Methods

Single‐centre study in Milan, Italy

Participants

N = 60. Inclusion criteria: term infants (37 to 42 weeks), 5 minute Apgar score > 7, absence of disease. Exclusion criteria: not mentioned
LCPUFA formula: N = 29 (GA 39.0 ± 1.3 weeks, BW 3.168 ± 0.448 kg)
Control formula: N = 31 (GA 39.4 ± 1.4 weeks, BW 3.299 ± 0.453 kg)

Interventions

Supplemented formula contained DHA (0.3%) and AA (0.44%). Control formula did not contain DHA nor AA. Study milk formulae were fed from within third day of life until 4 months. Source of LCPUFA was egg yolk phospholipids

Outcomes

Brunet‐Lezine test of global neurodevelopment at 4, 12 and 24 months, Plasma and RBC phospholipid DHA and AA at 4 months and 24 months, physical growth at 1 year

Notes

30 infants in the breast‐fed reference group. Study authors responded by providing additional information regarding study methods

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Use of a time balanced randomisation table

Allocation concealment (selection bias)

Low risk

Use of sealed envelopes

Blinding (performance bias and detection bias)
All outcomes

Low risk

Both investigators and family members were blinded to the intervention

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Follow‐up rate > 90%

Selective reporting (reporting bias)

Low risk

All prespecified outcomes were reported

Other bias

Low risk

Appears to be free of other biases

Methods

Three‐centre RCT in Kansas, Portland and Seattle

Participants

N = 134. Inclusion criteria: term infants ≥ 37 weeks' gestation, AGA. Exclusion criteria: Apgar score < 7 at 5 minutes, physical or metabolic defects, received IV lipid infusion or blood transfusion, mothers with diabetes, hyperlipidaemia or perinatal infection
LCPUFA (DHA and AA) group: N = 46 (GA 39.3 ± 1.3 weeks, BW 3.50 ± 0.46 kg)
LCPUFA (DHA alone) group: N = 43 (GA 39.7 ± 1.2 weeks, BW 3.54 ± 0.46 kg)
Control group: N = 45 (GA 39.8 ± 1.1 weeks, BW 3.600 ± 0.47 kg)

Interventions

DHA plus AA formula was enriched with DHA (0.13%) and AA (0.45%). DHA alone formula was enriched with DHA (0.2%). Control formula was standard milk without addition of DHA and AA. Infants were randomised within 9 days after birth. Study formulae were fed ad libitum as the sole source of nutrition for first 4 months and as exclusive milk beverage up to 12 months of age. Source of LCPUFA was egg yolk phospholipids

Outcomes

RBC fatty acid levels at 2, 4, 6 and 12 months. Growth measured at 1, 2, 4, 6, 9 and 12 months. Visual acuity at 2, 4, 6, 9, 12 and 39 months. Visual acuity measured by the Teller acuity card procedure or sweep spatial frequency VEP. Global development assessed at 1 year (BSID) and at 3 years (Stanford Binet IQ). Language development assessed at 14 months (McArthur Communicative Development Inventory) and at 3 years (Peabody Picture Vocabulary Test)

Notes

Breast‐fed reference group: n = 63. Study authors had provided additional information for the previous version of this review. We contacted them to request more information for this update. Study authors acknowledged receipt of our letter but did not provide requested information

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Centralised randomisation

Allocation concealment (selection bias)

Low risk

Centralised randomisation

Blinding (performance bias and detection bias)
All outcomes

Low risk

Assessors of developmental outcomes were unaware of infants' group assignment and medical history

Incomplete outcome data (attrition bias)
All outcomes

High risk

Outcomes of only infants who completed the study were reported. Less than 80% follow‐up for visual acuity outcomes at different ages

Selective reporting (reporting bias)

Low risk

All prespecified outcomes were reported

Other bias

Low risk

Appears to be free of other biases

Methods

RCT in 4 centres (Missouri, Arkansas, Pennsylvania and Arizona)

