Introduction

The purpose of this study was to conduct a systematic review of the scientific-medical literature to identify, appraise, and synthesize the human evidence for the effects of omega-3 fatty acids on eye health. The review was requested and funded by the Office of Dietary Supplements, National Institutes of Health. It was undertaken as part of a consortium involving three Evidence-based Practice Centers (EPCs), which investigated the value of omega-3 fatty acid supplementation across eleven health/disease areas. The three EPCs are Southern California-RAND, Tufts-New England Medical Center, and the University of Ottawa. To ensure consistency of approach, the three EPCs collaborated on selected methodologic elements, including literature search strategies, rating of evidence, and data table design.

Visual health is a broad topic, yet we focused on eye health conditions that have a large public health impact in North America. Impact was defined in various ways, which encompassed conditions demonstrating a high prevalence (e.g.., diabetic retinopathy, age-related macular degeneration [ARMD], retinal vascular occlusions), producing many potential years of vision loss in that they affect the young (e.g., retinitis pigmentosa [RP]), or constituting a challenge to health services in no small part because they are costly to treat (e.g., cataracts).

The brain and eye are highly enriched with omega-3 fatty acids, which accumulate in these tissues during late fetal and early neonatal life.¹ Very high levels of DHA are present in the retina, specifically in the disk membranes of the outer segments of photoreceptor cells. DHA accounts for over half the total fatty acyl groups present in the phospholipids of rod outer segment membranes, a proportion higher than is found in any other tissues.² Its specific role, however, is not well understood. The role of DHA may be related to its biophysical effects on the cell membrane. DHA influences the biophysical properties of membranes via its high polyunsaturation, and may help to create a membrane that accommodates the dynamic behavior of rhodopsin during the photoreceptive process.^3–5 In addition, DHA may modulate the activity of membrane bound enzymes and receptors, and the kinetics of membrane transport systems, as well as being a precursor for the synthesis of other biologically active molecules.

A number of studies in preterm and term human infants have suggested that a dietary supply of omega-3 fatty acids may be essential for optimal visual development.^6–8 Finally, animal data suggest that retinal degeneration in rats might be prevented by dietary intake of DHA,⁹ and DHA administered before ischemia may reduce pressure-induced retinal damage in monkeys.¹⁰ It is against this backdrop that various questions were investigated. Our project's overarching goal was to systematically review the human evidence to help develop a research agenda.

Key Questions

The key questions are organized by type of eye disease or visual impairment.

Methods

A Technical Expert Panel (TEP) was convened to provide advisory support to the project, including refining the questions and highlighting key variables requiring consideration in the evidence synthesis.

Results

Sixteen unique studies were identified, which addressed nine of the 23 questions posed by our project. Only two studies were randomized clinical trials (RCTs).^{12, 13} The vast majority of investigations employed either a before-after or observational study design. The paucity of interventional studies involving omega-3 fatty acids delivered as supplementation made it difficult to ascertain the rates or types of harm. The single, placebo-controlled RCT systematically reporting harm data revealed few minor, mainly gastrointestinal, effects associated with low-dose DHA supplementation.¹³

The most-frequently investigated question concerned the primary prevention of ARMD.^14–19 Designs included a single prospective cohort study,¹⁶ two case-control studies,^{14, 15} one retrospective population-based cohort study,¹⁹ and two single population cross-sectional studies.^{17, 18}

There are sufficient between and within study conflicts (e.g., results of univariate vs multivariate analyses) in the results to preclude drawing any inference that is conclusive with respect to the value of the intake of omega-3 fatty acids to prevent ARMD. If it can be assumed that the study designs likely best suited to address this question should be both controlled and prospective, none of the included studies would qualify.

The only prospective study included a large sample and appropriately conducted multivariate analysis, and controlled for key confounders.¹⁴ These investigators observed that the consumption of canned tuna fish or more than four fish servings per week each played a protective role against ARMD. However, their results also indicated that several types of oily fish well known to have high concentrations of DHA and EPA (i.e., sardines, mackerel) failed to show a similar, protective effect. These discordant observations will require an explanation before anything conclusive can be asserted based on this study alone. Moreover, their study design did not a priori employ a separate, unexposed cohort as a control.

The remaining studies cannot resolve the divergent primary prevention results described by this study, even though each of the former failed to demonstrate a statistically significant association between exposure and outcome.^{14, 15, 17–19} Foremost among reasons is the use of research designs that constitute less than ideal strategies to investigate this question. These studies also varied in their definitions of the exposure, clinical outcome and/or confounders, which together make it impossible to draw a definitive conclusion regarding the potential of the intake of omega-3 fatty acids to prevent the onset of either early or late ARMD.

The nature of the RCT design and the “cocktail-like” exposure employed by Scorolli et al. made it impossible to isolate the specific impact of omega-3 fatty acids on slowing the progression of ARMD.¹² A small sample size, the uncommonness and dubious clinical relevance of the visual recovery outcome, low study quality, and little or no applicability to the North American population suggest that there are, at present, no data with which to meaningfully address this research question.

