|Probiotics, prebiotics infant formula use in preterm or low birth weight infants: a systematic review
|Mugambi MN, Musekiwa A, Lombard M, Young T, Blaauw R
This review concluded that there was insufficient evidence to state that supplementation of preterm infant formula milk, with probiotics or prebiotics, improved growth and clinical outcomes for preterm infants. The conclusions of the review reflected the limited extent and quality of the evidence, and are likely to be reliable.
To assess whether the addition of probiotics or prebiotics, to infant formula milk, improved growth and clinical outcomes, for preterm or low birth-weight infants.
Eleven bibliographic sources were consulted, including MEDLINE up to April 2010 and EMBASE up to December 2009. Abstracts of major conference proceedings, references from specialist journals, and relevant trials and reviews were checked for additional studies. Field experts, manufacturers of infant formula milk, and websites of companies conducting relevant trials were consulted. Searches were not restricted by language and publication status. Search terms were reported.
Randomised controlled trials (RCTs) comparing preterm infant formula milk that contained any probiotic or prebiotic, with formula milk containing no probiotic or prebiotic, or with placebo, were included. Eligible trials were of babies born at less than 37 weeks gestation, or babies weighing less than 2.5kg at birth, who were hospitalised and receiving formula milk or parenteral feed, or both. Trials of babies on breast milk or mixed feeds were excluded. The main outcomes of interest were short-term growth, weight gain, linear growth, and head growth. Secondary outcomes included complications, feeding tolerance, stool characteristics, changes in intestinal permeability, and changes in gastrointestinal micro flora. All outcomes were specified before trial selection.
Across the included trials, the time of treatment initiation differed, and a variety of probiotic and prebiotic bacteria were used. Where reported, probiotic treatment lasted 30 days, and prebiotic treatment lasted from 14 to 28 days. Maltodextrin was the most common comparator. The included trials were published between 1986 and 2009.
Two reviewers independently selected the trials for inclusion. Disagreements were resolved through discussion or with a third reviewer as needed.
Assessment of study quality
Trial quality was assessed, using the Cochrane risk of bias tool, by two reviewers independently. Disagreements were resolved through discussion between three reviewers.
Outcomes data were extracted to calculate mean differences, risk ratios, and 95% confidence intervals. Trial authors were contacted for any missing data. Two reviewers independently extracted the data, with disagreements resolved through discussion.
Methods of synthesis
Where possible, the trial data were combined in a meta-analysis to calculate pooled risk ratios and mean differences. Heterogeneity was assessed using Ι², Χ², and visual inspection of forest plots. A fixed-effect model was used to pool the data, unless significant heterogeneity was found, in which case a random-effects model was used.
Trials of probiotics and those of prebiotics were analysed separately. The effects of different types of prebiotics (galacto-oligosaccharide with fructo-oligosaccharide versus fructo-oligosaccharide alone) were explored in subgroup analyses. If the trials were considered too diverse, a narrative synthesis was provided.
Results of the review
Eight trials, four on probiotics (212 infants) and four on prebiotics (126 infants), were included in the review. Random sequence generation was appropriately reported in three trials, allocation concealment in two trials, and blinding of care providers, participants and assessors in four trials. All eight trials reported appropriately on incomplete outcome data and selective reporting. One trial reported an unspecified imbalance in patient characteristics between groups at baseline.
Probiotics: There were no statistically significant differences in mean weight gain (two trials) between probiotics and control. Two other trials reported median weight gain, and neither found a statistically significant difference between groups. One trial reported linear growth and head growth, and found no statistically significant differences between the two groups. A meta-analysis of two trials found no statistically significant differences in risk of necrotising enterocolitis and sepsis between probiotics and control, and one trial found no statistically significant difference in mortality. Other outcomes were reported.
Prebiotics: A meta-analysis of three trials found no statistically significant difference between prebiotics and control, in weight gain and linear growth, and a meta-analysis of two trials found no significant differences in head growth. Subgroup analyses found that compared with control, fructo-oligosaccharide alone had a significantly negative effect on weight gain (MD -4.60g/day, 95% CI -8.24 to -0.96), but a significantly positive effect on linear growth (0.30cm/week, 95% CI 0.27 to 0.33; one trial). No differences, compared with control, were found in the subgroup of patients receiving galacto-oligosaccharide with fructo-oligosaccharide. No trial of prebiotics reported complications. Other outcomes were reported.
There was insufficient evidence to state that supplementation of preterm infant formula milk, with probiotics or prebiotics, improved growth and clinical outcomes, for preterm infants.
The review question and selection criteria were clearly presented. The authors made thorough attempts to identify published and unpublished trials, and no language restrictions were applied. Appropriate attempts were made to minimise reviewer error and bias in trial selection, data extraction and quality assessment.
There were significant gaps in the quality of the reporting of the trials, making the quality of the evidence difficult to assess. All trials were small, and as the authors suggested, they may not have been sufficiently powered to detect meaningful effects, even when pooling was possible. The meta-analyses appear to have been appropriate, but the results of subgroup analyses should be interpreted with caution, given their limitations and the small number of trials.
The conclusions reflected the limited extent and quality of the evidence, and are likely to be reliable.
Implications of the review for practice and research
Practice: The authors stated that their review did not support the routine supplementation of preterm formula with probiotics or prebiotics.
Research: The authors stated that large RCTs, with long-term follow-up, were needed to assess if the short-term benefits in stool frequency, and changes in gastrointestinal micro flora, translated into improved general health and reduced morbidity in preterm infants. They stated that well-designed RCTs were needed to assess the time to full enteral feeds, in preterm infants on probiotics with breast milk or mixed feeds.
Supported by the University of Stellenbosch, South Africa.
Mugambi MN, Musekiwa A, Lombard M, Young T, Blaauw R. Probiotics, prebiotics infant formula use in preterm or low birth weight infants: a systematic review. Nutrition Journal 2012; 11: 58
Subject indexing assigned by NLM
Child Development; Defecation; Energy Intake; Evidence-Based Medicine; Humans; Infant; Infant Formula /chemistry; Infant, Low Birth Weight; Infant, Newborn; Infant, Premature; Prebiotics; Probiotics /administration & Randomized Controlled Trials as Topic; Weight Gain; dosage
Date bibliographic record published
Date abstract record published
This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.