Participants

N = 404 (initially enrolled). Inclusion criteria: term infants between 37 and 42 weeks' gestation, ≤ 9 days, birth weight ≥ 2500 grams, 5 minute Apgar score ≥ 7, ability to tolerate milk‐based formula or breast milk. Exclusion criteria: significant cardiac, ophthalmological, gastrointestinal or hematological or metabolic disease, milk protein allergy, maternal medical history known to have adverse effects on the foetus, tuberculosis, HIV, perinatal infection, substance abuse
LCPUFA (DHA and AA) supplemented formula derived from egg triglyceride: N = 80 (GA 39 ± 1.3 weeks, BW 3.39 ± 0.47 kg)
LCPUFA (DHA and AA) supplemented formula derived from fish and fungus oil: N = 82 (GA 39.3 ± 1.2 weeks, BW 3.41 ± 0.41 kg)
Control formula: N = 7 (GA 39.4 ± 1.2 weeks, BW 3.45 ± 0.44 kg)

Interventions

Study formula was milk formula supplemented with DHA (0.13%) and AA (0.45%). Control formula was standard milk without DHA and AA added. Infants were randomised within 9 days of birth. Study formulae were fed ad libitum as the sole source of nutrition for first 4 months and as exclusive milk beverage up to 12 months of age. Source of LCPUFA was fish and fungus oil in one group and egg yolk triglyceride in the other

Outcomes

Fatty acid profiles in red cell lipids, physical growth at 1, 2, 4, 6, 9 and 12 months. Visual acuity measured by Teller acuity card procedure at 2, 4, 6 and 12 months, Fagan test of infant intelligence at 6 and 9 months, Bayley Scales of Infant Development at 6 and 12 months, language assessment with McArthur's communicative developmental inventories at 9 and 14 months, parental reporting of infant temperament at 6 and 12 months

Notes

Study authors reported outcome data separately for milk formula enriched with LCPUFA derived from fish/fungus oil and milk formula enriched with LCPUFA derived from egg triglyceride. Our outcome of interest was the effect of LCPUFA rather than the source of LCPUFA, so we asked study authors to provide combined outcome data. Study authors provided the requested data . Breast‐fed control group: N = 82

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated with a random permuted blocks algorithm

Allocation concealment (selection bias)

Low risk

Centralised randomisation

Blinding (performance bias and detection bias)
All outcomes

Low risk

Measures of growth, visual acuity, information processing, general development, language and temperament were assessed by masked clinical tests

Incomplete outcome data (attrition bias)
All outcomes

High risk

239 out of 404 enrolled infants completed the study, and only those results were reported. Less than 80% of enrolled infants completed the study

Selective reporting (reporting bias)

Low risk

All prespecified outcomes were reported

Other bias

Low risk

Appears to be free of other biases

Methods

Single‐centre RCT in China

Participants

N = 121. Included: infants of gestational age 37 to 40 weeks. Exclusion criteria: infants with congenital anomalies
LCPUFA supplemented formula: N = 69
Control formula: N = 52
Gestational age and birth weight details not available

Interventions

LCPUFA group was given milk formula enriched with DHA and AA. LCPUFA content of the formula was not clear. Control group was fed with standard milk formula without DHA and AA added. Infants were randomly assigned to the study formula before 2 weeks of life. Assigned diets were fed from day of enrolment to 6 months of age. Source of LCPUFA was not clear

Outcomes

Fatty acid profiles in red cell lipids, physical growth and neurodevelopmental outcomes at 3 and 6 months of age

Notes

Study authors published a short version of the article in a Chinese medical journal. The full article with raw data was provided by study authors on request. Study authors also clarified study methods. Breast‐fed reference group = 26

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Method used to generate random sequence was unclear

Allocation concealment (selection bias)

Unclear risk

Method used for allocation concealment was unclear

Blinding (performance bias and detection bias)
All outcomes

Low risk

Blinding of intervention and outcome assessors was performed

Incomplete outcome data (attrition bias)
All outcomes

High risk

Follow‐up rate was 48% at 3 months and 33% at 6 months

Selective reporting (reporting bias)

Unclear risk

Details not available

Other bias

Unclear risk

Details not available

Methods

Single‐centre RCT conducted in Dallas, Texas, USA

Participants

N = 79. Inclusion criteria: infants of gestational age 37 to 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, anaemia 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 birth weight: not given

Interventions

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 was fed standard milk formula without DHA and AA added. Infants were randomly assigned to the study formula between 1 and 5 days of life. Assigned diets were fed from within 5 days of birth until 17 weeks of age. Source of LCPUFA was single‐cell oil

