Methods

Randomised controlled study, single centre, Memphis.

Intervention and outcome assessment were blinded and follow‐up of subjects was complete.

Participants

Entry criteria included no need for mechanical ventilation and no significant IVH or retinopathy of prematurity. 10 subjects who could not tolerate enteral feeds were replaced. 79 infants were enrolled, 67 completed study (33 supplemented, 34 control). Subjects were predominantly from lower socio‐economic groups and black. Supplemented group GA 29 ± 2 wk, BW 1074 ± 193 g. Control group GA 29 ± 2 wk, BW 1133 ± 163 g.

Interventions

Preterm formula (PT) until discharge (approximately 1800 g) then term formula (T). Supplemented formula 18.7% & 32.6% (PT & T) LA, 3.1% & 4.9% (PT & T) ALA, 0.3% EPA, 0.2% DHA. Control formula 19.1% & 33.1% (PT & T) LA, 3.0% & 4.8% (PT & T) ALA.

Outcomes

Visual acuity (Teller acuity cards) and growth at term (0 months), and 2, 4, 6.5, 9 & 12 months post‐term.
Fagan infant test at 6.5, 9 and 12 months post‐term.
Red blood cell and plasma fatty acids.

Notes

Visual acuity and growth parameters given in Figures; investigators contacted for actual values but no response.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Can't tell

Allocation concealment (selection bias)

Unclear risk

Method used for allocation concealment not clear

Blinding (performance bias and detection bias)
All outcomes

Low risk

Blinding of intervention: yes

Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Follow‐up complete

Selective reporting (reporting bias)

Low risk

Yes

Other bias

Low risk

Yes

Methods

Randomised double‐blind trial, single centre, Memphis.

Intervention and outcome assessment were blinded. Follow‐up was complete. Infants were randomised by sealed envelopes, stratified by gender.

Participants

94 infants were recruited and 59 completed study through to 4 months. Selection criteria included birthweight between 747 and 1275 g. More controls dropped out than supplemented infants and replacements were added to balance the groups. 40% of subjects had bronchopulmonary dysplasia (defined as an oxygen requirement for > 28 days) which is associated with impaired vision and development. Therefore, data are given for subgroups of infants with or without bronchopulmonary dysplasia.
Supplemented group for visual acuity GA 28.5 ± 1.2 wk, BW 1069 ± 153 g no BPD & GA 27.0 ± 1.1 wk, BW 947 ± 130 g with BPD vs in control group GA 28.6 ± 1.3 wk, BW 1112 ± 106 g no BPD & GA 27.5 ± 1.6 wk, 975 ± 151 g.
For the Fagan test of infant development , supplemented group GA 27.9 ± 1.5 wk, BW 1027 ± 153 g, n = 15 vs control GA 28.2 ± 1.5 wk, BW 1050 ± 149 g, n = 12.

Interventions

Supplemented formula fed from 3 to 5 days of age to 48 wk PCA. Supplemented formula 21.2% LA, 2.4% ALA, 0.06% EPA, 0.20% DHA vs control formula 21.2% LA, 2.4% ALA. All fed standard formula from 2 months' PCA to 12 months' PCA (34.3% LA, 4.8% ALA).

Outcomes

Visual acuity (Teller acuity cards), plasma fatty acids and growth (including normalised data). Fagan test of infant development were reported for a subset at 12 months.

Notes

Change of test format for infant development resulted in a smaller sample size than planned (sample size required n = 60, sample size assessed n = 27) — the authors comment on type 2 error resulting from the unplanned loss of power. Only the results from infants tested with the same version of the Fagan test used in their 1993 study were published and therefore available for the review.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Can't tell

Allocation concealment (selection bias)

Low risk

Yes (sealed envelopes)

Stratification by gender

Blinding (performance bias and detection bias)
All outcomes

Low risk

Blinding of intervention: yes

Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Follow‐up complete

Selective reporting (reporting bias)

Low risk

Other bias

Low risk

Methods

Randomised controlled trial, single centre, the Netherlands.

Infants were randomised to 2 groups to receive supplemented or control formula. Method of randomisation and concealment of random allocation unclear. Blinding of intervention unclear. Outcome assessors were blinded. Follow‐up complete (100 %).

