Khalid AlFaleh1, Jasim Anabrees2, Dirk Bassler3, Turki Al-Kharfi4
Background - Methods - Results - Characteristics of Included Studies - References - Data Tables and Graphs
1Department of Pediatrics (Division of Neonatology), King Saud University, Riyadh, Saudi Arabia
2Neonatal Intensive Care, Dr Sulaiman Al Habib Medical Group, Riyadh, Saudi Arabia
3Department of Neonatology, University Children's Hospital, Tuebingen, Germany
4Department of Pediatrics (Division of Neonatology), King Saud University, King Khalid University Hospital and College of Medicine, Riyadh, Saudi Arabia
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.
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
| 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 |
| 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. |
| Date / Event | Description |
|---|---|
| 12 November 2008 Feedback incorporated | Feedback incorporated |
| 22 July 2008 Amended | Converted to new review format. |
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.
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.
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).
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.
Standard methods of the Cochrane Collaboration and its Neonatal Group were used to assess the methodologic quality of the trials, data collection and analysis.
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.
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.
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.
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).
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).
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).
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).
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).
Enteral administration of any live microbial supplement (probiotics) at any dose for more than seven days compared to placebo or no treatment.
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.
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)
The standard methods of the Cochrane Neonatal Review Group Guidelines were employed in creating this update.
Retrieved articles were assessed for eligibility independently by two review authors. Discrepancies were resolved by discussion and consensus.
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.
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 (≥ 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.
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.
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.
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.
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).
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).
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.
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.
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.
| Methods | Single centre randomized study |
|---|---|
| Participants | 145 infants less than 1500 g at birth |
| 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. |
| Outcomes | Stage 2 or 3 NEC. |
| Notes | Israel |
| 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 |
| 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 |
| Methods | Single center randomized double blind study |
|---|---|
| Participants | 87 infants, gestational age 28-32 weeks |
| 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. |
| Outcomes | NEC |
| Notes | Greece |
| 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 |
| Incomplete outcome data addressed? | Yes | Complete follow-up: Yes |
| Free of selective reporting? | Unclear | |
| Free of other bias? | Unclear |
| Methods | Multicenter randomized double blind study (12 centers) |
|---|---|
| Participants | 585 infants, < 33 weeks gestation or <1500 g birth weight enrolled. |
| 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. |
| Outcomes | Severe NEC |
| Notes | Italy |
| 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 |
| Incomplete outcome data addressed? | Yes | Complete Follow-up: Yes |
| Free of selective reporting? | Yes | |
| Free of other bias? | Yes |
| Methods | Single center randomized study |
|---|---|
| Participants | 91 infants, birth weight <1500 g enrolled. |
| 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 |
| Outcomes | Colonization rate |
| Notes | Japan |
| 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 |
| 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 |
| Methods | Single center randomized study |
|---|---|
| Participants | 30 infants, of low birth weight. |
| 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. |
| Outcomes | Colonization rate |
| Notes | Japan |
| 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 |
| 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 |
| Methods | Single centre randomized study |
|---|---|
| Participants | 367 infants less than 1500 g at birth, survived beyond 7 days of life, and started on enteral feed were enrolled |
| 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. |
| Outcomes | Death |
| Notes | Taiwan |
| 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 |
| Incomplete outcome data addressed? | Yes | Completeness of follow up: Yes |
| Free of selective reporting? | Yes | |
| Free of other bias? | Yes |
| Methods | Multicenter trial |
|---|---|
| Participants | Very low birth weight infants (birth weight ≤1500 g) |
| 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. |
| Outcomes | Death or severe NEC |
| Notes | 7 NICUs in Taiwan |
| 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. |
| Incomplete outcome data addressed? | Yes | Completeness of follow up: Yes |
| Free of selective reporting? | Yes | |
| Free of other bias? | Yes |
| Methods | Single randomized study |
|---|---|
| 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 |
| 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. |
| Outcomes | Fungal colonization rates |
