The impact of dietary long-chain polyunsaturated fatty acids on respiratory illness in infants and children.

Increasing evidence suggests that intake of long-chain polyunsaturated fatty acids (LCPUFA), especially omega-3 LCPUFA, improves respiratory health early in life. This review summarizes publications from 2009 through July 2012 that evaluated effects of fish, fish oil or LCPUFA intake during pregnancy, lactation, and early postnatal years on allergic and infectious respiratory illnesses. Studies during pregnancy found inconsistent effects in offspring: two showed no effects and three showed protective effects of omega-3 LCPUFA on respiratory illnesses or atopic dermatitis. Two studies found that infants fed breast milk with higher omega-3 LCPUFA had reduced allergic manifestations. Earlier introduction of fish improved respiratory health or reduced allergy in four studies. Three randomized controlled trials showed that providing LCPUFA during infancy or childhood reduced allergy and/or respiratory illness while one found no effect. Potential explanations for the variability among studies and possible mechanisms of action for LCPUFA in allergy and respiratory disease are discussed.

Evaluation of bioequivalency and toxicological effects of three sources of arachidonic acid (ARA) in domestic piglets.

Arachidonic acid (ARA) and docosahexaenoic acid (DHA) are routinely added to infant formula to support growth and development. We evaluated the bioequivalence and safety of three ARA-rich oils for potential use in infant formula using the neonatal pig model. The primary outcome for bioequivalence was brain accretion of ARA and DHA. Days 3-22 of age, domestic pigs were fed one of three formulas, each containing ARA at ∼0.64% and DHA at ∼0.34% total fatty acids (FA). Control diet ARA was provided by ARASCO and all diets had DHA from DHASCO (Martek Biosciences Corp., Columbia, MD). The experimental diets a1 and a2 provided ARA from Refined Arachidonic acid-rich Oil (RAO; Cargill, Inc., Wuhan, China) and SUNTGA40S (Nissui, Nippon Suisan Kaisha, Ltd., Tokyo, Japan), respectively. Formula intake and growth were similar across all diets, and ARA was bioequivalent across treatments in the brain, retina, heart, liver and day 21 RBC. DHA levels in the brain, retina and heart were unaffected by diet. Liver sections, clinical chemistry, and hematological parameters were normal. We conclude that RAO and SUNTGA40S, when added to formula to supply ∼0.64% ARA are safe and nutritionally bioequivalent to ARASCO in domestic piglets.

The DIAMOND (DHA Intake And Measurement Of Neural Development) Study: a double-masked, randomized controlled clinical trial of the maturation of infant visual acuity as a function of the dietary level of docosahexaenoic acid.

BACKGROUND: The range of human milk docosahexaenoic acid (DHA) concentrations worldwide is much broader than the range explored in randomized clinical trials to date. OBJECTIVE: The primary objective was to determine the effect of 4 amounts of DHA supplementation on the visual acuity of formula-fed infants at 12 mo of age. Secondary objectives were to evaluate visual acuity maturation, red blood cell fatty acids, tolerance, anthropometric measures, and adverse events. DESIGN: This double-masked, randomized trial was conducted at 2 sites (Dallas and Kansas City). Three hundred forty-three healthy, term, formula-fed infants were enrolled at 1-9 d of age and were randomly assigned to be fed 1 of the following 4 infant formulas containing equivalent nutrient amounts, except for long-chain polyunsaturated fatty acids: control (0% DHA), 0.32% DHA, 0.64% DHA, or 0.96% DHA; DHA-supplemented formulas also provided 0.64% arachidonic acid. Visual acuity was measured by visual evoked potentials in 244 infants who completed the 12-mo primary outcome examination. RESULTS: Infants fed control formula had significantly poorer visual evoked potential visual acuity at 12 mo of age than did infants who received any of the DHA-supplemented formulas (P < 0.001). There were no significant differences in visual evoked potential visual acuity between the 3 amounts of DHA supplementation for either site at any age tested. CONCLUSIONS: DHA supplementation of infant formula at 0.32% of total fatty acids improves visual acuity. Higher amounts of DHA supplementation were not associated with additional improvement of visual acuity. This trial was registered at clinicaltrials.gov as NCT00753818.

Toward optimizing vision and cognition in term infants by dietary docosahexaenoic and arachidonic acid supplementation: a review of randomized controlled trials.

