Home > Health & Research > Health Education Campaigns & Programs > Cochrane Neonatal Review > Probiotics for prevention of necrotizing enterocolitis in preterm infants

Probiotics for prevention of necrotizing enterocolitis in preterm infants

Skip sharing on social media links
Share this:

Authors

Khalid AlFaleh1, Jasim Anabrees2, Dirk Bassler3, Turki Al-Kharfi4

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Department of Pediatrics (Division of Neonatology), King Saud University, Riyadh, Saudi Arabia [top]
2Neonatal Intensive Care, Dr Sulaiman Al Habib Medical Group, Riyadh, Saudi Arabia [top]
3Department of Neonatology, University Children's Hospital, Tuebingen, Germany [top]
4Department of Pediatrics (Division of Neonatology), King Saud University, King Khalid University Hospital and College of Medicine, Riyadh, Saudi Arabia [top]

Citation example: AlFaleh K, Anabrees J, Bassler D, Al-Kharfi T. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No.: CD005496. DOI: 10.1002/14651858.CD005496.pub3.

Contact person

Khalid AlFaleh

Department of Pediatrics (Division of Neonatology)
King Saud University
King Khalid University Hospital and College of Medicine
Department of Pediatrics (39), P.O. Box 2925
11461 Riyadh
Saudi Arabia

E-mail: kfaleh@ksu.edu.sa
E-mail 2: kmfaleh@hotmail.com

Dates

Assessed as Up-to-date: 03 November 2010
Date of Search: 15 October 2010
Next Stage Expected: 03 November 2012
Protocol First Published: Issue 4, 2005
Review First Published: Issue 1, 2008
Last Citation Issue: Issue 3, 2011

What's new

Date / Event Description
03 November 2010
Updated

This updates the review "Probiotics for prevention of necrotizing enterocolitis in preterm infants" published in the Cochrane Database of Systematic Reviews (Al Faleh 2008).

New authorship: Khalid AlFaleh, Jasim Anabrees, Dirk Bassler, Turki Al-Kharfi.

Updated search identified seven new trials for inclusion in this review update.

03 November 2010
New citation: conclusions changed

With the addition of seven new trials to this update, it brings the total to sixteen eligible trials randomizing 2842 infants. The previous review included nine eligible trials, randomizing 1425 infants.

History

Date / Event Description
12 November 2008
Feedback incorporated

Feedback incorporated

22 July 2008
Amended

Converted to new review format.

Abstract

Background

Necrotizing enterocolitis (NEC) and nosocomial sepsis are associated with increased morbidity and mortality in preterm infants. Through prevention of bacterial migration across the mucosa, competitive exclusion of pathogenic bacteria, and enhancing the immune responses of the host, prophylactic enteral probiotics (live microbial supplements) may play a role in reducing NEC and associated morbidity.

Objectives

To compare the efficacy and safety of prophylactic enteral probiotics administration versus placebo or no treatment in the prevention of severe NEC and/or sepsis in preterm infants.

Search methods

For this update, searches were made of MEDLINE (1966 to October 2010), EMBASE (1980 to October 2010), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2010), and abstracts of annual meetings of the Society for Pediatric Research (1995 to 2010).

Selection criteria

Only randomized or quasi-randomized controlled trials that enrolled preterm infants < 37 weeks gestational age and/or < 2500 g birth weight were considered. Trials were included if they involved enteral administration of any live microbial supplement (probiotics) and measured at least one prespecified clinical outcome.

Data collection and analysis

Standard methods of the Cochrane Collaboration and its Neonatal Group were used to assess the methodologic quality of the trials, data collection and analysis.

Results

Sixteen eligible trials randomizing 2842 infants were included. Included trials were highly variable with regard to enrollment criteria (i.e. birth weight and gestational age), baseline risk of NEC in the control groups, timing, dose, formulation of the probiotics, and feeding regimens. Data regarding extremely low birth weight infants (ELBW) could not be extrapolated. In a meta-analysis of trial data, enteral probiotics supplementation significantly reduced the incidence of severe NEC (stage II or more) (typical RR 0.35, 95% CI 0.24 to 0.52) and mortality (typical RR 0.40, 95% CI 0.27 to 0.60). There was no evidence of significant reduction of nosocomial sepsis (typical RR 0.90, 95% CI 0.76 to 1.07). The included trials reported no systemic infection with the probiotics supplemental organism. The statistical test of heterogeneity for NEC, mortality and sepsis was insignificant.

Authors' conclusions

Enteral supplementation of probiotics prevents severe NEC and all cause mortality in preterm infants. Our updated review of available evidence supports a change in practice. More studies are needed to assess efficacy in ELBW infants and assess the most effective formulation and dose to be utilized.

Plain language summary

Probiotics for prevention of necrotizing enterocolitis in preterm infants

Necrotizing enterocolitis (NEC) is a serious disease that affects the bowel of premature infants in the first few weeks of life. Although the cause of NEC is not entirely known, milk feeding and bacterial growth play a role. Probiotics (dietary supplements containing potentially beneficial bacteria or yeast) have been used to prevent NEC. Our review of studies found that the use of probiotics reduces the occurrence of NEC and death in premature infants born less than 1500 grams. There is insufficient data with regard to the benefits and potential adverse effects in the most at risk infants less than 1000 grams at birth.

[top]

Background

Description of the condition

Necrotizing enterocolitis (NEC) is the most common serious acquired disease of the gastrointestinal tract in preterm infants (Lee 2003). It is characterized by bowel wall necrosis of various length and depth. Bowel perforation occurs in one third of the affected infants (Kafetzis 2003). Although 5 to 25% of cases occur in term infants, it is primarily a disease of preterm infants, with the majority of cases occurring in very low birth weight infants (infants with birth weight < 1500 g) (Kosloske 1994). NEC is categorized into three different stages, with clinical symptoms varying from feeding intolerance to severe cardiovascular compromise, coagulopathy, and peritonitis with or without pneumoperitoneum (Bell 1978). The incidence of NEC varies among countries and neonatal centers. It has been reported to affect up to 10% of very low birth weight infants (VLBW) (Kosloske 1994).

The pathogenesis of NEC remains incompletely understood. NEC most likely represents a complex interaction of factors causing mucosal injury (Neu 1996). It is speculated that NEC occurs with the coincidence of two of the following three pathologic events; intestinal ischemia, colonization of the intestine by pathologic bacteria, and excess protein substrate in the intestinal lumen (Kosloske 1984; La Gamma 1994). Bacterial colonization is necessary for the development of NEC (Kosloske 1990; Musemeche 1986). When compared to term infants, VLBW infants at risk of NEC have abnormal fecal colonization, demonstrate a paucity of normal enteric bacterial species, and have delayed onset of bacterial colonization (Goldmann 1978; Gewolb 1999).
Nosocomial infection is also a frequent complication in VLBW infants. Data from the NICHD Network demonstrated that as many as 25% of these infants have at least one or more positive blood cultures, and 5% have positive cerebrospinal fluid cultures over the course of their hospitalization (Stoll 1996). Late onset sepsis is associated with an increased risk of death, neonatal morbidity and prolonged hospitalization (Stoll 2002a; Stoll 2002b).

Description of the intervention

Probiotic bacteria are live microbial supplements that colonize the gastrointestinal tract and potentially provide benefit to the host (Millar 2003). The most frequently used probiotics are lactobacillus and bifidobacterium. There is increasing interest in the potential health benefits of proactive colonization of the gastrointestinal tract of preterm infants (Millar 2003).

How the intervention might work

Potential mechanisms by which probiotics may protect high risk infants from developing NEC and/or sepsis include increased barrier to migration bacteria and their products across the mucosa (Orrhage 1999; Mattar 2001), competitive exclusion of potential pathogens (Reid 2001), modification of host response to microbial products (Duffy 2000), augmentation of IGA mucosal responses, enhancement of enteral nutrition that inhibit the growth of pathogens, and up-regulation of immune responses (Link-Amster 1994).

Why it is important to do this review

VLBW infants with NEC have a mortality rate up to 20% (Caplan 2001; Holman 1997). Approximately 27 to 63% of affected infants require surgical intervention (Lee 2003). Strictures, primarily in the colon, occur in more than one third of affected infants (Ricketts 1994). Increased rate of total parenteral nutrition (TPN) related complications and extended hospitalization have been reported (Bisquera 2002). Recent data from the National Institute of Child Health and Human Development Network (NICHD) suggest an increase in neurodevelopmental impairment rates among infants with NEC and sepsis (Stoll 2004). There is a theoretical risk of bacteremia secondary to enterally administered probiotics strains, though few data support this concern. Bacillus species administered as probiotics were reported to be associated with invasive disease in target populations (Richard 1988).

Objectives

The primary objective was to compare the effectiveness and safety of prophylactic enteral probiotics administration versus placebo or no treatment in the prevention of severe (stage II or more) NEC and/or sepsis in preterm infants.

The secondary objective was to conduct a subgroup analysis to investigate the effect of probiotics in extreme low birth weight infants (infants with birth weight < 1000 g).

[top]

Methods

Criteria for considering studies for this review

Types of studies

Only randomized and quasi-randomized controlled trials were included.

Types of participants

Preterm infants < 37 weeks and/or birth weight < 2500 g.

Types of interventions

Enteral administration of any live microbial supplement (probiotics) at any dose for more than seven days compared to placebo or no treatment.

Types of outcome measures

Primary outcomes
  • Severe NEC (stage II or more) as per Bell's criteria (Bell 1978; Walsh 1986), diagnosed prior to discharge.
  • Nosocomial sepsis, defined as positive blood or cerebrospinal fluid cultures taken beyond 5 days of age.
Secondary outcomes
  • All cause neonatal mortality.
  • Any NEC (according Bell's criteria).
  • The composite of nosocomial sepsis or NEC or death.
  • Systemic infection with the supplemented organism.
  • Duration of total parenteral nutrition (days).
  • Time to establish full enteral feeds (days).
  • Duration of hospitalization (days).
  • Neurodevelopmental impairment i.e. rates of cerebral palsy, cognitive delay, deafness, blindness or their composite reported at 18 months corrected age or later.

Search methods for identification of studies

Electronic searches

Our search was updated from December 2006 to October 2010. We used the standard search strategy for the Cochrane Neonatal Review Group. Randomized and quasi-randomized controlled trials that compared enteral probiotics to placebo or no treatment in premature infants were identified from OVID MEDLINE-National Library of Medicine (1966 to October 2010) using the following subject headings (MeSH) and text word terms: "neonate(s), newborn(s), infant(s), probiotics, lactobacillus, bifidobacterium, saccharomyces and publication type 'controlled trial'. No language restrictions were applied.

