Longchain polyunsaturated fatty acid supplementation in preterm infants

Review question: Whether feeding premature babies with formula milk supplemented with longchain polyunsaturated fatty acids (LCPUFA) results in improved vision and overall neurodevelopment.
LCPUFA are a type of fatty acid necessary for the maturation of the brain and retina. Unlike breast milk that contains high levels of LCPUFA, most infant formulae are known to only contain minimal amounts of LCPUFA. Babies fed with breast milk are known to have more mature visual skills and a higher IQ (intelligence quotient) than babies fed with formula milk. It has been suggested that the relatively high levels of LCPUFA found in breast milk may contribute to the higher IQ levels and visual skills. Some milk formulae are available with added LCPUFA, usually as fish oil.
Study characteristics:
Studies that compared the outcomes of premature babies (born at < 37 weeks of pregnancy) who were given formula milk enriched with LCPUFA versus formula milk without enrichment with LCPUFA were analysed in this review.
Key results:
The researchers found that premature babies fed formula milk supplemented with LCPUFA do not have better outcomes compared to those fed formula milk without LCPUFA.
Quality of evidence:
The overall quality of evidence was considered low.

Authors' conclusions: 

Infants 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. On pooling of results, no clear long-term benefits or harms were demonstrated for preterm infants receiving LCPUFA-supplemented formula.

Read the full abstract...

Controversy exists over whether longchain polyunsaturated fatty acids (LCPUFA) are essential nutrients for preterm infants because they may not be able to synthesise sufficient amounts of LCPUFA to meet the needs of the developing brain and retina.


To assess whether supplementation of formula milk with LCPUFA is safe and of benefit to preterm infants. The main areas of interest were the effects of supplementation on the visual function, development and growth of preterm infants.

Search strategy: 

Trials were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2) in the Cochrane Library (searched 28 February 2016), MEDLINE Ovid (1966 to 28 February 2016), Embase Ovid (1980 to 28 February 2016), CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1980 to 28 February 2016), MEDLINE In Process & Other Non-indexed Citations (1966 to 28 February 2016) and by checking reference lists of articles and conference proceedings. We also searched ClinicalTrials.gov (13 April 2016). No language restrictions were applied.

Selection criteria: 

All randomised trials evaluating the effect of LCPUFA-supplemented formula in enterally-fed preterm infants (compared with standard formula) on visual development, neurodevelopment and physical growth. Trials reporting only biochemical outcomes were not included.

Data collection and analysis: 

All authors assessed eligibility and trial quality, two authors extracted data separately. Study authors were contacted for additional information.

Main results: 

Seventeen trials involving 2260 preterm infants were included in the review. The risk of bias varied across the included trials with 10 studies having low risk of bias in a majority of the domains. The median gestational age (GA) in the included trials was 30 weeks and median birth weight (BW) was 1300 g. The median concentration of docosahexaenoic acid (DHA) was 0.33% (range: 0.15% to 1%) and arachidonic acid (AA) 0.37% (range: 0.02% to 0.84%).

Visual acuity

Visual acuity over the first year was measured by Teller or Lea acuity cards in eight studies, by visual evoked potential (VEP) in six studies and by electroretinogram (ERG) in two studies. Most studies found no significant differences in visual acuity between supplemented and control infants. The form of data presentation and the varying assessment methods precluded the use of meta-analysis. A GRADE analysis for this outcome indicated that the overall quality of evidence was low.

Three out of seven studies reported some benefit of LCPUFA on neurodevelopment at different postnatal ages. Meta-analysis of four studies evaluating Bayley Scales of Infant Development at 12 months (N = 364) showed no significant effect of supplementation (Mental Development Index (MDI): MD 0.96, 95% CI −1.42 to 3.34; P = 0.43; I² = 71% — Psychomotor DeveIopment Index (PDI): MD 0.23, 95% CI −2.77 to 3.22; P = 0.88; I² = 81%). Furthermore, three studies at 18 months (N = 494) also revealed no significant effect of LCPUFA on neurodevelopment (MDI: MD 2.40, 95% CI −0.33 to 5.12; P = 0.08; I² = 0% — PDI: MD 0.74, 95% CI −1.90 to 3.37; P = 0.58; I² = 54%). A GRADE analysis for these outcomes indicated that the overall quality of evidence was low.

Physical growth
Four out of 15 studies reported benefits of LCPUFA on growth of supplemented infants at different postmenstrual ages (PMAs), whereas two trials suggested that LCPUFA-supplemented infants grow less well. One trial reported mild reductions in length and weight z scores at 18 months. Meta-analysis of five studies (N = 297) showed increased weight and length at two months post-term in supplemented infants (Weight: MD 0.21, 95% CI 0.08 to 0.33; P = 0.0010; I² = 69% — Length: MD 0.47, 95% CI 0.00 to 0.94; P = 0.05; I² = 0%). Meta-analysis of four studies at a corrected age of 12 months (N = 271) showed no significant effect of supplementation on growth outcomes (Weight: MD −0.10, 95% CI −0.31 to 0.12; P = 0.34; I² = 65% — Length: MD 0.25; 95% CI −0.33 to 0.84; P = 0.40; I² = 71% — Head circumference: MD −0.15, 95% CI −0.53 to 0.23; P = 0.45; I² = 0%). No significant effect of LCPUFA on weight, length or head circumference was observed on meta-analysis of two studies (n = 396 infants) at 18 months (Weight: MD −0.14, 95% CI −0.39 to 0.10; P = 0.26; I² = 66% — Length: MD −0.28, 95% CI −0.91 to 0.35; P = 0.38; I² = 90% — Head circumference: MD −0.18, 95% CI −0.53 to 0.18; P = 0.32; I² = 0%). A GRADE analysis for this outcome indicated that the overall quality of evidence was low.