotic supplementation in reducing the risk of LOS in preterm infants.

    Methods

    Guidelines from the Cochrane Neonatal Review Group (http://neonatal.cochrane.org/resources-review-authors),35 Centre for Reviews and Dissemination (http://www.york.ac.uk/crd/guidance/), and the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement36 were followed for undertaking and reporting this systematic review and meta-analysis. Ethics approval was not required.

    Eligibility Criteria

    Types of Studies

    Only RCTs were included in the review. Observational studies, narrative reviews, systematic reviews, case reports, letters, editorials, and commentaries were excluded but read to identify potential additional studies.

    Types of Participants

    Preterm neonates born at a gestational age <37 weeks, low birth weight (<2500 g), or both (same criteria as the Cochrane Review, 2014).

    Intervention and Comparison

    Enteral administration of probiotic supplement versus placebo or control.

    Outcomes

    LOS, defined as the presence of positive blood or cerebrospinal fluid culture on a sample collected 48 to 72 hours after birth2,8,20

    Search Strategy

    The databases PubMed (www.ncbi.nlm.nih.gov, 1966–2015), Embase (Excerpta Medica dataBASE) via Ovid (http://ovidsp.tx.ovid.com, 1980–2015), Cochrane Central Register of Controlled Trials (www.thecochranelibrary.com, through August 2015), Cumulative Index of Nursing and Allied Health Literature via Ovid (http://ovidsp.tx.ovid.com, 1980–August 2015), and E-abstracts from the Pediatric Academic Society meetings (www.abstracts2view.com/pasall, 2000–August 2015) were searched in August 2015. A similar search was also done in June 2015. Abstracts of other conference proceedings such as Perinatal Society of Australia and New Zealand, European Academy of Pediatric Societies, and the British Maternal and Fetal Medicine Society were searched in Embase. Google Scholar was searched for articles that might not have been cited in the standard medical databases. Gray literature was searched through the national technical information services (http://www.ntis.gov/), Open Grey (http://www.opengrey.eu/), and Trove (http://trove.nla.gov.au/). The reference lists of eligible studies and review articles were searched to identify additional studies. Reviewers S.C.R., G.K.A.J., and G.C.D. conducted the literature search independently. No language restriction was applied. The non-English studies were identified by reading through the recently published systematic reviews of probiotic supplementation on the incidence of necrotizing enterocolitis (NEC).37,38 Search of Embase also identified 1 non-English study. Full texts of all the non-English studies were obtained via the library of University of Sydney. A research officer from the University of Sydney translated the articles. Attempts were made to contact the authors for additional data and clarification of methods, but there was no response. Only published data were used for those studies, where available.

    We searched PubMed for the following terms: (((“Infant, Newborn”[Mesh]) OR (“Infant, Extremely Premature”[Mesh] OR “Infant, Premature”[Mesh])) OR (“Infant, Low Birth Weight”[Mesh] OR “Infant, Extremely Low Birth Weight”[Mesh] OR “Infant, Very Low Birth Weight”[Mesh])) AND “Probiotics”[Majr]. We also searched for ((“Infant, Extremely Premature”[Mesh] OR “Infant, Extremely Low Birth Weight”[Mesh] OR “Infant, Very Low Birth Weight”[Mesh] OR “Infant, Small for Gestational Age”[Mesh] OR “Infant, Premature, Diseases”[Mesh] OR “Infant, Premature”[Mesh] OR “Infant, Newborn, Diseases”[Mesh] OR “Infant, Newborn”[Mesh] OR “Infant, Low Birth Weight”[Mesh])) AND (“Bifidobacterium”[Mesh]) OR (“Lactobacillus”[Mesh]) OR “Saccharomyces”[Mesh]))). The other databases were searched for similar terms.

    Study Selection

    Abstracts of the citations obtained from the initial broad search were read independently by 3 reviewers (S.C.R., G.K.A.J., and G.C.D.) to identify potentially eligible studies. Full-text articles of these studies were obtained and assessed for eligibility by 3 reviewers independently (S.C.R., G.K.A.J., and G.C.D.), under the predefined eligibility criteria. Differences in opinion were resolved by group discussion among all reviewers to reach consensus. Care was taken to ensure that multiple publications of the same study were identified and excluded to avoid duplication of the data.

    Data Extraction

    Reviewers S.C.R., G.K.A.J., and G.C.D. extracted the data independently by using a data collection form designed for this review. The number of patients with LOS and the number of patients analyzed in each treatment group of each trial were entered into the form. Information about the study design and outcomes was verified by all reviewers. Discrepancies during the data extraction process were resolved by discussion and consensus among all reviewers. We contacted authors for additional information and clarifications when details on LOS were not available in published manuscripts. Such studies were excluded if there was no response from the authors.