The question of whether a dietary supply of docosahexaenoic acid (DHA) and arachidonic acid (ARA) imparts advantages to visual or cognitive development in term infants has been debated for many years. DHA and ARA are present in human milk, and nursing infants consume these fatty acids needed for rapid synthesis of cell membranes, particularly neural cells. The reported mean DHA and ARA levels of human milk worldwide are 0.32% and 0.47% of total fatty acids, respectively. Prior to 2002 in the US, formula-fed infants did not receive these fatty acids and relied solely on endogenous conversion of the dietary essential omega-3 (n-3) and omega-6 (n-6) fatty acids, alpha-linolenic and linoleic acids, to DHA and ARA, respectively. Formula-fed infants were found to have significantly less accretion of DHA in brain cortex after death than breastfed infants. Numerous studies have found positive correlations between blood DHA levels and improvements in cognitive or visual function outcomes of breastfed and formula-fed infants. Results of randomized controlled clinical trials of term formula-fed infants evaluating functional benefits of dietary DHA and ARA have been mixed, likely due to study design heterogeneity. A comparison of visual and cognitive outcomes in these trials suggests that dietary DHA level is particularly relevant. Trials with formulas providing close to the worldwide human milk mean of 0.32% DHA were more likely to yield functional benefits attributable to DHA. We agree with several expert groups in recommending that infants receive at least 0.3% DHA, with at least 0.3% ARA, in infant feedings; in addition, some clinical evidence suggests that an ARA:DHA ratio greater than 1:1 is associated with improved cognitive outcomes.

Soy-based infant formula supplemented with DHA and ARA supports growth and increases circulating levels of these fatty acids in infants.

Healthy term infants (n = 244) were randomized to receive: (1) control, soy-based formula without supplementation or (2) docosahexaenoic acid-arachidonic acid (DHA + ARA), soy-based formula supplemented with at least 17 mg DHA/100 kcal (from algal oil) and 34 mg ARA/100 kcal (from fungal oil) in a double-blind, parallel group trial to evaluate safety, benefits, and growth from 14 to 120 days of age. Anthropometric measurements were taken at 14, 30, 60, 90, and 120 days of age and 24-h dietary and tolerance recall were recorded at 30, 60, 90, and 120 days of age. Adverse events were recorded throughout the study. Blood samples were drawn from subsets of 25 infants in each group. Capillary column gas chromatography was used to analyze the percentages of fatty acids in red blood cell (RBC) lipids and plasma phospholipids. Compared with the control group, percentages of fatty acids such as DHA and ARA in total RBC and plasma phospholipids were significantly higher in infants in the DHA + ARA group at 120 days of age (P < 0.001). Growth rates did not differ significantly between feeding groups at any assessed time point. Supplementation did not affect the tolerance of formula or the incidence of adverse events. Feeding healthy term infants soy-based formula supplemented with DHA and ARA from single cell oil sources at concentrations similar to human milk significantly increased circulating levels of DHA and ARA when compared with the control group. Both formulas supported normal growth and were well tolerated.

Differential tissue dose responses of (n-3) and (n-6) PUFA in neonatal piglets fed docosahexaenoate and arachidonoate.

Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are commonly added to infant formula worldwide; however, dietary concentrations needed to obtain optimal tissue levels have not been established. Hence, we studied tissue responses in piglets fed various doses of DHA and ARA. Doses were 0, 1, 2, and 5 times those used in U.S. infant formulas and DHA/ARA in Diet 0, Diet 1, Diet 2, and Diet 5 were 0, 4.1/8.1, 8.1/16.2, and 20.3/40.6 mg/100 kJ formula, respectively. Supplementation of dietary DHA and ARA increased DHA in brain, retina, liver, adipose tissue, plasma, and erythrocyte by 1.1- to 25.8-fold of Diet 0 (P-trend < 0.01). Tissue ARA (1.1- to 6.0-fold of Diet 0) responded to dietary ARA in liver, adipose tissue, plasma, and erythrocytes (P-trend < 0.05); brain and retina ARA was, however, unresponsive to dietary DHA and ARA. Plasma and erythrocyte DHA were positively associated with DHA in neural (brain and retina) and visceral (liver and adipose) tissues (r(2) = 0.11-0.56; P < 0.001-P = 0.042). Plasma and erythrocyte ARA did not correlate with neural ARA. Only plasma ARA was associated with liver ARA (r(2) = 0.222; P = 0.02) and adipose ARA (r(2) = 0.867; P < 0.001) and erythrocyte ARA correlated with adipose ARA (r(2) = 0.470; P < 0.001). We conclude that dietary DHA supplementation affords an effective strategy for enhancing tissue DHA, ARA in visceral but not neural tissues is sensitive to dietary ARA, and erythrocyte and plasma DHA can be used as proxies for tissue DHA, although blood-borne ARA is not an indicator of neural ARA.

