Ординатура / Офтальмология / Английские материалы / Handbook of Nutrition and Ophthalmology_Semba_2007

VEP, visual evoked potential; DHA, docosahexaenoic acid; AA, arachidonic acid; LC-PUFAs, longchain polyunsaturated fatty acids, ERG, electroretinogram.

breast-fed and formula-fed term in visual acuity assessed by Teller cards at 7 mo of age (92), and a study of preterm infants in Australia found no difference in ERGs and visual acuity assessed by Teller cards at 40 wk postconceptual age among preterm infants with a high and low intake of human milk (93).

Potential confounding factors in observational studies include tobacco and alcohol use during pregnancy, socioeconomic status, cultural differences among mothers who decide to breast feed or use infant formula, educational differences, and birth weight (92,94). Investigators turned to randomized, controlled clinical trials in order to address the issue whether n-3 fatty acids were essential for visual development in preterm and term infants.

11.3. Clinical Trials in Preterm Infants

A series of controlled clinical trials has recently suggested that n-3 PUFAs improve the visual development of preterm infants (95). At least five clinical trials have evaluated the role of supplemental DHA or DHA plus AA in the visual development of preterm infants (Table 6) (96–108). The characteristics of masking, randomization, assessment methods,

aThe main n used in the actual statistical analysis; some n may vary at different follow-up visits. VEP, visual evoked potential; LC-PUFA, long-chain polyunsaturated fatty acids; DHA, docosahexaenoic

acid; ERG, electroretinogram.

duration of supplementation, balance of essential fatty acids in formula, and follow-up of these trials has been reviewed in detail elsewhere (95,109).

An early trial, covered in several reports, showed that preterm infants given formula supplemented with LC-PUFAs had better visual acuity as assessed by VEP at 36 wk and VEP and Teller cards at 57 wk (96–100). Two other arms of the study included control formulas that contained linoleic acid and linoleic and linolenic acids, respectively. In addition, rod thresholds of the ERG were lower among the infants who received supplemental LC-PUFAs. In a study from Memphis, preterm infants were randomized to received control formula without DHA and formula with dexahexaenoic acid (101–104). Visual acuity, as assessed by Teller cards, was significantly better at 2 and 4 mo among infants who received supplemental DHA compared with control formula, but no differences were found at 6.5, 9, and 12 mo (Fig. 7). In a second trial from Memphis, better visual recognition memory and visual attention as assessed by the Fagan test was found among preterm infants supplemented with DHA compared with control formula (105,106).

In a clinical trial conducted in Italy, infants who received supplemental LC-PUFAs had significantly different flash VEP latency at 52 wk postconceptional age compared with

Fig. 8. Meta-analysis of the effect of docosahexaenoic acid on visual acuity of healthy preterm infants, showing differences in visual acuity as assessed by behavioral tests (A) and visual evoked potential

(B). Error bars are 95% confidence intervals. Individual studies are indicated by fine error bars. Large diamonds with bold bars indicate combined visual acuity difference estimates, and bars that do not span zero (horizontal line) indicate significant results. (Reproduced from ref. 110, with permission of the American Academy of Pediatrics.)

fact that four trials utilized formulas with DHA alone (111,113,116,121), which resulted in depletion of AA status of the infants (95).

In a controlled clinical trial in Australia, infants who were randomized to receive formula containing supplemental DHA and eicosapentaenoic acid had better VEP acuity at 16 and 30 wk compared with infants who received control formula (111). There were no significant differences in VEP acuity between breast-fed and supplemented infants. Better sweep VEP acuity was found among term infants at 2 mo who were breast-fed or received formula supplemented with DHA and AA compared with infants randomized

aThe main n used in the actual statistical analysis; some n may vary at different follow-up visits. EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; VEP, visual evoked potential; AA, arachidonic

acid.

to receive control formula, but these differences were no longer significant at 4, 6, 9, or 12 mo of age (112). In contrast, a multicenter study in the United States found no differences in visual acuity assessed by sweep VEP and Teller cards at 2, 4, 6, 9, and 12 mo between term infants randomized to receive control formula, or formula supplemented

with DHA and/or AA (113). Longer term follow-up at 39 mo also showed no differences in visual motor function or visual acuity between formula or breastfed groups (124). In a study conducted in the United States, term infants who received a formula containing both DHA and AA had better VEP acuity than the control group at 6, 17, 26, and 52 wk of age (123).

Better sweep VEP acuity was found among term infants at 6, 17, and 52 wk among infants randomized to received formula containing DHA or DHA plus AA compared with control formula (117). In contrast, no difference was found in sweep VEP acuity at 4 mo between infants who received supplemental DHA compared with controls in Denmark (116). Another trial in Australia also found no differences in VEP acuity at 16 and 34 wk between term infants who received control formula vs formula supplemented with DHA (121,122).