    Assessment of Risk of Bias

    We assessed risk of bias (ROB) by using the Cochrane “Risk of Bias Assessment Tool.”35 Authors S.C.R. and G.K.A.J. independently assessed the ROB in all domains including random number generation, allocation concealment, blinding of intervention and outcome assessors, completeness of follow-up, selectivity of reporting, and other potential sources of bias. For each domain, the ROB was assessed as low, high, or unclear risk based on the Cochrane Collaboration guidelines.

    Data Synthesis

    Meta-analysis was conducted in Review Manager 5.3 (Cochrane Collaboration, Nordic Cochrane Centre, Copenhagen, Denmark). A fixed-effects model (FEM) (Mantel–Haenszel method) was used. However, analysis using random effects model (REM) was also conducted to ensure that the results and conclusions were not influenced by the type of model used for the meta-analysis. Effect size was expressed as RR and 95% CI.

    Statistical heterogeneity was assessed with the χ2 test and I2 statistic and by visual inspection of the forest plot (overlap of CIs). A P value <.1 on the χ2 statistic was considered to indicate heterogeneity. I2 statistic values were interpreted according to the guidelines of Cochrane Handbook as follows: 0% to 40%, might not be important; 30% to 60%, may represent moderate heterogeneity; 50% to 90%, may represent substantial heterogeneity; 75% to 100%, considerable heterogeneity.35 The risk of publication bias was assessed by visual inspection of the funnel plot.39

    Subgroup Analysis

    Infants <28 weeks’ gestation or <1000 g.

    Sensitivity Analysis

    Considering the importance of random sequence generation and allocation concealment in RCTs,40 we conducted sensitivity analyses by excluding studies that had high ROB in these 2 domains separately. Because the risk of LOS is higher in infants born at <32 weeks or <1500 g,3,4 we conducted sensitivity analysis by excluding RCTs where the inclusion criteria were ≥32 weeks or ≥1500 g.

    Similar analyses were also conducted for studies where Bifidobacterium was or was not part of the supplement and studies where Lactobacillus was or was not part of the supplement, given the importance of these microorganisms in the neonatal gut flora.41

    There is some evidence that multistrain probiotics may be more effective than single strains.42 We therefore conducted analyses separately for studies that used single-strain supplements and multistrain probiotics. Lastly, we also conducted analyses separately for studies where LOS was the primary outcome of interest.

    Summary of Findings Table

    The key information about the quality of evidence, the magnitude of effect of the intervention, and the sum of available data on the main outcome was presented in the summary of findings table according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) guidelines.43

    Results

    The literature search retrieved 1736 potential relevant citations, of which 1685 were excluded and 51 RCTs were considered eligible for inclusion. Finally, 37 RCTs were included in the systematic review and meta-analysis.44–80 The remaining 14 studies had to be excluded because of lack of information from the published manuscripts.81–94 The flow diagram of the study selection process is given in Fig 1.

    FIGURE 1
    FIGURE 1

    Flow diagram of search strategy and study selection. PAS, Pediatric Academic Societies meeting.

    Out of the 37 included studies, LOS was the primary outcome of interest in only 9 studies, whereas in the remaining 28 it was a secondary outcome. Single-strain probiotics were used in 23 studies, whereas 14 used multiple strains. Lactobacillus was part of the supplementation in 21 studies; Bifidobacterium was part of the supplementation in 22 studies. The detailed characteristics of the included studies including the dose and duration of supplementation are given in Table 1.

    View this table:
    TABLE 1

    Characteristics of the Included Studies

    ROB of Included Studies

    Of the 37 included studies, 28 (76%) were judged to have low ROB for the domain of “random sequence generation,” and 24 (65%) were considered to have low ROB for “allocation concealment.” Details of the ROB analysis are given in Table 2.

    View this table:
    TABLE 2

    Assessment of the ROB of Included RCTs

    Outcome of Interest

    The pooled meta-analysis (FEM) of 37 RCTs (n = 9416) that compared “probiotics” with “placebo” or “no probiotics” showed that probiotic supplementation resulted in a statistically significant reduction in the incidence of LOS (675/4852 [13.9%] vs 744/4564 [16.3%]; RR 0.86; 95% CI, 0.78–0.94; P = .0007; χ2 statistic for heterogeneity P = .02; I2 = 35%; number needed to treat, 44) (Fig 2). The results were significant even when REM was used (RR 0.85; 95% CI, 0.75–0.95, P = .007; χ2 statistic for heterogeneity P = .02, I2 = 35%). Visual inspection of the funnel plot suggested that there was no publication bias (Fig 3).