Outcomes

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

Notes

Breast‐fed reference: n = 29

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Use of block randomisation schedule

Allocation concealment (selection bias)

Low risk

Use of sealed envelopes

Blinding (performance bias and detection bias)
All outcomes

Low risk

Investigators conducting blood lipid analysis and visual function testing were masked to type of formula provided to infants

Incomplete outcome data (attrition bias)
All outcomes

High risk

70% to 86% follow up for different outcomes

Selective reporting (reporting bias)

Low risk

All prespecified outcomes were reported

Other bias

Low risk

Appears to be free of other biases

Methods

Single‐centre RCT conducted in Dallas, Texas, USA

Participants

N = 103. Included: infants of gestational age 37 to 40 weeks, singleton births, 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, anaemia 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 weight not given

Interventions

'LCPUFA' group was given milk formula enriched with DHA (0.36%) and AA (0.72%). Control group was fed standard milk formula without DHA and AA added. Infants were randomly assigned to study formula between 1 and 5 days of life. Assigned diets were fed from day of enrolment to 52 weeks of age. Source of DHA was single‐cell algal oil (Crypthecodinium cohnii); source of AA was fungal oil (Mortierella alpina)

Outcomes

Fatty acid profiles in red cell lipids, physical growth, visual outcomes: sweep VEP acuity, random dot stereo acuity

Notes

Study authors clarified method details and provided additional information on outcome data. No breast‐fed control group

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Use of single randomisation schedule at a central location. Randomisation schedule had random‐length blocks (block length varied from 6 to 12)

Allocation concealment (selection bias)

Low risk

Use of sealed envelopes

Blinding (performance bias and detection bias)
All outcomes

Low risk

Each diet was masked by 2 colour codes and 2 number codes, for a total of 4 possible diet assignments. Study authors informed that outcome assessors were blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

83% to 92% follow‐up rates for different outcomes at different stages

Selective reporting (reporting bias)

Low risk

All prespecified outcomes were reported

Other bias

Low risk

Appears to be free of other biases

Methods

Randomised controlled trial conducted in Dallas (5 hospitals) and Kansas (2 hospitals)

Participants

N = 170. Included: healthy, full‐term (37 to 42 weeks) formula‐fed infants. Excluded: infants who had received human milk within 24 hours of randomisation, with disease or congenital anomaly likely to affect visual development and neurodevelopment, poor formula intake, known or suspected intolerance to cow's milk formula. Also excluded were infants born to mothers with chronic illnesses such as HIV, renal or hepatic disease, diabetes, alcoholism or substance abuse
LCPUFA supplemented formula: N = 84
Control formula: N = 86

Interventions

'LCPUFA' group was given milk formula enriched with DHA (0.32%) and AA (0.64%). Control group was fed standard milk formula without DHA and AA added. Infants were randomly assigned to study formula between 1 and 9 days of life. Assigned diets were fed from day of enrolment to 1 year of age. Assigned formula was the sole source of nutrition until ≈4 months of age. Source of DHA was single‐cell algal oil (Crypthecodinium cohnii); source of AA was fungal oil (Mortierella alpina)

Outcomes

Sweep VEP acuity, fatty acid profiles in red cell lipids, anthropometry, formula intake and tolerance at 1.5, 4, 6, 9 and 12 months of age. VEP visual acuity at 12 months of age was the primary outcome of interest. Quality of attention, heart rate, age‐appropriate standardised and specific cognitive tests (18 months to 6 years every 6‐monthly), growth until 6 years of age, school readiness and receptive vocabulary were other long‐term outcomes of interest

Notes

The study included 4 groups: control (0% DHA), 0.32% DHA, 0.64% DHA, 0.96% DHA. For this review, we used the 0.32% DHA group as the intervention arm. DHA supplemented formulae also provided 0.64% arachidonic acid. Study authors clarified a few method issues and provided requested information. Standard errors of means were provided by study authors, and Cochrane review authors converted them into standard deviations

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

A computer programme with a random number generation function was used to create the randomisation sequence

Allocation concealment (selection bias)

Low risk

Use of sealed envelopes

Blinding (performance bias and detection bias)
All outcomes

Low risk

Each infant's study formula group allocation was masked until all infants had reached 12 months of age and data collection had been completed, validated and locked

