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 CaliforniaRAND, 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. Our definition

encompassed conditions that either demonstrate

high prevalence (e.g., diabetic retinopathy, agerelated macular degeneration [ARMD], and

retinal vascular occlusions), produce many

potential years of vision loss in that they affect

the young (e.g., retinitis pigmentosa [RP]), or

constitute 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 docosahexaenoic acid (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

Evidence Report/Technology Assessment

Number 117

Effects of Omega-3 Fatty Acids on Eye Health

Summary

Authors: Hodge W, Barnes D, Schachter HM, Pan Y, