Effect of long-chain polyunsaturated fatty acids in infant formula on problem solving at 10 months of age. Randomized, double-blind trial of long-chain polyunsaturated fatty acid supplementation with fish oil and borage oil in preterm infants. Evaluation of a long-chain polyunsaturated fatty acid supplemented formula on growth, tolerance, and plasma lipids in preterm infants up to 48 weeks postconceptional age. A critical appraisal of the role of dietary long-chain polyunsaturated fatty acids on neural indices of term infants: a randomized, controlled trial. Visual maturation of term infants fed long-chain polyunsaturated fatty acid-supplemented or control formula for 12 mo. Growth and development of preterm infants fed infant formulas containing docosahexaenoic acid and arachidonic acid. A novel infant formula milk with added long-chain polyunsaturated fatty acids from single-cell sources: a study of growth, satisfaction and health. The use of low-EPA fish oil for long-chain polyunsaturated fatty acid supplementation of preterm infants. Assessment of the efficacious dose of arachidonic and docosahexaenoic acids in preterm infant formulas: fatty acid composition of erythrocyte membrane lipids.
Long-chain polyunsaturated fatty acids (LCPUFA) are important for normal visual and brain development. Although present in human milk, LCPUFA have until recently been absent from artificial formulas, and infants may have limited ability to synthesise LCPUFA. To determine the clinical significance of this relative deficiency of LCPUFA, we undertook a randomised trial of the relation between LCPUFA supplementation and infant cognitive behaviour.
                44 term infants had been randomised to a formula supplemented with LCPUFA (21) or not supplemented with LCPUFA (23), which they had taken from birth to age 4 months. Infant cognitive behaviour was assessed at 10 months of age by a means-end problem-solving test--the intentional execution of a sequence of steps to achieve a goal. The problem required three intermediate steps to achieve the final goal, uncovering and retrieving a hidden toy.
                Infants who received LCPUFA-supplemented formula had significantly more intentional solutions than infants who received the no-LCPUFA formula (median 2.0 vs 0, p=0.021). Intention scores (median 14.0 vs 11.5 [maximum 18]) were also increased in this group (p=0.035).
                These findings suggest that term infants may benefit from LCPUFA supplementation, and that the effects persist beyond the period of supplementation. Since higher problem-solving scores in infancy are related to higher childhood IQ scores, supplementation with LCPUFA may be important for the development of childhood intelligence. To test the efficacy and safety of long-chain polyunsaturated fatty acid (LCPUFA) supplementation with gamma-linolenic acid, a precursor of arachidonic acid, and docosahexaenoic acid in preterm infants.
                Preterm (<35 weeks, < or =2000 g birth weight) infants (n=238) randomly assigned to unsupplemented or LCPUFA-supplemented formula to 9 months after term. The main outcome measure was the Bayley Mental and Psychomotor Indexes (MDI, PDI) at 18 months after term. Safety outcome measures were anthropometry (9 and 18 months), feed tolerance, infection, and clinical complications.
                There were no significant differences in neurodevelopment between groups overall. In preplanned subgroup analyses, LCPUFA-supplemented boys had significantly higher Bayley MDI than did control boys (difference, 5.7 points; 95% CI, 0.3 to 11.1; P=.04). LCPUFA-supplemented infants showed significantly greater weight gain (difference, 310 g; 95% CI, 30 to 590 g; P=.03) and length gain (difference, 1.0 cm; 95% CI, 0.02 to 1.9; P=.05) between birth and 9 months, with greater effect in boys (weight difference at 9 months, 510 g; 95% CI, 80 to 930 g; P=.02; length difference at 18 months, 1.8 cm; 95% CI, 0.1 to 1.8; P=.03).
                This trial, using the strategy of providing gamma-linolenic acid as a source of arachidonic acid, showed efficacy for growth and for neurodevelopment in boys, with no adverse effects. These data have important implications for LCPUFA-supplementation strategy in preterm infants. The last trimester of pregnancy is a period of rapid accretion of long-chain polyunsaturated fatty acids, both in the central nervous system and the body as a whole. Human milk contains these fatty acids, whereas some preterm infant formulas do not. Infants fed formulas without these fatty acids have lower plasma and erythrocyte concentrations than infants fed human milk. Preclinical and clinical studies have demonstrated that single-cell sources (algal and fungal) of long-chain polyunsaturated fatty acids are bioavailable. A balanced addition of fatty acids from these oils to preterm formula results in blood fatty acid concentrations in low birth weight infants comparable to those of infants fed human milk.
