Longchain polyunsaturated fatty acid supplementation in infants
born at term
Simmer K, Patole SK, Rao SC
Dates
Date edited: 12/11/2007
Date of last substantive update: 02/09/2007
Date of last minor update: / /
Date next stage expected 08/11/2009
Protocol first published: Issue 4, 1998
Review first published: Issue 4, 1998
Contact reviewer
Prof Karen Simmer
Professor of Neonatal Medicine
Neonatal Clinical Care Unit
King Edward Memorial Hospital for Women and Princess Margaret Hospital for Children
Bagot Road
Subiaco
WA AUSTRALIA
6008
Telephone 1: +61 08 9340 1262
Facsimile: +61 8 9340 1266
E-mail: Karen.Simmer@health.wa.gov.au
Contribution of reviewers
Prof. Karen Simmer was the author of the previous reviews and updates.
For this update, she was the referee author in case of disagreement between Sanjay Patole and Shripada Rao. She was also responsible for checking and editing the manuscript.
Sanjay Patole searched the literature, selected the trials eligible for inclusion, assessed the methodology, extracted the data, verified the data entered into RevMan by Shripada Rao and edited the manuscript.
Shripada Rao searched the literature, selected the trials eligible for inclusion, assessed the methodology, contacted the authors of the originial trials, extracted the data from the studies, entered them in the RevMan and wrote the review.Internal sources of support
King Edward Memorial Hospital For Women, Perth, AUSTRALIA
Princess Margaret Hospital For Childern, Perth, AUSTRALIA
External sources of support
NoneWhat's new
This review updates the existing review "Longchain polyunsaturated fatty acid supplementation of infants born at term" published in The Cochrane Library, Issue 4, 2001 (Simmer 2001). Six new randomised trials have been added to this review update. Subgroup analysis has been done based on the type of LCPUFA supplementation (DHA plus AA versus DHA alone).
Dates
Date review re-formatted: 12/09/1999
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: 31/03/2007
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /
Text of review
Synopsis
It has been suggested that low levels of long chain polyunsaturated fatty acids (LCPUFA) found in formula milk may contribute to lower IQ levels and vision skills in term infants. Some milk formulas with added LCPUFA are commercially available. This review found that feeding term infants with milk formula enriched with LCPUFA had no proven benefit regarding vision, cognition or physical growth.
Abstract
Background
The n-3 and n-6 fatty acids linolenic acid and linoleic acid are precursors of the n-3 and n-6 long chain fatty acids (LCPUFA). Infant formula has historically only contained the precursor fatty acids. Controversy exists over whether LCPUFA are also essential nutrients in infancy. Over the last few years, some manufacturers have added LCPUFA to formulae and marketed them as providing an advantage for the development of term infants.
Objectives
To assess whether supplementation of formula with LCPUFA is safe and of benefit to term infants.
Search strategy
Eligible studies were identified by searching MEDLINE (March 2007), EMBASE 1980 - 2007, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2007) and CINAHL (December 1982 - March 2007). Abstracts of the Society for Pediatric Research were hand searched from 1980 to 2006 inclusive. Reference lists of published narrative and systematic reviews were also reviewed. No language restrictions were applied.
Selection criteria
All randomised and quasi randomised trials comparing LCPUFA supplemented formula milk vs. non-supplemented formula milk and with clinical endpoints were reviewed.
Data collection & analysis
Methodological quality of eligible studies was assessed according to allocation concealment, blinding of intervention, blinding of outcome assessment and completeness of follow up. Data were sought regarding effects on visual acuity, neurodevelopmental outcomes and physical growth. When appropriate, meta-analysis was conducted to provide a pooled estimate of effect. Continuous data were analysed using weighted mean difference (WMD). There were no categorical outcomes in this review.
Main results
Twenty randomised studies were identified. Fourteen were included (n = 1719) and six excluded. Eleven included studies were of good quality. The main outcomes assessed were visual acuity, neurodevelopmental and physical growth.
Visual acuity was measured at various stages throughout the first three years of life by nine studies. Visual evoked potential was used to assess visual acuity in five studies. The remaining four used Teller visual acuity cards. The results were inconsistent. Three studies reported beneficial effect of LCPUFA supplementation on visual acuity while the remaining six did not.
Neurodevelopmental outcome was measured at different ages throughout the first two years by eleven studies. Bayley scales of infant development (BSID) was used in eight studies. Only one showed beneficial effect of LCPUFA supplementation on BSID scales. Pooled meta-analysis of the data also did not show any statistically significant benefit of LCPUFA supplementation on either mental or psychomotor developmental index of BSID. One study reported better novelty preference measured by Fagan Infant test at nine months in supplemented infants compared with controls. Another study reported better problem solving at 10 months with supplementation. One study used Brunet and Lezine developmental test to assess the developmental quotient and did not find beneficial effects of LCPUFA supplementation.
Physical growth was measured at various ages throughout first three years of life by twelve studies. Some studies reported the actual measurements while some reported the rate of growth over a time period. Some studies z scores. Irrespective of the type of LCPUFA supplementation, duration of supplementation and method of assessment, none of the individual studies found beneficial or harmful effects of LCPUFA supplementation. Meta-analysis of relevant studies also did not show any effect of LCPUFA supplementation on growth of term infants.
Reviewers' conclusions
The results of most of the well conducted RCTS have not shown beneficial effects of LCPUFA supplementation of formula milk on the physical, visual and neurodevelopmental outcomes of infants born at term. Only one group of researchers have shown some beneficial effects on VEP acuity. Two groups of researchers have shown some beneficial effect on mental development. Routine supplementation of milk formula with LCPUFA to improve the physical, neurodevelopmental or visual outcomes of infants born at term can not be recommended based on the current evidence. Further research is needed to see if the beneficial effects demonstrated by Dallas 2005 trial of Birch et al can be replicated in different settings.
Background
Dietary fat in infancy is fundamental for the provision of energy, fat soluble vitamins and essential fatty acids. Interest has recently focused on the importance of long chain polyunsaturated fatty acids (LCPUFA) such as docosahexaenoic acid (DHA) and arachidonic acid (AA) in infant nutrition. These fatty acids are found in high proportions in the structural lipids of cell membranes, particularly those of the central nervous system and retina (Fleith 2005). Their accretion primarily occurs during the last trimester of pregnancy and the first year of life (Clandinin 1980). LCPUFA are supplied during pregnancy via placental transfer and through breast milk after birth. Standard infant formulae contain only the precursor essential fatty acids (EFA), alpha-linolenic acid (ALA, the omega 3 precursor) and linoleic acid (LA, the omega 6 precursor) from which formula-fed infants must synthesise their own DHA and AA, respectively. The absence of LCPUFA in formula may be further exacerbated by inhibition of incorporation of endogenously produced LCPUFA by the high concentrations of LA in some formulae. Biochemical studies in both term and preterm infants indicate that infants fed formula unsupplemented with LCPUFA have significantly less DHA and AA in their erythrocytes relative to those fed breast milk (Clark 1992). Studies have also demonstrated that infants fed formula milk have lower levels of LCPUFA in the cerebral cortex compared to breast fed infants (Farquharson 1995) suggesting that infant formulae containing only LA and ALA may not be effective in meeting the full EFA requirements of infants.
Evidence to suggest that breast fed infants have a long-term IQ advantage over those who have been fed infant formula has been evident in the literature for many years (Rogers 1978; Morrow-Tlucak 1988; Lucas 1992; Temboury 1994). These studies are usually not randomised and therefore the majority of comparisons between breast fed and formula fed infants are confounded by genetic and socioeconomic factors. Although most of these studies do not relate their findings to fatty acid supply, some reports suggest that the low levels of LCPUFA, such as DHA, found in formula-fed infants may contribute to the lower IQ scores reported in formula-fed infants (Rogers 1978; Bjerve 1992; Neuringer 1986).
In a non-randomised, observational study, term infants fed breast milk had better VEP acuities and higher DHA levels than those receiving formula and visual function was found to correlate with DHA status (Makrides 1993). Over the last few years, some manufacturers have added LCPUFA to formulas for term infants. These formulas are frequently marketed as providing an advantage to infant development. The cost of supplemented formulas is generally higher than the unsupplemented formulas. A systematic review of both randomised and non-randomised controlled trials in term infants concluded that use of term formula supplemented with DHA can improve the visual acuity at two and probably at four months of age (SanGiovanni 2000). Another review of both animal and human studies (McCann 2005) concluded that animals with experimentally induced severe DHA deficiency benefit from DHA supplementation in their diets, but results of human studies on cognitive outcomes are inconclusive. The meta-analysis by Makrides et al (Makrides 2005) found neither benefit or harm on physical growth of term infants supplemented with either DHA alone or DHA and AA. In the past few years, further well conducted RCTs have been published addressing the issue of LCPUFA supplementation in term infants. Hence, update of this Cochrane review was undertaken to clarify the various issues regarding the role of supplementation of LCPUFA to formula fed term infants.
Objectives
To assess whether supplementation of formula with LCPUFA is safe and of benefit to term infants. The main areas of interest were the effects of LCPUFA supplementation on visual function, physical growth and neurodevelopment.
Criteria for considering studies for this review
Types of studies
Only randomised and quasi-randomised clinical trials were eligible for inclusion. A trial was defined as quasi-random if the method used to allocate study infants to the study milk formula groups was either not statistically random or was not clearly stated.
Types of participants
Healthy infants ≥ 37 weeks gestation at birth.
Types of interventions
Milk formula enriched with DHA plus AA or DHA alone compared to standard milk formula. LCPUFA supplements could be from any source including fish oil, egg triglycerides or fungal oils.
To be eligible for inclusion, the trial should have met all of the following criteria:
1. Study formula was commenced within two weeks after birth.
2. Study formula was the only source of milk from the time of randomisation until at least 8 weeks of age.
3. A minimum of three months follow-up data on clinical outcomes of interest was available.
The following trials were not eligible for inclusion:
1. Trials which used breast milk in addition to study formula during the first 8 weeks of life
2. Trials reporting on only biochemical outcomes.
Types of outcome measures
Visual acuity: measured using either using Tellers cards or visual evoked potentials.
Physical growth: weight, length and head circumference.
Neurodevelopmental outcomes: General Quotient, Intelligent Quotient and other measures of cognitive functions.
Biochemical outcomes have not been reported in this review.
Search strategy for identification of studies
The standard search strategy of the Cochrane Neonatal Review Group was used. This included electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2007, EMBASE (1980 - March 2007) and CINAHL (1982 - March 2007). Abstracts of Paediatric Academic Societies meetings published in Pediatric Research (1995 - 2006) were hand searched. Pub Med and EMBASE were searched for relevant articles using the following MeSH terms or text words: Fatty acids, Unsaturated OR Arachidonic Acid OR Docosahexanoic acid OR Fatty acids, Omega-3 OR fatty acids Omega-6 OR fatty acids, essential AND Infant, Newborn OR Neonate AND clinical trial OR Randomised Controlled Trial. Reference lists of published narrative and systematic reviews were also reviewed. No language restrictions were applied. Two review authors (SR and SP) independently searched various databases to identify the trials eligible for inclusion. The authors of studies were contacted to clarify reported data or provide additional data including details of methodology. They were sent a standardised table and asked to provide missing data not included in their article. China 2004; Dallas 2005; France 2000; Milan 1995; Netherlands 2005; Portland 2001; Wales 2000 and Scotland 1998 provided additional information from their studies. Adelaide 1995; Adelaide 1996 and Portland 1997 had provided additional information for the previous version of this review. The authors of England 1999 and Memphis 1996 were not directly contacted because all of the required information was available from the published literature. Hungary 1995 and Munich 1996 acknowledged the request but did not provide necessary information.