Other databases were searched including: EMBASE (1980 to October 2010), Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2010). Authors performed the electronic database search independently.

Searching other resources

A manual search of the abstract books published from the Society of Pediatric Research (SPR) and the European Society of Pediatric Research (ESPR) for the period of 1998 to 2010 were performed. Additional citations were sought using references in articles retrieved from searches. Subject experts were contacted to identify the unpublished and ongoing studies. Authors of the published trials were contacted to clarify or provide additional information. Authors independently screened candidate articles to check the eligibility for inclusion in the review.

We also searched clinical trials registries for ongoing or recently completed trials (clinicaltrials.gov; controlled-trials.com; and who.int/ictrp)

Data collection and analysis

The standard methods of the Cochrane Neonatal Review Group Guidelines were employed in creating this update.

Selection of studies

Retrieved articles were assessed for eligibility independently by two review authors. Discrepancies were resolved by discussion and consensus.

Data extraction and management

Data was abstracted independently by two review authors. Discrepancies were resolved by discussion and consensus. Where data were incomplete, the primary investigator was contacted for further information and clarification.

Assessment of risk of bias in included studies

Standard methods of the Cochrane Collaboration and the Neonatal Review Group were used to assess the methodological quality (validity criteria) of the trials. For each trial, information was sought regarding the method of randomization, blinding and reporting of all outcomes of all the infants enrolled in the trial. Each criteria was assessed as yes, no, can't tell.

Two review authors separately assessed each study. Any disagreement was resolved by discussion. This information was added to the table 'Characteristics of Included Studies'.

In addition, for the update in 2010, the following issues were evaluated and entered into the Risk of Bias table:

  1. Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?
    For each included study, we categorized the method used to generate the allocation sequence as:
    • adequate (any truly random process e.g. random number table; computer random number generator);
    • inadequate (any non random process e.g. odd or even date of birth; hospital or clinic record number);
    • unclear.
  2. Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?
    For each included study, we categorized the method used to conceal the allocation sequence as:
    • adequate (e.g. telephone or central randomization; consecutively numbered sealed opaque envelopes);
    • inadequate (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
    • unclear.
  3. Blinding (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment?
    For each included study, we categorized the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding was assessed separately for different outcomes or classes of outcomes. We categorized the methods as:
    • adequate, inadequate or unclear for participants;
    • adequate, inadequate or unclear for personnel;
    • adequate, inadequate or unclear for outcome assessors.
  4. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were incomplete outcome data adequately addressed?
    For each included study and for each outcome, we described the completeness of data including attrition and exclusions from the analysis. We noted whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomized participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes.Where sufficient information was reported or supplied by the trial authors, we re-included missing data in the analyses. We categorized the methods as:
    • adequate (< 20% missing data);
    • inadequate (greater than/or equal to 20% missing data):
    • unclear.
  5. Selective reporting bias. Are reports of the study free of suggestion of selective outcome reporting?
    For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. We assessed the methods as:
    • adequate (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);
    • inadequate (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
    • unclear.
  6. Other sources of bias. Was the study apparently free of other problems that could put it at a high risk of bias?
    For each included study, we described any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as:
    • yes;no;or unclear.

If needed, we planned to explore the impact of the level of bias through undertaking sensitivity analyses.

Measures of treatment effect

For dichotomous outcomes, relative risk (RR) risk difference (RD) and the number needed to treat (NNT) and its associated confidence interval were calculated. For continuous outcomes, treatment effect was expressed as mean difference and its calculated standard deviation.

Assessment of heterogeneity

Heterogeneity was defined as a significant test of heterogeneity (p < 0.1) and differences in the treatment effects across studies. Tests for between-study heterogeneity (including the I2 test) were applied. If noticed, possible sources of heterogeneity were examined, including differences in the type or dose of probiotics used, the population under study (VLBW versus ELBW infants), and the quality of the study.

Data synthesis

If appropriate, meta-analysis of pooled data was performed assuming a fixed effect model. Review Manager 5.0.25 software was used for statistical analysis. For estimates of typical relative risk and risk difference, we used the Mantel-Haenszel method. For measured quantities, we used the inverse variance method. All meta-analyses were done using the fixed effect model.

A subgroup analysis to investigate the effect of probiotics in extreme low birth weight infants was conducted.

Subgroup analysis and investigation of heterogeneity

The secondary objective was to conduct a subgroup analysis to investigate the effect of probiotics in extreme low birth weight infants.

Sensitivity analysis

A sensitivity analysis was carried out to assess the effect of trials methodological quality on results of the meta-analysis. Studies were considered of high quality if allocation was concealed and adequately described.

[top]

Results

Description of studies

See tables 'Characteristics of included and excluded studies'. Our updated search in October 2010 yielded seven additional studies meeting our inclusion criteria. Therefore, a total of 16 randomized trials are included in our updated review. Excluded studies and reasons for exclusion are outlined in characteristics of excluded studies. The details of four identified ongoing studies are provided in the tables of ongoing studies.

Participants

Sixteen included studies reported outcomes on 1371 infants treated with probiotics and 1376 control infants. While all studies enrolled infants < 37 weeks and/or birth weight < 2500 g, entry criteria varied between studies. Li 2004, Reuman 1986, Kitajima 1997, Lin 2005, Lin 2008, Bin-Nun 2005, Manzoni 2009, and Manzoni 2006 enrolled infants based on birth weight criteria. On the other hand, Millar 1993, Mohan 2006, Stratiki 2007, and Costalos 2003 enrolled infants based on their gestational age. Dani 2002, Rougé 2009, Samanta 2009, and Sari 2010 utilized both criteria to enrolls infants. None of the included studies limited their enrolment to ELBW infants.

Intervention

Included studies randomized infants to different preparations and dosages of probiotics. While Reuman 1986, Millar 1993, Dani 2002, Manzoni 2006, Manzoni 2009, Rougé 2009, and Sari 2010 administered Lactobacillus species to the intervention groups; Kitajima 1997, Mohan 2006, Stratiki 2007 and Li 2004 utilized the Bifidobacterium species and Costalos 2003 utilized Saccharomyces boulardii. Lin 2005, Lin 2008, Samanta 2009 and Bin-Nun 2005 used a mixture of two to three species of probiotics (L acidophilus - B infantis, and Lactobacillus bifidus-streptococcus thermophillus-bifidobactrium infantis).

The time of initiation and duration of therapy was different among included studies. Probiotics were administered either during the first 24 hours of life (Reuman 1986; Kitajima 1997; Li 2004), at the third day of life (Manzoni 2009), at the time of the first feed (Millar 1993; Dani 2002; Lin 2005; Lin 2008; Rougé 2009; Samanta 2009; Sari 2010), or during the first week when enteral feeds were tolerated (Costalos 2003; Manzoni 2006, Mohan 2006). The duration of probiotics administration varied from two weeks (Reuman 1986), four to six weeks (Kitajima 1997; Costalos 2003; Lin 2008; Manzoni 2009), or until discharge (Dani 2002; Li 2004; Lin 2005; Manzoni 2006; Rougé 2009; Samanta 2009, Sari 2010).

Outcomes

The major outcomes reported in included studies were severe stage II-III NEC (Dani 2002; Costalos 2003; Lin 2005; Lin 2008; Bin-Nun 2005; Manzoni 2006; Manzoni 2009; Kitajima 1997; Mohan 2006; Rougé 2009; Samanta 2009; Sari 2010; Stratiki 2007), all causes mortality (Kitajima 1997; Reuman 1986;Dani 2002; Lin 2005; Lin 2008; Bin-Nun 2005; Manzoni 2006; Manzoni 2009; Rougé 2009; Samanta 2009) and sepsis (Millar 1993; Kitajima 1997; Costalos 2003; Dani 2002; Lin 2005; Lin 2008; Bin-Nun 2005; Manzoni 2006; Manzoni 2009, Rougé 2009, Samanta 2009, Sari 2010; Stratiki 2007). Weight gain was reported in three studies (Reuman 1986; Millar 1993; Costalos 2003; Sari 2010) using different measurement scales. Only one study reported data on apnea and long term neurosensory outcomes (Kitajima 1997).

Risk of bias in included studies

Details of included studies are presented in the table 'Characteristics of Included Studies'. The methodologic details of the studies were extracted from the published data and by contacting the primary author. However, a response was only received from one primary author (Dani 2002).

