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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. York (UK): Centre for Reviews and Dissemination (UK); 1995-.

Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Effect of long-chain polyunsaturated fatty acid supplementation of preterm infants on disease risk and neurodevelopment: a systematic review of randomized controlled trials

LG Smithers, RA Gibson, A McPhee, and M Makrides.

Review published: 2008.

Link to full article: [Journal publisher]

CRD summary

The authors concluded that long-chain polyunsaturated fatty acid-supplemented formula did not alter neurodevelopment or risks of necrotising enterocolitis and sepsis. There was insufficient evidence for bronchopulmonary dysplasia, retinopathy of prematurity and intraventricular haemorrhage. Potential methodological limitations in the search strategy, quality assessment, and reporting of the review process make the reliability of these conclusions unclear.

Authors' objectives

To evaluate the effects of long-chain polyunsaturated fatty acid (LC-PUFA) supplementation in pre-term formula feed.


MEDLINE and EMBASE were searched to January 2007. Search terms were reported. No language restrictions were applied. Reference lists of eligible articles were scanned for further studies.

Study selection

Randomised controlled trials (RCTs) of preterm infants (less than 37 weeks gestation) fed with standard preterm formula (without LC-PUFAs) compared with those fed with formula containing n-3 and/or n-6 LC-PUFAs for one month or more were eligible for inclusion in the review. All included trials used a standard cow milk-based formula. LC-PUFA supplementation was based on fish oils, egg triacylglycerol or phospholipids, and algal and fungal oils. Some trials permitted breast-milk feeding in addition to the study interventions. Intervention periods spanned from one month to more than one year. Healthy infants and those with typical preterm concomitant morbidities were included. Studies had to report at least one of the following outcomes: neurodevelopmental assessment (using age-standardised clinically relevant techniques); sepsis; necrotising enterocolitis; bronchopulmonary dysplasia; retinopathy of prematurity; and intraventricular haemorrhage. Neurodevelopment was assessed with version I or II of the Bayley Scales of Infant Development (BSID-I and BSID-II).

The authors stated neither how the papers were selected for the review nor how many reviewers performed the selection.

Assessment of study quality

Study quality was assessed according to allocation concealment and intention to treat.

The authors did not state how many reviewers performed the validity assessment.

Data extraction

Data were extracted in order to calculate mean differences for neurodevelopmental outcomes and relative risks (RR) for disease-related outcomes, along with 95% confidence intervals (CI). Data extraction was undertaken by one reviewer. Authors were contacted for missing data, where necessary.

Methods of synthesis

Weighted mean differences (WMD) in mental development index (MDI) and psychomotor development index (PDI) scores, or relative risks that related to necrotising enterocolitis, sepsis, retinopathy of prematurity, intraventricular haemorrhage and bronchopulmonary dysplasia, were pooled in meta-analyses. Fixed-effect or random-effects models were considered, depending on the level of heterogeneity assessed using the Χ2 and I2 statistics. Subgroup analyses were conducted on the two versions of BSID using combined 12-month and 18-month age-corrected data. Subgroup analysis was conducted on severe retinopathy of prematurity and intraventricular haemorrhage (grade 3 and above). Further separate analyses were conducted on trials according to diagnostic criteria as follows: sepsis (confirmed by isolation of a pathogenic micro-organism); necrotising enterocolitis (confirmed by radiology, surgery or postmortem examination); bronchopulmonary dysplasia (requirement for oxygen therapy at 36-week postmenstrual age); and retinopathy of prematurity and intraventricular haemorrhage (according to internationally accepted definitions). Neurodevelopment data from two trials with multiple treatment groups were interpolated. Sensitivity analyses included trials with adequate allocation concealment and use of intention to treat. Publication bias was not assessed.

Results of the review

Ten RCTs (n=1,688) were included in the review. Sample sizes were small (range 28 to 427). Attrition ranged from 11% to 50%. Allocation concealment was reported adequate in six trials. Intention to treat was reported in two trials. Sensitivity analyses were conducted using two trials (n=433).

Neurodevelopment outcomes: Using BSID-II, MDI was significantly higher in infants fed with supplemented formula (WMD 3.44, 95% CI 0.56 to 6.31, p=0.02; five trials, n=879). Using BSID-I, PDI was significantly decreased in infants fed with supplemented formula (WMD -7.99, 95% CI -14 to -1.99, p=0.009; two trials, n=87). There were no other statistically significant differences between the study groups.

Sensitivity analyses revealed no differences in MDI or PDI, although results were restricted by small sample size. Moderate heterogeneity was reported (X2=14.5 to 20.72, p<0.02).

Diseases associated with prematurity: There were no statistically significant differences in all analyses of infants fed with supplemented formula compared with control for sepsis, necrotising enterocolitis, retinopathy of prematurity, intraventricular haemorrhage or bronchopulmonary dysplasia. Sensitivity analysis did not alter this result.

Authors' conclusions

LC-PUFA-supplemented formula did not show any significant benefit on global assessments of mental or psychomotor developments. The risk of necrotising enterocolitis or sepsis was unaltered. There was insufficient data to conclude benefits for retinopathy of prematurity, intraventricular haemorrhage and bronchopulmonary dysplasia.

CRD commentary

The review presented a clear research question and this was supported by explicit and potentially reproducible inclusion criteria. Although the potential for language bias was minimised, the search strategy was limited to two electronic databases and was without apparent reference to unpublished material, so relevant studies may have been missed and publication bias could not be ruled out. There was some assessment of study quality and this was used as the basis for sensitivity analysis. However, it was unclear why quality criteria were restricted to two elements. Study details were adequately supplied and the method of synthesis appeared to be appropriate in the presence of heterogeneity. The authors appropriately advised a cautious interpretation of the results due to small sample sizes and the dominance of certain trials in some analyses. A substantial threat to the reliability of this review is the authors' failure to disclose details about how studies were selected and how the validity assessment was conducted, and the extraction of data by only one reviewer. The authors conclusions reflected the evidence presented, but the extent to which these are reliable is unclear. Potential conflicts of interest were noted in relation to authors' work and infant formula manufacture.

Implications of the review for practice and research

Practice: The authors did not state any implications for practice.

Research: The authors stated that methodologically robust trials were necessary to investigate the extent of benefit from LC-PUFA-supplemented formula feed on the neurodevelopmental outcomes of preterm infants. Safety issues and inclusion of human milk-fed infants were other areas that required exploration.


Not stated.

Bibliographic details

Smithers LG, Gibson RA, McPhee A, Makrides M. Effect of long-chain polyunsaturated fatty acid supplementation of preterm infants on disease risk and neurodevelopment: a systematic review of randomized controlled trials. American Journal of Clinical Nutrition 2008; 87(4): 912-920. [PubMed: 18400714]

Indexing Status

Subject indexing assigned by NLM


Child Development /drug effects /physiology; Cognition /drug effects; Dietary Supplements; Fatty Acids, Unsaturated /administration & dosage /metabolism /pharmacology; Female; Humans; Infant; Infant Formula /chemistry; Infant Nutritional Physiological Phenomena /physiology; Infant, Newborn; Infant, Premature /growth & development; Male; Mental Health; Nutritional Status; Randomized Controlled Trials as Topic; Risk Factors; Sepsis /epidemiology; Visual Acuity /drug effects



Database entry date


Record Status

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.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 18400714

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