Methods of the review
Two review authors (SR and SP) assessed eligibility of studies for inclusion independently. The criteria and standard methods of the Cochrane Neonatal Review Group were used to assess the methodological quality of the included trials. Quality of the trials included was evaluated in terms of allocation concealment, adequate randomisation, blinding of parents or caregivers and assessors to intervention, and completeness of follow up (intention to treat) in all randomised individuals. This was defined as yes, no or can't tell for each category. Differences in the inclusion of trials according to their quality were resolved after consultation with the third review author (KS). A data collection form was used to aid extraction of relevant information and data from each included study. Two review authors (SR and SP) extracted the data separately, compared data, and resolved differences by consensus. Any disagreement between SR and SP was resolved by consultation with the third reviewer (KS). Data entry into RevMan was done by SR and checked by SP.
The standard methods of the Neonatal Review Group were used to synthesize the data. Effects were expressed as weighted mean difference (WMD) and 95% CI for continuous data.
There were no categorical outcome data in the review. The fixed effect model was used for meta-analysis. Heterogeneity in the results of the trials were examined using the I squared statistic.
Subgroup analysis was done based on the type of LCPUFA supplementation (DHA alone and DHA plus AA). In the studies of Adelaide 1996; Dallas 1998 and Portland 1997, there were three groups of study infants: DHA plus AA, DHA alone and control formula. The outcome data from each of these studies was entered in the RevMan as if they were two separate studies ie., DHA plus AA versus control and DHA versus control group. However, while doing the meta-analysis, the data of DHA plus AA versus control and DHA versus control were not pooled because the control group infants were the same for both DHA alone and DHA plus AA group of infants.
Portland 2001 examined the effect of two different sources of LCPUFA (egg yolk triglyceride and fish/fungus oil) versus control formula and reported the outcome the data separately. Since the aim of our review was to compare LCPUFA (irrespective of the source) versus standard formula, the authors were asked to provide combined outcome data for both sources of LCPUFA infants. The authors kindly obliged and provided the combined outcome data.
Description of studies
Twenty studies were identified as potentially eligible and fourteen were included and six excluded. Details of the patients and methods are summarised in the Table "Characteristics of Included Studies". All the trials enrolled infants ≥37 weeks of gestation at birth. The source of LCPUFA was egg yolk phospholipids in Portland 1997; Memphis 1996; Adelaide 1996; Milan 1995; England 1999. It was derived from fish oil and evening primrose oil in Adelaide 1995. Dallas 1998; Dallas 2005 and Wales 2000 used single cell oils as the source of LCPUFA. Netherlands 2005 used LCPUFA derived from egg yolk, tuna oil and single cell oil produced by soil fungus, Mortierella alpina. Scotland 1998 used LCPUFA derived from egg lipids, milk fat and vegetable oils. Portland 2001 fish and fungus oil in one group and egg yolk triglyceride derived LCPUFA in other group of their study infants. France 2000 used LCPUFA derived from fish oil. The source of LCPUFA in China 2004 was not clear.
The trial formula in all the studies was commenced within the first two weeks of life. The duration of use of the study formula varied among the studies. It was two months in Netherlands 2005, three months in Wales 2000 , four months in Dallas 1998; France 2000; Milan 1995; Scotland 1998, six months in China 2004; England 1999, 7 months in Adelaide 1995 and one year in Adelaide 1996; Dallas 2005; Memphis 1996; Portland 1997 and Portland 2001.
Adelaide 1995 and France 2000 compared DHA enriched versus normal term formula. Adelaide 1996; Dallas 1998; Portland 1997 randomised infants into three groups: DHA alone, DHA plus AA and control formula. All other studies compared formula enriched with DHA plus AA versus the control formula.
Six studies were excluded. Scandinavia 1996 was excluded because the supplements were not commenced until 3-4 weeks of age. Dallas 2002 was excluded because infants were randomised to receive the study formula at six weeks of age. Houston 2002 was excluded because the they compared milk formulae with different amounts of alpha linolenic acid levels. Hungary 1995 and Munich 1996 were excluded because the methodology was not clear and the required data on outcome of interest was not available. The authors acknowledged our letter but did not provide the required information. Kansas 1999 was excluded because the authors of the trial expressed concerns about the possibility of significant methodological issues in their study.
Methodological quality of included studies
The quality of the trials was assessed using the standard criteria of the Cochrane Neonatal Review Group. Assessment was based on allocation concealment, blinding of intervention, blinding of outcome assessment and completeness of follow up. Based on these criteria, Adelaide 1996; Dallas 1998; Dallas 2005; England 1999; France 2000; Memphis 1996; Milan 1995; Netherlands 2005; Portland 1997; Portland 2001; Scotland 1998 and Wales 2000 were considered to be of good quality. Follow-up rate in China 2004 was very low with only 33% of the study infants being followed at six months for the primary outcome. Adelaide 1995 had unequal distribution of number of infants randomised to each group. The follow-up rates ranged from 60 to 90% in different studies for various outcomes. Sample size and power calculation were described in Adelaide 1995; Adelaide 1996; Dallas 1998; Dallas 2005; England 1999; Memphis 1996; Milan 1995; Netherlands 2005; Portland 2001 and Scotland 1998. It was not clear in China 2004; France 2000; Portland 1997 and Wales 2000. The details of methodology are given in the table "Characteristics of included trials".
Results
Visual acuity - assessment methods:
Visual acuity is a measure of the smallest element that can be resolved and can be assessed in infants by using gratings which consist of black and white stripes or checkerboard patterns. Grating acuity can be measured by using behavioural or visual evoked potential (VEP) methods. Each pairing of a black and white stripe is referred to as a cycle and the spatial frequency of a grating is defined by the number of cycles per degree of viewing angle. As grating spatial frequency increases, the stripes become finer and are more difficult to discriminate, eventually appearing as an even grey to the observer. Grating acuity is the highest spatial frequency where the stripes can be resolved.
The VEP is the electrical activity of the brain that is generated in response to a reversing contrast checkerboard or grating. The VEP is recorded from an electrode placed over the occipital pole and is classified as being transient, steady state or sweep. A transient VEP is elicited by a checkerboard reversing between 1 - 3 times/second while a steady-state VEP is elicited by a checkerboard reversing between 6-20 times/second. For a sweep VEP, black and white striped grating is used. The amplitude of the VEP increases linearly with spatial frequency near the visual acuity threshold. Linear regression is used to fit a straight line through the linear portion of the VEP amplitude versus spatial frequency curve and visual acuity is determined from the intercept of the regression line with the spatial frequency axis. VEP are reported as log MAR (minimum angle of resolution) which corresponds to the smallest black and white check pattern which the infant can discriminate from a grey background (smaller the value, the better the acuity), or as cycles/degree(larger the value, better the acuity).
Behavioural methods for assessing visual acuity rely on the strong preference shown by infants for patterned stimuli over non-patterned stimuli. Both the acuity card procedure (ACP) and the forced preferential looking (FPL) procedure have been used in conjunction with the Teller acuity cards for measuring the development of visual acuity in infants. The FPL procedure tests binocular grating acuity; the tester views the infant through a peephole, without knowledge of the spatial-frequency gratings on the cards, and makes a forced-choice judgement about which card the infant prefers. Individual acuities are converted to cycles/degree and SD are in octaves which are determined by dividing one log SD by 0.3.
LCPUFA SUPPLEMENTED VS. CONTROL FORMULA (COMPARISON 01):
Visual acuity
Visual acuity at four months of age: Steady state VEP, logMAR (Outcome 01.01):
Studies using DHA plus AA: Adelaide 1996 reported on this outcome. They did not find statistically significant differences between LCPUFA and control groups( 0.74 ± 0.09 vs. 0.73 ± 0.12 respectively).
Studies using DHA alone: Adelaide 1995 and Adelaide 1996 reported this outcome. Adelaide 1995 reported statistically significant differences between the LCPUFA and control groups. Infants in the LCPUFA group had better visual acuity at four months than the controls. Adelaide 1996 did not show statistically significant differences. Pooled meta-analysis of the two trials did not show statistically significant differences between LCPUFA and controls (WMD -0.03;95% CI -0.10, 0.03).
Visual acuity at four months of age using sweep VEP (logMAR) (Outcome 01.02):
Studies using both DHA and AA: Dallas 1998 and Dallas 2005 reported this outcome. Both studies showed statistically significant differences between LCPUFA and control groups. Infants in the LCPUFA group had better visual acuity than control group. Pooled meta-analysis of both studies also showed statistically significant benefit of LCPUFA on visual acuity
(WMD -0.07; 95% CI -0.10, -0.04).
Studies using DHA alone: Dallas 1998 reported this outcome. They showed statistically significant benefit on visual acuity for infants in the LCPUFA group compared to controls (0.46 ± 0.08 vs. 0.54 ± 0.13).
Visual acuity at four months of age using Sweep VEP, cycles/degree (Outcome 01.03):
Studies using DHA plus AA: Portland 1997 reported on this outcome. They did not find statistically significant differences between LCPUFA and control groups (6.61 ± 1.21 vs. 7.08 ± 1.35.
Studies using DHA alone: Portland 1997 reported on this outcome. The values were given in graphs. They did not find statistically significant differences between the LCPUFA and control groups.
Visual acuity at four months of age using Teller cards (cycles/degree) (Outcome 01.04):
Studies using DHA plus AA: Memphis 1996; Portland 1997 and Portland 2001 reported on this outcome. None of the three studies showed statistically significant differences between LCPUFA and control groups. Pooled meta-analysis of Memphis 1996; Portland 1997 and Portland 2001 showed no statistically significant difference between the LCPUFA and control group (WMD -0.11; 95% CI -0.24, 0.02).
Studies using DHA alone: Portland 1997 reported on this outcome. They did not find statistically significant differences between LCPUFA and control groups. The results were given in graphs.
Visual acuity at six months of age using Sweep VEP (cycles/degree) (Outcome 01.05):
Studies using DHA and AA: Portland 1997 reported this outcome. They did not find statistically significant differences between LCPUFA and control groups(13.18 ± 1.38 vs. 13.49 ± 1.35).
Studies using DHA alone: Portland 1997 reported this outcome. They did not find statistically significant differences between LCPUFA and control groups. The results were given as graphs.
Visual acuity at six months of age using Teller cards (cycles/degree) (Outcome 01.06):
Studies using DHA plus AA: Memphis 1996; Portland 1997 and Portland 2001 reported this outcome. None of the studies reported statistically significant differences between LCPUFA and control groups. Pooled meta-analysis of the data from Memphis 1996; Portland 1997 and Portland 2001 also did not show statistically significant differences between LCPUFA and control groups (WMD 0.02; 95% CI -0.11, 0.15).
Studies using DHA alone: Portland 1997 reported this outcome. They did not find statistically significant differences between LCPUFA and control groups. The results were given as graphs.
Visual acuity at 7-8 months of age using Steady state VEP (logMAR) (Outcome 01.07);
Studies using DHA plus AA: Adelaide 1996 reported on this outcome. They did not show statistically significant differences between LCPUFA and control groups (0.39 ± 0.17 vs. 0.39 ± 0.19).