Participants

Healthy preterm infants (n = 22), "normally growing", were randomised to supplemented or control formula. Specific health characteristics, age at enrolment, and milk and caloric intake are not reported. Exclusion criteria not reported. Gestational age and birth weight in LCPUFA vs control groups were 31.0 ± 2.0 wk vs 31.0 ± 2.0 wk, and 1.16 ± 0.27 kg vs 1.15 ± 0.36 kg, respectively).

Interventions

Infants in both groups were fed study formulae (80 kcal/100 mL) from enrolment until 7 months postnatal age. Composition of study formulae was nearly identical except for DHA and AA which were not present in control formula. Supplemented formula contained 0.64% DHA and 0.84% AA derived from single‐cell oils.

Outcomes

Plasma phospholipid fatty acids, estimation of endogenous LCPUFA synthesis, weight at 7 months postnatal age.

Notes

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Can't tell

Allocation concealment (selection bias)

Unclear risk

Can't tell

Blinding (performance bias and detection bias)
All outcomes

Low risk

Blinding of intervention: can't tell

Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Follow‐up complete

Selective reporting (reporting bias)

Low risk

Other bias

Low risk

Methods

Randomised controlled study, single centre, Canada.

Intervention and outcome assessments were blinded and all subjects were followed.

Participants

Medically stable preterm infants (n = 84), with AGA birth weights, who were receiving full enteral feeds by day 14 were randomised to control or one of three supplemented formulae. Infants were excluded or withdrawn (n = 18) if they received parenteral nutrition after 14 days of age, or they received steroids, red cell or plasma transfusions, or intravenous lipid after 8 days of age. 18 infants received the medium level LC PUFA supplement vs 18 the control formula (GA 31.9 ± 1.8 wk, BW 1.73 ± 0.44 kg vs GA 31.6 ± 2.3 wk, BW 1.74 ± 0.30 kg).

Interventions

The control formula contained 12.8% LA and 1.4% ALA. There were three supplemented formulae: low (0.32% AA & 0.24% DHA), medium (0.49% AA & 0.35% DHA) and high (1.1% AA & 0.76% DHA). The AA and DHA were obtained from single cell oils.

Outcomes

Fatty acids in erythrocyte membrane phospholipids, lymphocyte membrane phospholipids and plasma phospholipids were measured at 2 and 6 wk. Anthropometric measurements were recorded at birth, and at 2 and 6 wk of age. (6 wk measurement/38 weeks PMA entered as term data)

Notes

The formula‐fed group receiving the medium level of LCPUFA supplementation had erythrocyte fatty acids similar to the breast milk‐fed group and therefore are included as the comparison with controls for this review.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Can't tell

Allocation concealment (selection bias)

Low risk

Blinding (performance bias and detection bias)
All outcomes

Low risk

Blinding of intervention: yes

Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Follow‐up complete

Selective reporting (reporting bias)

Low risk

Other bias

Low risk

Methods

Randomised, double‐blinded, controlled trial, multicentre.

Infants were randomised, stratified by birthweight (< 1000g, 1000 to 1500g, > 1500g), by computer‐generated assignment schedules to receive control formula or one of two supplemented formulae. Interventions and assessors of outcomes were blinded. Follow‐up was incomplete (50% to 60% for the primary outcome, 44% to 46% for neurodevelopment).

Participants

Preterm infants ≤ 35 weeks were eligible if they had received < 10 days of enteral feedings > 30 ml/kg/day. Exclusion criteria: GI tract and liver abnormalities and/or disease including confirmed NEC, congenital abnormalities or diseases likely to interfere with evaluation. 361 infants were enrolled. BW (GA): algal/fungal DHA group: 1189 ± 34 g (29.4 ± 0.3 wk), fish/fungal DHA group: 1107 ± 31 g (28.8 ± 0.2 wk), BW of the control group: 1215 ± 33 g (29.6 ± 0.3 wk). In addition, there was a non‐randomised reference group of 105 breast‐fed term infants.