Docosahexaenoic and arachidonic acid concentrations in human breast milk worldwide.

Concentrations of the long-chain polyunsaturated fatty acids (LCPUFAs) docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6) in human breast milk are important indicators of infant formula DHA and AA concentrations, and recent evidence suggests that neural maturation of breastfed infants is linked to breast-milk LCPUFA concentrations. We report a descriptive meta-analysis that considered 106 studies of human breast milk culled to include only studies that used modern analysis methods capable of making accurate estimates of fatty acid (FA) profiles and criteria related to the completeness of reporting. The final analysis included 65 studies of 2474 women. The mean (+/-SD) concentration of DHA in breast milk (by wt) is 0.32 +/- 0.22% (range: 0.06-1.4%) and that of AA is 0.47 +/- 0.13% (range: 0.24-1.0%), which indicates that the DHA concentration in breast milk is lower than and more variable than that of AA. The highest DHA concentrations were primarily in coastal populations and were associated with marine food consumption. The correlation between breast-milk DHA and AA concentrations was significant but low (r = 0.25, P = 0.02), which indicates that the mean ratio of DHA to AA in regional breast milk varies widely. This comprehensive analysis of breast-milk DHA and AA indicates a broad range of these nutrients worldwide and serves as a guide for infant feeding.

The influence of moderate and high dietary long chain polyunsaturated fatty acids (LCPUFA) on baboon neonate tissue fatty acids.

Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are now common ingredients in commercial infant formulas, however, the optimal levels have not been established. Our previous data showed that the current amount of DHA in U.S. term formulas, 0.3%w/w, is insufficient to normalize cerebral cortex DHA to levels in breastfed baboon neonate controls (Diau et al.: BMC Medicine 3: 11, 2005). Here, we report on the influence of higher formula DHA levels on 12-wk-old full-term baboon CNS and visceral organs. Fourteen nursery-reared baboons were randomized to one of three diets: control (C, no DHA-ARA); moderate LCPUFA (L, 0.33%DHA-0.67%ARA); high LCPUFA (L3, 1.00%DHA-0.67%ARA). DHA increased significantly in liver, heart, and plasma (all C < L < L3), RBC (C < L, L3), and CNS regions: precentral gyrus (C < L < L3), frontal cortex, inferior and superior colliculi, globus pallidus, and caudate (all C < L, L3). These data extend previous observations indicating that 1) tissue DHA is more sensitive to diet than ARA; 2) cerebral cortex DHA increases with higher levels of DHA than in present commercial formulas; and 3) basal ganglia and limbic system DHA saturate with levels of DHA currently available in formulas. These results imply that higher levels of DHA are necessary to normalize cortex DHA to those found in breastfed animals.

Docosahexaenoic acid in red blood cells of term infants receiving two levels of long-chain polyunsaturated fatty acids.

OBJECTIVES: A randomized, double-blind, prospective trial assessed effects of different formula levels of polyunsaturated fatty acids on blood phospholipid docosahexaenoic (DHA; 22:6omega3) and arachidonic acids (ARA; 20:4omega6) in term infants at 120 days of age. METHODS: Healthy, formula-fed term infants (n = 78) were randomized to 1) routine milk-based formula with 8 mg DHA, 21 mg ARA, 110 mg alpha-linolenic (ALA; 18:3omega3), and 1,000 mg linoleic acids (LA; 18:2omega6) per 100 kcal (Lower-long-chain polyunsaturated fatty acids [LCPUFA]; n = 39) or 2) routine milk-based formula with 17 mg DHA, 34 mg ARA, 85 mg ALA, and 860 mg LA per 100 kcal (Higher-LCPUFA; n = 39). Fatty acid methyl esters from red blood cell (RBC) and plasma phospholipid fractions were assessed using capillary column gas chromatography. RESULTS: Compared with infants fed Lower-LCPUFA formula, the Higher-LCPUFA group had significantly greater percentages of fatty acids as DHA in RBC phosphatidylethanolamine (PE), RBC phosphatidylcholine (PC), total RBC, and plasma phospholipids (P < 0.001). Infants fed Lower-LCPUFA formula had higher percentages of precursor omega6 fatty acids in the desaturation/elongation pathway but lower percentages of ARA (RBC PE, RBC PC, and plasma phospholipid, P < 0.001; total RBC, P = 0.017) compared with the Higher-LCPUFA group. CONCLUSIONS: Greater amounts of dietary ALA do not produce as great an increase in DHA in blood lipids as preformed dietary DHA. Infants fed DHA at levels similar to human milk had significantly greater percentage of DHAat 120 days of age compared with the Lower-LCPUFA group despite higher precursor levels of ALA.

