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Original Research Communication |
1 From the Retina Foundation of the Southwest, Dallas (EEB, DRH, YSC, SLF, DGB, and RDU); the Departments of Ophthalmology (EEB, SLF, and DGB) and Pediatrics (DRH), University of Texas Southwestern Medical Center, Dallas; and the Instituto de Nutricion y Technologia Alimentos, University of Chile, Santiago (RDU).
2 Supported by NIH grant HD22380. Milk-based infant formulas were generously provided by the Mead Johnson Nutritional Group (Evansville, IN).
3 Address reprint requests to EE Birch, Retina Foundation of the Southwest, 9900 North Central Expressway, Suite 400, Dallas, TX 75231. E-mail: ebirch{at}retinafoundation.org.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: The aim of the present study was to determine the relative importance for maturation of the visual cortex of the dietary supply of LCPs during the first 6 wk of life compared with that during weeks 7–52.
Design: A randomized controlled clinical trial of LCP supplementation in 65 healthy term infants who were weaned from breast-feeding at 6 wk of age was conducted to determine whether the dietary supply of LCPs after weaning influenced the maturation of visual acuity and stereoacuity.
Results: Despite a dietary supply of LCPs from breast milk during the first 6 wk of life, infants who were weaned to formula that did not provide LCPs had significantly poorer visual acuity at 17, 26, and 52 wk of age and significantly poorer stereoacuity at 17 wk of age than did infants who were weaned to LCP-supplemented formula. Better acuity and stereoacuity at 17 wk was correlated with higher concentrations of docosahexaenoic acid in plasma. Better acuity at 52 wk was correlated with higher concentrations of docosahexaenoic acid in plasma and red blood cells. No significant effects of diet on growth were found.
Conclusion: The results suggest that the critical period during which the dietary supply of LCPs can influence the maturation of cortical function extends beyond 6 wk of age.
Key Words: n-3 Fatty acids • docosahexaenoic acid • infants • visual acuity • stereoacuity • weaning • nutrition
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The potential importance of the dietary supply of LCPs during the first few months of life is supported by the finding that neural tissues in the brain show progressive enrichment of phospholipids with LCPs, especially during the last trimester of fetal development and the first 3–6 mo after birth (11–15). Of particular relevance to the clinical trial reported here, the early postnatal months are a period of rapid increase in the number of synapses and dendritic arborizations in the visual cortex (16–18). Because maturation of the visual cortex requires the deposition of LCPs in neuronal membranes, any limitation of the LCP supply during infancy may adversely influence the growth and function of the visual cortex.
The aim of the randomized clinical trial reported here was to evaluate the relative importance for maturation of the visual cortex of the dietary supply of LCPs during the first 6 wk of life compared with that during weeks 7–52. This study represents a first step in delineating the critical period for cortical LCP accretion by comparing the neurodevelopmental outcomes of term infants who were weaned from breast-feeding at 6 wk of age and randomly assigned to consume diets that either did or did not provide dietary LCPs during weeks 7–52. If the critical period for accretion of LCPs by the brain extends beyond 6 wk of age, we would expect that providing dietary LCP supplements in infant formula would benefit the functioning of the visual cortex in term infants weaned from breast-feeding at 6 wk of age.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Parents of eligible neonates were provided a brief information sheet about the study and were asked to call if they were planning to wean the infant from breast-feeding at 
6 wk of age. Parents also were informed that the American Academy of Pediatrics recommends breast-feeding for 12 mo and that other ongoing studies in our laboratory were available for infants who are breast-fed for >6 wk. Informed consent was obtained from one or both parents at the 6-wk appointment, before the infant's participation. This research protocol observed the tenets of the Declaration of Helsinki and was approved by the Institutional Review Boards of the University of Texas Southwestern Medical Center (Dallas), Presbyterian Medical Center (Dallas), and Medical City Columbia Hospital (Dallas).
Randomization
Infants were randomly assigned on the day of enrollment (target age of 6 wk; range: 4–8 wk; 
± SD age: 5.1 ± 1.2 wk) to consume 1 of the 2 diets described in the paragraph below. Most families were recruited from 2 separate hospitals to encourage ethnic and socioeconomic diversity in the cohort; a few infants were recruited at other sites when their parents learned about the study from friends or relatives and contacted us. All infants were randomly assigned with the use of a single randomization schedule at a central location. Both diets were masked by 2 color and 2 number codes, for a total of 4 possible diet assignments for each infant. Diet assignments, based on a blocked randomization schedule (with variable-length blocks), were provided in sealed envelopes to the study site.