  • Bin-Nun 2005: This was a single centre study. Infants less than 1500 g were randomized to receive either probiotics mixture (Lactobacillus bifidus, streptococcus thermophillus, and bifidobactrium infantis) or placebo. Information regarding allocation concealment was not specified, intervention was masked, and blinding of outcome assessment was not specified. Of note, this trial was published in an abstract form on two previous occasions at the Society of Pediatrics Research (SPR 2003, 2005) with different inclusion criteria and clinical outcomes, which suggests a change in the a priorispecified criteria and multiple looks at the trials results.
  • Costalos 2003: This was a single center study. Infants were randomized to receive either enteral probiotics (Saccharomyces boulardii) added to preterm formula or the same formula with maltodextrins. Allocation concealment was apparently adequate. Intervention and outcome assessment were masked. All infants were accounted for in the final results. There was a discrepancy with regard to the infants enrolled in both groups (51 in the treatment group and 36 in the control). The author presented no explanation of whether this discrepancy was a result of imbalance in the randomization process or a loss to follow-up.
  • Dani 2002: This was a multicenter study. Infants were randomized to receive either enteral probiotics (Lactobacillus GG) or placebo. Allocation was adequately concealed. The intervention was masked. All enrolled infants were accounted for and outcome measurement was blinded.
  • Kitajima 1997: This was a single center study. 91 infants were randomized to receive enteral probiotics (Bifidobacterium breve) or control. It was unclear whether allocation was concealed, intervention blinded, or the outcome assessment was blinded. Not all enrolled infants accounted for the final results (six infants excluded for various reasons).
  • Li 2004: This was a single center study. Infants were randomized in three groups to receive either enteral probiotics (Bifidobacterium breve) (group A, B) or control (group C). Allocation concealment was not described. It was unclear whether the intervention or outcome assessment were blinded and whether all infants were included its final results.
  • Lin 2005: This was a single centre study, infants less than 1500 g were randomized to either probiotics (Infloran® - L acidophilus and B infantis) or to a control group (breast milk only). Allocation was adequately concealed. Intervention was masked (except for investigators and breast milk team). All enrolled infants were accounted for. Outcomes measurement was blinded.
  • Lin 2008: This was a multicenter trial, infants less than 1500g were randomized to either probiotics (217) were given Bifidobacterium bifidum and Lactobacillus acidophilus, added to breast milk or mixed feeding (breast milk and formula), twice daily for six weeks or to control (217) were fed with breast milk or mixed feeding. Allocation was adequately concealed. Intervention was masked. All enrolled infants were accounted for. Outcomes measurement was blinded.
  • Manzoni 2006: This was a single centre study, infants less than 1500 g were randomized to either probiotics (Dicoflor Lactobacillus casei) or to a control group (breast or donor milk only). Although authors utilized computer generated randomization, allocation concealment was not described. Intervention was masked from human bank and microbiology workers, however, it was unclear whether care givers are masked or not. All enrolled infants were accounted for. Blinding of outcomes measurement was reported.
  • Manzoni 2009: This was a multicenter study, infants less than 1500 g younger than 3 days were randomized to either received BLF (100mg/d) (LF100; Dicofarm SpA, Rome, Italy) alone or BLF (bovine Lactoferrin) plus LGG (6109colony-forming units/d) (Dicoflor60;Dicofarm SpA); the control group received placebo (2 mL of a 5% glucose solution). Treatment lasted 6 (birth weight 1000 g) or 4 (birth weight 1001-1500 g) weeks, unless neonates were discharged earlier. Drug administration began on the third day of life with 1 daily dose; all doses including placebo were diluted in prepared milk so as to maintain blinding. Allocation was adequately concealed. Intervention was masked. All enrolled infants were accounted for. Outcomes measurement was blinded.
  • Millar 1993: This was a single center study. Twenty infants were randomized to receive either enteral probiotics (Lactobacillus GG) or control. The intervention was masked. All infants enrolled were accounted for. It was unclear whether the outcome assessment was blinded or not.
  • Mohan 2006: This was a single center study. Infants less than 37 weeks were randomized to probiotic (37) and placebo (32) groups. The formula-based placebo (Nestle´ FM 2000B) and verum (Nestle´ FM 2000A) preparations were supplied by Nestle´, Konolfingen, Switzerland.The verum contained 2 X109 cells of Bifidobacterium lactis Bb12 per gram of powder. The administration of the study preparation started on the first day after birth and continued for 21 days. The study ended at the 35th day after birth or when the infant was discharged from the hospital, if earlier. Allocation concealment was not described. The intervention was double masked; however it was unclear whether outcomes assessment was masked or not. All enrolled infants were accounted for. Of note, clinical data obtained through contact with the corresponding author were different from those recently published by Deshpande 2010.
  • Reuman 1986: This was a single center study. Three groups of infants were randomized to receive either enteral probiotics (Lactobacillus) or control. Randomization and allocation concealment were clearly inadequate. The intervention was double masked. All infants enrolled were accounted for and outcome assessment was blinded.
  • Rougé 2009: This trial was conducted in two centers, infants less than 1500 g and gestational age < 32 weeks were randomized to either Probiotic group (45) 108 lyophilized cells per unit of the probiotics L. rhamnosus GG (Valio, Ltd) and B. longum BB536 (Morinaga Milk Industry Co, Ltd, Tokyo, Japan) and maltodextrin beginning on the day when enteral feeding started until discharge or Placebo group (49) Receive 4 daily capsules of a supplement containing either maltodextrin alone. Allocation was adequately concealed. Intervention was masked. All enrolled infants were accounted for. Outcomes measurement was blinded.
  • Samanta 2009: This was a single center study. Infants < 32 weeks and < 1500 g started feed enterally and survived beyond 48 h of life were randomized to receive a probiotic mixture (Bifidobacteria infantis, Bifidobacteria bifidum, Bifidobacteria longum and Lactobacillus acidophilus, each 2.5 billion CFU) with expressed breast milk twice daily, the dosage being 125 g kg -1 till discharge or breast milk only (control). Allocation concealment, and blinding of Intervention and outcome was not adequately described. All enrolled infants were accounted for.
  • Sari 2010: This was a single center study. Infants < 33 weeks and < 1500 g infants who survived to start enteral feeding were randomized into two groups. Infants in study group received L. sporogenes with a dose of 350.000.000 colony forming units added to breast milk or formula once a day starting with first feed until discharge. Infants in control group received no supplementation. Allocation concealment, blinding of Intervention and outcome was adequately described. All enrolled infants were accounted for.
  • Stratiki 2007: This was a single center study. Infants (81 infants) with gestational age between 27 and 37 weeks, stable state, formula fed were randomized to group A given a BL supplemented preterm formula - Prenan Nestlé - (BLSPF) at a concentration of 2×107 cfu/g of milk powder or group B (control) received exactly the same formula but without the addition of BL. Allocation concealment was not described. The intervention and outcome assessment were blinded and all infants were included its final results.

Effects of interventions

PROBIOTICS VS. CONTROL (COMPARISON 1):

Severe stage II-III necrotizing enterocolitis (Outcome 1.1):

Thirteen studies reported on severe stage II-III NEC (Dani 2002; Costalos 2003; Lin 2005; Lin 2008; Bin-Nun 2005; Manzoni 2006; Manzoni 2009; Kitajima 1997; Mohan 2006; Rougé 2009; Samanta 2009; Sari 2010; Stratiki 2007). The administration of prophylactic probiotics significantly reduced the incidence of severe stage II -III NEC [typical RR 0.35 (95% CI 0.24 to 0.52); typical RD -0.04 (95% CI -0.06 to -0.02), NNT 25]. This effect is maintain even for subgroup of weight less than 1500 g at birth [typical RR 0.34 (95% CI 0.23 to 0.50)] and high quality studies [typical RR 0.25 (95% CI 0.13 to 0.49)]. Data pertaining to the most vulnerable infants (ELBW) could not be abstracted from the included studies. Figure 1

Mortality (Outcome 1.2):

Ten studies reported on mortality (Kitajima 1997; Reuman 1986;Dani 2002; Lin 2005; Lin 2008; Bin-Nun 2005; Manzoni 2006; Manzoni 2009; Rougé 2009; Samanta 2009). The number of deaths was significantly lower in the probiotics group [typical RR 0.40 (95% CI 0.27 to 0.60); typical RD -0.04 95% CI (-0.06 to -0.01), NNT 25]. Five studies (Bin-Nun 2005; Dani 2002; Kitajima 1997; Lin 2008; Sari 2010) reported NEC-related mortality. The number of NEC related deaths was also significantly lower in the probiotics group [typical RR 0.31 (95% CI 0.10 to 0.94).

Sepsis (Outcome 1.3):

Thirteen studies reported on sepsis (Millar 1993; Kitajima 1997; Costalos 2003; Dani 2002; Lin 2005; Lin 2008; Bin-Nun 2005; Manzoni 2006; Manzoni 2009; Rougé 2009; Samanta 2009; Sari 2010; Stratiki 2007). There was no significant difference among both groups in the rate of culture proven sepsis [typical RR 0.90 (95% CI 0.76, 1.07).

Days on total parenteral nutrition (Outcome 1.4):

Two studies reported this outcome. No statistical difference was found in either of the studies. Dani 2002 reported a mean of 12.8 (13.9) days in the probiotics group, and a mean of 14.7(18.7) days in the control group [WMD -1.9 (-4.6 to 0.77)]. Lin 2005 reported a mean of 14.7 (5.7) days in the probiotics group and 13.9 (5.0) days in the control group [WMD 0.80 (-0.3 to 1.9)]. Other studies report incomplete data to be pooled. Due to the significant test of heterogeneity, these results were not pooled.

Hospitalization days (Outcome 1.5):

Five studies reported this outcome (Lin 2005; Lin 2008; Reuman 1986; Rougé 2009; Samanta 2009). Pooled Data of five studies shows significant reduction in hospitalization days [typical WMD -6.08 (95% CI -7.08 to -5.09).

Weight gain (Outcome 1.6):

Four studies (Reuman 1986; Millar 1993; Costalos 2003; Sari 2010) reported weight gain results. No significant statistical difference in weight gain among study groups was observed. Due to the use of different scales i.e. g/week, g/day and g/kg/day, these results were not pooled.

Time to full enteral feeds (Outcome 1.7):

Three studies (Manzoni 2009; Samanta 2009; Sari 2010) reported time to full enteral feeds results. Pooled data of studies shows significant reduction in time to reach full enteral feeds [typical WMD -4.28 (-4.81 to -3.75)].

The composite of death or severe NEC or sepsis (Outcome 1.8):

Only one study reported this outcome (Lin 2005). Probiotics significantly reduced the incidence of this composite [typical RR 0.54 (95% CI 0.37 to 0.79)].

Systemic infection with the supplemented organism

None of the included studies reported a systemic infection caused by the supplemented probiotics organisms.

Long-term Outcomes (Outcome 1.9):

Kitajima 1997 reported mental retardation and cerebral palsy outcome at six years. No significant statistical difference among study groups was observed.

A subgroup analysis to demonstrate the effect of probiotics administration in ELBW infants was not performed since data pertains to this high risk group could not be extracted from the included studies.

Discussion

Our updated review summarizes the evidence of probiotics efficacy in preterm infants. Sixteen randomized trials and more than 2700 preterm infants are included. Since the publication of our first review, we noted a tremendous increase in published studies, reviews of editorials addressing the efficacy and safety of probiotics utilization in the preterm host.

Our update shows with more robust data that enteral administration of probiotics reduces the incidence of severe NEC, mortality, and NEC related mortality. The administration of probiotic organisms also resulted in a shorten time to full feeds. Our data shows a trend toward a benefit in reduction of sepsis, however, this didn't reach statistical significance. We believe that based on the available evidence for probiotics use in the preterm infant, the number of included infants, the narrow confidence interval, that a change in practice is warranted at this stage. More studies to address the precise efficacy in ELBW infants, the optimal preparation, dosing and duration of therapy are still needed.

Four of our included trials were classified as high quality based on adequacy of allocation concealment procedures and blinding of intervention.
Although all included trials evaluated probiotics use in preterm infants, the trials were highly variable with regard to enrolment criteria (i.e. birth weight, and gestational age), baseline risk of NEC in control groups, timing, dose, formulation of probiotic used and feeding regimens. Most of included trials enrolled preterm infants less than 1500 g at birth; however, specific efficacy and safety data on most vulnerable infants (ELBW) couldn't be evaluated.