Interventions

Infants were fed preterm formula from enrolment until near discharge (24 kcal/oz), discharge formula to 3 months post‐term (22 kcal/oz), and term formula to 12 months post‐term (20 kcal/oz). Each study group was provided with ready‐to‐use formulae, the only differences being the polyunsaturated fatty acid profiles due to absence of DHA and AA in control formula. There were 2 supplemented groups (algal/fungal oil or fish/fungal oil) and for the meta‐analysis in this review, we chose the algal/fungal group because a) microbial oils are very similar to human milk fat and b) results of the trial suggested superiority of algal/fungal over fish/fungal oil for the primary outcome of the trial. The supplemented formulae contained either 17 mg/100 kcal algal DHA and 34 mg/100 kcal fungal AA or 17 mg/100 kcal fish DHA and 34 mg/100 kcal fungal AA. The preterm supplemented formulae contained 18.6% LA and 2.4% ALA, 0.33% algal DHA, 0.33% fungal DHA vs 18.7% LA and 2.4% ALA in the control formula.

Outcomes

Primary outcome was weight at 4 months and 12 months post‐term. Secondary outcomes included several anthropometric measurements over the first 18 months, neurodevelopment assessed by Bayley Scales of Infant Development (MDI, PDI) at 18 months post‐term, data on fluid intake, feeding tolerance and a range of blood tests (blood picture, cholesterol, glucose, tryglycerides, electrolytes and minerals, liver and kidney function tests), and adverse events.

Notes

Change of enrolment criteria during study. Initially infants > 1500 g were included in the study. After an amendment of the protocol, only infants ≤ 1500 g were enrolled. Authors provided numerical data for growth and neurodevelopmental outcome (these appeared only in Figures in the publication) as well as methodological details.
This study was sponsored by Mead Johnson Nutritionals, Indiana, USA, who also provided the study formulae.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Yes (computer‐generated randomisation schedules)

Allocation concealment (selection bias)

Low risk

Yes (using sealed opaque envelopes)

Blinding (performance bias and detection bias)
All outcomes

Low risk

Blinding of intervention: yes

Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias)
All outcomes

High risk

Follow‐up incomplete:

Primary outcome of weight at 4 months and 12 months post‐term: 50% to 60%

Neurodevelopment: 44% to 46%

Selective reporting (reporting bias)

Low risk

Other bias

Low risk

Methods

Infants were randomised to receive control formula or 1 of 2 supplemented formulae. It is unclear whether assessment was blinded or whether follow up was complete.

Participants

Preterm infants (n = 194) with BW 0.86 to 1.56 kg.

Interventions

The supplemented formulae contained either 0.15% algal DHA or 0.14% algal DHA and 0.27% fungal AA. The LA:ALA ratio of the control formula is not available.

Outcomes

Anthropometric measurements and visual acuity (Teller acuity cards) were recorded at 2 and 4 months postconceptional age.

Notes

Abstract only is available. The formula supplemented with DHA and AA was compared with control formula for this review. There was a breast milk‐fed reference group (n = 80). 194 infants were randomised. An assumption was made for this review that there were 64 per group.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Can't tell

Allocation concealment (selection bias)

Unclear risk

Can't tell

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Can't tell

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Can't tell

Selective reporting (reporting bias)

Unclear risk

Can't tell

Other bias

Unclear risk

Can't tell

Methods

Randomised controlled trial, single centre, Italy.

Infants were randomised on day 10 to supplemented or control formula. No allocation concealment and interventions were not blinded. It is not stated whether assessment of outcome was blinded. Follow‐up of subjects is complete.

Participants

Preterm AGA infants were included if > 50% nutrition was enteral on day 10. Supplemented group: GA 31.1 ± 1.2 wk, BW 1583 ± 310 g, n = 21. Control group: GA 31.3 ± 1.2 wk, 1463 ± 273 g, n = 25.

Interventions

Supplemented formula LA 10.8% to 12.2%, ALA 0.40% to 0.73%, DHA 0.23%, AA 0.23%.
Control formula LA 18.6% to 19.4%, ALA 0.25% to 0.9%, DHA 0.01%, AA 0.02%.

Outcomes

At 52 weeks PCA, flash visual evoked potentials (VEP), electroretinograms (ERG) and auditory responses were measured.
RBC total fatty acids were also measured.

Notes

66 infants were enrolled, 17 of whom formed a breast milk‐fed reference group. The formula groups received up to 25% milk as breast milk.
Methodology of assessment for VEP and ERG deviate from international standards and therefore interpretation is difficult.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Can't tell

Allocation concealment (selection bias)

High risk

No

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Blinding of intervention: no

Blinding of outcome measurement: can't tell

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Follow‐up complete

Selective reporting (reporting bias)

Low risk

Other bias

High risk

Formula groups received up to 25% of milk as breast milk

Methodology of assessment of VEP and ERG deviate from international standards

Methods

Double‐blind randomised controlled trial, single centre, Taiwan.