Studies using DHA alone: Adelaide 1995 and Adelaide 1996 reported this outcome. Adelaide 1995 reported statistically significant benefit of LCPUFA supplementation on visual acuity. Adelaide 1996 did not show statistically significant differences between LCPUFA and controls. Pooled meta analyses of both the studies did not show statistically significant differences between LCPUFA and control groups (WMD -0.02; 95% CI -0.14, 0.10).
Visual acuity at 12 months of age using sweep VEP (logMAR) (Outcome 01.08):
Studies using DHA plus AA: Dallas 1998 and Dallas 2005 reported this outcome. Both the studies showed statistically significant differences between LCPUFA and control groups. Infants in the LCPUFA group had better visual acuity than controls. Pooled meta-analysis of both the studies also showed statistically significant differences between LCPUFA and control group (WMD -0.16; 95% CI -0.19, -0.12).
Studies using DHA alone: Dallas 1998 reported on this outcome. They found statistically significant benefit on visual acuity in the LCPUFA group compared to control group(0.19 ± 0.12 vs. 0.33 ± 0.10).
Visual acuity at 12 months of age using Sweep VEP (cycles/degree) (Outcome 01.09):
Studies using DHA and AA: Portland 1997 reported this outcome. They did not find statistically significant differences between LCPUFA and control groups (15.48 ± 1.32 v 15.48 ± 1.32).
Studies using DHA alone: Portland 1997 reported this outcome. They did not find statistically significant differences between LCPUFA and control groups. The results were given in graphs.
Visual acuity at twelve months of age using Teller cards (cycles/degree) (Outcome 01.10):
Studies using DHA plus AA: Memphis 1996; Portland 1997 and Portland 2001 reported this outcome. None of the studies reported statistically significant differences between LCPUFA and control groups. Pooled meta-analysis of the data from Memphis 1996; Portland 1997 and Portland 2001 also did not show statistically significant differences between LCPUFA and control groups( WMD -0.01; 95% CI -0.12, 0.11).
Studies using DHA alone: Portland 1997 reported this outcome. They did not find statistically significant differences between LCPUFA and control groups. The results were given in graphs.
Visual acuity at three years of age using Teller cards (cycles/degree) (Outcome 01.11):
Studies using DHA plus AA: Portland 1997 reported on this outcome. They did not find statistically significant differences between LCPUFA and control groups (28.2 ± 0.6 vs. 30.3 ± 0.7; p value: 0.74).
Studies using DHA alone: Portland 1997 reported on this outcome. They did not find statistically significant differences between LCPUFA and control groups (27.5 ± 0.6 vs. 30.3 ± 0.7;p value: 0.74)).
Neurodevelopmental outcomes:
Bayley's scales of infant development:
Neurodevelopmental outcomes were assessed at various ages using Bayley's scales of infant development by Adelaide 1995; Adelaide 1996; China 2004; Dallas 1998; England 1999; Netherlands 2005; Portland 1997 and Portland 2001.
Bayley assessment at 3 months, MDI (Outcome 01.12):
Studies using DHA plus AA: China 2004 reported on this outcome. They did not find any statistically significant differences in the MDI scores between the LCPUFA and control groups (107.88 ± 7.91 vs. 105.4 ± 9.2 respectively).
Studies using DHA alone: None
Bayley assessment at 3 months, PDI (Outcome 01.13):
Studies using DHA plus AA: China 2004 reported this outcome. They did not find any statistically significant differences in the PDI scores between the LCPUFA and control groups (110.06 ± 6.17 vs. 106.4 ± 6.37 respectively).
Studies using DHA alone: None
Bayley assessment at 6 months, MDI (Outcome 01.14):
Studies using DHA plus AA: China 2004 and Portland 2001 reported this outcome. Both showed no statistically significant difference in the MDI scores between LCPUFA and control groups. Pooled meta-analysis of the data from these two studies also did not show statistically significant difference in the MDI scores between LCPUFA and control groups (WMD -0.59; 95% CI -2.26, 1.07).
Studies using DHA alone: None
Bayley assessment at 6 months, PDI (Outcome 01.15):
Studies using DHA plus AA: China 2004 and Portland 2001 reported this outcome. Both of them showed no statistically significant difference in the PDI scores between LCPUFA and control groups. Pooled meta-analysis of the data from these two studies also did not show any statistically significant difference in the PDI scores between LCPUFA and control groups (WMD 0.23; 95% CI -2.47, 2.94).
Studies using DHA alone: None
Bayley assessment at one year, MDI (Outcome 01.16):
Studies using DHA plus AA: Adelaide 1996, Portland 1997 and Portland 2001 reported this outcome. No studies showed statistically significant differences in the MDI scores between LCPUFA and control groups. Pooled analysis of the three trials did not reveal statistically significant differences in the MDI scores between LCPUFA and control groups (WMD -0.95; 95% CI -3.38, 1.49).
Studies using DHA alone: Adelaide 1995; Adelaide 1996; Portland 1997 reported this outcome. No studies showed statistically significant differences in MDI scores between LCPUFA and control group. Pooled meta-analysis of the data from all these three trials also did not find statistically significant differences in MDI scores between LCPUFA and control groups (WMD -0.27; 95% CI -4.36, 3.83).
Bayley assessment at one year, PDI (Outcome 01.17):
Studies using DHA plus AA: Adelaide 1996; Portland 1997 and Portland 2001 reported this outcome. No studies showed statistically significant differences in PDI scores between LCPUFA and control groups. Pooled meta-analysis of the three trials did not reveal statistically significant differences in PDI scores between LCPUFA and control groups(WMD -2.48; 95% CI -5.83, 0.86).
Studies using DHA alone: Adelaide 1995; Adelaide 1996 and Portland 1997 reported this outcome. No studies reported statistically significant differences in PDI scores between LCPUFA and control group. Pooled meta-analysis of the data from all these three trials also did not find statistically significant differences in PDI scores between LCPUFA and control groups for (WMD -1.70; 95% CI -6.62, 3.22).
Bayley assessment at 18 months, MDI (Outcome 01.18):
Studies using DHA plus AA: Dallas 1998; England 1999 and Netherlands 2005 reported this outcome. Dallas 1998 showed statistically significant improvement in MDI scores at 18 months in the LCPUFA supplemented group. England 1999 and Netherlands 2005 did not show any statistically significant differences in MDI scores at 18 months. A pooled meta-analysis of the data from all the three trials did not find statistically significant differences in MDI scores between LCPUFA and control groups (WMD -0.78, 95% CI -2.98, 1.42).
Studies using DHA alone: None
Bayley assessment at 18 months, PDI (Outcome 01.19):
Studies using DHA plus AA: Dallas 1998; England 1999 and Netherlands 2005 reported this outcome. No studies showed statistically significant differences in PDI scales between LCPUFA and control groups. Pooled meta-analysis of the data from all the three trials did not find statistically significant differences in PDI scores between LCPUFA and control groups (WMD 0.25, 95% CI -1.33, 1.82).
Studies using DHA alone: None
Bayley assessment at 2 years, MDI (Outcome 01.20):
Studies using DHA plus AA: Adelaide 1996 reported this outcome. They did not find statistically significant differences in MDI scores between LCPUFA and control groups (102.00 ± 23.00 vs. 104.00 ± 13.00).
Studies using DHA alone: Adelaide 1996 reported on this outcome. They did not find statistically significant differences in MDI scores between LCPUFA and control groups (108 ± 16 vs. 104 ± 13).
Bayley assessment at 2 years, PDI (Outcome 01.21):
Studies using DHA plus AA: Adelaide 1996 reported this outcome and did not find statistically significant differences in PDI scores between LCPUFA and control groups (96.00 ± 21.00 vs. 97.00 ± 15.00).
Studies using DHA alone: Adelaide 1996 reported on this outcome and did not find statistically significant differences in PDI scores between LCPUFA and control groups (104.00 ± 17.00 vs. 97.00 ± 15.00).
Other tests of cognitive function:
England 1999 assessed development using Knobloch, Passamanik and Sherrards Development Screening Inventory at 9 months. They did not find statistically significant differences between LCPUFA and control infants (103.8 ± 8.3 vs. 104.4 ± 8.7 in LCPUFA v control group respectively).
Milan 1995 assessed the developmental quotient (DQ) using Brunet and Lezine developmental test. They reported higher DQ at four months of age for the LCPUFA infants compared to controls. However, repeat assessments at 12 and 24 months using the same assessment demonstrated no difference in DQ between the LCPUFA and control groups.
DQ at 4 months: 105.3 ± 9.4 vs. 96.5 ± 10.9 in LCPUFA versus control group respectively; p value:0.009
DQ at 12 months: 101.5 ± 9.2 vs. 101.2 ± 8.0 in LCPUFA versus control group respectively; p value:0.4
DQ at 24 months: 101 ± 10.3 vs. 99.1 ± 7.1 in LCPUFA versus control group respectively .p value: 0.89
Portland 1997 assessed the IQ of the study infants at 3.25 years of age using Standford-Binet scales. They did not find statistically significant differences in the IQ scores between DHA, DHA plus AA and control groups (DHA and AA: 101 ± 13; DHA: 99 ± 12 and Control: 103 ± 15; ANNOVA p value: 0.14).
The Portland 2001 used the Fagan Infant Test of Development which measures novelty preference based on the observation that after habituation to a familiar stimulus has occurred, a preference will be shown for a different (novel) stimulus if both the familiar and novel stimuli are presented together. A novelty preference score is derived for the average percent of total time spent viewing the novel stimuli on ten discrete paired comparison tests. Infants with average scores of > 57% are said to have a significant novelty preference i.e. the time spent looking at the novel stimuli compared with the familiar stimuli is greater than by chance alone. Novelty preference has been interpreted as an early measure of information processing capacity (Fagan 1970). The Portland 2001 did not find any statistically significant differences between the LCPUFA and control groups in novelty preference (57.8 ± 6.7 vs. 57.1 ± 5.3 respectively).
Scotland 1998 assessed infant cognitive behaviour at 10 months of age using problem solving assessment. They found a statistically significant benefit of LCPUFA supplementation. Infants who received LCPUFA supplemented formula had significantly more intentional solutions than infants who received the control formula (Median 2.0 v 0, p value: 0.021). Intention scores were also higher in the LCPUFA group [14.0 (11.8, 17.1) vs. 11.5 (10.0, 13.3), p = 0.035].
Physical growth:
Weight at four months (Outcome 01.22):
Studies using DHA plus AA: Adelaide 1996; Portland 1997 and Portland 2001 reported this outcome. Portland 2001 reported the outcomes as figures. Portland 1997 reported the outcomes as Z scores. No studies found statistically significant differences between LCPUFA and control groups. Meta-analysis was not possible because only Adelaide 1996 provided the data as mean and standard deviations.
Studies using DHA alone: Adelaide 1996; France 2000 and Portland 1997 reported this outcome. Portland 1997 reported this outcome as z scores. None of the studies reported statistically significant differences between LCPUFA and control groups. Meta-analysis of Adelaide 1996 and France 2000 studies did not reveal statistically significant differences between the LCPUFA and control groups (WMD -0.03; 95% CI -0.33, 0.27).
Length at four months (Outcome 01.23):
Studies using DHA plus AA: Adelaide 1996; Portland 1997 and Portland 2001 reported this outcome. Portland 2001 reported the outcomes in graphs. Portland 1997 reported the outcomes as Z scores. None of the studies reported statistically significant differences between LCPUFA and control groups. Meta-analysis was not possible because only Adelaide 1996 provided the data as mean and standard deviations.