Incomplete outcome data (attrition bias)
All outcomes

High risk

Only 120/170 enrolled infants (70.5%) completed the study

Selective reporting (reporting bias)

Low risk

For the primary outcome, reporting was free of selective reporting bias

Other bias

High risk

Bayley Scale scores at 18 months of age were reported only for study participants from the Dallas centre. Results for study participants at the Kansas centre were not reported. Study authors mention in the manuscript that this occurred because this phase 2 trial was done separately by study centres using different protocols and data collection and analysis

Methods

Single‐centre RCT conducted in Netherlands

Participants

N = 315. Included: infants of gestational age 37 to 42 weeks. Exclusion criteria: 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

Interventions

'LCPUFA' group was given milk formula enriched with DHA (0.3%) and AA (0.45%). Control group was fed standard milk formula without DHA and AA added. Infants were randomly assigned to the study formula between 1 and 5 days of life. Assigned diets were fed from day of enrolment for 2 months. Source of LCPUFA was egg yolk, tuna oil and single‐cell oil produced by the soil fungus, Mortierella alpina

Outcomes

Neurodevelopmental assessment using Hempel and Bayley Scales. Hempel assessment is a standardised technique designed for detection of minor signs of neurological dysfunction and physical growth. Anthropometric, cardiovascular, cognitive and behavioural assessments were done at nine years of age

Notes

Study authors provided additional information regarding various outcomes. Breast‐fed reference group: 160

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Use of central computerized randomisation with blocked design

Allocation concealment (selection bias)

Low risk

Central computerised randomisation

Blinding (performance bias and detection bias)
All outcomes

Low risk

Parents and examiners were unaware of the type of formula feeding that infants received

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Follow‐up was 92%

Selective reporting (reporting bias)

Low risk

All prespecified outcomes were reported

Other bias

Low risk

Appears to be free of other biases

Methods

Single‐centre RCT conducted in Memphis, Tennessee, USA

Participants

N = 39. Inclusion criteria: infants born at term (37 to 43 weeks' PMA) without IUGR and with no medical problems likely to influence long‐term growth and development. Exclusion criteria: not mentioned
LCPUFA: N = 19 (GA 39.8 ± 1.2 weeks, BW 3.285 ± 0.448 kg)
Control formula: N = 20 (GA 40.3 ± 0.9 weeks, BW 3.327 ± 0.331 kg)

Interventions

Supplemented formula was enriched with DHA (0.10%) and AA (0.43%). Control formula did not include DHA and AA. Infants were randomised within 24 hours of birth to receive study milk formula. Study formula was fed for 1 year. Source of LCPUFA was egg yolk phospholipids

Outcomes

RBC and plasma fatty acid levels at 2, 4, 6 and 12 months
Visual acuity (Teller acuity cards) at 2, 4, 6, 9 and 12 months

Notes

Breast‐fed reference group: N = 19

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Allocation concealment (selection bias)

Low risk

Sealed envelopes

Blinding (performance bias and detection bias)
All outcomes

Low risk

Two investigators were unaware of infants' dietary treatments and results of earlier acuity tests

Incomplete outcome data (attrition bias)
All outcomes

High risk

58 of the initially recruited 90 completed the study (LCPUFA: 20; control formula: 19; breast‐fed reference group: 19). 36 were lost to follow‐up (LCPUFA: 9; control formula: 11; breast‐fed reference group: 16)

Selective reporting (reporting bias)

Low risk

All prespecified outcomes were reported

Other bias

Low risk

Appears to be free of other biases

Methods

Single‐centre RCT conducted in France

Participants

N = 24. Inclusion criteria: healthy term appropriate for gestational age infants. Exclusion criteria: infants of mothers who had history of cocaine or alcohol abuse, hyperlipidaemia, diabetes, strict vegetarian or vegan diets
LCPUFA supplemented formula: N = 12 (GA 39.3 ± 1.1 weeks, BW 3.378 ± 0.426 kg)
Control formula: N = 12 (GA 40.1 ± 1.2 weeks, BW 3.311 ± 0.0448 kg)