Infants were randomised by drawing lots, intervention was double blinded, assessors of outcomes were probably blinded, follow‐up rate of neurodevelopmental assessment at 12 months was 81% to 94%.

Participants

Preterm AGA 30 to 37 wk were eligible if they had normal fundus oculi and had not been started on oral feeds. 27 infants (intervention group: n = 16, control group: n = 11) were enrolled. Supplemented group BW 1980 ± 110 g, GA 33.3 ± 0.5 wk. Control group BW 1990 ± 120 g, GA 33.0 ± 0.5 wk. Exclusion criteria: breastfeeding, maternal diabetes or drug abuse, sepsis, chronic lung disease, PVL, surgical NEC, administration of products containing DHA or AA, mechanical ventilation after introducing feeds, and various other conditions and diseases.

Interventions

Supplemented formula ("Neoangelac Plus") LA/ALA 10:1, DHA 0.05% and AA 0.1% from unicellular organisms. Control formula ("Neoangelac") LA/ALA 10:1, no added DHA/AA. Study formula was given from reaching 32 wk postconceptional age and weight > 2000 g for 6 months.

Outcomes

Outcomes included neurodevelopment at 6 months and 12 months post‐term (Bayley Scales of Infant Development (MDI, PDI)), anthropometric measurements at 1, 2, 3, 4, 5, 6, 12 months, and visual acuity by steady state VEP, Lea grating cards, and 'Hiding Heidi' low contrast cards at 4 and 6 months after enrolment.

Notes

Initially the authors planned to enrol 30 infants in each group, but because of increase in breastfeeding, strict exclusion criteria and an outbreak of SARS the number of included subjects was lower.
Study formula was provided by Multipower Enterprise Corporation.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Probably adequate (drawing lots)

Allocation concealment (selection bias)

Unclear risk

Method used for allocation concealment not clear

Blinding (performance bias and detection bias)
All outcomes

Low risk

Blinding of intervention: yes

Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Follow‐up rate of primary outcome 81% to 94%

Selective reporting (reporting bias)

Low risk

Other bias

Low risk

Methods

Double‐blind randomised controlled trial, multicentre, UK.

Infants were randomised, double‐blind, stratified by birthweight (< & > 1200g), centre‐wise in permuted blocks by independent personnel to receive supplemented or control formula. Assessment was blinded and follow‐up was complete.

Participants

Preterm infants (n = 195) from 3 centres were included if BW < 1750g and fully formula fed by 10 days, and no congenital malformations. Supplemented group BW 1336 ± 284 g, GA 30.4 ± 2.3 wk. Control group BW 1353 ± 274 g, GA 30.3 ± 2.4 wk.

Interventions

Control preterm formula contained 10.6 % fa LA and 0.7% fa ALA. Supplemented preterm formula contained 0.17% fa DHA, 0.31% fa AA and 0.04% fa EPA. Trial formula was fed for a mean ± SD of 33 ± 17 days.

Outcomes

Primary outcome was neurodevelopment at 18 months post‐term. Bayley Scales of Infant Development (MDI, PDI) at 18 months post‐term. Knoblock, Passamanik & Sherrard's Developmental Screening Inventory at 9 months post‐term. Neurological impairment at 9 and 18 months post‐term. Growth in hospital and at 9 and 18 months post‐term.

Notes

Funded by Numico Research BV (Wageningen, The Netherlands).

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Yes

Allocation concealment (selection bias)

Low risk

Blinding of randomisation: yes

Stratification by birth weight

Blinding (performance bias and detection bias)
All outcomes

Low risk

Blinding of intervention: yes

Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

More than 80% follow‐up. Neurodevelopment follow‐up: at 9 months: 80/100 control & 78/95 intervention; at 18 months: 81/100 control & 69/95 intervention

Growth follow‐up: at 9 months: 80/100 control & 78/95 intervention; at 18 months: 84/100 control & 74/95 intervention

Selective reporting (reporting bias)

Low risk

Other bias

Low risk

Methods

Randomised, double‐blinded trial, multicentre, UK.