Seddon et al.'s single prospective cohort study found that fish intake did not affect the progression to advanced ARMD overall, or in a high LA consumption group, but did protect against the progression to advanced ARMD in the low (below median consumption) LA consumption group.²⁰ This parallels what was observed exclusively via a significant test for trend in the Seddon et al. study described earlier with reference to its investigation of the influence of the intake of omega-3 fatty acids on preventing the onset of advanced ARMD.¹⁵ However, the results from neither study can be used as yet to provide a conclusive answer to their respective research questions. Both require replication and a plausible explanation.

The four studies examining whether the intake of omega-3 fatty acids slows the progression of RP do not provide a conclusive answer to this question.^{13, 21, 22} Hoffman et al.'s good quality RCT constituted the most rigorous test and revealed conflicting results.¹³ That said, rod and cone functional loss showed effect modification by age, with rod loss significantly reduced in the prepuberty group supplemented with DHA compared with placebo, and cone loss significantly reduced in the post-puberty group supplemented with DHA compared with placebo. The observation that certain analyses failed to reveal statistically significant between-group differences could be explained by this having been an underpowered trial.¹³

By virtue of its research design, which did not permit the isolation of the specific impact of omega-3 fatty acids on slowing the progression of RP, results from Dagnelie et al.'s internet-based comparative before-after study cannot be used to meaningfully address this question.²¹ In Hoffman et al.'s two very small noncomparative before-after studies of short duration, ERG results did not reveal statistically significant changes following supplementation.²² Thus, until Hoffman et al.'s RCT¹³ is replicated with a much larger sample size, little that is conclusive can be said about the potential value of the intake of omega-3 fatty acids in slowing the progression of RP.

Sorokin, et al.'s noncomparative before-after study received a low study quality score and failed to resolve the questions of whether the intake of omega-3 fatty acids can slow the progression of either proliferative retinopathy or clinically significant macular edema in patients with diabetic retinopathy.²³ This study did not constitute the best test of either of these possibilities, however. The most relevant clinical outcome by North American standards entailed fundus assessments, yet few details were reported. Covariates were not measured, and the univariate analysis of the data was flawed. Thus, the results of this study are inconclusive with respect to these two possible benefits of the intake of omega-3 fatty acids in diabetic retinopathy.

Although both the Arnarsson, et al.²⁴ and Cumming, et al.²⁵ studies are well known population-based risk factor studies, in neither of them was the association between the intake of foods or oils containing omega-3 fatty acids and age-related cataract prevalence the primary question. That said, no statistically significant associations were observed. Cross-sectional designs constitute very limited evaluations of this question.

Suzuki et al.'s noncomparative before-after study did not assess cataract status as its clinical outcome, preferring instead to examine visual acuity.²⁶ Thus, with improvements in visual acuity unlikely to have been produced by reduced cataract formation, this study does not directly address the question of whether the intake of omega-3 fatty acids can slow the rate of progression of age-related cataracts.

A paucity of data prevented us from examining the possible influence on efficacy, association, or safety evidence of various covariates, which included both population (e.g., age at onset or diagnosis; smoking; alcohol consumption) and intervention/exposure factors (e.g., source, type, dose, and method to deliver omega-3 fatty acids; intake of omega-6 fatty acids).

Discussion

Based on the studies identified by this review, it is apparent that clinical research has only scratched the surface with respect to understanding the possible utility of the intake of omega-3 fatty acids as a primary or secondary prevention in eye health. Moreover, seen from the point of view of clinical research's typical, linear arc—which moves from basic science to observational research to RCTs, and culminating in the systematic review/meta-analysis of the observations obtained by these primary studies—there is a paucity of solid observational research with which to construct an experimental framework affording the meaningful conduct of RCTs. For example, there is little understanding of the exact sources, types and doses of omega-3 fatty acids, or even the possible duration of their use, which might usefully serve as definitions of a prevention-centered “intervention” for any of the eye diseases/visual impairments examined in our review. Moreover, a single study reporting adverse event data likely does not permit laying to rest all possible concerns regarding the short- or long-term safety of such an intervention.

It is therefore our view that much more research will need to be conducted before anything conclusive can be asserted with respect to the effects of omega-3 fatty acids on eye health. It is also our understanding that sorting out the possible benefits of the intake of omega-3 fatty acids in eye health might profit from taking into consideration the impact of the concurrent intake of omega-6 fatty acids and, by definition, the omega-6/omega-3 fatty acid intake ratio. Finally, any notable causal or correlational relationships observed between the omega-6/omega-3 fatty acid intake ratio and the development or progression of eye disease/visual impairment may then be “explained” by future studies, which focus on observing patterns of omega-6/omega-3 fatty acid content in peripheral, or even brain, biomarkers.

Availability of Full Report

The full evidence report from which this summary was taken was prepared for the Agency for Healthcare Research and Quality (AHRQ) by the University of Ottawa Evidence-based Practice Center under Contract No. 290-02-0021. Printed copies may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requesters should ask for Evidence Report/Technology Assessment No. 117, Effects of Omega-3 Fatty Acids on Eye Health.

The Evidence Report is can also be downloaded as a PDF file (1.5 MB). PDF Help.

AHRQ Publication Number 05-E008-1 Current as of July 2005

Internet Citation:

Hodge W, Barnes D, Schachter HM, et al. Effects of Omega-3 Fatty Acids on Eye Health. Summary, Evidence Report/Technology Assessment: Number 117. AHRQ Publication No. 05-E008-1, July 2005. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/o3eyesum.htm

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