Interventions

'LCPUFA' group was given milk formula enriched with DHA (0.31%). Control group was fed standard milk formula without DHA added. Assigned diets were fed from day 3 of life until 4 months of age. Source of LCPUFA was fish oil

Outcomes

Fatty acid levels in RBCs at 4 months; weight, length and head circumference at 2 and 4 months of age

Notes

Study authors responded by providing additional information regarding study methods

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Use of computer‐generated random allocation list

Allocation concealment (selection bias)

Low risk

Use of sealed opaque envelopes

Blinding (performance bias and detection bias)
All outcomes

Low risk

Caregivers, parents and outcome assessors were blinded to the intervention group

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Follow‐up > 80%

Selective reporting (reporting bias)

Low risk

All prespecified outcomes were reported

Other bias

Low risk

Appears to be free of other biases

Methods

Two‐centre RCTs conducted in Nottingham and Leicester, England

Participants

N = 309. Inclusion criteria: term infants ≥ 37 weeks' gestation and appropriate for gestational age singletons. Exclusion criteria: presence of congenital anomalies
LCPUFA: 154 (GA 40.0 ± 1.29 weeks and BW 3542 ± 409 grams)
Control formula: 155 (GA 40.1 ± 1.30 weeks and BW 3648 ± 459 grams)

Interventions

'LCPUFA' group was given milk formula enriched with DHA (0.32%) and AA (0.30%). Control group was fed standard milk formula without DHA and AA added. Infants were assigned to study formula within first week of life. Study formula was continued for 6 months. Source of LCPUFA was egg yolk phospholipids

Outcomes

Primary endpoint was development at 18 months assessed by Bayley Scales of Infant Development (MDI and PDI). Secondary endpoint was development at 9 months assessed by Knobloch, Passamanick and Sherrards tests. Growth and gastrointestinal tolerance were also assessed at 6, 9 and 18 months. Incidences of atopy, eczema, wheeze and infection were documented

Notes

Infants who were breast‐fed for at least 6 weeks were a reference group (n = 138). Study authors published a correction to outcomes reported in 2002, stating that they inadvertently reversed the 2 diet codes. Hence the outcomes of standard formula were those of infants fed LCPUFA formula, and vice versa. We have entered the correct data into this review

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

A random permuted block design stratified by centre and by sex was used to generate the allocation schedule

Allocation concealment (selection bias)

Low risk

Use of sealed opaque envelopes

Blinding (performance bias and detection bias)
All outcomes

Low risk

Mothers and study personnel were unaware of the dietary allocation

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Follow‐up rates of 81%

Selective reporting (reporting bias)

Low risk

All prespecified outcomes were reported

Other bias

Low risk

Appears to be free of other biases

Methods

Single‐centre RCT conducted in Adelaide

Sample size calculation: yes
Concealment of allocation: yes
Blinding to intervention: yes
Blinding to outcome assessment: yes
Completeness of follow‐up: no (60% to 81% for various primary outcomes)

Participants

N = 32. Inclusion criteria: healthy term appropriate for gestational age infants born at 37 to 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 ± 1.7 weeks, BW 3.288 ± 0.525 kg)
Control formula: N = 19 (GA 39.6 ± 1.2 weeks, BW 3.650 ± 0.0416 kg)

Interventions

'LCPUFA' group was given milk formula enriched with DHA (0.35%). In addition, formula was enriched with EPA and GLA. Control group was fed standard milk formula without DHA and AA added. Assigned diets were fed from birth to 30 weeks of life. Source of LCPUFA was fish oil and evening primrose oil

Outcomes

Plasma and red blood cell fatty acid levels at 6, 16 and 30 weeks; visual evoked potential acuity at 16 and 30 weeks; Bayley Scales of Infant Development at 1 year

Notes

Breast‐fed reference group, n = 28

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Use of central computerised randomisation

Allocation concealment (selection bias)

Low risk

Adequate; use of sealed opaque envelopes

Blinding (performance bias and detection bias)
All outcomes

Low risk

Mothers were unaware of formula type

Incomplete outcome data (attrition bias)
All outcomes

High risk

60% to 81% follow‐up for various primary outcomes

Selective reporting (reporting bias)