Studies using DHA alone: Adelaide 1996;France 2000 and Portland 1997 reported this outcome. Portland 1997 reported this outcome as z scores. Meta-analysis of the pooled data from Adelaide 1996 and France 2000 did not reveal statistically significant differences between LCPUFA and control groups (WMD 0.03; 95% CI -1.00, 1.06).
Head circumference at four months (Outcome 01.24):
Studies using DHA plus AA: Adelaide 1996; Portland 1997 and Portland 2001 reported this outcome. Portland 2001 reported the outcomes as figures. Portland 1997 reported the outcomes as z scores. None of the studies reported statistically significant differences between LCPUFA and control groups. Meta-analysis was not possible because only Adelaide 1996 provided the data as mean and standard deviations.
Studies using DHA alone: Adelaide 1996; France 2000 and Portland 1997 reported this outcome. Portland 1997 reported this outcome as z scores. Meta-analysis of the pooled data from Adelaide 1996 and France 2000 did not reveal statistically significant differences between LCPUFA and control groups(WMD -0.01; 95% CI -0.53 , 0.51).
Weight at six months (kg) (Outcome 01.25):
Studies using DHA plus AA: China 2004; Dallas 1998; England 1999; Netherlands 2005; Portland 1997; Portland 2001 and Wales 2000 reported this outcome. Dallas 1998 and Portland 1997 reported the outcomes as z scores. China 2004 reported the outcomes as rate of growth per week. None of the studies reported statistically significant differences between LCPUFA and control groups. Data from England 1999; Netherlands 2005; Portland 2001 and Wales 2000 was available in a format for meta-analysis. The pooled meta-analysis of these three studies also did not show statistically significant difference between LCPUFA and control groups (WMD 0.01; 95% CI -0.11, 0.13).
Studies using DHA alone: None
Length at six months (cm) (Outcome 01.26):
Studies using DHA plus AA: China 2004; Dallas 1998; England 1999; Netherlands 2005; Portland 1997; Portland 2001 and Wales 2000 reported this outcome. Dallas 1998 and Portland 1997 reported the outcomes as z scores. China 2004 reported the outcomes as rate of growth. None of the studies reported statistically significant differences between LCPUFA and control groups. Data from England 1999; Netherlands 2005; Portland 2001 and Wales 2000 was available in a format for meta-analysis. The pooled meta-analysis of these three studies did not show statistically significant difference between LCPUFA and control groups (WMD -0.13; 95% CI -0.47, 0.21).
Studies using DHA alone: None
Head circumference at six months (cm) (Outcome 01.27):
Studies using DHA plus AA: China 2004; Dallas 1998; England 1999; Netherlands 2005; Portland 1997; Portland 2001 and Wales 2000 reported this outcome. Dallas 1998 and Portland 1997 reported the outcomes as z scores. China 2004 reported the outcomes as rate of growth. None of the studies reported statistically significant differences between LCPUFA and control groups. Data from England 1999; Netherlands 2005; Portland 2001 and Wales 2000 was available in a format for meta-analysis. The pooled meta-analysis of these three studies did not show statistically significant difference between LCPUFA and control groups (WMD -0.06; 95% CI -0.25, 0.13).
Studies using DHA alone: None
Weight at one year (kg) (Outcome 01.28):
Studies using DHA plus AA: Adelaide 1996; Dallas 1998; Dallas 2005; Milan 1995; Netherlands 2005; Portland 1997; Portland 2001 and Wales 2000 reported this outcome. Dallas 1998 reported data in graphs. None of the studies reported statistically significant differences between LCPUFA and control groups. Pooled meta-analysis of the data from Adelaide 1996; Milan 1995; Netherlands 2005; Portland 2001 and Wales 2000 did not show any statistically significant differences between LCPUFA and control groups (WMD -0.11; 95% CI -0.28, 0.05).
Studies using DHA alone: Adelaide 1995; Adelaide 1996 and Portland 1997 reported this outcome. None of the studies found statistically significant differences between LCPUFA and control groups. Pooled meta-analysis from Adelaide 1995 and Adelaide 1996 did not show statistically significant differences between LCPUFA and control groups (WMD -0.43; 95% CI -0.96,0.09).
Weight at one year (z scores) (Outcome 01.29):
Studies using DHA plus AA: Dallas 1998; Dallas 2005; Milan 1995 and Portland 1997 reported this outcome. Dallas 1998 reported data in graphs. None of the studies reported statistically significant differences between LCPUFA and control groups. However, pooled meta-analysis of the z scores from Dallas 2005; Milan 1995; Portland 1997 and Portland 2001 showed statistically significant lower weight in the LCPUFA group compared to the control group(WMD -0.27; 95% CI -0.46, -0.08).
Studies using DHA alone: Portland 1997 reported this outcome. They did not find statistically significant differences between LCPUFA and control groups.
Length at one year (cm) (Outcome 01.30):
Studies using DHA plus AA: Adelaide 1996; Milan 1995; Netherlands 2005; Portland 2001 and Wales 2000 reported this outcome. None of the individual studies find statistically significant differences between LCPUFA and control groups. Pooled meta-analysis of the data from Adelaide 1996; Milan 1995; Netherlands 2005; Portland 2001 and Wales 2000 did not show any statistically significant differences between LCPUFA and control groups (WMD -0.15; 95% CI -0.57, 0.28).
Studies using DHA alone: Adelaide 1995 and Adelaide 1996 reported this outcome. None of the individual studies reported statistically significant differences between LCPUFA and control groups. Pooled meta-analysis of the data from Adelaide 1995 and Adelaide 1996 did not find statistically significant differences between LCPUFA and control groups (WMD -0.95; 95% CI -2.05,0.15).
Length at one year (z scores) (Outcome 01.31):
Dallas 1998; Dallas 2005; Milan 1995; Portland 1997 and Portland 2001 reported these outcomes. Dallas 1998 reported data in figures. None of the individual studies find statistically significant differences between LCPUFA and control groups. Pooled meta-analysis of the z scores from Dallas 2005; Milan 1995; Portland 1997 and Portland 2001 also did not find statistically significant differences between LCPUFA and control groups (WMD -0.04; 95% CI -0.22, 0.15).
Studies using DHA alone: Portland 1997 reported this outcome and did not find statistically significant differences between LCPUFA and control groups (0.09 ± 0.98 vs. -0.01 ± 1.15).
Head circumference at one year (cm) (Outcome 01.32):
Studies using DHA plus AA: Adelaide 1996; Netherlands 2005; Portland 2001 and Wales 2000 reported this outcome. None of the individual studies reported statistically significant differences between LCPUFA and control groups. Pooled meta-analysis of data from Adelaide 1996; Netherlands 2005; Portland 2001 and Wales 2000 did not show any statistically significant differences between LCPUFA and control groups (WMD -0.13; 95% CI -0.36, 0.11).
Studies using DHA alone: Adelaide 1995; Adelaide 1996 reported this outcome. None of the individual studies reported statistically significant differences between LCPUFA and control groups. Pooled meta-analysis of the data from Adelaide 1995 and Adelaide 1996 did not show statistically significant differences between LCPUFA and controls (WMD -0.22; 95% CI -0.80,0.37).
Head circumference at one year (z scores) (Outcome 01.33):
Studies using DHA plus AA: Dallas 1998; Dallas 2005; Portland 1997 and Portland 2001 reported outcome. Dallas 1998 reported the data in figures. None of the studies reported statistically significant differences between LCPUFA and control groups. Pooled meta-analysis z scores from Dallas 2005; Portland 1997 and Portland 2001 also did not find statistically significant differences between LCPUFA and control groups (WMD -0.07; 95% CI -0.29, 0.15).
Studies using DHA alone: Portland 1997 reported this outcome and did not find statistically significant differences between LCPUFA and control groups (0.25 ± 0.92 vs. 0.18 ± 1.01)
Weight at 18 months (kg) (Outcome 01.34):
Studies using DHA plus AA: England 1999 and Netherlands 2005 reported this outcome. They did not find statistically significant differences between the two groups. Pooled meta-analysis of both the trials also did not find statistically significant differences between LCPUFA and control groups (WMD -0.04; 95% CI -0.25, 0.17).
Studies using DHA alone: None
Length at 18 months (cm) (Outcome 01.35):
Studies using DHA plus AA: England 1999 and Netherlands 2005 reported this outcome. They did not find statistically significant differences between the two groups. Pooled meta-analysis of both the trials also did not find statistically significant differences between LCPUFA and control groups (WMD -0.19; 95% CI -0.71, 0.34).
Studies using DHA alone: None
Head circumference at 18 months (cm) (Outcome 01.36):
Studies using DHA plus AA: England 1999 and Netherlands 2005 reported this outcome. They did not find statistically significant differences between the two groups. Pooled meta-analysis of both the trials also did not find statistically significant differences between LCPUFA and control groups (WMD -0.07; 95% CI -0.32, 0.19).
Studies using DHA alone: None
Weight at two years (kg) (Outcome 01.37):
Studies using DHA plus AA: Adelaide 1996 reported this outcome and did not find any statistically significant differences between LCPUFA and control formula (12.78 ± 1.53 vs. 13.54 ± 1.40)
Studies using DHA alone: Adelaide 1996 reported this outcome and did not find statistically significant differences between LCPUFA and control groups (12.75 ± 1.47 vs. 13.54 ± 1.39).
Length at 18 months (cm) (Outcome 01.38):
Studies using DHA plus AA: Adelaide 1996 reported this outcome and did not find any statistically significant differences between LCPUFA and control formula.
Studies using DHA alone: Adelaide 1996 reported this outcome. They did not find statistically significant differences between LCPUFA and control groups.
Head circumference at 18 months (cm) (Outcome 01.39):
Studies using DHA plus AA: Adelaide 1996 reported this outcome and did not find any statistically significant differences between LCPUFA and control formula.
Studies using DHA alone: Adelaide 1996 reported this outcome and did not find statistically significant differences between LCPUFA and control groups.
Physical growth at three years:
Studies using DHA plus AA: Portland 1997 described the outcomes separately for boys and girls at 3.25 years of age. They did not find statistically significant differences between LCPUFA and control groups in both sexes for length, weight and head circumference at 3.25 years of age.
Studies using DHA alone: Portland 1997 described the outcomes separately for boys and girls at 3.25 years of age. They did not find statistically significant differences between LCPUFA and control groups in both sexes for length, weight and head circumference at 3.25 years of age.
Discussion
Data from 1719 term infants from 14 randomised controlled trials have been reported in this review. There was significant variation among various studies regarding the type, concentration and duration of supplementation of LCPUFA. Variation was also noted in the outcomes assessed and methods used for assessing the outcomes. In different studies, the visual acuity was measured at four, six, twelve months and three years. Depending on the study, visual acuity was tested using sweep VEP, steady state VEP and teller cards in different studies. The neurodevelopmental outcomes were assessed at three, four, six, twelve months, two year and three year in different studies. In the majority of studies, neurodevelopmental outcome was by using Bailey's scores. Physical growth was assessed at four, six, twelve months, two years and three years in different studies. Some studies used the standard physical measurements like weight (kg), length (cm) and head circumference (cm). Some studies described the z scores for physical measurements. Although varied in their timing and definition, data from these randomised clinical trials do not demonstrate a clear and consistent benefit of supplementing formula with LCPUFA on visual acuity, neurodevelopmental outcomes and physical growth in term infants.