Case reports of systemic infections caused by probiotic organisms are reported in biomedical literature. None of our included studies reported this adverse effect. The use of probiotics was described as safe and well tolerated. Our update provide a more robust safety data of probiotics use.

This review utilized a very thorough and comprehensive search strategy. All attempts were made to minimize the potential of a publication bias. Only randomized or quasi-randomized controlled trials were included. To minimize the reviewer bias, all steps of this review were conducted independently by review authors. The validity of our review's results is potentially compromised by the following: included trials utilized different preparations and dosing regimens of the intervention under study; data on the highest risk population (ELBW infants) could not be retrieved.

Our updated review includes five more randomized controlled trials compared to the recent review by Deshpande and coworkers (Deshpande 2010). The results of our updated review are in line with the published data of Deshpande 2010, but allow for a more precise estimate of effect given the larger sample of trials. The issue of whether it is time to change practice and adopt the use of probiotics as a standard of care in preterm infants has been widely discussed in the medical literature of the last year. While some advocate a change in practice based on significant reduction in severe NEC and all cause mortality (Tarnow-Mordi 2010), others suggest to wait until further precise data of efficacy and safety in ELBW infants are available in addition to the determination of the most effective preparation and dosing to be utilized (Soll 2010). We believe that based on the available evidence and in comparison to other effective interventions in neonatal medicine such as induced hypothermia in hypoxic ischemic encephalopathy, a change in practice at this stage is warranted. Parents of preterm infants should be informed of the current evidence if placebo controlled trials are to continue.

Four ongoing studies are identified and will be included into updates of our review in the future.

Authors' conclusions

Implications for practice

Enteral supplementation of probiotics prevents severe NEC and all cause mortality in preterm infants. Our updated review of available evidence supports a change in practice.

Implications for research

Our updated review of available evidence supports a change in practice. More studies are needed to assess efficacy in ELBW infants and to assess the most effective formulation and dose to be utilized.

Acknowledgements

We would like to acknowledge Dr Gordon Guyatt (McMaster University, Hamilton Ontario) for his thoughtful comments on the methodology of this review.

Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.

Contributions of authors

KA developed the protocol.
KA and DB assessed trials for eligibility, quality and extracted the data independently for initial review.
KA wrote the manuscript with revisions made by DB.
KA, TA and JA updated the review.

Declarations of interest

  • None noted.

Differences between protocol and review

  • None noted.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

[top]

Characteristics of studies

Characteristics of Included Studies

Bin-Nun 2005

Methods

Single centre randomized study
Method of generating randomization sequence: not described
Blinding of randomization: not described
Blinding of intervention: yes
Blinding of outcome measurement: yes
Completeness of follow-up: not specified

Participants

145 infants less than 1500 g at birth
Demographic data:
Probiotics Group N=72, Gestational age (weeks) 29.2(2.6), birth weight 1152 (262)
Placebo Group
N=73, Gestational age (weeks) 29.3 (4.3), birth weight 1111 (278)

Interventions

Probiotics group (N=72) received mixture of Lactobacillus bifidus, streptococcus thermophillus, and bifidobactrium infantis added to 3 ml of expressed breast milk or premature formula enteral feeds.
Control group (N=73) received 3 ml of expressed milk or premature formula with no supplements added.

Outcomes

Stage 2 or 3 NEC.
Mortality
NEC or mortality
Sepsis
Days to full feeds
Days till TPN stopped

Notes

Israel
Period of study: Sept 2001-Sept 2004
Published: Journal of Pediatrics 2005
Source of
Funding: ABC Dophilus

Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear

Method of generating randomization sequence: not described

Allocation concealment? Unclear

Blinding of randomization: not described

Blinding? Yes

Blinding of intervention: yes
Blinding of outcome measurement: yes

Incomplete outcome data addressed? Unclear

Completeness of follow-up: not specified

Free of selective reporting? Yes

All clinically important outcomes are described

Free of other bias? Unclear

Costalos 2003

Methods

Single center randomized double blind study
Method of generating randomization sequence:Cards in sealed envelopes
Allocation concealment: Possibly adequate
Blinding of intervention: Yes
Blinding of outcome measurement: Not described
Complete follow-up: Yes

Participants

87 infants, gestational age 28-32 weeks
Exclusion criteria:
Major anomalies, receiving antibiotics or anti -fungals, receiving breast milk
Demographic data:
Probiotics Group N=51, Gestational age (weeks) 31.1(2.5), birth weight 1651 (470)
Placebo Group N=36, Gestational age (weeks) 31.8 (2.7), birth weight 1644 (348)

Interventions

Probiotics group (N=51) received preterm formula containing approximately 15 nmol/dl polyamines with added Saccharomyces boulardii 50mg/kg every 12 hours during the first week of life when enteral feed are tolerated for 30 days.
Placebo group (N=36) received same formula with maltodextrins

Outcomes

NEC
Weight gain
Abdominal distension
Vomiting
Gastric retention
Stool characteristics
Sepsis

Notes

Greece
Period of study: not specified
Published: 2003
Source of Funding: Unclear

Risk of bias table
Item Judgement Description
Adequate sequence generation? Yes

Method of generating randomization sequence: Cards in sealed envelopes

Allocation concealment? Yes

Allocation concealment: Possibly adequate

Blinding? Unclear

Blinding of intervention: Yes
Blinding of outcome measurement: Not described

Incomplete outcome data addressed? Yes

Complete follow-up: Yes

Free of selective reporting? Unclear
Free of other bias? Unclear

Dani 2002

Methods

Multicenter randomized double blind study (12 centers)
Method of generating randomization sequence: not described
Allocation concealment: Clearly adequate
Blinding of intervention: Yes
Blinding of outcome measurement: Yes
Complete follow-up: Yes

Participants

585 infants, < 33 weeks gestation or < 1500 g birth weight enrolled.
Exclusion criteria:
Congenital malformation and death within two weeks of birth
Demographic data:
Probiotics Group N=295, gestational age (weeks) 30.8(2.4), birth weight 1325 (361)
Placebo Group N=290, gestational age (weeks) 30.7 (2.3), birth weight 1345 (384)

Interventions

Probiotics group (N=295) received standard milk with Lactobacillus GG (Dicoflor®, Dicofarm, Rome, Italy) with an added dose of 6×109 colony forming units (cfu) once a day until discharge, starting with first feed.
Placebo group (N=290) received standard milk with placebo which was an indistinguishable dried powder of maltodextrins.

Outcomes

Severe NEC
Incidence of PDA
Duration of parenteral nutrition
Urinary tract infection
Bacterial sepsis (culture proven)
Stage 2 and 3 NEC
Single course of antibiotics treatment
NEC related mortality

Notes

Italy
Period of study: not specified in paper
Published: 2002
Source of Funding: not specified in paper

Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear

Method of generating randomization sequence: not described

Allocation concealment? Yes

Allocation concealment: clearly adequate

Blinding? Yes

Blinding of Intervention: Yes
Blinding of outcome measurement: Yes

Incomplete outcome data addressed? Yes

Complete Follow-up: Yes

Free of selective reporting? Yes
Free of other bias? Yes

Kitajima 1997

Methods

Single center randomized study
Method of generating randomization sequence: Not described
Allocation concealment: Not described
Blinding of intervention: Not described
Blinding of outcome measurement: Not described
Complete follow-up: No (6 patients dropped)

Participants

91 infants, birth weight < 1500 g enrolled.
Exclusion criteria:
Major anomalies, severe asphyxia, severe IUGR
Demographic data:
Probiotics Group N=45, gestational age (weeks) 28.3(2.3), birth weight 1026 (24)
Placebo Group N=46, gestational age (weeks) 28.2 (2.1), birth weight 1026 (205)

Interventions

Probiotics group (N=45) received 1 ml supplement of Bifidobacterium breve with distilled water 0.5×109 of live B. breve within the 1st 24 hrs of life once per day for 28 days
Control group (N=46) received distilled water

Outcomes

Colonization rate
Mean aspired air volume
Vomiting times/week
Apnoea times/week
Weight gain
Mental retardation and cerebral palsy outcome at 6 years

Notes

Japan
Period of study: May 1990-April 1991
Published: 1997
Source of Funding: Unclear

Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear

Method of generating randomization sequence: Not described

Allocation concealment? Unclear

Allocation concealment: Not described

Blinding? Unclear

Blinding of Intervention: Not described
Blinding of outcome measurement: Not described

Incomplete outcome data addressed? No

Complete Follow-up: No (6 patients dropped)

Free of selective reporting? No

Important patient oriented outcomes are not included

Free of other bias? Unclear

Li 2004

Methods

Single center randomized study
Method of generating randomization sequence: Unclear
Allocation concealment: Not described
Blinding of intervention: Not described
Blinding of outcome measurement: Not described
Complete follow-up: Unclear

Participants

30 infants, of low birth weight.
Exclusion criteria:
Major anomalies, chromosomal anomalies, intrauterine infection
Demographic data:
Probiotics Group A N=10, gestational age (weeks) 33.8(2.9), birth weight 1523 (490)
Probiotics Group B N=10, gestational age (weeks) 33.8(3.2), birth weight 1354 (280)
Control (C) Group N=10, gestational age (weeks) 32.4 (3.1), birth weight 1480 (237)

Interventions

Probiotics group (N=10) received through gastric tube Bifidobacterium breve twice a day with feeds till discharge. Group A within several hours of birth, while group B after the 1st 24 hrs.
Control group (N=10) received no supplement

Outcomes

Colonization rate
NEC
Sepsis

Notes

Japan
Period of study: Jan 2000- Aug 2002
Published: 2004
Source of Funding: Morinaja Milk industry and Meiji Dairies

Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear

Method of generating randomization sequence:unclear

Allocation concealment? Unclear

Allocation concealment: Not described

Blinding? Unclear

Blinding of intervention: Not described
Blinding of outcome measurement: Not described

Incomplete outcome data addressed? Unclear

Complete follow-up: Unclear

Free of selective reporting? No

Important patient oriented outcomes are not included

Free of other bias? Unclear

Lin 2005

Methods

Single centre randomized study
Method of generating randomization sequence: Random-number table sequence.
Allocation concealment: Clearly adequate
Blinding of intervention: Yes, only investigators and breast milk team were unblinded.
Blinding of Outcome measurement: Yes
Completeness of follow up: Yes

Participants

367 infants less than 1500 g at birth, survived beyond 7 days of life, and started on enteral feed were enrolled
Demographic data:
Probiotics Group N=180, gestational age (weeks) 28.5(2.5), birth weight 1104 (242)
Placebo Group N=187, gestational age (weeks) 28.2 (2.5), birth weight 1071 (243)

Interventions

Probiotics group (N=180) received Infloran® (L acidophilus and B infantis) obtained from the American Type Culture Collection in 1973, 125 mg/kg/dose twice daily with breast milk until discharge. All enrolled infants received maternal or banked breast milk.
Control group (N=187) received breast milk without any addition (no placebo).