Diets
The study diets were commercial infant formula (Enfamil with iron; Mead Johnson Nutritional Group, Evansville, IN) or the same commercial infant formula supplemented with 0.36% of total fatty acids as docosahexaenoic acid (DHA; 22:6n-3) and 0.72% as arachidonic acid (AA; 20:4n-6). The fatty acid composition of both formulas and of human milk is summarized in Table 1
. Both formulas provided 15% linoleic acid (LA; 18:2n-6) and 1.5% 
-linolenic acid (-LNA; 18:3n-3). The LCP (DHA+AA)-supplemented formula contained single-cell oils (DHASCO and ARASCO; Martek Biosciences, Columbia, MD). Both formulas were provided in 946-mL ready-to-feed cans and provided 14.7 g protein/L, 37.5 g fat/L, 69.0 g carbohydrate/L, and 2805 kJ/L. All nutrients met existing standards for commercial formula established by the Infant Formula Act (19). Assigned diets were fed between 6 and 52 wk of age. None of the infants had solid food before 17 wk of age, and most infants had no solid food other than cereal until 26 wk of age.
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Sweep acuity, as measured by cortical visual evoked potentials (VEPs), and growth were measured at 6, 17, 26, and 52 wk. The 6-wk time point provided a baseline measurement at the time of randomization. The 17- and 26-wk time points were included because they allow for maximum exposure to LCP supplementation (because little or no solid food was given to infants before 17 or 26 wk) and because sweep VEP acuity normally develops rapidly during that time (20–22). The 52-wk time point was included because it represents the maximum length of exposure to LCP-supplemented formula and because sweep VEP acuity is relatively mature at this time point [0.3 log of the minimum angle of resolution (log MAR) below the adult value] (20–22).
Stereoacuity was assessed at 17, 26, 39, and 52 wk of age. The 6-wk time point was excluded because <5% of infants would be expected to demonstrate stereoacuity at this early age (23, 24). The 17-, 26-, and 52-wk time points correspond to those for VEP and growth measurements, and the 39-wk time point was added to provide more detailed information for assessment of the rate of maturation because this outcome variable had not been used previously in a randomized clinical trial of infant nutrition.
Sample size
Sample sizes were estimated by using the method described by Rosner (25) for = 0.05 and 1 - ß = 0.90. With the use of standard deviations for sweep VEP (0.1 log MAR; ie, one line on an eye chart; 9) from our present and past studies of term infants, the final sample size per group at 12 mo required to detect a 1-SD difference between groups is 21 infants. This sample size will also be sufficient to detect a 1-SD difference between groups in random dot stereoacuity (0.2 log s; eg, 40 s compared with 60 s; 24) and a <1% difference in the DHA or AA fatty acid composition of red blood cells (RBCs) (9). Anticipating a 20–25% loss to follow-up over 12 mo, we planned to recruit 30 infants for each of the 2 diet groups and achieved enrollment of 32 and 33 per group.
A summary of enrollment and loss to follow-up is presented in Table 2. Seven infants (10.7%) were lost to follow-up during the course of the study. Of those 7, 5 infants (7.6%) dropped out of the study after the initial appointment at 6 wk. In 3 cases, the infants were withdrawn from the study because of their pediatricians' recommendation to switch to a soy-protein-based formula after the infants had symptoms suggestive of intolerance to lactose or cow milk protein. In one case, the mother was unable to wean the infant to formula, and in another case the parent could not be contacted to schedule a visit. Of the 60 infants who remained in the study after randomization at 6 wk of age, 58 (96.7%) completed the protocol through 12 mo of age. Two children dropped out of the study after the 26-wk visit: one because of asthma possibly related to milk allergy and one because the parent could not be contacted to schedule a visit. Sample sizes at 12 mo were 28 in the LCP-supplemented-formula group and 30 in the control-formula group.