Adelaide 1995; Dallas 1998; Dallas 2005 and Scotland 1998 group have demonstrated some beneficial effects of LCPUFA supplementation on either visual acuity and/or cognitive development. However,the results of Adelaide 1995 may have been affected because of unequal sample sizes between LCPUFA and control group. In addition, follow up was poor in Adelaide 1995. Clear benefit of LCPUFA supplementation on visual acuity was demonstrated by good quality studies of Dallas 1998 and Dallas 2005. In addition Dallas 1998 also showed benefits of LCPUFA supplementation on MDI scores at 18 months. Scotland 1998 have demonstrated that LCPUFA supplementation resulted in better problem solving skills at 10 months of age. These beneficial effects on vision and neurodevelopmental outcomes have not been replicated in other well conducted good quality RCTs of adequate sample sizes including Adelaide 1996; England 1999; Memphis 1996; Milan 1995; Netherlands 2005; Portland 1997; Portland 2001 and Wales 2000. The reasons for such inconsistent results are unclear. A theory proposed by Lauritzen 2001 is that higher dose of DHA may be necessary to achieve beneficial effects. Uauy 2003 supporting Dallas 2005 study, proposes both higher dose as well as longer duration of LCPUFA supplementation. However studies which used LCPUFA supplementation until one year of age including Adelaide 1996; Memphis 1996; Portland 1997 and Portland 2001 failed to demonstrate beneficial effects of LCPUFA supplementation. But the LCPUFA content in these trials was lower than Dallas group.
None of the studies showed either beneficial or harmful effects of LCPUFA supplementation on weight, length and head circumference until three years of age. The results were same irrespective of the type, concentration and duration of LCPUFA supplementation.
Reviewers' conclusions
Implications for practice
Data from randomised trials do not support the need for routine supplementation of formula for term infants with LCPUFA to improve visual acuity, neurodevelopment or physical growth.
Implications for research
Repeating the trials using relatively higher doses of both DHA and AA for longer duration similar to Dallas 2005 protocol is necessary to find out if the beneficial effects of LCPUFA supplementation can be replicated in different settings. In addition it is important to follow the study infants from the trials in this review to see if there are any differences at early school age regarding visual, cognitive and physical development.
Acknowledgements
Maria Makrides, Nancy Auestad, Xiaoming Ben, Eileen Birch, Susan Carlson, Carlo Agostoni, Geraint Morris, Mijna Hadders-Algra, Dennis Hoffman, Alexandre Lapillone and Peter Willatts for clarifying the existing data, clarifying the methodology and providing additional information from their studies.
Potential conflict of interest
None
Characteristics of included studies
| Study | Methods | Participants | Interventions | Outcomes | Notes | Allocation concealment |
| Adelaide 1995 | Sample size calculation: Yes
Concealment of allocation - Yes. Using central computerized randomization
Blinding of intervention - Yes
Blinding of outcome assessment - Yes
Completeness of follow up - No (60 to 81% for various primary outcomes). | N=32. Inclusion criteria: Healthy term appropriate for gestational age infants born at 37-42 weeks. Exclusion criteria: Infants of mothers who had history of lipid metabolism disorders, diabetes, drug or alcohol abuse.
LCPUFA supplemented formula: N=13 (GA 39.1+/-1.7w, BW 3.288+/-0.525kg).
Control formula: N = 19 ( GA 39.6+/-1.2w, BW 3.650+/-0.0416kg).
| 'LCPUFA' group were given milk formula enriched with DHA (0.35%). In addition, it was also enriched with EPA and GLA . Control group were fed with standard milk formula without the addition of DHA and AA. Assigned diets were fed from birth to 30 weeks week of life. | Plasma and red blood cell fatty acid levels at 6, 16 and 30 w; visual evoked potential acuity at 16 and 30w, Bayley Scales of Infant Development at 1y. | Breastfed reference group, n=28. | A |
| Adelaide 1996 | Sample size calculation: Yes
Concealment of allocation - Yes. Using sealed opaque envelopes.
Blinding of intervention - Yes
Blinding of outcome assessment - Yes
Completeness of follow up - No (60-85%) for various outcomes | N = 83. Inclusion criteria: Healthy term infants. Exclusion criteria: Small for gestational age, congenital disease, infants of insulin dependent diabetic mothers, history of drug or alcohol abuse in the mother.
LCPUFA (DHA and AA) supplemented formula: N=28 GA 39.8+/-1.3w; BW 3549+/-521g
LCPUFA (DHA alone) supplemented formula: N= 27. GA: 39.6+-1.1 W, BW 3378+-431g
Control formula: N = 28. 39.6+/-1.5w, 3549+/-497g.
| 'LCPUFA' group were given milk formula enriched with DHA (0.34%)and AA (0.34%). Another LCPUFA group received milk formula enriched with DHA alone(0.34%). Control group were fed with standard milk formula without the addition of DHA and AA. Infants were randomly assigned to the study formula within 7 days of life. Assigned milk formula was the sole source of nutrition for 4 months. Subsequently the study formula was the only source of milk till one year of age. | Plasma and RBC fatty acid levels at 6, 16, 34 weeks and one year of age. Physical growth at 6, 16, and 34 weeks, and at 1 and 2 years. VEP at 16 and 34 weeks. Bayley Scales of Infant Development at 1 and 2 years. | Breastfed reference group n=63. | A |
| China 2004 | Sample size calculation: No
Concealment of allocation - Not clear
Blinding of intervention - Yes
Blinding of outcome assessment - Yes
Completeness of follow up - No. Follow up rate was 48% at three months and 33% at six months. | N = 121. Infants of gestational age 37-40 weeks. Exclusion criteria: Infants with congenital anomalies.
LCPUFA supplemented formula: N=69. GA and
Control formula: N = 52.
Gestational age and birthweight details were not available | LCPUFA' group were given milk formula enriched with DHA and AA. The LCPUFA content of the formula was not clear. Control group were fed with standard milk formula without the addition of DHA and AA. Infants were randomly assigned to the study formula before two weeks of life. Assigned diets were fed from day of enrolment to six months of age. | Fatty acid profiles in red cell lipids, physical growth and neurodevelopmental outcomes at 3 and six months of age. | The authors published a short version of the article in the Chinese medical journal. The full article with the raw data was provided by the authors on request. Methodology was also clarified by the authors. Breast fed reference group=26 | B |
| Dallas 1998 | Sample size calculation: Yes
Concealment of allocation - Yes. Using sealed envelopes.
Blinding of intervention - Yes
Blinding of outcome assessment - Yes
Completeness of follow up - No. 70-86% follow up for different outcomes | N = 79. inclusion criteria: Infants of gestational age 37-40 weeks, singleton births and appropriate for gestational age. Exclusion criteria: family history of milk protein allergy or genetic or familial eye disease, maternal vegetarian or vegan dietary pattern, maternal metabolic disease, anemia or infection, congenital malformation or infection, jaundice, perinatal asphyxia, meconium aspiration syndrome, admission to NICU.
LCPUFA (DHA and AA) supplemented formula: N=27;
LCPUFA (DHA alone) supplemented formula: N= 26
Control formula: N = 26
Mean gestational age and birthweight: not given | One group was fed with formula milk enriched with DHA (0.36%) and AA (0.72%). Another group was fed formula milk enriched with DHA alone (0.36%). Control group were fed with standard milk formula without the addition of DHA and AA. Infants were randomly assigned to the study formula between 1-5 days of life. Assigned diets were fed from within five days of birth till 17 weeks of age. | Blood lipids were measured at 17 and 52 weeks. Growth, sweep VEP and forced preferential looking were measured at 6, 17, 26 and 52 weeks. Bayley Scales of Infant Development were measured at 18 months. | Breastfed reference n=29.
| A |
| Dallas 2005 | Sample size calculation: Yes
Concealment of allocation - Yes. Using sealed envelopes.
Blinding of intervention - Yes
Blinding of outcome assessment - Yes
Completeness of follow up - Yes. 83-92% follow up for different outcomes | N = 103. Infants of gestational age 37-40 weeks, singleton births, appropriate for gestational age were included. Exclusion criteria were family history of milk protein allergy or genetic or familial eye disease, maternal vegetarian or vegan dietary pattern, maternal metabolic disease, anemia or infection, congenital malformation or infection, jaundice, perinatal asphyxia, meconium aspiration syndrome, admission to NICU.
LCPUFA supplemented formula: N=51
Control formula: N = 52.
Mean gestational age and birth weights were not given. | 'LCPUFA' group were given milk formula enriched with DHA (0.36%) and AA (0.72%). Control group were fed with standard milk formula without the addition of DHA and AA. Infants were randomly assigned to the study formula between 1-5 days of life. Assigned diets were fed from day of enrolment to 52 weeks of age. | Fatty acid profiles in red cell lipids, physical growth, Visual outcomes: Sweep VEP acuity, Random dot stereoacuity. | Authors clarified the details of methodology and also provided more information on outcome data. No breastfed control group. | A |
| England 1999 | Sample size calculation: Yes
Allocation concealment: Yes, Using sealed envelopes
Blinding of Intervention: Yes
Blinding of outcome assessment: Yes
Completeness of follow up: Yes (81%) | N=309. Inclusion criteria were term infants >=37 weeks gestation and appropriate for gestational age singletons. Exclusion criteria was the presence of congenital anomalies.
LCPUFA : 154 (GA 40.0+/- 1.29wks and BW 3542+/- 409g)
Control formula: 155 (GA 40.1+/- 1.30 wks and BW 3648+/- 459g). | 'LCPUFA' group were given milk formula enriched with DHA (0.32%) and AA (0.30%). Control group were fed with standard milk formula without the addition of DHA and AA. Infants were assigned to the study formula within first week of life. The study formula was continued for six months. | Primary endpoint was development at 18m assessed by the Bayley scales of infant development (MDI & PDI). Secondary endpoint was development at 9 m assessed by Knobloch, Passamanick and Sherrards tests. Growth and gastro-intestinal tolerance were also assessed at 6, 9 and 18m. The incidence of atopy, eczema, wheeze and infection was also documented. | Infants who were breastfed for at least 6 weeks were a reference group n=138. The authors published a correction to the reported outcomes in 2002 stating that the two diet codes were inadvertently reversed. Hence the outcomes of Standard formula were those of infants fed LCPUFA formula and vice versa. The correct data have been entered in this review | A |
| France 2000 | Sample size calculation: Not clear
Concealment of allocation - Yes
Blinding of intervention - Yes
Blinding of outcome assessment - Yes
Completeness of follow up - Yes | N=24. Inclusion criteria: Healthy term appropriate for gestational age infants. Exclusion criteria: Infants of mothers who had history of cocaine or alcohol abuse, hyperlipidemia, diabetes, strict vegetarian or vegan diets.
LCPUFA supplemented formula: N=12 (GA 39.3+/-1.1w, BW 3.378+/-0.426kg)
Control formula: N = 12 ( GA 40.1+/-1.2w, BW 3.311+/-0.0448kg). | 'LCPUFA' group were given milk formula enriched with DHA (0.31%). Control group were fed with standard milk formula without the addition of DHA. Assigned diets were fed from day 3 of life till 4 months of age. | Fatty acid levels in RBCs at four months, weight, length and head circumference at 2 and 4 months of age. | The authors responded by providing additional information regarding the methodology of the study. Quality of allocation concealment: Adequate | A |
| Memphis 1996 | Sample size calculation: Yes
Concealment of allocation - Yes.
