BackgroundThe n-3 and n-6 essential fatty acids alpha linolenic acid (ALA) and linoleic acid (LA) are the precursors of the n-3 and n-6 longchain polyunsaturated fatty acids (LCPUFA). Controversy exists over whether LCPUFA are essential nutrients for preterm infants, who may not be able to synthesise sufficient amounts of LCPUFA to satisfy the needs of the developing brain and retina.ObjectivesThe aim of this review is to assess whether supplementation of formula with LCPUFA is safe and of benefit to preterm infants.Search strategyTrials were identified by MEDLINE (February 2007), Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2007) and by checking reference lists of relevant articles and conference proceedings.Selection criteriaAll randomised trials of formula supplemented with LCPUFA and with clinical endpoints were reviewed.Data collection and analysisFifteen randomised trials assessing the clinical effects of feeding formula supplemented with LCPUFA were included in the review.Main resultsOf the fifteen randomised trials included in the review, four of these were not classified as of high quality, due to low follow-up, uncertainty regarding concealment of patient allocation and randomisation, and problems with assessment methodology.Visual acuityVisual acuity over the first year was measured by Teller or Lea acuity cards in eight studies, by VEP in six studies and by ERG in two studies. Most studies found no significant differences in any visual assessment between supplemented and control infants.DevelopmentMost of the trials have used Bayley Scales of Infant Development (BSID) at 12 to 24 months post- term with three out of seven studies reporting some benefit of LCPUFA in different populations of supplemented infants at different postnatal ages. Meta-analysis of BSID of four studies at 12 months (N = 364) and three studies at 18 months (N = 494) post- term showed no significant effect of supplementation on neurodevelopment. Carlson 1992 and Carlson 1996 demonstrated lower novelty preferences (possibly predictive of lower intelligence) in the supplemented compared with the control group. The investigators however concluded that supplemented infants may have more rapid visual information processing given that they had more looks and each look was of shorter duration.GrowthFour out of thirteen studies reported benefits of LCPUFA on growth of supplemented infants at different postnatal ages. Two trials (Carlson 1992; Carlson 1996) suggested that LCPUFA supplemented infants grow less well than controls, possibly due to a reduction in AA levels that occurs when n-3 supplements are used without n-6 supplements. Recent trials with addition of AA to the supplement have reported no significant negative effect on growth. Fewtrell 2002 reported mild reductions in length and weight z scores at 18 months. Contrary to these results, meta-analysis of five studies (Uauy 1990; Carlson 1996; Hansen 1997; Vanderhoof 1999; Innis 2002) showed increased weight and length at two months post-term in supplemented infants. Meta-analysis of four studies at 12 months (N = 271) and two studies at 18 months (N = 396) post-term showed no significant effect of supplementation on weight, length or head circumference.Side effectsUauy 1992 reported no significant effect of LCPUFA supplementation on bleeding time and red cell membrane fragility.Authors' conclusionsInfants enrolled in the trials were relatively mature and healthy preterm infants. Assessment schedule and methodology, dose and source of supplementation and fatty acid composition of the control formula varied between trials. When the results of the RCT's are pooled, no clear long-term benefits were demonstrated for infants receiving formula supplemented with LCPUFA. There was no evidence that supplementation of formula with n-3 and n-6 LCPUFA impaired the growth of preterm infants.