| Notes | Italy |
| 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 |
| Incomplete outcome data addressed? | Yes | Completeness of follow up: Yes |
| Free of selective reporting? | Yes | |
| Free of other bias? | Unclear |
| Methods | Multicenter trial |
|---|---|
| Participants | VLBW neonates younger than 3 days |
| Interventions | Infants received either BLF (Bovine Lactoferrin) (100mg/d) (LF100; Dicofarm SpA, Rome, Italy) alone or BLF plus LGG (6X109 colony-forming units/d) (Dicoflor60;Dicofarm SpA); the control group received placebo (2 mL of a 5% glucose solution). |
| Outcomes | First episode of late-onset sepsis |
| Notes | 11 Italian tertiary NICU |
| 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 |
| Incomplete outcome data addressed? | Yes | Completeness of follow up: Yes |
| Free of selective reporting? | Yes | |
| Free of other bias? | Yes |
| Methods | Single center randomized blinded study |
|---|---|
| Participants | 20 infants, < 33 weeks gestation enrolled. |
| Interventions | Probiotics group received milk feeds with Lactobacillus GG 108 (cfu) twice a day for 14 days, starting with first feed. |
| Outcomes | Weight gain |
| Notes | UK |
| 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 |
| 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 |
| Methods | A double-blind, placebo-controlled, randomized trial |
|---|---|
| Participants | Gestational age of less than 37 weeks |
| Interventions | 69 preterm infants |
| Outcomes | No clinical outcomes were presented in the published data |
| Notes | The Ernst von Bergmann hospital, Potsdam, Germany |
| 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 |
| 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 |
| Methods | Randomized double blind study |
|---|---|
| Participants | 45 infants, <2000 gm at birth weight who survived beyond first 24 hrs and are younger than 72 hrs |
| Interventions | Probiotics group received at least 1 ml of formula containing lactobacillus. 5×1010 organisms/ml preparation diluted 100 times in infants formula. |
| Outcomes | Death |
| Notes | US |
| 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 |
| Incomplete outcome data addressed? | Yes | Complete follow-up: Yes |
| Free of selective reporting? | No | |
| Free of other bias? | Unclear |
| Methods | Two centers |
|---|---|
| Participants | Gestational age, <32 wk, a birth weight, <1500 g |
| Interventions | Placebo group (N 49) Receive 4 daily capsules of a supplement containing maltodextrin alone |
| Outcomes | The percentage of infants receiving more than 50% of their nutritional needs via enteral feeding on the 14th day of life. |
| Notes | France |
| 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 |
| Incomplete outcome data addressed? | Yes | Complete follow-up: Yes |
| Free of selective reporting? | Yes | |
| Free of other bias? | Yes |
| Methods | Prospective randomized double-blind control trial |
|---|---|
| Participants | Gestational age <32 weeks and VLBW infants (<1500 g) started feed enterally and survived beyond 48 h of life |
| 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 |
| Notes | Neonatal Care Unit of Medical College and Hospital, Kolkata, India |
| 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 |
| Incomplete outcome data addressed? | Yes | Complete follow-up: Yes |
| Free of selective reporting? | Unclear | |
| Free of other bias? | Unclear |
| Methods | Single Center |
|---|---|
| Participants | Gestational age <33 weeks or birth weight <1500 g |
| Interventions | VLBW infants who survived to start enteral feeding were randomized |
| Outcomes | Death or severe NEC |
| Notes | Turkey |
| 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 |
| Incomplete outcome data addressed? | Yes | Complete follow-up: Yes |
| Free of selective reporting? | Yes | |
| Free of other bias? | Unclear |
| Methods | Single Center |
|---|---|
| Participants | Gestational age between 27 and 37 weeks, stable state, formula fed |
| Interventions | 81 infants |
| Outcomes | Intestinal permeability |
| Notes | Greece |
| 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 |
| 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 |
| Reason for exclusion | No clinical outcomes were presented |
|---|
| Reason for exclusion | No clinical outcomes were presented |
|---|
| Reason for exclusion | Data included full term infants |
|---|
| 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: |
| Outcomes | Primary: |
| Starting date | Not mentioned |
| Contact information | Prof Taciana Duque-Braga |
| Notes | Brazil |
| 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 |
| Interventions | Bifidobacterium breve strain BBG (B breve BBG). |
| Outcomes | Primary: |
| Starting date | 01/12/2009 |
| Contact information | Prof Kate Costeloe |
| Notes | UK |
| 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 |
| 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. |
| Outcomes | Primary Outcome Measures: Number of deaths and episodes of nosocomial sepsis among probiotic exposed and non-exposed preterm infants. |
| Starting date | Recruiting |
| Contact information | Juan M Lozano, MD, Msc jmlozano@javeriana.edu.co |
| Notes | Colombia |
| 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. |
| 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. |
| Outcomes | Primary: |
| Starting date | 1/03/2007 |
| Contact information | Dr Jacinta Tobin |
| Notes | Australia |
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| 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] |
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.
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.
This review is published as a Cochrane review in The Cochrane Library, Issue 3, 2011 (see http://www.thecochranelibrary.com 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 version of the review. |
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