Blinding of intervention - Yes
Blinding of outcome assessment - Yes
Completeness of follow up - Yes | N=39. Inclusion criteria: Infants born at term (37-43 weeks PMA) without IUGR and without any medical problems likely to influence long term growth and development. Exclusion criteria were not mentioned.
LCPUFA: n=19 (GA 39.8+/-1.2w , BW 3.285+/-0.448kg)
Control formula: N= 20 (GA 40.3+/-0.9w, BW 3.327+/-0.331kg).
| Supplemented formula was enriched with DHA (0.10%) and AA (0.43%). Control formula did not have DHA and AA. Infants were randomised within 24 hours of birth to receive the study milk formula. The study formula was fed for one year. | RBC and Plasma fatty acid levels at 2,4,6 and 12m.
Visual acuity (Teller acuity cards) at 2,4,6,9 and 12m. | Breastfed reference group: n=19 | A |
| Milan 1995 | Sample size calculation: Yes
Concealment of allocation - Yes. Using a computer generated random-allocation list
Blinding of intervention - Yes
Blinding of outcome assessment - Yes
Completeness of follow up - Yes. | N=60. Inclusion criteria: Term infants (37-42 weeks) , 5 minute Apgar score more than 7, and absence of disease. Exclusion criteria were not mentioned.
LCPUFA formula: N=29 (GA 39.0+/- 1.3w, BW 3.168+/-0.448kg)
Control formula: N=31( GA 39.4+/- 1.4w, BW 3.299+/-0.453kg).
| Supplemented formula contained DHA (0.3%)and AA (0.44%). Control formula did not contain DHA or AA. The study milk formulas were fed from within 3rd day of life till 4 months. | Brunet-Lezine test of global neurodevelopment at 4,12 and 24 months, Plasma and RBC phospholipid DHA & AA at 4 months and 24 months. | 30 infants in the breastfed reference group. The authors responded by providing additional information regarding the methodology of the study.
| A |
| Netherlands 2005 | Sample size calculation: Yes
Concealment of allocation - Yes. Using central computerized randomization
Blinding of intervention - Yes
Blinding of outcome assessment - Yes
Completeness of follow up - Yes (92%). | N = 315. Infants of gestational age 37-42 weeks. Exclusion criteria were congenital anomalies, infants from multiple births, mothers with significant disability, mothers with insufficient mastery of Dutch language, adopted or foster infants and formula fed infants who had received human milk for more than 5 days.
LCPUFA supplemented formula: N=146
Control formula: N = 169 | 'LCPUFA' group were given milk formula enriched with DHA (0.3%)and AA (0.45%). Control group were fed with standard milk formula without the addition of DHA and AA. Infants were randomly assigned to the study formula between 1-5 days of life. Assigned diets were fed from day of enrolment for two months. | Neurodevelopmental assessment using Hempel and Bayley scales. Hempel assessment is a standardised technique designed for the detection of minor signs of neurological dysfunction, | Authors provided additional information regarding various outcomes. Breast fed reference group: 160 | A |
| Portland 1997 | Sample size calculation: Not clear
Concealment of allocation - Yes.
Blinding of intervention - Yes
Blinding of outcome assessment - Not clear.
Completeness of follow up - No. less than 80% follow up for visual acuity outcomes at different ages.
| N= 134. Inclusion criteria: Term infants >=37 weeks gestation, AGA. Exclusion criteria: Apgar score< 7 at five minutes, physical or metabolic defects, those who received IV lipid infusion or blood transfusion, infants of mothers with diabetes, hyperlipidemia or perinatal infections.
LCPUFA (DHA and AA) group: N=46 (GA 39.3+/-1.3w & BW 3.50+/-0.46kg).
LCPUFA (DHA alone) group: N=43, GA: 39.7+-1.2 w, BW: 3.54+-0.46kg
Control group: N=45 (GA 39.8+/-1.1w & BW 3.600+/-0.47kg. | The DHA plus AA formula was enriched with DHA(0.13%) and AA (0.45%). The DHA alone formula was enriched with DHA (0.2%).The control formula was standard milk without addition of DHA and AA. Infants were randomized within 9 days after birth. The study formulas were fed ad libitum as the sole source of nutrition for the first 4 months and as the exclusive milk beverage up to 12 months of age. | RBC fatty acid levels at 2, 4, 6 & 12m. Growth measured at 1, 2, 4, 6, 9 & 12m. Visual acuity at 2, 4, 6, 9 ,12 and 39m. Visual acuity was measured by the Teller acuity card procedure or sweep spatial frequency VEP. Global development was assessed at 1y (BSID) and at 3y (Stanford Binet IQ). Language development was assessed at 14 m (McArthur Communicative Development Inventory) and at 3y (Peabody Picture Vocabulary Test). | Breastfed reference group: n=63. The authors had provided additional information for the previous version of this review. They were contacted for some more information for this update. The authors acknowledged the receipt of our letter, but did not provide the required information.
| A |
| Portland 2001 | Sample size calculation: Yes
Concealment of allocation - Yes. Using computerized randomization
Blinding of intervention - Yes
Blinding of outcome assessment - Yes
Completeness of follow up - No. Less than 80 % of the enrolled infants completed the study | N = 239. Inclusion criteria: Term infants between 37-42 weeks gestation, <=9 days, birth weight.>=2500g, 5 minute Apgar score>=7, ability to tolerate milk based formula or breast milk. Exclusion criteria: significant cardiac, ophthalmologic, gastrointestinal or hematological or metabolic disease, milk protein allergy, or a maternal medical history known to have adverse effects on the fetus, tuberculosis, HIV, or perinatal infections, or substance abuse.
LCPUFA (DHA and AA) supplemented formula derived from egg triglyceride: N=80. GA: 39+-1.3W, BW: 3.39+-0.47kg
LCPUFA (DHA and AA) supplemented formula derived from fish and fungus oil: N=82, GA: 39.3+-1.2 W, BW: 3.41+-0.41kg
Control formula: N = 77; GA 39.4+-1.2, BW: 3.45+-0.44 kg | The study formula was milk formula supplemented with DHA (0.13%) and AA (0.45%). The control formula was standard milk without addition of DHA and AA. The infants were randomised within 9 days of birth. The study formulas were fed ad libitum as the sole source of nutrition for the first 4 months and as the exclusive milk beverage up to 12 months of age. | Fatty acid profiles in red cell lipids, physical growth at 1, 2,4,6,9 and 12 months. Visual acuity using teller acuity card procedure at 2, 4, 6, and 12 months, Fagan test of infant intelligence at 6 and 9 months, Bayley scale of infant development at 6 and 12 months, language assessment using McArthur's communicative developmental inventories at 9 and 14 months, parental reporting of infant temperament at 6 and 12 months. | The authors reported the outcome data separately for milk formula enriched with LCPUFA derived from fish/ fungus oil and the milk formula enriched with LCPUFA derived from egg triglyceride. Since our outcome of interest was the effect of LCPUFA rather than the source of LCPUFA, we requested the authors to give combined outcome data. The authors provided the requested data . Breast fed control group: N=82. | A |
| Scotland 1998 | Sample size calculation: Yes
Concealment of allocation - Yes.
Blinding of intervention - Yes
Blinding of outcome assessment - Yes
Completeness of follow up - No. 44 out of 72 (61%) infants completed the outcome assessment of the study. | N = 72. Term infants (37-42 weeks) with birth weight between 2.5-4kg. Exclusion criteria: not mentioned.
LCPUFA supplemented formula: N=34
Control formula: N = 38
Mean birth weight and gestational age data of study infants was not given. | The LCPUFA formula was enriched with DHA (0.15% to 0.25%) and AA (0.3% to 0.4%). The control formula did not contain DHA or AA. The study milk formula was given from birth till 4 months of age. | Infant cognition measured by a means-end problem solving test at 10m. | Results are given as medians and quartiles and are therefore given in the text, not the Tables. No breastfed control group. | A |
| Wales 2000 | Sample size calculation: not clear
Concealment of allocation - Yes
Blinding of intervention - Yes
Blinding of outcome assessment - Yes
Completeness of follow up - Yes | N = 109. Infants full term gestation and birth weight 2.5 to 4.5 kg. Exclusion criteria were congenital anomalies and infants from multiple births.
LCPUFA supplemented formula: N=54. Birth weight: 3.31+-0.48kg
Control formula: N = 55. Birth weight:3.35+-0.46 kg
Mean gestational age of the study infants was not given. | The LCPUFA formula was enriched with DHA (0.2%) and AA (0.4%). The control formula was not enriched with DHA and AA. Study formula was started within 72 hours of birth and given for the first 12 weeks. | Physical growth at six weeks, 3 months, 6 months and 1 year and general health of infants. | The authors replied with clarification regarding the methodology of study. No breastfed control group. | A |
Characteristics of excluded studies
| Study | Reason for exclusion |
| Dallas 2002 | Late age (six weeks) at which study formula was commenced. |
| Houston 2002 | Milk formulas with different amounts of alpha linolenic acid levels were compared. |
| Hungary 1995 | Methodology not clear. Outcomes of interest not available. |
| Kansas 1999 | Methodology not clear. Outcomes of interest not available. Authors of the study expressed concerns about methodological issues of their study. |
| Munich 1996 | Methodology not clear. Time of starting the study formula and duration of supplementation not clear. |
| Scandinavia 1996 | Late age at which supplementation was commenced |
References to studies
References to included studies
Adelaide 1995 {published and unpublished data}Makrides M, Neumann M, Simmer K, Pater J, Gibson R. Are long-chain polyunsaturated fatty acids essential nutrients in infancy? Lancet 1995;345:1463-8.
Adelaide 1996 {published and unpublished data}
* Makrides M, Neumann MA, Simmer K, Gibson RA. A critical appraisal of the role of long-chain polyunsaturated fatty acids on neural indices of term infants: a randomised controlled trial. Pediatrics 2000;105:32-8.
Makrides M, Neumann MA, Simmer K, Gibson RA. Dietary long-chain polyunsaturated fatty acids do not influence growth of term infants: a randomised clinical trial. Pediatrics 1999;104:468-75.
China 2004 {published data only}
Ben XM, Zhou XY, Zhao WH, Yu WL, Pan W, Zhang WL et al. Growth and development of term infants fed with milk with long-chain polyunsaturated fatty acid supplementation. Chinese Medical Journal (English) 2004;117:1268-70.
Dallas 1998 {published data only}
* Birch EE, Garfield S, Hoffman DR, Uauy R, Birch DG. A randomised controlled trial of early dietary supply of LCPUFA and mental development in term infants. Developmental Medicine and Child Neurolology 2000;42:174-81.
Birch EE, Hoffman DR, Uauy R, Birch DG, Prestidge C. Visual acuity and the essentiality of docosahexaenoic acid and arachidonic acid in the diet of term infants. Pediatric Research 1998;44:201-9.
Hoffman DR, Birch EE, Birch DG, Uauy R, Castaneda YS, Lapus MG, Wheaton DH. Impact of early dietary intake and blood lipid composition of long-chain polyunsaturated fatty acids on later visual development. Journal of Pediatric Gastroenterology and Nutrition 2000;31:540-53.