Infants were randomised, double‐blind, stratified by birthweight (< & > 1200g), centre‐wise in permuted blocks by independent personnel to receive supplemented or control formula. Outcome assessors were blinded and follow‐up rate for the primary outcome was 87% and 80% in treatment and control group respectively.

Participants

Preterm infants (n = 238) from 5 UK centres were included if BW ≤ 2000 g and < 35 wk gestation if they received at least some of their enteral feeds as formula milk. They were enrolled when the attending paediatrician decided that infant formula should be started. Age at randomisation: supplemented group 14.3 ± 9.6 days. Control group 13.9 ± 10.4 days. Supplemented group BW 1487 ± 342 g, GA 31.2 ± 2.1 wk. Control group BW 1510 ± 326 g, GA 31.1 ± 1.9 wk. Exclusion criteria: congenital abnormalities known to affect growth or neurodevelopment.

Interventions

Infants were fed preterm formula until the infant reached 2 kg or was discharged. After this point, post‐discharge (nutrient‐enriched) formula was given. Control preterm formula contained 11.5 % LA and 1.6 % ALA. Supplemented preterm formula contained 12.3 % LA, 1.5 % ALA, 0.5 % DHA, 0.9% C18:3 n‐6 gamma‐LA, 0.04 % AA and 0.1 % EPA (borage/fish oil) . Formula was given from enrolment to 9 months post term.

Outcomes

Primary outcome was neurodevelopment at 18 months post‐term. Bayley Scales of Infant Development (MDI, PDI) at 18 months post‐term. Knoblock, Passamanik & Sherrard's Developmental Screening Inventory at 9 months post‐term. Neurological impairment at 9 and 18 months post‐term. Growth in hospital and at 9 and 18 months post‐term. Adverse events.

Notes

Supported by a grant from H. J. Heinz Company who also provided the study formulas.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Yes. Infants were randomised, double‐blind, stratified by birthweight (< & > 1200g), centre‐wise in permuted blocks by independent personnel to receive supplemented or control formula.

Allocation concealment (selection bias)

Low risk

Yes "dietary allocations stored in sealed opaque envelopes"

Blinding (performance bias and detection bias)
All outcomes

Low risk

Blinding of intervention: yes

Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Follow‐up rate of primary outcome 80% to 87%

Selective reporting (reporting bias)

Low risk

Other bias

Low risk

Methods

Double blind, randomised, controlled study, multicentre, USA.

Infants were randomised, double‐blind, to 3 groups based on gender and stratified by birth weight (750 to 1250 g/1251 to 1800 g) in permuted blocks to receive supplemented or control formula. Intervention was blinded. Outcome assessors were blinded. Follow‐up rate of anthropometrics at 4 months was 92% and 77% in treatment and control group respectively. Follow‐up rate at 12 months was 77% in both treatment and control group.

Participants

40 infants < 33 wk gestation and between 750 and 1800 g birth weight and < 28 days (control n = 13, fungal/fish n = 13, egg‐TG/fish N = 14). Supplemented groups: fungal/fish: BW 1424 ± 331 g, GA 30.6 ± 2.5 wk; egg/fish: BW 1367 ± 242 g, GA 30.4 ± 2.1 wk; control group BW 1322 ± 270 g, GA 30.0 ± 2.3 wk. Exclusions include serious congenital malformations, major surgery, asphyxia, PVL and IVH > grade 2 and serious systemic infection.

Interventions

Infants were fed preterm formula until term‐corrected age then post‐discharge nutrient‐enriched formula until 12 months post‐term. There were two supplemented groups (fungal/fish oil or egg‐TG/fish oil) and, for this meta‐analysis and review, we chose the fungal/fish group as microbial oils are more similar to human milk fat than egg‐TG. Supplemented formula contained 0.42% AA and 0.27% DHA until term, and then 0.42% AA and 0.16% DHA until 12 months. Control formula contained 16% to 19% LA and 2.5% ALA. Infants in all groups also received human milk, for example at term, 33% control and 50% supplemented infants consumed human milk at least once per day.

Outcomes

Primary outcome was body composition as measured by absorptiometric x‐ray techniques (DEXA) at 4 months post‐term. Other outcomes included body composition and anthropometrics at 35 wk and 40 wk corrected age, 4 months and 12 months post‐term. Biochemical outcomes included blood fatty acid profiles.

