Eileen E. Birch

A randomized controlled trial of early dietary supply of long-chain polyunsaturated fatty acids and mental development in term infants

The effects of dietary docosahexaenoic acid (DHA) supply during infancy on later cognitive development of healthy term infants were evaluated in a randomized clinical trial of infant formula milk supplemented with 0.35% DHA or with 0.36% DHA and 0.72% arachidonic acid (AA), or control formula which provided no DHA or AA. Fifty‐six 18‐month‐old children (26 male, 30 female) who were enrolled in the trial within the first 5 days of life and fed the assigned diet to 17 weeks of age were tested using the Bayley Scales of Infant Development, 2nd edition (BSID‐II) (Bayley 1993) at the Retina Foundation of the Southwest, Dallas, TX. These children had also been assessed at 4 months and 12 months of age for blood fatty‐acid composition, sweep visual evoked potential (VEP) acuity, and forced‐choice preferential looking (FPL) acuity (Birch et al. 1998). Supplementation of infant formula with DHA+AA was associated with a mean increase of 7 points on the Mental Development Index (MDI) of the BSID‐II. Both the cognitive and motor subscales of the MDI showed a significant developmental age advantage for DHA‐ and DHA+AA‐supplemented groups over the control group. While a similar trend was found for the language subscale, it did not reach statistical significance. Neither the Psychomotor Development Index nor the Behavior Rating Scale of the BSID‐II showed significant differences among diet groups, consistent with a specific advantage of DHA supplementation on mental development. Significant correlations between plasma and RBC‐DHA at 4 months of age but not at 12 months of age and MDI at 18 months of age suggest that early dietary supply of DHA was a major dietary determinant of improved performance on the MDI.

Effect of Dietary Omega-3 Fatty Acids on Retinal Function of Very-Low-Birth-Weight Neonates

ABSTRACT: Retinal function was assessed by electroretinogram in 32 neonates randomly assigned to formulas of different ω-3 fatty acid content and in 10 infants fed human milk. All neonates had a birth weight of 1000-1500 g and were fed study diets from d 10 to 45 or discharge. Group A received formula containing predominantly 18:2 ω-6. Group B received a balanced mix of 18:2 ω-6 and 18:3 ω- 3. Group C was given a formula containing both essential fatty acids and supplemented with marine oil to provide 22:6 ω-3 content similar to that of human milk. The fatty acid composition of plasma and red blood cell (RBC) lipids were similar for all groups on entry but marked dietinduced differences were found after feeding the study diets. Group C was comparable to the human milk-fed group, but group A had lower 22:6 ω-3 and ω-3 long-chain polyunsaturated fatty acids (LCPUFA) in plasma and RBC membranes. Cone function was not affected by dietary essential fatty acids. Rod electroretinogram thresholds were significantly higher for group A relative to the human milk-fed group and group C and significantly correlated with RBC ω-3 LCPUFA (r = -0.63, p < 0.0001); 44% of the variance could be explained by RBC and plasma ω-3 LCPUFA content. Rod electroretinogram amplitude was significantly lower for group A relative to the human milkfed group and group C and related to plasma 22:6 ω-3 (r = 0.55) and total ω-3 LCPUFA (r = 0.58) (both p < 0.0001); 42% of the variance was explained by plasma ω-3 LCPUFA, the ratio of ω-6/ω-3 LCPUFA in RBC, and gestational age at birth. Our results support an essential role for ω-3 fatty acids in retinal development.

Visual acuity and the essentiality of docosahexaenoic acid and arachidonic acid in the diet of term infants