Growth and development of preterm infants fed infant formulas containing docosahexaenoic acid and arachidonic acid.

OBJECTIVES: 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. STUDY DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.

Comparison of triglycerides and phospholipids as supplemental sources of dietary long-chain polyunsaturated fatty acids in piglets.

Addition of arachidonic acid (AA) and docosahexaenoic acid (DHA) to infant formula promotes visual and neural development. This study was designed to determine whether the source of dietary long-chain polyunsaturated fatty acids (LCPUFA) affected overall animal health and safety. Piglets consumed ad libitum from 1 to 16 d of age a skim milk-based formula with different fat sources added to provide 50% of the metabolizable energy. Treatment groups were as follows: control (CNTL; no added LCPUFA), egg phospholipid (PL), algal/fungal triglyceride (TG) oils, TG plus PL (soy lecithin source) added to match phospholipid treatment (TG + PL) and essential fatty acid deficient (EFAD). Formulas with LCPUFA provided 0.6 and 0.3 g/100 g total fatty acids as AA and DHA, respectively. CNTL piglets had 40% longer ileal villi than PL piglets (P < 0.03), but the TG group was not different from the CNTL group. Gross liver histology did not differ among any of the formula-fed groups (P > 0.1). Apparent dry matter digestibility was 10% greater in CNTL, TG and TG + PL groups compared with PL piglets (P < 0.002). No differences in alanine aminotransferase were detected among treatments, but aspartate aminotransferase was elevated (P < 0.03) in PL piglets compared with TG + PL piglets. Total plasma AA concentration was greater in the TG group compared with CNTL piglets (P < 0.05). Total plasma DHA concentrations were greater in TG piglets compared with PL (P < 0.06) or CNTL (P < 0.02) piglets. These data demonstrate that the algal/fungal TG sources of DHA and AA may be a more appropriate supplement for infant formulas than the egg PL source based on piglet plasma fatty acid profiles and apparent dry matter digestibilities.

Docosahexaenoic acid and arachidonic acid enhance growth with no adverse effects in preterm infants fed formula.

OBJECTIVE: To determine if docosahexaenoic acid (DHA) and arachidonic acid (ARA) supplementation influences growth or visual acuity of formula-fed premature infants. STUDY DESIGN: Double-blind, multi-center study of 194 premature infants given preterm formula with no DHA or ARA (control), 0.15% energy DHA, or 0.14% DHA + 0.27% ARA from single-cell triglycerides for at least 28 days and then fed term formula (no DHA or ARA) to 57 weeks postmenstrual age (PMA), with 90 breast-fed term infants as reference. RESULTS: Infants fed DHA+ARA formula gained weight significantly faster (post-hoc analysis) during preterm formula feeding than control infants (34.7 vs. 30.7 g/d) and had weights and weight:length ratios not different from term breast-fed infants at 48 and 57 weeks PMA. Infants fed control or DHA formula had lower body weights than term infants. Red blood cell phosphatidylethanolamine ARA was significantly correlated to weight gain during preterm formula feeding and to weight and length at 40, 48, and 57 weeks PMA (r = 0.19 to 0.24, P =.004-.02). Providing DHA or DHA+ARA during the preterm period had no effect on subsequent visual acuity or incidence of adverse events. CONCLUSIONS: Feeding DHA+ARA from single-cell triglycerides enhances weight gain in formula-fed premature infants with no evidence of adverse effects.