Low risk

All prespecified outcomes were reported

Other bias

Low risk

Appears to be free of other biases

Methods

Single‐centre RCT conducted in Adelaide

Participants

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 ± 1.3 weeks; BW 3549 ± 521 grams)
LCPUFA (DHA alone) supplemented formula: N = 27 (GA 39.6 ± 1.1 weeks, BW 3378 ± 431 grams)
Control formula: N = 28 (GA 39.6 ± 1.5 weeks, BW 3549 ± 497 grams)

Interventions

'LCPUFA' group was 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 was fed standard milk formula without DHA and AA added. Infants were randomly assigned to study formula within 7 days of life. Assigned milk formula was sole source of nutrition for 4 months. Subsequently, study formula was the only source of milk until 1 year of age. Source of LCPUFA was egg yolk phospholipids (DHA + AA group) and tuna oil (DHA group)

Outcomes

Plasma and RBC fatty acid levels at 6, 16 and 34 weeks and 1 year of age. Physical growth at 6, 16 and 34 weeks and at 1 and 2 years of age. VEP at 16 and 34 weeks. Bayley Scales of Infant Development at 1 and 2 years

Notes

Breast‐fed reference group, n = 63

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated random numbers

Allocation concealment (selection bias)

Low risk

Adequate; use of sealed opaque envelopes

Blinding (performance bias and detection bias)
All outcomes

Low risk

Investigators and families were blinded to randomisation

Incomplete outcome data (attrition bias)
All outcomes

High risk

60% to 85% for various outcomes

Selective reporting (reporting bias)

Low risk

All prespecified outcomes were reported

Other bias

Low risk

Appears to be free of other biases

Methods

Single‐centre RCT in Wales

Participants

N = 109. Included: infants at full‐term gestation with birth weight 2.5 to 4.5 kg. Exclusion criteria: congenital anomalies, infants from multiple births
LCPUFA supplemented formula: N = 54 (BW 3.31 ± 0.48 kg)
Control formula: N = 55 (BW 3.35 ± 0.46 kg)
Mean gestational age of study infants was not given

Interventions

LCPUFA formula was enriched with DHA (0.2%) and AA (0.4%). Control formula was not enriched with DHA and AA. Study formula was started within 72 hours of birth and was given for first 12 weeks. Source of LCPUFA was single‐cell oils

Outcomes

Physical growth at 6 weeks, 3 months, 6 months and 1 year; general health of infants

Notes

Study authors replied with clarification regarding study methods. No breast‐fed control group

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

"block randomisation in double blind fashion"

Allocation concealment (selection bias)

Unclear risk

Details were not available

Blinding (performance bias and detection bias)
All outcomes

Low risk

Parents, caregivers and professionals were blinded to milk type

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Follow‐up 78%

Selective reporting (reporting bias)

Low risk

All prespecified outcomes were reported

Other bias

Low risk

Appears to be free of other biases

Methods

Single‐centre RCT in Scotland

Participants

N = 72. Included: term infants (37 to 42 weeks) with birth weight between 2.5 and 4 kg. Exclusion criteria: not mentioned
LCPUFA supplemented formula: N = 34
Control formula: N = 38
Mean birth weight and gestational age data of study infants not given

Interventions

LCPUFA formula was enriched with DHA (0.15% to 0.25%) and AA (0.3% to 0.4%). Control formula did not contain DHA or AA. Study milk formula was given from birth until 4 months of age. Source of LCPUFA was egg lipids, milk fat and vegetable oils

Outcomes

Infant cognition measured by a means‐end problem‐solving test at 10 months. Assessments of intelligence quotient (IQ), attention control (Day‐Night Test) and speed of processing on Matching Familiar Figures Test (MFFT) was done at 6 years for enrolled infants

Notes

Results are given as medians and quartiles and therefore are provided in text, not in tables. No breast‐fed control group

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Use of computer‐generated randomisation table. Randomisation was stratified to ensure sex matching

Allocation concealment (selection bias)

Low risk

Pharmacy coded formulae administered to babies

Blinding (performance bias and detection bias)
All outcomes

Low risk

Mothers and investigators were unaware of group assignments

Incomplete outcome data (attrition bias)
All outcomes

High risk

Completeness of follow‐up: 44 of 72 (61%) infants completed study outcome assessment

Selective reporting (reporting bias)

Low risk

All prespecified outcomes were reported

Other bias

Low risk

Appears to be free of other biases