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Stereoacuity
Random dot stereoacuity was assessed with the use of forced-choice preferential looking and the infant random dot stereocards (24). Random dot stereoacuity was chosen as an outcome measure because it directly reflects cortical processing; detection of the disparate stimulus depends on the cortical combination of monocular images that lack any form information. The random dot stereocards consist of a series of test cards with disparities ranging from 1735 to 45 s arc in approximate octave steps. The cards are presented in a 2-down, 1-up staircase protocol. The infant views the test cards while wearing polarizing filters mounted in spectacle frames especially designed for infants, and an observer judges on each trial whether the infant prefers to look at a disparate or a nondisparate stereogram. Stereoacuity is obtained by averaging (geometric mean) the last 6 of 8 reversals or by maximum likelihood estimation (26). To avoid bias introduced by basement effects in low-vision eyes, we established criteria for switching over to the block method (26). Stereoacuity was expressed in log s (log of the minimum detectable binocular disparity; eg, a 40-s disparity corresponds to 1.60 log s). As noted in Table 2
, the stereoacuity test could not be completed on all infants at all visits because the polarized glasses required could not be placed on the child because of conjunctivitis (1 child in the LCP-supplemented-formula group at 26 wk and 1 child in the control-formula group at 39 wk), because the child refused to wear the glasses (1 child in the LCP-supplemented-formula group at 26 wk, 1 child in the LCP-supplemented-formula group and 2 children in the control-formula group at 39 wk, and 3 children in the LCP-supplemented-formula group and 2 children in the control-formula group at 52 wk), or because the child had a tropia at the time of testing (1 child in the LCP-supplemented-formula group and 1 child in the control-formula group at 17 wk and 1 child in the LCP-supplemented-formula group at 26 wk).
Growth
Weight was measured by using a pediatric strain gauge scale (Healthometer, Bridgeview, IL) accurate to 1 g. Length was measured by using length boards (Ellard Instrumentation Ltd, Seattle) accurate to 0.1 cm. Growth data were normalized by expressing them as z scores for term infants of the appropriate age and sex and by using the LMS parameters provided in the data files from the Centers for Disease Control and Prevention (CDC) growth charts released in 2000 by the Department of Health and Human Services as part of the National Health and Nutrition Examination Survey (27).
Blood lipids
Blood samples (2.0 mL) were collected at 17 and 52 wk by heel stick aided by infant heel warming packs into tubes (Microtainer; Becton Dickinson, Franklin Lakes, NJ) containing EDTA. Plasma and RBCs were separated by centrifugation at 3000 x g for 10 min at 4 °C, lipids were extracted and transmethylated with boron trifluoride–methanol, and methylesters were analyzed by capillary gas chromatography with flame ionization detection (28). Fatty acid peaks were identified by comparison with the GLC68+11 standard and by using custom software that semiautomated data processing. Concentrations were obtained as mass concentrations (mg/L plasma or packed RBCs) on the basis of the addition of an internal standard (23:0).
Statistical analyses
During the course of the study, all data were handled in a coded manner. The data were analyzed with two-way repeated-measures analysis of variance after verifying that they met normality criteria. Planned comparisons were carried out to compare the means of the 2 diet groups at each age point. Because 4 pairwise comparisons were conducted for each of the vision outcome variables (acuity and stereoacuity), only planned comparisons with P < 0.01 were considered significant (Bonferroni adjustment of 0.05/4, or 0.0125). Linear regression was conducted to examine the association between blood lipid concentrations and visual outcomes. Because linear regression was conducted to examine the relation between 4 major fatty acids (LA, -LNA, AA, and DHA), only regression coefficients associated with P < 0.01 were considered significant (Bonferroni adjustment of 0.05/4, or 0.0125).
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. There were no significant differences between the groups in recruitment site, sex representation, ethnicity, or maternal and paternal variables assessed.
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and 5, respectively. At 17 wk of age, both plasma and RBC concentrations of DHA were significantly higher in infants who consumed LCP-supplemented formula than in those who consumed control formula. At 52 wk, plasma and RBC concentrations of DHA were similar to those at 17 wk; ie, plasma and RBC concentrations of DHA were significantly higher in infants who consumed LCP-supplemented formula than in those who consumed control formula. Moreover, there was an even greater difference between the 2 diet groups in the RBC concentrations of DHA at 52 wk than at 17 wk. There were no significant differences in the concentrations of -LNA or eicosapentaenoic acid in plasma at either age, but n-3 docosapentaenoic acid (n-3 DPA; 22:5n-3) was significantly lower in the LCP-supplemented-formula group than in the control-formula group at both ages. In RBC lipids, there were no significant differences in -LNA concentrations, whereas eicosapentaenoic acid and n-3 DPA were lower in the LCP-supplemented-formula group than in the control-formula group at both 17 and 52 wk.
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The ratio of DHA to n-6 DPA was significantly lower whereas the ratio of n-6 to n-3 LCPs was significantly higher in the control-formula group than in the LCP-supplemented-formula group at both 17 and 52 wk. The ratio of Mead acid (20:3n-9) to AA was significantly higher in the control-formula group than in the LCP-supplemented-formula group at both 17 and 52 wk, and the unsaturation index was significantly higher in the LCP-supplemented-formula group at both ages.