Outcomes

Death
Stage 2 or 3 NEC
Sepsis (culture proven)
Composite outcomes of death+ NEC, sepsis+ NEC, death+ NEC+ Sepsis
Duration of parenteral nutrition
Hospitalization days

Notes

Taiwan
Period of study: July 1999- December 2003
Published: 2005
Source of Funding: supported by research department of China medical university hospital.

Risk of bias table
Item Judgement Description
Adequate sequence generation? Yes

Method of generating randomization sequence: Random-number table sequence.

Allocation concealment? Yes

Allocation concealment: Clearly adequate

Blinding? Yes

Blinding of intervention: Yes, only investigators and breast milk team were unblinded
Blinding of outcome measurement: Yes

Incomplete outcome data addressed? Yes

Completeness of follow up: Yes

Free of selective reporting? Yes
Free of other bias? Yes

Lin 2008

Methods

Multicenter trial
Method of generating randomization sequence: Sequential numbers generated at the computer center
Allocation concealment: Adequate
Blinding of intervention: Yes
Blinding of outcome measurement: Yes
Completeness of follow up: Yes

Participants

Very low birth weight infants (birth weight less than/or equal to1500 g)
Demographic data:
The study group N=217, birth weight 1028.9 (246)
The control Group N=217, birth weight 1077 (214.4)

Interventions

Infants in the study group were given Bifidobacterium bifidum and Lactobacillus acidophilus, added to breast milk or mixed feeding (breast milk and formula), twice daily for 6 weeks.
Infants in the control group were fed with breast milk or mixed feeding.

Outcomes

Death or severe NEC
NEC, greater than/or equal to stage2
Death not attributable to NEC
Death attributable to NEC
Sepsis
CLD
PVL
IVH, greater than/or equal to grade3

Notes

7 NICUs in Taiwan
Period of study: January 2005 - May 2007
Published: 2008
Sources of support: National Science Council of Taiwan

Risk of bias table
Item Judgement Description
Adequate sequence generation? Yes

Method of generating randomization sequence: Sequential numbers generated at the computer center.

Allocation concealment? Yes

Allocation concealment: Adequate

Blinding? Yes

Blinding of intervention: Yes.
Blinding of outcome measurement: Yes

Incomplete outcome data addressed? Yes

Completeness of follow up: Yes

Free of selective reporting? Yes
Free of other bias? Yes

Manzoni 2006

Methods

Single randomized study
Method of generating randomization sequence: Computer generated randomization
Allocation concealment: Unclear
Blinding of intervention: Can't tell
Blinding of outcome measurement: Can't tell
Completeness of follow up: Yes

Participants

80 infants less than 1500 g at birth, survived beyond 3 days of life, and started on human or donor milk enteral feed were enrolled
Demographic data:
Probiotics Group N=39, gestational age (weeks) 29.6 (5), birth weight 1212 (290)
Placebo Group N=41, gestational age (weeks) 41(4), birth weight 1174 (340)

Interventions

Probiotics group (N=39) received LGG [Diclofor 60;Dicofarm spa]; single dose (1/2 packet of Diclofor 60) daily mixed with human or donor milk till end of the sixth week or discharge.
Control group (N=41) received human or donor milk without any addition (no placebo).

Outcomes

Fungal colonization rates
Stage 2 or 4 NEC
Death
Sepsis (culture proven)
Time to full feeds

Notes

Italy
Period of study: 12 months
Published: 2006
Sources of support: non reported

Risk of bias table
Item Judgement Description
Adequate sequence generation? Yes

Method of generating randomization sequence: computer generated randomization

Allocation concealment? Unclear

Allocation concealment: Unclear

Blinding? Unclear

Blinding of intervention: Can't tell
Blinding of outcome measurement: Can't tell

Incomplete outcome data addressed? Yes

Completeness of follow up: Yes

Free of selective reporting? Yes
Free of other bias? Unclear

Manzoni 2009

Methods

Multicenter trial
Method of generating randomization sequence: using ralloc.ado version 3.2.5 in Stata 9.2 (Stata-Corp, College Station, Texas)
Allocation concealment: Yes
Blinding of intervention: Yes
Blinding of outcome measurement: Yes
Completeness of follow up: Yes

Participants

VLBW neonates younger than 3 days
Demographic data:
Probiotics Group N=151, gestational age (weeks) 29.8 (23-35), birth weight 1138 (550-1500)
Control Group N=153, gestational age (weeks) 29.5 (23-39), birth weight 1109 (437-1500)

Interventions

Infants received either BLF (Bovine Lactoferrin) (100mg/d) (LF100; Dicofarm SpA, Rome, Italy) alone or BLF plus LGG (6X109colony-forming units/d) (Dicoflor60;Dicofarm SpA); the control group received placebo (2 mL of a 5% glucose solution).
Treatment lasted 6 (birth weight 1000 g) or 4 (birth weight 1001-1500 g) weeks, unless neonates were discharged earlier.
Drug administration began on the third day of life with 1 daily dose; all doses including placebo were diluted in prepared milk so as to maintain blinding.

Outcomes

First episode of late-onset sepsis
Incidence of gram-positive/gram-negative bacterial and fungal sepsis
Mortality prior to discharge
Incidence of urinary tract infections, fungal colonization, progression from fungal colonization to invasive
fungal infection
Severe NEC
Threshold ROP
Severe (grade 3-4) IVH
BPD
Alteration of liver function
Adverse effects or intolerance

Notes

11 Italian tertiary NICU
Period of study: October 1, 2007, and July 31, 2008
Published: 2009
Source of Funding: Dicofarm SpA

Risk of bias table
Item Judgement Description
Adequate sequence generation? Yes

Method of generating randomization sequence:using ralloc.ado version 3.2.5 in Stata 9.2 (Stata-Corp, College Station, Texas)

Allocation concealment? Yes

Allocation concealment: Yes

Blinding? Yes

Blinding of intervention: Yes
Blinding of outcome measurement: Yes

Incomplete outcome data addressed? Yes

Completeness of follow up: Yes

Free of selective reporting? Yes
Free of other bias? Yes

Millar 1993

Methods

Single center randomized blinded study
Method of generating randomization sequence: Not described
Allocation concealment: Not described
Blinding of Intervention: Yes
Blinding of outcome measurement: Unclear
Complete follow-up: Yes

Participants

20 infants, < 33 weeks gestation enrolled.
Demographic data:
Probiotics Group N=10, gestational age (weeks) 30.5(26-33), birth weight 1445 (800-2560)
Placebo Group N=10, gestational age (weeks) 30.0 (24-33), birth weight 1500 (830-2150)

Interventions

Probiotics group received milk feeds with Lactobacillus GG 108 (cfu) twice a day for 14 days, starting with first feed.
Placebo group received unsupplemented milk

Outcomes

Weight gain
Sepsis clinical or lab proven
Antibiotics treatment
Oxygen and ventilatory requirements
Hospital stay
Perineal candidal infection
Duration of hospital stay

Notes

UK
Period of study: Sept 1991-Jan 1992
Published: 1993
Source of Funding: Wessex Medical Trust

Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear

Method of generating randomization sequence: Not described

Allocation concealment? Unclear

Allocation concealment: Not described

Blinding? Unclear

Blinding of intervention: Yes
Blinding of outcome measurement: Unclear

Incomplete outcome data addressed? Yes

Complete follow-up: Yes

Free of selective reporting? No

Important patient oriented outcomes are not included

Free of other bias? Unclear

Mohan 2006

Methods

A double-blind, placebo-controlled, randomized trial
Method of generating randomization sequence: Randoma software version 4.3
Allocation concealment: Not described
Blinding of intervention: Yes
Blinding of outcome measurement: Unclear
Complete follow-up: Yes

Participants

Gestational age of less than 37 weeks
No demographic data were provided

Interventions

69 preterm infants
The probiotic and placebo groups contained 37 and 32 preterm infants, respectively.
The verum contained 2 X109 cells of Bifidobacterium lactis Bb12 per gram of powder. The concentration of Bb12 in 1 ml solution of verum in water was 4 X108. The verum group received 1.6 X109 cells on day 1 to 3 and 4.8 X109 cells from day 4 onward. Started on the first day after birth and continued for 21 days. The study ended at the 35th day after birth or when the infant was discharged from the hospital, if earlier.

Outcomes

No clinical outcomes were presented in the published data
NEC and sepsis data were collected by contacting the corresponding author

Notes

The Ernst von Bergmann hospital, Potsdam, Germany
Period of study: August 2003 - June 2005
Published: 2006
Source of funding: Not reported

Risk of bias table
Item Judgement Description
Adequate sequence generation? Yes

Method of generating randomization sequence: Randoma software version 4.3

Allocation concealment? Unclear

Allocation concealment: Not described

Blinding? Unclear

Blinding of intervention: Yes
Blinding of outcome measurement: Unclear

Incomplete outcome data addressed? Yes

Complete follow-up: Yes

Free of selective reporting? No

Improtant patient oriented outcomes are not included

Free of other bias? Unclear

Reuman 1986

Methods

Randomized double blind study
Method of generating randomization sequence: random number charts and the last digit of patient's chart number, the next matched infants is assigned to the opposite group
Allocation concealment: clearly inadequate
Blinding of intervention: Yes
Blinding of outcome measurement: Yes
Complete follow-up: Yes

Participants

45 infants, < 2000 gm at birth weight who survived beyond first 24 hrs and are younger than 72 hrs
Demographic data:
Probiotics Group N=15, gestational age (weeks) 30.6(2.7), birth weight 1366 (302)
Placebo Group N=15, gestational age (weeks) 30.5 (2.8), birth weight 1377 (344)
Untreated group N=15, gestational age(weeks) 30.7(2.9), birth weight 1329(337)

Interventions

Probiotics group received at least 1 ml of formula containing lactobacillus. 5×1010 organisms/ml preparation diluted 100 times in infants formula.
Placebo group received 1 ml of formula with no added lactobacillus
Both groups started within 72 hrs of birth
The untreated group received nothing per mouth for 2 weeks

Outcomes

Death
Colonization rates
Hospitalization duration
Daily weight gain
Hospital acquired infection

Notes

US
Period of study: not specified in paper
Published: 1986
Source of
Funding: not specified in paper

Risk of bias table
Item Judgement Description
Adequate sequence generation? No

Method of generating randomization sequence: random number charts and the last digit of patient's chart number, the next matched infants is assigned to the opposite group

Allocation concealment? No

Allocation concealment: Clearly inadequate

Blinding? Yes

Blinding of intervention: Yes
Blinding of outcome measurement: Yes

Incomplete outcome data addressed? Yes

Complete follow-up: Yes

Free of selective reporting? No
Free of other bias? Unclear

Rougé 2009

Methods

Two centers
Method of generating randomization sequence: In-house software (Nantes University Hospital, Nantes, France)
Allocation concealment: Possibly adequate
Blinding of intervention: Yes
Blinding of outcome measurement: Yes
Complete follow-up: Yes

Participants

Gestational age, < 32 wk, a birth weight, < 1500 g
Demographic data:
Probiotics Group N=45, gestational age (weeks) 28.1 (1.9), birth weight 1115 (251)
Placebo Group N=49, gestational age (weeks) 28.1 (1.8), birth weight 1057 (260)

Interventions

Placebo group (N 49) Receive 4 daily capsules of a supplement containing maltodextrin alone
Probiotic group (N 45) 108 lyophilized cells per unit of the probiotics L. rhamnosus GG (Valio, Ltd) and B. longum BB536 (Morinaga Milk Industry Co, Ltd, Tokyo, Japan) and maltodextrin beginning on the day when enteral feeding started until discharge.

Outcomes

The percentage of infants receiving more than 50% of their nutritional needs via enteral feeding on the 14th day of life.
Nutrition on day 14 (more than 50% of calories received enterally and total calories delivered enterally)
Nosocomial infections
Sepsis with positive blood culture
Duration of antibiotic use
Necrotizing enterocolitis
Duration of ventilatory support
Duration of CPAP
Duration of oxygen therapy
Systemic postnatal corticoid treatment
Duration of hospital stay
Death

Notes

France
Period of study: Aprill 2005 - January 2007
Published: 2009
Source of Funding:from the Programme Hospitalier de Recherche Clinique of the French Ministry of Health and the De´le´gation a` la Recherche Clinique, CHU de Nantes.

Risk of bias table
Item Judgement Description
Adequate sequence generation? Yes

Method of generating randomization sequence: In-house software (Nantes University Hospital, Nantes, France)

Allocation concealment? Yes

Allocation concealment: Possibly adequate

Blinding? Yes

Blinding of intervention: Yes
Blinding of outcome measurement: Yes

Incomplete outcome data addressed? Yes

Complete follow-up: Yes

Free of selective reporting? Yes
Free of other bias? Yes

Samanta 2009

Methods

Prospective randomized double-blind control trial
Method of generating randomization sequence: Can't tell
Allocation concealment: Can't tell
Blinding of intervention: Can't tell
Blinding of outcome measurement: Can't tell
Complete follow-up: Yes

Participants

Gestational age < 32 weeks and VLBW infants (< 1500 g) started feed enterally and survived beyond 48 h of life
Demographic data:
Probiotics Group N=91, gestational age 30.12 (weeks) (1.63), birth weight 1172 (143)
Control Group N=95, gestational age 30.14 (weeks) (1.59), birth weight 1210 (143)

Interventions

The probiotic group received a probiotic mixture (Bifidobacteria infantis, Bifidobacteria bifidum, Bifidobacteria longum and Lactobacillus acidophilus, each 2.5 billion CFU) with expressed breast milk twice daily, the dosage being 125 g kg-1 till discharge. The control group was fed with breast milk only.

Outcomes

Feed tolerance in terms of days required to reach full enteral feeding
Length of hospital stay
NEC
Sepsis
Death due to NEC or sepsis

Notes

Neonatal Care Unit of Medical College and Hospital, Kolkata, India
Period of study: October 2007 - March 2008
Published: 2009
Source of Funding: not specified in paper

Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear

Method of generating randomization sequence: Can't tell

Allocation concealment? Unclear

Allocation concealment: Can't tell

Blinding? Unclear

Blinding of intervention: Can't tell
Blinding of outcome measurement: Can't tell

Incomplete outcome data addressed? Yes

Complete follow-up: Yes

Free of selective reporting? Unclear
Free of other bias? Unclear

Sari 2010

Methods

Single Center
Method of generating randomization sequence: Sequential numbers generated at the computer center of the NICU
Allocation concealment: Can't tell
Blinding of intervention: Can't tell
Blinding of outcome measurement: Yes
Complete follow-up: Yes

Participants

Gestational age < 33 weeks or birth weight < 1500 g
Demographic data:
Probiotics Group N=110, gestational age 29.5 (weeks) (2.4), birth weight 1231 (262)
Control Group N=111, gestational age 29.7 (weeks) (2.4), birth weight 1278 (282)

Interventions

VLBW infants who survived to start enteral feeding were randomized
The study group were given L. sporogenes with a dose of 350.000.000 colony forming units added to breast milk or formula once a day starting with first feed until discharge.
The control group were fed without L. sporogenes supplementation.

Outcomes

Death or severe NEC
NEC (stage 2, 3, greater than/or equal to 2)
Death (attributable to NEC, not attributable to NEC)
Total parental nutrition
Intraventricular hemorrhage, grade 3-4,
Sepsis (culture proven, gram negative, gram positive, fungus)
NICU stay
Feeding (amount, full feeding, intolerance)
Weight gain

Notes

Turkey
Period of study: October 2008 and June 2009
Published: Unpublished
Source of Funding: not specified in paper

Risk of bias table
Item Judgement Description
Adequate sequence generation? Yes

Method of generating randomization sequence: Sequential numbers generated at the computer center of the NICU

Allocation concealment? Unclear

Allocation concealment: Can't tell

Blinding? Unclear

Blinding of intervention: Can't tell
Blinding of outcome measurement: Yes

Incomplete outcome data addressed? Yes

Complete follow-up: Yes

Free of selective reporting? Yes
Free of other bias? Unclear

Stratiki 2007

Methods

Single Center
Method of generating randomization sequence: Can't tell
Allocation concealment: Can't tell
Blinding of intervention: Yes
Blinding of outcome measurement: Yes
Complete follow-up: Yes

Participants

Gestational age between 27 and 37 weeks, stable state, formula fed
Demographic data:
Probiotics Group N=, gestational age (weeks), birth weight
Control Group N=, gestational age (weeks), birth weight

Interventions

81 infants
Group A (study group) was given a BL supplemented preterm formula – Prenan Nestlé – (BLSPF) at a concentration of 2×107 cfu/g of milk powder.
Group B (control) received exactly the same formula but without the addition of BL.

Outcomes

Intestinal permeability
Somatic growth
Tolerance
Sepsis
Necrotizing enterocolitis

Notes

Greece
Period of study: January 2004 - December 2005
Published: 2007
Source of Funding: not specified in paper (Nestlé Company, Vevey provide the B. lactis supplemented milk formula)

Risk of bias table
Item Judgement Description
Adequate sequence generation? Unclear

Method of generating randomization sequence: Can't tell

Allocation concealment? Unclear

Allocation concealment: Can't tell

Blinding? Yes

Blinding of intervention: Yes
Blinding of outcome measurement: Yes

Incomplete outcome data addressed? Yes

Complete follow-up: Yes

Free of selective reporting? No

Important patient oriented clinical outcomes are not included

Free of other bias? Unclear

Agarwal 2003

Reason for exclusion

No clinical outcomes were presented

Stansbridge 1993

Reason for exclusion

No clinical outcomes were presented

Uhlemann 1999

Reason for exclusion

Data included full term infants

Braga

Study name

The efficacy of probiotics for prevention of necrotising enterocolitis in very low birth weight infants: a randomised clinical trial

Methods

Randomised controlled trial

Participants

Infants with birth weight from 750 g to 1500 g admitted in the Neonatal intensive Care Unit of the Institute for Maternal/Infant Health (Instituto Materno Infantil de Pernambuco [IMIP]).

Interventions

The participants will be randomised into two groups of 315 infants:
Control group: 3 ml of pasteurised human milk once a day on the second to the 30th day of life, or at the discharge if it happens before the 30th day.
Intervention group: Lactobacillus casei and Bifidobacterium breve (Yakult - LB) diluted with 3 ml of pasteurised human milk once a day on the second to the 30th day of life, or at the discharge if it happens before the 30th day.

Outcomes

Primary:

The frequency of the necrotising enterocolitis classified as higher or equal to 2 according to Bell's criteria

Secondary:

  1. The frequency of pathogenic bacteria in the faeces
  2. The duration of birth weight recovery
  3. Time to reach full enteral feeds
  4. The hospital stay
Starting date

Not mentioned

Contact information

Prof Taciana Duque- Braga
IMIP - UTI Neonatal
Rua dos Coelhos, 300

Notes

Brazil
IsrcTN67165178

Costeloe

Study name

The administration of probiotic to premature babies to prevent infection, severe intestinal complication (i.e. necrotising enterocolitis) and death

Methods

Multi-centre double-blind placebo-controlled randomised trial

Participants
  1. Both males and females, born before 31 completed weeks of gestation, i.e. up to and including 30 weeks + 6 days by the best estimate of Expected Date of Delivery
  2. Less than 48 hours old
  3. With written informed parental consent
  4. Babies already on antibiotics for suspected or proven infection are eligible for recruitment to the study
Interventions

Bifidobacterium breve strain BBG (B breve BBG).
The placebo is corn starch alone.
Both products are manufactured in identical foil sachets each containing 1 gram of product.
The intervention will be given once daily starting as soon as possible after randomisation and continuing until 36 completed weeks of post-menstrual age (36 weeks + 0 days) or death or discharge from hospital if sooner.
1, 300 babies will be recruited over 30 months.