Dallas 2005 {published data only}
Birch EE, Castaneda YS, Wheaton DH, Birch DG, Uauy RD, Hoffman DR. Visual maturation of term infants fed long-chain polyunsaturated fatty acid-supplemented or control formula for 12 mo. American Journal of Clinical Nutrition 2005;81:871-9.
England 1999 {published data only}
Lucas A, Morley R, Stephenson T, Elias-Jones A. Long-chain polyunsaturated fatty acids and infant formula. Lancet 2002;360:1178.
Lucas A, Stafford M, Morley R, Abbott R, Stephenson T, Macfadyen U, Elias-Jones A, Clements H. Efficacy and safety of long-chain polyunsaturated fatty acid supplementation of infant-formula milk: a randomised trial. Lancet 1999;354:1948-54.
France 2000 {published data only}
Lapillonne A, Brosssard N, Claris O, Reygrobellet B, Salle BL. Erythrocyte fatty acid composition in term infants fed human milk or a formula enriched with a low eicosapentanoic acid fish oil for 4 months. European Journal of Pediatrics 2000;159:49-53.
Memphis 1996 {published data only}
Carlson SE, Ford AJ, Werkman SH, Peeples JM, Koo WWK. Visual acuity and fatty acid status of term infants fed human milk and formulas with and without docosahexaenoate and arachidonate from egg yolk lecithin. Pediatric Research 1996;39:882-8.
Milan 1995 {published data only}
* Agostini C, Trojan S, Bellu R, Riva E, Bruzzese MG, Giovannini M. Developmental quotient at 24 months and fatty acid composition of diet in early infancy: a follow up study. Archives of Diseases in Childhood 1997;76:421-4.
Agostini C, Trojan S, Bellu R, Riva E, Giovannini M. Neurodevelopmental quotient of healthy term infants at 4 months and feeding practice: the role of long-chain polyunsaturated fatty acids. Pediatric Research 1995;38:262-6.
Agostoni C, Riva E, Scaglioni S, Marangoni F, Radaelli G, Giovannini M. Dietary fats and cholesterol in italian infants and children. American Journal of Clinical Nutrition 2000;72:1384S-91S.
Netherlands 2005 {published data only}
Bouwstra H, Dijck-Brouwer DA, Boehm G, Boersma ER, Muskiet FA, Hadders-Algra M. Long-chain polyunsaturated fatty acids and neurological developmental outcome at 18 months in healthy term infants. Acta Paediatrica 2005;94:26-32.
Portland 1997 {published and unpublished data}
* Auestad N, Montalto MB, Hall RT, Fitzgerald KM, Wheeler RE, Connor WE et al. Visual acuity, erythrocyte fatty acid composition, and growth in term infants fed formulas with long-chain polyunsaturated fatty acids for one year. Pediatric Research 1997;41:1-10.
Auestad N, Scott DT, Janowsky JS, Jacobsen C, Carroll RE, Montalto MB et al. Visual, cognitive, and language assessments at 39 months: a follow-up study of children fed formulas containing long-chain polyunsaturated fatty acids to 1 year of age. Pediatrics 2003;112:e177-83.
Scott DT, Janowsky JS, Carroll RE, Taylor JA, Auestad N, Montalto MB. Formula supplementation with long-chain polyunsaturated fatty acids: are there developmental benefits? Pediatrics 1998;102:e59.
Portland 2001 {published data only}
Auestad N, Halter R, Hall RT, Blatter M, Bogle ML, Burks W et al. Growth and development in term infants fed long-chain polyunsaturated fatty acids: a double-masked, randomized, parallel, prospective, multivariate study. Pediatrics 2001;108:372-81.
Scotland 1998 {published data only}
Willatts P, Forsyth JS, DiModugno MK, Varma S, Colvin M. Effect of long-chain polyunsaturated fatty acids in infant formula on problem solving at 10 months of age. Lancet 1998;352:688-91.
Wales 2000 {published data only}
Morris G, Moorcraft J, Mountjoy A, Wells JC. A novel infant formula milk with added long-chain polyunsaturated fatty acids from single-cell sources: a study of growth, satisfaction and health. European Journal of Clinical Nutrition 2000;54:883-6.
References to excluded studies
Dallas 2002 {published data only}Birch EE, Hoffman DR, Castaneda YS, Fawcett SL, Birch DG, Uauy RD. A randomized controlled trial of long-chain polyunsaturated fatty acid supplementation of formula in term infants after weaning at 6 wk of age. American Journal of Clinical Nutrition 2002;75:570-80.
Houston 2002 {published data only}
Voigt RG, Jensen CL, Fraley JK, Rozelle JC, Brown FR 3rd, Heird WC. Relationship between omega3 long-chain polyunsaturated fatty acid status during early infancy and neurodevelopmental status at 1 year of age. Journal of Human Nutrition and Diet 2002;15:111-20.
Hungary 1995 {published data only}
Decsi T, Koletzko B. Growth, fatty acid composition of plasma lipid classes, and plasma retinol and alpha-tocopherol concentrations in full-term infants fed formula enriched with omega-6 and omega-3 long-chain polyunsaturated fatty acids. Acta Paediatrica;84:725-32.
Kansas 1999 {published data only}
* Carlson SE, Mehra S, Kagey WJ, Merkel KL, Diersen-Schade DA, Harris CL and Hansen JW. Growth and development of term infants fed formulas with docosahexaenoic acid (DHA) from algal oil or fish oil and arachidonic acid from fungal oil. In: Pediatric Research. Vol. 45. 1999:278A.
Munich 1996 {published data only}
Clausen V, Damli A, Schenck UV, Koletzko B. Influence of long-chain polyunsaturated fatty acids (LCPUFA) on early visual acuity and mental development of term infants. In: Proceedings of the American Oil Chemists' Society. Barcelona, 1996.
Scandinavia 1996 {published data only}
Horby Jorgensen M, Holmer G, Lund P, Hernell O, Michaelsen KF. Effect of formula supplemented with docosahexaenoic acid and gamma-linolenic acid on fatty acid status and visual acuity in term infants. Journal of Pediatric Gastroenterology and Nutrition 1998;26:412-21.
Jorgenson MH, Hernell O, Lund P, Holmer G, Michaelson KF. Visual acuity of 4 month term infants in relation to docosahexaenoic acid intake, a randomised study. Journal of Pediatric Gastroenterology and Nutrition 1996;22:436.
* indicates the primary reference for the study
Other references
Additional references
Birch 1992Birch EE, Birch DG, Hoffman DR, Uauy R. Dietary essential fatty acid supply and visual acuity development. Investigative Ophthalmology & Visual Science 1992;33:3245-53.
Bjerve 1992
Bjerve KS, Bredde OL, Bonaa K, Johnson H, Vatten L, Vik T. Clinical and epidemiological studies with alpha linolenic acid and longchain n-3 fatty acids. In: Sinclair AJ. Gibson RA, editor(s). Essential Fatty Acids and Eicosanoids. Third International Conference on Essential Fatty Acids and Eicosanoids. Illinois: AOCS, 1992.
Carlson 1993
Carlson SE, Werkman SH, Peeples JM, Cooke RJ, Tolley EA. Arachidonic acid status correlates with first year growth in preterm infants. Proceedings of the National Academy of Science 1993;90:1073-7.
Clandinin 1980
Clandinin MT, Chapell JE, Leong S, Heim T, Swyer PR, Chance GW. Intrauterine fatty acid accretion rates in human brain: implications for fatty acid requirements. Early Human Development 1980;4:121-9.
Clark 1992
Clark KJ, Makrides M, Neumann MA, Gibson RA. Determination of the optimal ratio of linoleic acid to alpha linolenic acid in infant formulas. Journal of Pediatrics 1992;120:S151-8.
Fagan 1970
Fagan JF. Memory in the infant. Journal of Experimental Child Psychology 1970;9:217-26.
Fagan 1983
Fagan JF, Singer LT. Infant recognition memory as a measure of infant intelligence. In: Lipsitt LP, editor(s). Advances in Infant Research. Vol. 2. Norwood: Ablex, 1983:31-72.
Farquharson 1995
J Farquharson, EC Jamieson, KA Abbasi, WJ Patrick, RW Logan and F Cockburn. Effect of diet on the fatty acid composition of the major phospholipids of infant cerebral cortex. Archives of Disease in Childhood 1995;72:198-203.
Fleith 2005
Fleith M, Clandinin MT. Dietary PUFA for preterm and term infants: review of clinical studies. Critical Reviews in Food Science and Nutrition 2005;45:205-29.
Forsyth 2003
Forsyth JS, Willatts P, Agostoni C, Bissenden J, Casaer P, Boehm G. Long chain polyunsaturated fatty acid supplementation in infant formula and blood pressure in later childhood: follow up of a randomised controlled trial. BMJ 2003;326:953.
Jensen et al 1997
Jensen CL, Prager TC, Fraley KJ, Chen H, Anderson RE, Heird WC. Effect of dietary linoleic/alpha-linolenic acid ratio on growth and visual function of term infants. Journal of Pediatrics 1997;131:200-9.
Lauritzen 2001
Lauritzen L, Hansen HS, Jorgensen MH, Michaelsen KF. The essentiality of long chain n-3 fatty acids in relation to development and function of the brain and retina. Progress in Lipid Research 2001;40:1-94.
Lucas 1992
Lucas A, Morley R, Cole TJ, Lister G, Leeson-Payne C. Breastmilk and subsequent intelligence quotient in children born preterm. Lancet 1992;339:261-4.
Makrides 1993
Makrides M, Simmer K, Goggin M, Gibson RA. Erythrocyte docosahexaenoic acid correlates with the visual response of the healthy, term infant. Pediatric Research 1993;33:3242-53.
Makrides 2005
Makrides M, Gibson RA, Udell T, Ried K; International LCPUFA Investigators. Supplementation of infant formula with long-chain polyunsaturated fatty acids does not influence the growth of term infants. American Journal of Clinical Nutrition 2005;81:1094-1101.
McCann 2005
McCann JC, Ames BN. Is docosahexaenoic acid, an n-3 long-chain polyunsaturated fatty acid, required for development of normal brain function? An overview of evidence from cognitive and behavioral tests in humans and animals. American Journal of Clinical Nutrition 2005;82:281-95.
Morrow-Tlucak 1988
Morrow-Tlucak M, Haude RH, Ernhart CB. Breastfeeding and cognitive development in the first two years of life. Social Science & Medicine 1988;26:635-9.
Neuringer 1986
Neuringer M, Connor WE, Lin DS, Barstad L, Luck S. Biochemical and functional effects of prenatal and postnatal n-3 fatty acids on retina and brain in rhesus monkeys. Proceedings of the National Academy of Sciences of the United States of America 1986;83:4021-5.
Oddy 2003
Oddy WH, Kendall GE, Blair E, De Klerk NH, Stanley FJ, Landau LI, Silburn S, Zubrick S. Breast feeding and cognitive development in childhood: a prospective birth cohort study. Paediatric and Perinatal Epidemiology 2003;17:81-90.
Rogers 1978
Rogers B. Feeding in infancy and later ability and attainment; a longitudinal study. Developmental Medicine and Child Neurology 1978;20:241-6.
SanGiovanni 2000
SanGiovanni JP, Berkey CS, Dwyer JT, Colditz GA. Dietary essential fatty acids, long-chain polyunsaturated fatty acids, and visual resolution acuity in healthy fullterm infants: a systematic review. Early Human Development 2000;57:165-88.