The need for a dietary supply of docosahexaenoic acid (DHA) and arachidonic aid (AA) in term infants was evaluated in a double-masked randomized clinical trial of the effects of supplementation of term infant formula with DHA (0.35% of total fatty acids) or with DHA (0.36%) and AA(0.72%) on visual acuity development. One hundred and eight healthy term infants were enrolled in the study; 79 were exclusively formula-fed from birth (randomized group) and 29 were exclusively breast-fed (gold standard group). Infants were evaluated at four time points during the first 12 mo of life for blood fatty acid composition, growth, sweep visual evoked potential(VEP) acuity, and forced choice preferential looking acuity. Supplementation of term infant formula with DHA or with DHA and AA during the first 4 mo of life yields clear differences in total red blood cell (RBC) lipid composition. Supplementation of term infant formula with DHA or with DHA and AA also yields better sweep VEP acuity at 6, 17, and 52 wk of age but not at 26 wk of age, when acuity development reaches a plateau. The RBC lipid composition and sweep VEP acuity of supplemented infants was similar to that of human milk-fed infants, whereas the RBC lipid composition and sweep VEP acuity of unsupplemented infants was significantly different from human milk-fed infants. Differences in acuity among diet groups were too subtle to be detected by the forced choice preferential looking protocol. Infants in all diet groups had similar rates of growth and tolerated all diets well. Thus, early dietary intake of preformed DHA and AA appears necessary for optimal development of the brain and eye of the human infant.

Essential fatty acids in visual and brain development

Essential fatty acids are structural components of all tissues and are indispensable for cell membrane synthesis; the brain, retina and other neural tissues are particularly rich in long-chain polyunsaturated fatty acids (LC-PUFA). These fatty acids serve as specific precursors for eicosanoids, which regulate numerous cell and organ functions. Recent human studies support the essential nature of n-3 fatty acids in addition to the well-established role of n−6 essential fatty acids in humans, particularly in early life. The main findings are that light sensitivity of retinal rod photoreceptors is significantly reduced in newborns with n−3 fatty acid deficiency, and that docosahexaenoic acid (DHA) significantly enhances visual acuity maturation and cognitive functions. DHA is a conditionally essential nutrient for adequate neurodevelopment in humans. Comprehensive clinical studies have shown that dietary supplementation with marine oil or single-cell oil sources of LC-PUFA results in increased blood levels of DHA and arachidonic acid, as well as an associated improvement in visual function in formula-fed infants matching that of human breast-fed infants. The effect is mediated not only by the known effects on membrane biophysical properties, neurotransmitter content, and the corresponding electrophysiological correlates but also by a modulating gene expression of the developing retina and brain. Intracellular fatty acids or their metabolites regulate transcriptional activation of gene expression during adipocyte differentiation and retinal and nervous system development. Regulation of gene expression by LC-PUFA occurs at the transcriptional level and may be mediated by nuclear transcription factors activated by fatty acids. These nuclear receptors are part of the family of steroid hormone receptors. DHA also has significant effects on photoreceptor membranes and neurotransmitters involved in the signal transduction process; rhodopsin activation, rod and cone development, neuronal dendritic connectivity, and functional maturation of the central nervous system.

A computerized method of visual acuity testing: adaptation of the early treatment of diabetic retinopathy study testing protocol.

PURPOSE To develop a computerized method of visual acuity testing for clinical research as an alternative to the standard Early Treatment for Diabetic Retinopathy Study (ETDRS) testing protocol, and to evaluate its test-retest reliability and concordance with standard ETDRS testing. DESIGN Test-retest reliability study. METHODS Multicenter setting of a study population of 265 patients at three clinical sites. Visual acuity was measured with both the electronic visual acuity testing algorithm (E-ETDRS) and standard ETDRS protocol (S-ETDRS) twice on one eye of each patient. E-ETDRS testing was conducted using the electronic visual acuity tester (EVA), which utilizes a programmed Palm (Palm, Inc, Santa Clara, California, USA) hand-held device communicating with a personal computer and 17-inch monitor at a test distance of 3 meters. RESULTS For the E-ETDRS protocol, test-retest reliability was high (r = 0.99; with 89% and 98% of retests within 0.1 logMAR and 0.2 logMAR of initial tests, respectively) and comparable with that of S-ETDRS testing (r = 0.99; with 87% and 98% of retests within 0.1 logMAR and 0.2 logMAR of initial test, respectively). The E-ETDRS and S-ETDRS scores were highly correlated (r = 0.96 for initial tests and r = 0.97 for repeat tests). Based on estimates of 95% confidence intervals, a change in visual acuity of 0.2 logMAR (10 letters) from a baseline level is unlikely to be related to measurement variability using either the E-ETDRS or the S-ETDRS visual acuity testing protocol. CONCLUSIONS The E-ETDRS protocol has high test-retest reliability and good concordance with S-ETDRS testing. The computerized method has advantages over the S-ETDRS testing in electronically capturing the data for each tested letter, requiring only a single distance for testing from 20/12 to 20/800, potentially reducing testing time, and potentially decreasing technician-related bias.