Outcomes

Primary:

  1. Any baby with an episode of blood stream infection, with any organism other than a skin commensal
  2. Necrotising enterocolitis, Bell stage II or III
  3. Death before discharge

Secondary:

  1. Number of babies with the composite outcome of any or a combination of the 3 primary outcomes
    Outcomes 2 to 7 are for samples taken more than 72 hours after birth and before death or discharge home:
  2. Number of babies with any positive blood culture with an organism recognised as a skin commensal e.g. CoNS or Corynebacteria
  3. Number of babies with blood cultures taken
  4. Number of blood cultures taken per baby
  5. Number of babies with episodes of blood stream infection with organisms other than skin commensals by organism
  6. Number of babies with isolates of organisms other than skin commensals from a normally sterile site other than blood
  7. Number of babies with a positive culture of B breve BBG from any normally sterile site
  8. Total duration of days of antibiotics and/or anti-fungals administered per baby after 72 hours and until death or discharge
  9. The number of babies colonised with the administered probiotic strain
  10. Stool flora
  11. Age at achieving full enteral nutrition (defined as 150 ml/kg/day for 1 day)
  12. Change of weight Z score from birth to 36 weeks post-menstrual age or discharge from hospital if sooner
  13. Broncho-pulmonary dysplasia
  14. Hydrocephalus and/or intraparenchymal cysts confirmed by cerebral ultrasound scan performed during the baby's in-patient stay
  15. Worst stage of retinopathy of prematurity in either eye at discharge or death
  16. Length of stay in intensive, high dependency and special care (British Association of Perinatal Medicine (BAPM) 2001: definitions)
Starting date

01/12/2009

Contact information

Prof Kate Costeloe
Barts and the London School of Medicine and Dentistry
Neonatal Unit
Homerton University Hospital
Homerton Row

Notes

UK
IsrcTN05511098

Lozano

Study name

Prophylactic Probiotics for the Prevention of Sepsis and NEC in Premature Infants in Colombia. A Randomized Double-Blind, Multicenter Trial

Methods

Randomized Double-Blind, Multicenter Trial

Participants

Admission to the NICU
Written parental consent
Birth weight < 2000 grams
Hemodynamically stable
Less than 48 hours of age

Interventions

Lactobacillus reuteri DSM 17938 will be administered at a dose of ten to the eighth colony-forming units in 5 drops of a commercially available oil suspension once per day until discharge from the hospital.
Dietary Supplement: Placebo 5 drops of an available oil suspension without Lactobacillus reuteri

Outcomes

Primary Outcome Measures: Number of deaths and episodes of nosocomial sepsis among probiotic exposed and non-exposed preterm infants.
Secondary Outcome Measures: Number of episodes of necrotizing enterocolitis experienced by each premature infant randomized to probiotic exposure or to placebo.

Starting date

Recruiting

Contact information

Juan M Lozano, MD, Msc jmlozano@javeriana.edu.co
Maria X Rojas, RN, Msc mxrojas@javeriana.edu.co

Notes

Colombia
NCT00727363

Tobin

Study name

The use of probiotics to reduce the incidence of sepsis in premature infants

Methods

Randomised placebo controlled trial

Participants

Infants born/transferred to participating hospital within 72 hrs of birth.
The birthweight of the infant is < 1500 g and < 32 weeks gestation.

Interventions

Probiotic combination (ABC Dophilus Infant Powder). The intervention ABC Dophilus infant powder contains 1x10^9 of total organisms, consisting of 3 bacterial strains (Bifidobacterium infantis, Bifidobacterium bifidus, Streptococcus thermophilus). This is presented in a powder form in a jar, which is opened, 0.5 teaspoon mixed with 3ml feed and given daily by mouth/nasogastric tube, from the start of milk feeds until discharged home or term (40 weeks post menstrual age), whichever comes first.
The placebo will appear identical to the probiotic and consists of maltodextrin.

Outcomes

Primary:

The incidence of proven or probable late onset sepsis (>48 hrs after birth)
Secondary:

The incidence of necrotising enterocolitis, death, length of the primary hospital admission including proportion experiencing prolonged hospital stay, number of courses of antibiotics, number of days until full oral feeds established (120 ml/kg).
Weight, length and head circumference
A maternal questionnaire will be used to report atopic eczema, but will also note food allergies, and wheeze from term until 12 months corrected age.

Starting date

1/03/2007

Contact information

Dr Jacinta Tobin
The Roayl Women's Hospital 132 Grattan Street Carlton VIC 3053

Notes

Australia
ACTRN12607000144415

[top]

References to studies

Included studies

Bin-Nun 2005

Bin-Nun A, Bromiker R, Wilschanski M, Kaplan M, Rudensky B, Caplan M, Hammerman C. Oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates. Journal of Pediatrics 2005;147:192-6.

Costalos 2003

Costalos C, Skouteri V, Gounaris A, Sevastiadou S, Triandafilidou A, Ekonomidou C et al. Enteral feeding of premature infants with Saccharomyces boulardii. Early Human Development 2003;74:89-96.

Dani 2002

Dani C, Biadaioli R, Bertini G, Martelli E, Rubaltelli F. Probiotics feeding in prevention of urinary tract infection, bacterial sepsis and necrotizing enterocolitis in preterm infants. A prospective double-blind study. Biology of the Neonate 2002;82:103-8.

Kitajima 1997

Kitajima H, Sumida Y, Tanaka R, Yuki, Takayama H, Fujimura M. Early administration of Bifidobacterium breve to preterm infants: randomised controlled trial. Archives of Disease in Childhood Fetal Neonatal Ed 1997;76:F101-7.

Li 2004

Li Y, Shimizu T, Hosaka A, Kaneko N, Ohtsuka Y, Yamashiro Y. Effects of bifidobacterium breve supplementation on intestinal flora of low birth weight infants. Pediatrics International 2004;46:509-5.

Lin 2005

Lin HC, Su BH, Chen AC, Lin TW, Tsai CH, Yeh TF, Oh W. Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2005;115:1-4.

Lin 2008

Lin HC, Hsu CH, Chen HL, Chung MY, Hsu JF, Lien RI, et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: a multicenter, randomized, controlled trial. Pediatrics 2008;122(4):693–700.

Manzoni 2006

Manzoni P, Mostert M, Leonessa ML, Priolo C, Farina D, Monetti C, et al. Oral supplementation with Lactobacillus casei subspecies rhamnosus prevents enteric colonization by Candida species in preterm neonates: a randomized study. Clinical Infectious Disease 2006;42(12):1735-42.

Manzoni 2009

Manzoni P, Rinaldi M, Cattani S, Pugni L, Romeo MG, Messner H, et al. Bovine lactoferrin supplementation for prevention of late-onset sepsis in very low-birth-weight neonates: a randomized trial. JAMA 2009;302(13):1421-8. [DOI: 10.1001/jama.2009.1403]

Millar 1993

Millar MR, Bacon C, Smith SL, Walker V, Hall MA. Enteral feeding of premature infants with Lactobacillus GG. Archives of Disease in Childhood 1993;69:483-7.

Mohan 2006

Published and unpublished data

Mohan R, Koebnick C, Schildt J, Schmidt S, Mueller M, Possner M, et al. Effects of Bifidobacterium lactis Bb12 supplementation on intestinal microbiota of preterm infants: a double-blind, placebo-controlled, randomized study. Journal of Clinical Microbiology 2006;44(11):4025–31. [DOI: 10.1128/JCM.00767-06]

Reuman 1986

Reuman PD, Duckworth DH, Smith KL, Kagan R, Bucciarelli RL, Ayoub EM. Lack of effect of Lactobacillus on gastrointestinal bacterial colonization in premature infants. Pediatric Infectious Disease 1986;5:663-8.

Rougé 2009

Rougé C, Piloquet H, Butel MJ, Berger B, Rochat F, Ferraris L, et al. Oral supplementation with probiotics in very low-birth-weight preterm infants: a randomized, double-blind, placebo-controlled trial. American Journal of Clinical Nutrition 2009;89(6):1828-35.

Samanta 2009

Samanta M, Sarkar M, Ghosh P, Ghosh J, Sinha M, Chatterjee S. Prophylactic probiotics for prevention of necrotizing enterocolitis in very low birth weight newborns. Journal of Tropical Pediatrics 2009;55(2):128-31.

Sari 2010

Published and unpublished data

Sari FN, Dizdar EA, Oguz S, Erdeve O, Uras N, Dilmen U. Oral probiotics: Lactobacillus sporogenes for prevention of necrotizing enterocolitis in very low-birth weight infants: a randomized, controlled trial. European Journal of Clinical Nutrition 2011;Jan 19:Epub ahead of print.

Stratiki 2007

Stratiki Z, Costalos C, Sevastiadou S, Kastanidou O, Skouroliakou M, Giakoumatou A, et al. The effect of a bifidobacter supplemented bovine milk on intestinal permeability of preterm infants. Early Human Development 2007;83(9):575–9.

Excluded studies

Agarwal 2003

Agarwal R, Sharma N, Chaudhry R, Deorari A, Paul VK, Gewolb IH, Panigrahi P. Effects of oral Lactobacillus GG on enteric microflora in low-birth-weight neonates. Journal of Pediatric Gastroenterology and Nutrition 2003;36:397-402.

Stansbridge 1993

Stansbridge EM, Walker V, Hall MA, Smith SL, Millar MR, Bacon C, Chen S. Effects of feeding premature infants with Lactobacillus GG on gut fermentation. Archives of Disease in Childhood 1993;69:488-92.

Uhlemann 1999

Uhlemann M, Heine W, Mohr C, Plath C, Pap S. Effects of oral administration of bifidobacteria on intestinal microflora in premature and newborn infants newborn infants. Zeitschrift fur Geburtshilfe und Neonatologie 1999;203:213-17.

Studies awaiting classification

  • None noted.