A clinical trial in Italy showed that infants supplemented with LC-PUFAs had a better Brunet-Lézine developmental quotient, a more global measure of development, at 4 mo of age but not at 24 mo of age (114,115). In two reports from one trial, there were no significant differences in means-end problem solving at 9 mo of age between infants randomized to receive control formula or formula supplemented with AA and DHA, but apparent differences were seen at 10 mo of age (118). In another trial that examined global development, no differences were found in Bayley mental or psychomotor development indices at 9 and 18 mo between infants randomized to receive control formula and formula supplemented with LC-PUFAs (120).

A meta-analysis of some of the randomized trials suggests that visual acuity at 2 mo of age is significantly better among term infants who received supplemental DHA, but there were no significant differences at other ages (Fig. 9) (125). The combined visual acuity difference (± standard error of the mean) measured by behavioral methods was 0.32 ± 0.09 octaves at 2 mo of age (125). Another analysis of 14 controlled trials in term infants used “meta-regression” to examine the relationship between visual acuity at 4 mo and the DHA effective dose. The results showed a strong and significant effect of DHA equivalent dose on visual acuity response at 4 mo of age, especially when 10% conversion of α-linoleic acid to DHA was considered (126).

11.5. Implications of the Clinical Trials

The clinical trials of n-3 LC-PUFAs generally show a beneficial effect on visual acuity in preterm infants and perhaps an effect in term infants. Some of the discrepancies among the clinical trials may be related to the use of infant formulas that contain inadequate n-3 fatty acids (<1.5–2.0% linolenic acid), differences in the source and composition of the oil used as the source for DHA, and presence or absence of AA and eicosapentaenoic acid (43). The period in which infants are vulnerable to low dietary n-3 fatty acid intakes appears to be short. Although dietary n-3 fatty acids appear to influence the development of visual acuity, the differences as demonstrated in these clinical trials disappear when children are evaluated at a later age. The transient nature of these effects may lead some to conclude that the differences have no lasting importance, but other studies on visual development suggest that early visual experience can be critical to later visual functioning (67). Whether a relative deficiency in DHA early in infancy is related to any subsequent visual problem, such as amblyopia or strabismus, or any later abnormality of cognitive or motor development is unclear.

Fig. 9. Visual acuity differences. Open symbols represent randomized comparisons (formula-fed groups with long-chain polyunsaturated fatty acids (LC-PUFAs) vs formula-fed groups with LCPUFAs). Shaded symbols represent nonrandomized comparisons (human milk vs formula without LCPUFAs). Diamonds represent combined acuity difference estimates of randomized comparisons.

(A) Acuity differences measured with behaviorally based tests. (B) Acuity differences measured with visual evoked potentials. (Reproduced from ref. 125, with permission from Elsevier Science.)

Observational studies that have compared breast-fed and formula-fed infants suggest that the expected difference or improvement in cognitive development with supplemental DHA would be about one-third of a standard deviation for the test scores. Using standard sample size and power calculations, about 144 subjects per group or 288 subjects total, would be needed to detect this difference with 80% power and a significant level of 0.05 (127). To date, none of the clinical trials of supplemental LC-PUFAs and neurodevelopment in infants, either preterm or term, have had adequate sample size and

power (127). Studies of infant nutrition require large sample sizes and long follow-up, and therefore can become extremely expensive to conduct (128). With recent recommendations regarding supplemental essential fatty acids (1), the provision of AA and DHA in all infant formulas is likely to become the standard of care, and further clinical trials or observational studies may become difficult to justify.

12. CONCLUSIONS AND RECOMMENDATIONS

The human retina contains an extremely high concentration of DHA, a PUFA of the n-3 (omega-3) family. DHA appears to play an important role in the retina and is necessary for the normal function of rhodopsin. Preterm infants are born with relatively low stores of DHA, and in the past, infant formulas did not contain this n-3 fatty acid. A recent series of clinical trials conducted with both preterm and term infants suggests that the addition of DHA to infant formula will improve the development of visual acuity in the first few months of life, especially among preterm infants. The differences in visual acuity between infants fed formula with and without DHA disappeared after 4 mo of age, and it is unclear whether there are long-term adverse consequences associated with lack of DHA in formula. A recent expert consensus has been reached regarding essential fatty acids for infant health, and it is now recommended that both AA and DHA be added to infant formula, and this recommendation is largely being followed by industry. The addition of LCPUFAs to infant formula has raised the cost of formula feeding, and the actual long term functional benefits still remain controversial (4).

Several important research issues remain to be addressed. The long-term effects of AA and DHA on eye health are not known and need further characterization. There is a need for adequate sample size and statistical power for clinical trials that assess the effects of essential fatty acids on infant neurodevelopment. The possible effects of trans unsaturated fatty acids on essential PUFA status of mothers and infants should be investigated. The use and optimal composition of n-6 and n-3 fatty acids in PUFA supplements for pregnant women is not well known. Finally, the precise role of DHA in rod and cone outer segments must be better characterized.

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