Temboury 1994
Temboury MC, Otero A, Ploanco I, Arribas E. Influence of breastfeeding on the infant's intellectual performance. Journal of Pediatric Gastroenterology and Nutrition 1994;18:32-6.
Uauy 1990
Uauy RD, Birch DG, Birch EE, Tyson JE, Hoffman DR. Effect of dietary n-3 fatty acids on retinal function of very low birthweight neonates. Pediatr Research 1990;28:485-92.
Uauy 2003
Uauy R, Hoffman DR, Mena P, Llanos A, Birch EE. Term infant studies of DHA and ARA supplementation on neurodevelopment: results of randomized controlled trials. Journal of Pediatrics 2003;143(4 suppl):S17-25.
Other published versions of this review
Simmer 1998Simmer K. Longchain polyunsaturated fatty acid supplementation of infants born at term. In: Cochrane Database of Systematic Reviews, Issue 4, 1998. Oxford: Update Software.
Simmer 2001
Simmer K. Longchain polyunsaturated fatty acid supplementation of infants born at term. In: Cochrane Database of Systematic Reviews, Issue 4, 2001.
Comparisons and data
| Comparison or outcome |
Studies |
Participants |
Statistical method |
Effect size |
| 01 LCPUFA supplemented vs control formula |
| 01 VEP acuity at 4 m (log MAR, steady state) |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 02 Sweep VEP acuity at 4m of age (logMAR) |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 03 Sweep VEP acuity at 4m(cycles/degree) |
1 |
54 |
WMD (fixed), 95% CI |
-0.47 [-1.16, 0.22] |
| 04 Visual acuity/Teller cards at 4 m (cycles/degree) |
3 |
264 |
WMD (fixed), 95% CI |
-0.11 [-0.24, 0.02] |
| 05 Sweep VEP acuity at 6m(cycles/degree) |
1 |
53 |
WMD (fixed), 95% CI |
-0.31 [-1.05, 0.43] |
| 06 Visual acuity/Teller cards at 6 m (cycles/degree) |
3 |
256 |
WMD (fixed), 95% CI |
0.02 [-0.11, 0.15] |
| 07 VEP acuity at 7-8 m (log MAR, steady state) |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 08 sweep VEP acuity at 12 months (LogMAR) |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 09 Sweep VEP acuity at 12m(cycles/degree) |
1 |
53 |
WMD (fixed), 95% CI |
0.00 [-0.71, 0.71] |
| 10 Visual acuity/Teller cards at 12 m (cycles/degree) |
3 |
256 |
WMD (fixed), 95% CI |
-0.01 [-0.12, 0.11] |
| 11 Visual acuity at 3 years (Teller acuity cards; cy/deg) |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 12 MDI (Bayley) score at 3months |
1 |
58 |
WMD (fixed), 95% CI |
2.48 [-1.90, 6.86] |
| 13 PDI (Bayley) score at 3months |
1 |
58 |
WMD (fixed), 95% CI |
3.66 [0.43, 6.89] |
| 14 MDI (Bayley) score at 6months |
2 |
207 |
WMD (fixed), 95% CI |
-0.59 [-2.26, 1.07] |
| 15 PDI (Bayley) score at 6months. |
2 |
206 |
WMD (fixed), 95% CI |
0.23 [-2.47, 2.94] |
| 16 MDI (Bayley score) at 1 year |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 17 PDI (Bayley score) at 1 year |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 18 MDI (Bayley score) at 18 m |
3 |
604 |
WMD (fixed), 95% CI |
-0.78 [-2.98, 1.42] |
| 19 PDI (Bayley score) at 18 m |
3 |
604 |
WMD (fixed), 95% CI |
0.25 [-1.33, 1.82] |
| 20 MDI (Bayley score) at 2 years |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 21 PDI (Bayley score) at 2 years |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 22 Weight at 4 months |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 23 Length at 4 months |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 24 Head circumference at 4 months |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 25 Weight at 6 m (kg) |
4 |
830 |
WMD (fixed), 95% CI |
0.01 [-0.11, 0.13] |
| 26 Length at 6 m (cm) |
4 |
830 |
WMD (fixed), 95% CI |
-0.13 [-0.47, 0.21] |
| 27 Head circumference at 6 m (cm) |
4 |
830 |
WMD (fixed), 95% CI |
-0.06 [-0.25, 0.13] |
| 28 Weight at 12 m (kg) |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 29 Weight at 12 m, z score |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 30 Length at 12 m (cm) |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 31 Length at 12 m, z score |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 32 Head circumference at 12 m (cm) |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 33 Head circumference at 12 m, z score |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 34 Weight at 18 m (kg) |
2 |
563 |
WMD (fixed), 95% CI |
-0.04 [-0.25, 0.17] |
| 35 Length at 18 m (cm) |
2 |
565 |
WMD (fixed), 95% CI |
-0.19 [-0.71, 0.34] |
| 36 Head circumference at 18 m (cm) |
2 |
565 |
WMD (fixed), 95% CI |
-0.07 [-0.32, 0.19] |
| 37 Weight at 2 years (kg) |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 38 Height at 2 years (cm) |
|
|
WMD (fixed), 95% CI |
Subtotals only |
| 39 Head circumference at 2 years (cm) |
|
|
WMD (fixed), 95% CI |
Subtotals only |
01 LCPUFA supplemented vs control formula
01.01 VEP acuity at 4 m (log MAR, steady state)
01.01.01 DHA and AA versus normal term formula
01.01.02 DHA versus normal term formula
01.02 Sweep VEP acuity at 4m of age (logMAR)
01.02.01 DHA and AA versus normal term formula
01.02.02 DHA versus normal term formula
01.03 Sweep VEP acuity at 4m(cycles/degree)
01.03.01 DHA and AA versus normal term formula
01.03.02 DHA versus normal term formula
01.04 Visual acuity/Teller cards at 4 m (cycles/degree)
01.04.01 DHA and AA versus normal term formula
01.04.02 DHA versus normal term formula
01.05 Sweep VEP acuity at 6m(cycles/degree)
01.05.01 DHA and AA versus normal term formula
01.05.02 DHA versus normal term formula
01.06 Visual acuity/Teller cards at 6 m (cycles/degree)
01.06.01 DHA and AA versus normal term formula
01.06.02 DHA versus normal term formula
01.07 VEP acuity at 7-8 m (log MAR, steady state)
01.07.01 DHA and AA versus normal term formula
01.07.02 DHA versus normal term formula
01.08 sweep VEP acuity at 12 months (LogMAR)
01.08.01 DHA and AA versus normal term formula
01.08.02 DHA versus normal term formula
01.09 Sweep VEP acuity at 12m(cycles/degree)
01.09.01 DHA and AA versus normal term formula
01.10 Visual acuity/Teller cards at 12 m (cycles/degree)
01.10.01 DHA and AA versus normal term formula
01.10.02 DHA versus normal term formula
01.11 Visual acuity at 3 years (Teller acuity
cards; cy/deg)
01.11.01 DHA and AA versus normal term formula
01.11.02 DHA versus normal term formula
01.12 MDI (Bayley) score at 3months
01.12.01 DHA and AA versus normal term formula
01.12.02 DHA versus normal term formula
01.13 PDI (Bayley) score at 3months
01.13.01 DHA and AA versus normal term formula
01.13.02 DHA versus normal term formula
01.14 MDI (Bayley) score at 6months
01.14.01 DHA and AA versus normal term formula
01.14.02 DHA versus normal term formula
01.15 PDI (Bayley) score at 6months.
01.15.01 DHA and AA versus normal term formula
01.15.02 DHA versus normal term formula
01.16 MDI (Bayley score) at 1 year
01.16.01 DHA and AA versus normal term formula
01.16.02 DHA versus normal term formula
01.17 PDI (Bayley score) at 1 year
01.17.01 DHA and AA versus normal term formula
01.17.02 DHA versus normal term formula
01.18 MDI (Bayley score) at 18 m
01.18.01 DHA and AA versus normal term formula
01.18.02 DHA versus normal term formula
01.19 PDI (Bayley score) at 18 m
01.19.01 DHA and AA versus normal term formula
01.19.02 DHA versus normal term formula
01.20 MDI (Bayley score) at 2 years
01.20.01 DHA and AA versus normal term formula
01.20.02 DHA versus normal term formula
01.21 PDI (Bayley score) at 2 years
01.21.01 DHA and AA versus normal term formula
01.21.02 DHA versus normal term formula
01.22 Weight at 4 months
01.22.01 DHA and AA versus normal term formula
01.22.02 DHA versus normal term formula
01.23 Length at 4 months
01.23.01 DHA and AA versus normal term formula
01.23.02 DHA versus normal term formula
01.24 Head circumference at 4 months
01.24.01 DHA and AA versus normal term formula
01.24.02 DHA versus normal term formula
01.25 Weight at 6 m (kg)
01.26 Length at 6 m (cm)
01.27 Head circumference at 6 m (cm)
01.28 Weight at 12 m (kg)
01.28.01 DHA and AA versus normal term infant
01.28.02 DHA versus normal term formula
01.29 Weight at 12 m, z score
01.29.01 DHA and AA versus normal term formula
01.29.02 DHA versus normal term formula
01.30 Length at 12 m (cm)
01.30.01 DHA and AA versus normal term formula
01.30.02 DHA versus normal term formula
01.31 Length at 12 m, z score
01.31.01 DHA and AA versus normal term formula
01.31.02 DHA versus normal term formula
01.32 Head circumference at 12 m (cm)
01.32.01 DHA and AA versus normal term formula
01.32.02 DHA versus normal term formula
01.33 Head circumference at 12 m, z score
01.33.01 DHA and AA versus normal term formula
01.33.02 DHA versus normal term formula
01.34 Weight at 18 m (kg)
01.34.01 DHA and AA versus normal term formula
01.34.02 DHA versus normal term formula
01.35 Length at 18 m (cm)
01.35.01 DHA and AA versus normal term formula
01.35.02 DHA versus normal term formula
01.36 Head circumference at 18 m (cm)
01.36.01 DHA and AA versus normal term formula
01.36.02 DHA versus normal term formula
01.37 Weight at 2 years (kg)
01.37.01 DHA and AA versus normal term formula
01.37.02 DHA versus normal term formula
01.38 Height at 2 years (cm)
01.38.01 DHA and AA vesus normal term formula
01.38.02 DHA versus normal term formula
01.39 Head circumference at 2 years (cm)
01.39.01 DHA and AA versus normal term formula
01.39.02 DHA versus normal term formula
Contact details for co-reviewers
Sanjay Patole, MD, DCH, FRACP
Staff Neonatologist, Senior Clinical Lecturer
Neonatal Paediatrics
King Edward Memorial Hospital for Women
Bagot Road
Subiaco
Perth AUSTRALIA
6008
Telephone 1: 61 08 93401260
Facsimile: 61 08 93401266
E-mail: Sanjay.Patole@health.wa.gov.au
Dr Shripada C Rao
Staff Specialist
Ward 6B, Neonatal Intensive Care Unit
Princess Margaret Hopsital for Children
Robert Road
Subiaco
AUSTRALIA
6008
Telephone 1: 0061 8 9340 8672
Facsimile: 0061 8 9340 8037
E-mail: shripad.rao@health.wa.gov.au
| This review is published as a Cochrane review in The Cochrane
Library, Issue 1, 2008 (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. |