    FIGURE 2
    FIGURE 2

    Forest plot: Probiotic supplementation to reduce LOS in preterm infants. M-H, Mantel–Haenszel.

    FIGURE 3
    FIGURE 3

    Funnel plot assessing publication bias.

    On sensitivity analysis (Table 3), the beneficial effects continued to be observed in studies that had low ROB for random sequence generation and also for allocation concealment. The results were also significant in studies that included only infants with gestational age <32 weeks or birth weight<1500 g (24 studies, sample size 7175), studies where Bifidobacterium was part of the supplementation (22 studies, sample size 6069), studies where Lactobacillus was part of the supplementation (21 studies, sample size 4608), studies where single-strain probiotics were used (23 studies, sample size 5961), and studies where multiple-strain supplements were used (14 studies, sample size 3455); however, on REM, statistical significance was lost for many of these analyses. The overall evidence according to GRADE guidelines is provided as a summary of findings table (Table 4).

    View this table:
    TABLE 3

    Results of the Sensitivity Analyses

    View this table:
    TABLE 4

    Summary of Findings According to GRADE Guidelines43

    Subgroup analysis of infants born at <28 weeks’ gestation or <1000 g revealed no significant benefits of probiotic supplementation in reducing LOS (Fig 4).

    FIGURE 4
    FIGURE 4

    Probiotic supplementation in infants born at <28 weeks or <1000 g. M-H, Mantel–Haenszel.

    Discussion

    Our systematic review of 37 RCTs (N = 9416) showed that probiotic supplementation leads to a statistically significant decrease in the risk of LOS in preterm infants born at <37 weeks or <2500 g. To our knowledge, this is the largest meta-analysis of probiotic supplementation in preterm neonates (4078 more than the previous ones). It is also the largest meta-analysis of RCTs for any intervention in neonatal medicine so far.

    Our results are in contrast to those of the latest meta-analyses33,34 (Alfaleh 2014 Cochrane review, 19 studies, N = 5338; Lau 2015, 17 studies, N = 5215) that did not find statistically significant benefit of probiotic supplementation in reducing LOS in preterm infants. The most likely reason for the difference between our meta-analysis and the previous ones is the sample size. The latest Cochrane Review33 found a “trend” toward reduction in LOS with probiotic supplementation (RR 0.91; 95% CI, 0.80–1.03), but probably the sample size was inadequate to detect a small but significant beneficial effect. Our systematic review has 4078 more preterm infants than the previous ones.33,34

    Our results are also in contrast to the recently concluded 2 large multicenter trials (ProPrems,68 N = 1099; PiPS,67 N = 1310). In the ProPrems trial, there was significant decrease in LOS in infants born at ≥28 weeks’ gestation (probiotics, 5.5%; placebo, 10.8%; P = .01); however, in the overall group born at <32 weeks’ gestation, there was no such benefit (probiotics, 13.1%; placebo, 16.2%; RR 0.81; 95% CI, 0.61–1.08; P = .16). The probable reason for nonsignificant results is the small sample size, because to detect a statistically significant benefit for an RR reduction of 20%, a sample size of ∼4500 (2250 in each arm) would be needed. The PiPS trial (of infants born at <31 weeks) also found no significant reduction in LOS in the probiotic group compared with the placebo group (11.2% vs 11.7%; adjusted RR 0.97; 95% CI, 0.73–1.29).67 The ProPrems trial used a multistrain probiotic supplement at a dosage of 1.0 × 109 colony-forming units (1 billion CFUs), whereas the PiPS trial used a single-strain probiotic at a dosage of 2.1 to 5.3 × 108 CFUs (0.2–0.53 billion CFUs) daily.

    In our review, it was reassuring to note that for the main analysis of LOS in preterm infants, the benefits continued to remain significant even when REM was used (FEM P = .0007; REM P = .007). However, for many of the sensitivity analyses, statistical significance was lost when REM was used (Table 3). There is ongoing debate about the pros and cons of FEM and REM.95–98 In a detailed analysis of the Cochrane Reviews in perinatal medicine, Villar et al95 found that the REM estimates showed wider CIs, particularly in those meta-analyses showing heterogeneity in the trial results. Schmidt et al98 compared the results of 68 meta-analyses in psychological medicine using REM and FEM. They reported that the published FE CIs around mean effect sizes were on average 52% narrower than their actual width, compared with the REM methods. They concluded that because most meta-analyses in the literature use FEM, the precision of findings in the literature has often been substantially overstated, with important consequences for research and practice. The Cochrane Neonatal Review Group recommends the use of FEM (http://neonatal.cochrane.org/resources-review-authors, accessed August 10, 2015). Considering these issues, it is prudent to check the results with both FEM and REM to increase their reliability.