                In the present study the growth, acceptance (overall incidence of discontinuation, reasons for discontinuation, overall incidence and type of individual adverse events), and plasma fatty acid concentrations were compared in three groups of infants fed a long-chain polyunsaturated fatty acid-supplemented preterm infant formula, an unsupplemented control formula, or human milk. The study was prospective, double-blind (formula groups only), and randomized (formula groups only). Two hundred eighty-eight infants were enrolled (supplemented formula group, n = 77; control formula group, n = 78; human milk group, n = 133).
                Anthropometric measurements at enrollment, at first day of full oral feeding, and at both 40 and 48 weeks postconceptional age did not differ between the formula groups, whereas the human milk-fed group initially grew at a lower rate. The incidence of severe adverse events was rare and not significantly different between formula groups. The groups fed either human milk or supplemented formula had long-chain polyunsaturated fatty acid concentrations higher than those in the control formula group.
                The results of this study demonstrate the safety and efficacy of a preterm formula supplemented with long-chain polyunsaturated fatty acids from single-cell oils. To determine whether dietary long-chain polyunsaturated fatty acids (LCPUFA), such as docosahexaenoic acid (DHA) and arachidonic acid, affect visual evoked potential (VEP) acuity of formula-fed infants, relative to breastfed infants. A secondary objective was to assess the effect of LCPUFA on Bayley's mental developmental index (MDI) and psychomotor developmental index (PDI).
                Formula-fed infants were randomly allocated, in a double-blind manner, to either a placebo (no LCPUFA; n = 21), DHA supplemented (n = 23), or DHA+arachidonic acid supplemented formula (n = 24). Infants were fed their assigned formula from the first week of life until 1 year of age. A parallel reference group of breastfed infants was recruited and followed (n = 46). Infant VEP acuity was assessed at 16 and 34 weeks, and Bayley's MDI and PDI were assessed at 1 and 2 years of age.
                There were no differences among the randomized formula groups for VEP acuity at either 16 or 34 weeks of age. Breastfed infants had better VEP acuity at 34 weeks of age, but not at 16 weeks, compared with all formula-fed infants. Bayley's MDI and PDI were similar in the 3 formula-fed groups at 1 and 2 years. Breastfed infants had higher MDI scores than formula-fed infants at 2 years of age even after adjusting for environmental variables.
                LCPUFA supplementation did not influence VEP acuity development in these well-nourished, formula-fed infants. Several studies found a benefit of long-chain polyunsaturated fatty acid (LCP) supplementation for visual or mental development, but others found no benefit. Likely contributors to differences among studies are the amount of LCP supplementation, functional outcomes, and sample size.
                We evaluated LCP supplementation in amounts typical for human milk (based on local and worldwide surveys) in a large cohort of infants by using sweep visual evoked potential (VEP) acuity as the functional outcome.
                The study was a double-masked, randomized, controlled clinical trial in 103 term infants. By age 5 d, infants were randomly assigned to receive either formula with no docosahexaenoic acid (DHA) or arachidonic acid (ARA) or formula supplemented with DHA and ARA as 0.36% and 0.72%, respectively, of total fatty acids. Sweep VEP acuity was the primary outcome. Random dot stereoacuity, blood lipid profile, growth, and tolerance were secondary outcomes.
                VEP acuity in the LCP-supplemented group was significantly better than that in the control group at ages 6, 17, 26, and 52 wk. Stereoacuity in the LCP-supplemented group was significantly better than that in the control group at age 17 wk but not at ages 39 and 52 wk. By ages 17 and 39 wk, the red blood cell DHA concentration in the LCP-supplemented group was more than double and more than triple, respectively, that in the control group. Growth of infants fed LCP-supplemented and control formulas did not differ significantly, and both diets were well tolerated.
                LCP supplementation of term infant formula during the first year of life yields clear differences in visual function and in total red blood cell lipid composition. To evaluate safety and benefits of feeding preterm infants formulas containing docosahexaenoic acid (DHA) and arachidonic acid (ARA) until 92 weeks postmenstrual age (PMA), with follow-up to 118 weeks PMA.
                This double-blinded study of 361 preterm infants randomized across three formula groups: (1) control, no supplementation; (2) algal-DHA (DHA from algal oil, ARA from fungal oil); and (3) fish-DHA (DHA from fish oil, ARA from fungal oil). Term infants breast-fed > or =4 months (n = 105) were a reference group. Outcomes included growth, tolerance, adverse events, and Bayley development scores.
                Weight of the algal-DHA group was significantly greater than the control group from 66 to 118 weeks PMA and the fish-DHA group at 118 weeks PMA but did not differ from term infants at 118 weeks PMA. The algal-DHA group was significantly longer than the control group at 48, 79, and 92 weeks PMA and the fish-DHA group at 57, 79, and 92 weeks PMA but did not differ from term infants from 79 to 118 weeks PMA. Supplemented groups had higher Bayley mental and psychomotor development scores at 118 weeks PMA than did the control group. Supplementation did not increase morbidity or adverse events.