Ongoing studies

Braga

Unpublished data only [IsrcTN: 67165178]

Costeloe

Unpublished data only [IsrcTN: 05511098]

Lozano

Unpublished data only [Other: NCT00727363]

Tobin

Unpublished data only [Other: ACTRN12607000144415]

Other references

Additional references

Bell 1978

Bell MJ, Ternberg JL, Feigin RD, Keating JP, Marshall R, Barton L, Brotherton T. Neonatal necrotizing enterocolitis. Therapeutic decisions based upon clinical staging. Annals of Surgery 1978;187:1-7. [MEDLINE: 44]

Bisquera 2002

Bisquera JA, Cooper TR, Berseth CL. Impact of necrotizing enterocolitis on length of stay and hospital charges in very low birth weight infants. Pediatrics 2002;109:423-8. [MEDLINE: 24]

Caplan 2001

Caplan MS, Jilling T. New concepts in necrotizing enterocolitis. Current Opinion in Pediatrics 2001;13:111-5. [MEDLINE: 20]

Deshpande 2010

Deshpande G, Rao S, Patole S, Bulsara M. Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates. Pediatrics 2010;125(5):921-30. [DOI: 10.1542/peds.2009-1301]

Duffy 2000

Duffy LC. Interactions mediating bacterial translocation in the immature intestine. Journal of Nutrition 2000;130:432S-36S. [MEDLINE: 39]

Gewolb 1999

Gewolb IH, Schwalbe RS, Taciak VL, Harrison TS, Panigrahi P. Stool microflora in extremely low birthweight infants. Archives of Disease in Childhood Fetal and Neonatal Edition 1999;80:F167-73. [MEDLINE: 34]

Goldmann 1978

Goldmann DA, Leclair J, Macone A. Bacterial colonization of neonates admitted to an intensive care environment. Journal of Pediatrics 1978;93:288-93. [MEDLINE: 33]

Holman 1997

Holman RC, Stoll BJ, Clarke MJ, Glass RI. The epidemiology of necrotizing enterocolitis infant mortality in the United States. American Journal of Public Health 1997;87:2026-31. [MEDLINE: 21]

Kafetzis 2003

Kafetzis DA, Skevaki C, Costalos C. Neonatal necrotizing enterocolitis: an overview. Current Opinion in Infectious Diseases 2003;16:349-55. [MEDLINE: 19]

Kosloske 1984

Kosloske AM. Pathogenesis and prevention of necrotizing enterocolitis: a hypothesis based on personal observation and a review of the literature. Pediatrics 1984;74:1086-92. [MEDLINE: 27]

Kosloske 1990

Kosloske AM. A unifying hypothesis for pathogenesis and prevention of necrotizing enterocolitis. Journal of Pediatrics 1990;117:S68-S74. [MEDLINE: 30]

Kosloske 1994

Kosloske AM. Epidemiology of necrotizing enterocolitis. Acta Paediatrica Suppl 1994;396:2-7.

La Gamma 1994

La Gamma EF, Browne LE. Feeding practices for infants weighing less than 1500 G at birth and the pathogenesis of necrotizing enterocolitis. Clinics in Perinatology 1994;21:271-306. [MEDLINE: 29]

Lee 2003

Lee JS, Polin RA. Treatment and prevention of necrotizing enterocolitis. Seminars in Neonatology 2003;8:449-59. [MEDLINE: 22]

Link-Amster 1994

Link-Amster H, Rochat F, Saudan KY, Mignot O, Aeschlimann JM. Modulation of a specific humoral immune response and changes in intestinal flora mediated through fermented milk intake. FEMS Immunology and Medical Microbiology 1994;10:55-63. [MEDLINE: 40]

Mattar 2001

Mattar AF, Drongowski RA, Coran AG, Harmon CM. Effect of probiotics on enterocyte bacterial translocation in vitro. Pediatric Surgery International 2001;17:265-8. [MEDLINE: 37]

Millar 2003

Millar M, Wilks M, Costeloe K. Probiotics for preterm infants? Archives of Disease in Childhood Fetal and Neonatal Edition 2003;88:F354-8. [MEDLINE: 35]

Musemeche 1986

Musemeche CA, Kosloske AM, Bartow SA, Umland ET. Comparative effects of ischemia, bacteria, and substrate on the pathogenesis of intestinal necrosis. Journal of Pediatric Surgery 1986;21:536-8. [MEDLINE: 31]

Neu 1996

Neu J. Necrotizing enterocolitis: the search for a unifying pathogenic theory leading to prevention. Pediatric Clinics of North America 1996;43:409-32. [MEDLINE: 26]

Orrhage 1999

Orrhage K, Nord CE. Factors controlling the bacterial colonization of the intestine in breastfed infants. Acta Paediatrica Suppl 1999;88:47-57. [MEDLINE: 36]

Reid 2001

Reid G, Howard J, Gan BS. Can bacterial interference prevent infection? Trends in Microbiology 2001;9:424-8. [MEDLINE: 38]

Richard 1988

Richard V, Van der Auwera AP, Snoeck R, Daneau D, Meunier F. Nosocomial bacteremia caused by Bacillus species. European Journal of Clinical Microbiology and Infectious Diseases 1988;7:783-5. [MEDLINE: 43]

Ricketts 1994

Ricketts RR. Surgical treatment of necrotizing enterocolitis and the short bowel syndrome. Clinics in Perinatology 1994;21:365-87. [MEDLINE: 23]

Soll 2010

Soll RF. Probiotics: are we ready for routine use? Pediatrics 2010;125(5):1071-2.

Stoll 1996

Stoll BJ, Gordon T, Korones SB, Shankaran S, Tyson JE, Bauer CR et al. Late-onset sepsis in very low birth weight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network. Journal of Pediatrics 1996;129:63-71. [MEDLINE: 28]

Stoll 2002a

Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, et al. Late-onset sepsis in very low birth weight neonates: the experience of the NICHD Neonatal Research Network. Pediatrics 2002;110(2 Pt 1):285-91.

Stoll 2002b

Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, et al. Changes in pathogens causing early-onset sepsis in very-low-birth-weight infants. New England Journal of Medicine 2002;347:240-7.

Stoll 2004

Stoll BJ, Hansen NI, ms-Chapman I, Fanaroff AA, Hintz SR, Vohr B, Higgins RD. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004;292:2357-65. [MEDLINE: 25]

Tarnow-Mordi 2010

Tarnow-Mordi WO, Wilkinson D, Trivedi A, Brok J. Probiotics reduce all-cause mortality and necrotizing enterocolitis: it is time to change practice. Pediatrics 2010;125(5):1068-70.

Walsh 1986

Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatric Clinics of North America 1986;33:179-201. [MEDLINE: 45]

Other published versions of this review

Al Faleh 2008

Alfaleh K, Bassler D. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD005496. DOI: 10.1002/14651858.CD005496.pub2 .

[top]

Data and analyses

1 Probiotics vs. control

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Severe necrotising enterocolitis (stage II-III) 13 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.1.1 All Infants 13 2747 Risk Ratio (M-H, Fixed, 95% CI) 0.35 [0.24, 0.52]
1.1.2 Less than 1500 g at birth 12 2678 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.23, 0.50]
1.1.3 High quality studies 4 1705 Risk Ratio (M-H, Fixed, 95% CI) 0.25 [0.13, 0.49]
1.2 Mortality 11 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
1.2.1 All cause neonatal mortality 10 2331 Risk Ratio (M-H, Fixed, 95% CI) 0.40 [0.27, 0.60]
1.2.2 NEC reported mortality 5 1476 Risk Ratio (M-H, Fixed, 95% CI) 0.31 [0.10, 0.94]
1.3 Sepsis 13 2706 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.76, 1.07]
1.3.1 Culture proven sepsis 13 2706 Risk Ratio (M-H, Fixed, 95% CI) 0.90 [0.76, 1.07]
1.4 Parenteral nutrition duration (days) 2 Mean Difference (IV, Fixed, 95% CI) Subtotals only
1.4.1 Dani 2002 1 585 Mean Difference (IV, Fixed, 95% CI) -1.90 [-4.57, 0.77]
1.4.2 Lin 2005 1 367 Mean Difference (IV, Fixed, 95% CI) 0.80 [-0.30, 1.90]
1.5 Hospitalization days 5 Mean Difference (IV, Fixed, 95% CI) Subtotals only
1.5.1 Mean (SD) 5 1111 Mean Difference (IV, Fixed, 95% CI) -6.08 [-7.08, -5.09]
1.6 Weight gain 4 Mean Difference (IV, Fixed, 95% CI) Subtotals only
1.6.1 g/week 1 87 Mean Difference (IV, Fixed, 95% CI) 7.20 [-0.06, 14.46]
1.6.2 g/day 1 30 Mean Difference (IV, Fixed, 95% CI) 1.00 [-3.35, 5.35]
1.6.3 g/kg/day 2 241 Mean Difference (IV, Fixed, 95% CI) 0.28 [-0.93, 1.49]
1.7 Time to full enteral feeds 3 726 Mean Difference (IV, Fixed, 95% CI) -4.28 [-4.81, -3.75]
1.8 Death or severe NEC or sepsis 1 367 Risk Ratio (M-H, Fixed, 95% CI) 0.54 [0.37, 0.79]
1.9 Long-term outcomes 1 85 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.15, 6.94]
1.9.1 Mental retardation and Cerebral palsy 1 85 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.15, 6.94]

[top]

Figures

Figure 1 (Analysis 1.1)

Refer to caption

Funnel plot of comparison: 1 Probiotics vs. control, outcome: 1.1 Severe Necrotising Enterocolitis (stage II-III).

Sources of support

Internal sources

  • McMaster University Medical Center, Canada

External sources

  • No sources of support provided.

Feedback

1 Davies, 09 May 2008

Summary

I read with interest the review by AlFaleh and Bassler. It was a well conducted systematic review that revealed that the use of probiotics in preterm infants significantly reduces the incidence of NEC and death in preterm infants. I am not sure why the authors have concluded that probiotics should only be used for preterm infants with a birth weight greater than 1000 grams. If we assume that the data on birth weight from individual studies are normally distributed, we can surmise from the mean birth weight and standard deviations that approximately 25% of babies included in the studies that contribute to the two main meta-analyses (for the outcomes of severe NEC and mortality) had a birth weight of less than 1000 grams. Only about 3% or less had a birth weight of greater than 1500 grams. The authors conclusions imply that the use of probiotics is supported for infants who are preterm (born at < 37 weeks gestational age) and who had a birth weight of >1500 grams (less than ~3% of the study population), but is not supported for infants who had a birth weight of < 1000 grams (~25% of the study population). The results of the review and its meta-analysis are highly significant, both statistically and clinically. They should be applicable to the population of infants that contributed to the pooled data, i.e., preterm babies who were (almost all) < 1500 grams at birth.

The authors should provide justification for their recommendation that extremely low birth weight infants should not be given this intervention that provides a 57% reduction in the risk of death. Also, if further large randomized controlled trial[s] are done they must include assessment of long-term neurodevelopmental outcomes, not just important intermediate neonatal outcomes.

Reply

We first would like to thank you for your thoughtful comments on our recently published systematic review. Your question/comment was a one that we have thought of and discussed quite extensively prior to the publication of the review.

Although we agree that the efficacy of the probiotics in prevention of NEC or mortality holds true for the ELBW infant, we could not ensure the safety of this new intervention in a highly vulnerable group with the number of infants enrolled; especially with few cases of probiotics species sepsis reported in the literature.

Contributors

Khalid M. Al-Faleh, July 2008


This review is published as a Cochrane review in The Cochrane Library, Issue 3, 2011 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent recent version of the review.