Growth
Box plots of z scores for weight, length, and head circumference for both diet groups are shown in Figure 1. All anthropometric outcome data were normally distributed. With the use of repeated-measures analysis of variance, no significant main effect of diet was found for weight, length, or head circumference. In addition, there were no significant differences between the diet groups in weight-for-length, subscapular fat, or triceps fat deposition (data not shown).
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. All acuity outcome data were normally distributed. There were significant main effects of diet and of age and a significant interaction between them. In the planned comparisons, there were no significant differences between the 2 diet groups at 6 wk of age, but acuity in the control-formula group was significantly poorer than in the LCP-supplemented group at 17, 26, and 52 wk of age.
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. There was no significant main effect of diet. There was a significant main effect of age and a significant interaction between diet and age. In planned comparisons, the LCP-supplemented-formula group had significantly better stereoacuity than did the control-formula group at 17 wk of age. There were no significant differences in stereoacuity between the control-formula group and the LCP-supplemented-formula group at 39 or 52 wk of age.
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). Because sweep VEP acuities were expressed in log MAR, negative regression coefficients would indicate that better acuity is associated with a higher concentration of LCPs whereas positive regression coefficients would indicate that poorer acuity is associated with a higher concentration of LCPs. Better sweep VEP acuity at 17 and 52 wk was associated with higher plasma concentrations of DHA and AA. Neither LA nor -LNA concentrations in plasma were associated significantly with sweep VEP acuity at either age. In RBCs, better sweep VEP acuity at 17 wk was only weakly associated with DHA concentration. At 52 wk, sweep VEP acuity was associated with higher concentrations of both DHA and AA in RBCs. Neither LA nor -LNA concentrations in RBCs were significantly associated with sweep VEP acuity at either age.
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). Because stereoacuity was expressed in log s, negative regression coefficients would indicate that better stereoacuity is associated with a higher concentration of LCPs whereas positive regression coefficients would indicate that poorer stereoacuity is associated with a higher concentration of LCPs. Better stereoacuity at 17 wk was associated with higher plasma DHA concentrations. AA, LA, and -LNA concentrations in plasma were not significantly associated with stereoacuity. In RBCs, a higher concentration of LA at 17 wk was associated with poorer stereoacuity. DHA, AA, and -LNA concentrations in RBCs were not significantly associated with stereoacuity. |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Both formulas were well tolerated by infants; the only intolerance, which was noted in 4 infants, was related to symptoms suggestive of intolerance to lactose or cow milk protein and occurred in both diet groups. Moreover, there were no significant differences in growth between the 2 diet groups. There was a trend for both diet groups to be slightly larger (both in weight and length) than the CDC's normative cohort; this probably reflects our eligibility criterion of birth weight 
2800 g (our working definition of the appropriate weight for a full-term birth) compared with the CDC eligibility criterion of 1500 g.
As in many earlier studies (1–10), consumption of LCP-supplemented formula by term infants resulted in higher plasma and RBC concentrations of DHA than did consumption of control formula; these higher concentrations are more like those of breast-fed term infants. The lower plasma and RBC concentrations of LA in the LCP-supplemented-formula group compared with the control-formula group at 17 wk may reflect, in part, displacement of LA by both DHA and AA. By 52 wk of age, the lower concentration of LA was no longer evident, possibly because of the introduction of solid foods and the concomitant reduction in study formula intake.
Plasma AA concentrations were higher in the LCP-supplemented-formula group throughout the study period, and RBC concentrations of AA were higher at 17 but not at 52 wk of age. This suggests that the infants who received control formula may have synthesized sufficient AA sometime after 17 wk of age. Low concentrations of AA in plasma and RBCs are associated with poorer growth in preterm infants (30); thus, it may be prudent to provide dietary supplementation of AA in conjunction with DHA to maintain a balanced ratio of n-3 to n-6 LCPs similar to that present in human milk (31, 32).
A small but significant reduction in the unsaturation index was found in the control-formula group throughout the study period. Changes in the unsaturation index can influence the function of various membrane-related enzymes, receptors, and nutrient transport systems (33). A higher ratio of Mead acid to AA was also present in the control-formula group. This finding is consistent with an excess conversion of oleic acid (18:1n-9) to Mead acid and is suggestive of essential fatty acid insufficiency (34).