Notes

20 of the 60 participants of this study are already included in the multicentre trial O'Connor 2001. The authors clarified methodological details and provided anthropometric raw data of the 40 infants who were not included in O'Connor 2001.
The study was supported by a grant from Ross Products Division, Abbott Laboratories.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Infants were randomised, double‐blind, to 3 groups based on gender and stratified by birth weight (750 to 1250 g/1251 to 1800 g) in permuted blocks to receive supplemented or control formula.

Allocation concealment (selection bias)

Low risk

Yes

Blinding (performance bias and detection bias)
All outcomes

Low risk

Blinding of intervention: yes

Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Follow‐up rate of primary outcome of body composition at 4 months post‐term: 77% to 92%

Follow‐up rate at 12 months post‐term: 77%

Selective reporting (reporting bias)

Low risk

Other bias

Low risk

Methods

Double‐blind randomised controlled study, multicentre, North America.

Double‐blind prospective randomised trial (blinding of assessment unclear). Infants randomised to 1 of 3 formulae by computer‐generated randomisation schedules. 2 different codes were used for each of the formulae to ensure blinding. Follow‐up was complete.

Participants

194 healthy preterm infants BW 846 to 1560 g. Exclusion: small for gestational age, > 24 days of age when full enteral feeds tolerated, NEC or other GI disease, impaired vision, disease/congenital malformation that may impair growth. Supplemented GA 29.7 ± 1.7 wk, BW 1.28 ± 0.18 g, n = 66. Control GA 29.5 ± 1.7 wk, BW 1.23 ± 0.18 g, n = 62.

Interventions

There were 3 preterm formulas: control (21% to 22% LA, 3% to 3.1% ALA); 2 supplemented (0.34% DHA from DHA‐enriched oil, or 0.33% DHA and 0.60% AA from algal/fungal oils; neither had EPA). For this meta‐analysis and review, we chose the supplement with DHA and AA. Formulae were fed from when 50 kcal/kg/d was tolerated, for at least 28 days until discharge. Term formula without DHA and AA was fed after discharge.

Outcomes

RBC fatty acids at discharge and 48 wk PMA. Anthropometrics at 40, 48 and 57 wk PMA. Visual acuity (Teller acuity cards) at 48 and 57 wk PMA.

Notes

Sponsored by Mead Johnson Nutritionals, Indiana.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Yes (computer‐generated randomisation schedules)

Allocation concealment (selection bias)

Unclear risk

Method used for allocation concealment not clear

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Blinding of intervention: yes

Blinding of outcome measurement: can't tell

Incomplete outcome data (attrition bias)
All outcomes

Low risk

173/194 "completed the premature formula feeding phase" "All infants with available data were included in the analysis of result". For growth, lowest follow‐up was 77%.

For visual acuity, follow‐up rates were: 51/62 control & 57/66 DHA + ARA at 48 weeks and 46/62 control & 55/66 DHA + ARA at 57 weeks

Selective reporting (reporting bias)

Low risk

Other bias

Low risk

Methods

Infants were randomised, double‐blind, to 2 groups to receive supplemented or control formula. Allocation was concealed using sealed opaque envelopes. Intervention was blinded. Outcome assessors were blinded. Follow‐up rate of anthropometrics at 3 months and 6 months post‐term was 100%.

Participants

23 healthy preterm infants, BW 700 to 1500 g. Exclusion: major neonatal morbidity (e.g. congenital malformations, respiratory treatment for more than 10 days, congenital infection, NEC, bowel resection), postnatal age > 21 days, supplemental oxygen, or treatments that could influence growth and development (e.g. diuretics or corticosteroids), failure to achieve full enteral feeds (150 ml/kg/d) by 21 days of life, maternal history of substance abuse, diabetes, hyperlipidaemia, or abnormal dietary patterns (strict vegetarian diet). Supplemented GA 29.4 ± 1.4 wk, BW 1.28 ± 0.17 kg, n = 11. Control GA 29.7 ± 1.7 wk, BW 1.24 ± 0.16 kg, n = 12.

Interventions

Enteral feeding of all infants was started during the first week of life using pooled, pasturized breast milk. Formula feeding began during the first 3 weeks of life if mothers had decided not to breast feed. Infants were fed preterm formula from enrolment until term‐corrected age. After this point, term formula was given until 4 months post‐term. Control preterm formula contained 18.0% LA and 1.6% ALA. Supplemented preterm formula contained 17.8% LA, 1.1% ALA, 0.37% DHA, 0.02% AA and 0.05% EPA (LCPUFA from fish oil).