    We conducted sensitivity analysis after excluding RCTs with high ROB because such studies are known to overestimate the effect size (by up to 30%),40 which can lead to spuriously optimistic results. It was reassuring to note that the results were significant with both FEM and REM even after we excluded studies that had high ROB on random sequence generation and allocation concealment separately.

    Subgroup analysis of extremely preterm infants (born at <28 weeks’ gestation or <1000 g) revealed no significant benefits of probiotic supplementation in reducing LOS, but the sample size was small. On the other hand, sensitivity analysis of 24 studies (n = 7175) where the inclusion criteria were more mature preterm infants (born at <32 weeks or <1500 g) found probiotic supplementation to be beneficial in reducing LOS (FEM RR 0.88; 95% CI, 0.80–0.98, P = .02; REM RR 0.89; 95% CI, 0.79–1.00; P = .06). Unlike the NICUs of the developed world, where the focus of attention is extremely preterm infants (born at <28 weeks or <1000 g), the majority of NICUs around the world cater to the needs of more mature infants (born at <32 weeks or <1500 g). Therefore, the positive results of probiotic supplementation for more mature infants could have global implications.

    The main strength of our systematic review is the large sample size and its exclusive focus on LOS (unlike the previous meta-analyses where the main attention was on NEC).

    The limitations of our systematic review include the fact that LOS was a secondary outcome of interest in majority of the studies, we lacked information from 14 RCTs, and minimal information was available on extremely preterm or extremely low birth weight infants. Another limitation was the fact that we could not objectively assess the effect of variables such as dosage and duration of supplementation on LOS in this review. These highly important questions are best addressed by head-to-head comparisons of different doses or durations in future RCTs.

    Now that our meta-analysis has shown that probiotic supplementation results in statistically significant benefits in reducing LOS, it is up to the individual units and clinicians to decide whether a 14% RR reduction or an absolute risk reduction of 2.4% is enough to warrant routine supplementation. If the evidence is considered sufficient, this intervention can be adopted after the safety and quality of the probiotic product are ensured.99,100

    If clinicians and researchers are not convinced that the evidence is strong enough, the other option is to conduct a multicenter RCT. If one were to do a megatrial, to detect a statistically significant difference of ∼14% RR reduction in the incidence of LOS (from 16.3% to 13.9%), with a power of 80% and an α error of 0.05, a sample size of ∼7152 preterm infants born at <37 weeks (3576 in each group) would be needed. To our knowledge, trials involving such large sample size have not been conducted in neonatal medicine so far. For the extremely preterm infants, the incidence of LOS is higher, and therefore the necessary sample size will be lower (to show a reduction in the incidence from 21% in the placebo to 17% in the probiotic group [20% RR reduction], with a power of 80% and an α error of 0.05, the total sample size needed is ∼3000). Because the number of extremely preterm infants is also low, such an RCT will also need multicenter coordination.

    Conclusions

    Given the serious consequences of LOS in preterm infants, we believe that a strategy that has been shown by this largest neonatal meta-analysis to date is worth consideration by health care policymakers, clinicians, and, most importantly, the parents of preterm infants. Another important factor that must be considered is the fact that probiotic supplementation has been shown to reduce the risk of NEC in preterm infants.33,34,68,101–103 If a simple intervention such as probiotic supplementation can reduce the risk of 2 of the most devastating conditions that affect preterm infants, it is worth paying attention.

    Acknowledgments

    We thank Mr Alexander Wong (NICU research officer at Nepean Hospital, NSW) for helping with translation of manuscripts in Chinese language.

    Footnotes

      • Accepted November 23, 2015.
    • Address correspondence to Shripada C. Rao, DM, FRACP, Neonatal ICU, Princess Margaret Hospital for Children, Roberts Road, Subiaco, WA, 6008, Australia. E-mail: shripada.rao{at}health.wa.gov.au

    • FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

    • FUNDING: No external funding.

    • POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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    Probiotic Supplementation and Late-Onset Sepsis in Preterm Infants: A Meta-analysis
    Shripada C. Rao, Gayatri K. Athalye-Jape, Girish C. Deshpande, Karen N Simmer, Sanjay K. Patole
    Pediatrics Mar 2016, 137 (3) e20153684; DOI: 10.1542/peds.2015-3684
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