                Feeding formulas with DHA and ARA from algal and fungal oils resulted in enhanced growth. Both supplemented formulas provided better developmental outcomes than unsupplemented formulas. To evaluate the growth, feeding and health of babies fed a novel infant formula milk with added long chain polyunsaturated fatty acids (LCPs) produced from single-cell sources, at concentrations similar to those found in mature breast milk.
                Randomized double-blind control trial.
                One-hundred and forty healthy, full-term infants of birth weight 2.5-4.5 kg born at the Maternity Department, East Glamorgan General Hospital, Wales, whose mothers had already decided to bottle feed.
                Subjects were randomized to two groups; one (control group) to receive a standard formula milk and the other to receive the trial milk with added LCPs. Milks were supplied in a double-blind fashion and given for the first 12 weeks of life. Anthropometric measurements were made at recruitment, 3 months, 6 months and 1 y. Feeding diaries were completed at 6 weeks and 3 months, and a parental record was kept of any ill health suffered by the subjects during the first year of life.
                Of 140 infants recruited, 31 did not complete the protocol. Small but statistically significant differences were found only in the subscapular skinfold thickness at 6 weeks and 3 months, that in the trial group being slightly higher, but unlikely to be of any clinical importance. No differences were found in the feeding patterns of the infants in the two groups. Stool patterns were similar, as were the frequencies of illness and allergy.
                This study supports the view that LCPs from single-cell sources do not have detrimental effects on the growth, feeding and general health of infants. Because docosahexaenoic acid (DHA) may be an essential nutrient for the visual and early cognitive development of preterm infants, DHA enrichment of preterm formulas has been recommended. This randomized trial was designed to study the n-6 and n-3 fatty acid status of healthy preterm infants fed a formula enriched with a low eicosapentaenoic-fish oil until 4 mo corrected age compared with that of infants fed a standard formula. A reference group of breast-fed infants was studied concurrently. The fatty acid content of red blood cell (RBC) phospholipid was assessed at enrollment, hospital discharge, expected term, and 3 and 6 mo postterm. The DHA content of RBC phospholipid was higher in infants fed the enriched versus the standard formula at hospital discharge, expected term, and 3 and 6 mo postterm. However, compared with infants fed the standard formula, infants fed the enriched formula had also higher RBC phospholipid eicosapentaenoic content (0.69 +/- 0.15% versus 0.25 +/- 0.12%, p < 0.001), and lower RBC phospholipid arachidonic acid content (15.1 +/- 0.93% versus 18.8 +/- 0.89%; p < 0.001). We conclude that supplementing preterm infants with low-eicosapentaenoic fish oil is effective in improving DHA status, but results in worsening of n-6 fatty acid status. We speculate that preterm infants may require a dietary supply of arachidonic acid as well as DHA if the same fatty acid status as that of breast-fed infants is to be achieved. The nutritional requirements of preterm infants for the long chain polyunsaturated essential fatty acids, arachidonic acid (AA) and docosahexaenoic acid (DHA), have not been clearly defined. The present study evaluated preterm infants of less than 2.3 kg birth weight fed a commercial formula (Preemie SMA) devoid of AA and DHA and compared this control group with similar infant groups fed one of three formulas containing a range of 0.32 to 1.1% AA and 0.24 to 0.76% DHA. An analogous group of infants fed their mothers' breast milk and a breast milk fortifier (when indicated) was also studied. Erythrocyte membrane phospholipids were isolated from blood samples collected at 12 d of age and after a further 4 wk of feeding. Infants fed the formula without AA and DHA showed a reduction in AA level in erythrocyte phosphatidylcholine, and a reduced level of DHA in phosphatidylethanolamine in comparison with infants fed breast milk or infant formula containing AA and DHA. Supplementing infant formula with increasing levels of AA and DHA produced a clear dose response in the levels of AA and DHA found in erythrocyte membrane phospholipids. From comparison of membrane phospholipid fatty acid composition it appears that a formula level of 0.32-1.1% AA and 0.24-0.76% DHA provides sufficient levels of these fatty acids to achieve a similar fatty acid composition to that of infants fed human milk for most of the lipid fractions examined.
Infants enrolled in the trials were relatively mature and healthy preterm infants. Assessment schedule and methodology, dose and source of supplementation and fatty acid composition of the control formula varied between trials. On pooling of results, no clear long-term benefits or harms were demonstrated for preterm infants receiving LCPUFA-supplemented formula.