Outcomes

RBC fatty acids and anthropometrics at enrolment, discharge, term‐corrected age, 3 and 6 months post‐term. Primary outcome was RBC DHA content.

Notes

This study also reported on a non‐randomised control group of breast‐fed infants (n = 10) who are not subject of this review.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Yes

Allocation concealment (selection bias)

Low risk

Yes (using sealed envelopes)

Blinding (performance bias and detection bias)
All outcomes

Low risk

Blinding of intervention: yes

Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Follow‐up complete

Selective reporting (reporting bias)

Low risk

Other bias

Low risk

Methods

Double‐blind, randomised controlled study, multicentre, UK and North America.

Infants were randomised to 3 groups based on centre, gender, BW stratified 750 to 1250 g and 1251 to 1800 g. Infants were enrolled from 8 centres in UK and North America. It is assumed that the study was double‐blind but this is not clearly stated. Assessment was blinded and follow‐up was complete.

Participants

470 infants < 33 wk gestation and between BW 750 and 1805 g and < 28 days age (control n = 144, fungal/fish n = 140, egg‐TG/fish N = 143, human milk exclusively n = 43). Exclusions include serious congenital malformations, major surgery, asphyxia, PVL and IVH > grade 2 and serious systemic infection. Supplemented group BW 1305 ± 293.

Interventions

Infants fed preterm formula until term corrected age then post‐discharge (nutrient‐enriched) formula until 12 months post‐term. There were 2 supplemented groups (fish/fungal oil or egg‐TG/fish oil) and, for this meta‐analysis and review, we chose the fish/fungal group as microbial oils are more similar to human milk fat than egg‐TG, and there were minimal differences between fish/fungal and egg‐TG/fish groups. Supplemented formula contained 0.42% AA and 0.26% DHA until term, and then 0.42% AA and 0.16% DHA until 12 months. Control formula contained 16% to 19% LA and 2.5% ALA. Infants in all groups also received human milk, for example at term, 35% control and 28% supplemented infants consumed human milk at least once per day.

Outcomes

Primary outcome was Bayley Scales of Infant development at 12 months. Visual acuity was assessed by Teller acuity cards at 2, 4 and 6 months' corrected age, and by VEP in 2/8 centres at 4 and 6 months' corrected age. Fagan test of Infant Intelligence was administered at 6 and 9 months' corrected age. MacArthur Communicative Development Inventories was administered at 9 and 14 months' corrected age. Growth was measured at term and 2, 4, 6, 9 and 12 months.

Notes

Sponsored by Ross Products Division, Abbott Laboratories, Ohio.
Authors contacted to provide data for growth and visual acuity, as these appear only in Figures in the publication.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Yes

Allocation concealment (selection bias)

Low risk

Yes

Stratification by gender and birth weight

Blinding (performance bias and detection bias)
All outcomes

Low risk

Blinding of intervention: yes

Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

80% of the enrolled infants completed the study to 12 months' corrected age.

Selective reporting (reporting bias)

Low risk

Other bias

Low risk

Methods

Outcome assessment was blinded but it is not stated whether randomisation and intervention were blinded. Follow‐up of subjects was complete.

Participants

Supplemented group GA 30.7 ± 1.2 wk, BW 1281 ± 101 g. Control groups a) GA 30.9 ± 1.6 wk, BW 1340 ± 106 g, b) GA 29.6 ± 1.6 wk, BW 1224 ± 92 g.

Interventions

Infants were fed study formulae, on average, from day 10 to day 45. Infants were randomised to the supplemented group who received soy/marine oil (LA 20.4%, ALA 1.4%, n‐6 0.1%, n‐3 1.0%) or control group a) corn oil (LA 24.2%, ALA 0.5%) or control group b) soy oil (LA 20.8%, ALA 2.7%).

Outcomes

ERG at 36 wk and 57 wk PCA. VEP acuity at 36 & 57 wk PCA. FPL acuity at 57 wk PCA. Lipid peroxidation products (TBARS) or thiobarbituric acid reactive substances expressed as ‐azide/+azide × 100% which normalises for individual variation, high % suggests a high capacity for lipid peroxidation. Infant bleeding times 57 wk PCA. RBC membrane fluidity at 25 and 37 degrees. Growth at 40 wk, 48 wk and 57 wk PCA.