Breast-Feeding and Optimal Visual Development

The goal of the present study was to determine whether dietary supply of omega-3 essential fatty acid (EFA) influences visual development in healthy pre-term and full-term infants. Visual status was examined in human milk-fed infants (ample dietary omega-3 EFA supply) and corn oil-based formula-fed infants (no dietary omega-3 EFA; standard formula prior to 1987). At 57 weeks postconception (4 months adjusted age), both pre-term and full-term human milk-fed infants had significantly better visual evoked potential (VEP) and forced-choice preferential-looking (FPL) acuity than formula-fed infants. Acuity was correlated with a dietary omega-3 sufficiency index from red blood cell membranes obtained at 57 weeks postconception. At 36 months, full-term human milk-fed children had significantly better random dot stereo acuity and letter matching ability than formula-fed children. Stereo acuity and performance on the letter matching test were correlated with a dietary omega-3 sufficiency index from red blood cell membranes obtained at 4 months. These results suggest that dietary omega-3 fatty acids play an important role in visual development.

Computerized method of visual acuity testing: Adaptation of the Amblyopia Treatment Study visual acuity testing protocol

PURPOSE To report a computerized method for determining visual acuity in children using the Amblyopia Treatment Study visual acuity testing protocol. METHODS A computerized visual acuity tester was developed that uses a programmed handheld device that uses the Palm operating system (Palm, Inc, Santa Clara, California). The handheld device communicates with a personal computer running a Linux operating system and 17-inch monitor. At a test distance of 3 m, single letters can be displayed from 20/800 to 20/12. A C program on the handheld device runs the Amblyopia Treatment Study visual acuity testing protocol. Using this method, visual acuity was tested in both the right and left eyes, and then the testing was repeated in 156 children age 3 to 7 years at four clinical sites. RESULTS Test-retest reliability was high (r =.92 and 0.95 for and right and left eyes, respectively), with 88% of right eye retests and 94% of left eye retests within 0.1 logarithm of minimal angle of resolution (logMAR) units of the initial test. The 95% confidence interval for an acuity score was calculated to be the score +/- 0.13 logMAR units. For a change between two acuity scores, the 95% confidence interval was the difference +/- 0.19 logMAR units. CONCLUSIONS We have developed a computerized method for measurement of visual acuity. Automation of the Amblyopia Treatment Study visual acuity testing protocol is an effective method of testing visual acuity in children 3 to 7 years of age.

ROLE OF ESSENTIAL FATTY ACIDS IN THE FUNCTION OF THE DEVELOPING NERVOUS SYSTEM

The basis for n-3 fatty acid essentiality in humans includes not only biochemical evidence but functional measures associated with n-3 deficiency in human and nonhuman primates. Functional development of the retina and the occipital cortex are affected by α-linolenic acid deficiency and by a lack of docosahexaenoic acid (DHA) in preterm infant formulas and, as reported more recently, in term diets. Functional effects of n-3 supply on sleep-wake cycles and heart rate rhythms support the need for dietary n-3 fatty acids during early development. Our results indicate that n-3 long-chain polyunsaturated fatty acids should be considered provisionally essential for infant nutrition. DHA may also be required by individuals with inherited metabolic defects in elongation and desaturation activity, such as patients with peroxisomal disorders and some forms of retinitis pigmentosa.

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.

Amblyopia and Binocular Vision

Amblyopia is the most common cause of monocular visual loss in children, affecting 1.3%-3.6% of children. Current treatments are effective in reducing the visual acuity deficit but many amblyopic individuals are left with residual visual acuity deficits, ocular motor abnormalities, deficient fine motor skills, and risk for recurrent amblyopia. Using a combination of psychophysical, electrophysiological, imaging, risk factor analysis, and fine motor skill assessment, the primary role of binocular dysfunction in the genesis of amblyopia and the constellation of visual and motor deficits that accompany the visual acuity deficit has been identified. These findings motivated us to evaluate a new, binocular approach to amblyopia treatment with the goals of reducing or eliminating residual and recurrent amblyopia and of improving the deficient ocular motor function and fine motor skills that accompany amblyopia.