Although there was no significant difference in sweep VEP acuity between the 2 groups of infants at the last visit before weaning, a clear difference was present at 9–11 wk after weaning (at the 17-wk visit), and the acuity difference persisted at 26 and 52 wk of age. The average difference between the LCP-supplemented-formula and control-formula groups is equivalent to one line on an eye chart; eg, at 52 wk of age, the Snellen equivalents of the LCP-supplemented-formula and control-formula groups are 20/30 and 20/40, respectively.
In an earlier study of term infants fed the same control or LCP-supplemented formulas from birth through 17 wk of age, infants who consumed LCP-supplemented formula had better VEP acuity at 17 and 52 wk of age but not at 26 wk of age (9). A comparison of acuity results from both studies is provided in Figure 4. In the present study, the acuity of both groups of infants at 6 wk (when they were breast-feeding) was better than the acuity of the control-formula group in the earlier study and similar to the acuity of the infants fed formula supplemented with DHA and AA. At both 17 and 52 wk, there is good agreement between the 2 studies. It is only at 26 wk that there is a significant difference in the outcomes of the 2 studies. In the present study, the LCP-supplemented-formula group had somewhat better acuity than in the earlier study, whereas the control-formula group had somewhat poorer acuity than in the earlier study. It is possible that continued feeding of LCP-supplemented formula beyond 4 mo of age enhanced the development of the visual cortex. It is also possible that the initial 6 wk of LCP supply via breast-feeding before the initiation of formula feeding had an imprinting effect that altered the effects of subsequent LCP-supplemented or control formula on the maturation of the visual cortex.
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There have been 2 previous reports of random dot stereoacuity differences between breast-fed and formula-fed children who were evaluated at 3 or 3.5 y of age (37, 38). Thus, it may seem somewhat surprising that the stereoacuity difference observed in the present study did not persist. However, the earlier studies differ from the present study in 2 important ways: in the earlier studies, the children were not randomly assigned to infant diet groups and, because those cohorts were studied over 10 y ago, the control formula not only lacked LCPs but also had very low -LNA (0.5% of total fatty acids). Either or both of these factors may have contributed to the persistence of stereoacuity differences into early childhood. There is some evidence that random dot stereoacuity outcomes correlate with cognitive outcomes (C Williams, J Bell, P Warnes, et al, unpublished observations, 1999); thus, it is possible that breast-feeding is associated with better stereoacuity and IQ, independent of nutrition. However, this is unlikely because the statistical analysis controlled for maternal and environmental variables (38). In addition, this same study found that the amount of oily fish (a good source of n-3 LCPs) in the maternal diet was also associated with stereoacuity outcome (38). It is possible that the absence of -LNA as well as of LCPs in the control formula may have contributed to the persistence of stereoacuity differences in both of the earlier studies with 3-y-old children (37, 38). There is evidence that infants can synthesize DHA from dietary -LNA, although it appears unlikely that this process is efficient enough to yield sufficient DHA to meet accretion demands during the period of rapid brain development (39, 40). Thus, the availability of -LNA in the control formula used in the present study may provide sufficient DHA to reduce the difference in stereoacuity performance between the LCP-supplemented-formula and control-formula groups to such an extent that it is difficult to detect except during the period of most rapid development, ie, at 17 wk.
According to the most recent statistics available from the National Center for Health Statistics (41), 46% of US newborns are breast-fed and 54% are formula-fed from the time of birth. Particularly relevant to the study presented here, 56% of those infants who are breast-fed initially are weaned by 26 wk of age. Maternal health may also influence the duration of breast-feeding. For example, a recent analysis suggests that there is a crossover in the risk-to-benefit ratio for breast-feeding for HIV-1– infected mothers by 3 mo postpartum in developing countries and possibly earlier in developed countries (42). Thus, there is a clear need to define safe and effective alternatives to breast-feeding after weaning to infant formula. The results presented here suggest that LCP-supplemented formula is well tolerated and beneficial to the maturation of the visual cortex in term infants weaned at 6 wk of age.
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ACKNOWLEDGMENTS |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-6 and -3 fatty acids in healthy term gestation infants. Am J Clin Nutr 1994;60:347–52.-3 and -6 fatty acid status. World Rev Nutr Diet 1994;75:63–9.[Medline]
-3 fatty acids for premature infants: plasma and red blood cell fatty acid composition. Lipids 1992;27:886–95.[Medline]
-linolenic intake on incorporation of docosahexaenoic and arachidonic acids into plasma phospholipids of term infants. Lipids 1996;31(suppl):S131–5.
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