Notes

For the purpose of this analysis, control group b) was used as the LA:ALA ratio is most similar to other studies and current commercial formula.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Can't tell

Allocation concealment (selection bias)

Unclear risk

Method used for allocation concealment not clear.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Blinding of intervention: can't tell

Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Follow‐up rate of 95% (42/44).

Selective reporting (reporting bias)

Low risk

Other bias

Low risk

Methods

Double‐blind, randomised controlled study, single centre, Sweden.

Double‐blind study with complete follow‐up. Infants were randomised using computer‐generated random list and applied by an independent research officer. Assessment was blinded and follow up was complete.

Participants

Preterm infants (< 34 wk GA and < 1750 g). Supplemented group BW 1.282 ± 0.316 kg, GA 30.4 ± 1.5 wk, n = 22. Control group BW 1.30 ± 0.257 g, GA 30.4 ± 1.6 wk , n = 20. Inclusion criteria: normal neurological examination and cerebral ultrasounds. Exclusion criteria: significant cerebral damage, retinopathy, chronic disease or feeding problems.

Interventions

Supplemented preterm and term formula contained 0.34% DHA and 0.68% AA from micro algae. LA and ALA levels are not given. Preterm formula was fed until a weight of 3 kg. Infants then received a term formula with or without supplement as per randomisation until 6 months' corrected age.

Outcomes

Cerebral myelination assessed by magnetic resonance imaging (MRI). Bayley Scales of Infant Development (MDI, PDI), visual acuity by flash VEP and Teller cards, RBC and plasma fatty acids.

Notes

Sponsored by Nutricia, Numico Research.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Yes (computer‐generated randomisation schedules)

Allocation concealment (selection bias)

Low risk

Yes

Blinding (performance bias and detection bias)
All outcomes

Low risk

Blinding of intervention: yes

Blinding of outcome measurement: yes

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Follow‐up complete

Selective reporting (reporting bias)

Low risk

Other bias

Low risk

Methods

Randomisation computerised and stratified by BW (750 to 1000 g, 1001 to 1500 g, 1501 to 2000 g). Blinding by coded labels and verified by "trained sensory panel". It is unclear whether assessment was blinded. Follow‐up was complete.

Participants

Supplemented group BW 1522 ± 370 g, GA 31.0 ± 2.5 wk, n = 77. Control group BW 1484 ± 365, GA 30.8 ± 2.7, n = 78. Inclusion criteria: preterm BW 750 to 2000 g, 0 to 28 days of age, medically stable, received enteral feeds for < 24 h, AGA. Exclusion criteria: significant acute/chronic illness, systemic infections, major congenital malformations, IVH > grade 2, PVL, seizures. Withdrawal criteria: if BW > 1000g and full enteral feeds not attained by day 28; if BW 750 to 1000 g and full enteral feeds not attained by day 42; for all infants, if unable to tolerate full enteral feeds; or need for mechanical ventilation after full enteral feeds attained; or oxygen dependency at 36 wk PCA; and/or > 5‐day course steroids. Infants enrolled from 16 sites.

Interventions

Supplemented preterm formula LA 12.1% fa, ALA 1.5% fa, AA 0.50% fa and DHA 0.35% (LCPUFA from single cell oil source). Control preterm formula LA 12.8% fa, ALA 1.4% fa, AA and DHA 0%. Infants were fed 1 of 2 preterm formulas, with or without LCPUFA, until 48 weeks PCA . All infants were then fed a standard term formula (unsupplemented) until 92 wk PCA.

Outcomes

Anthropometrics, adverse events and plasma fatty acids were measured to 92 wk PCA.

Notes

Sponsored by Wyeth Nutritionals International, Philadelphia, Pennsylvania, USA

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Yes (computer‐generated randomisation schedules)

Allocation concealment (selection bias)

Low risk

Yes (coded labels)

Stratification by birth weight

Blinding (performance bias and detection bias)
All outcomes

Unclear risk

Blinding of intervention: yes

Blinding of outcome measurement: can't tell

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Follow up complete.

Selective reporting (reporting bias)

Low risk

Other bias

Low risk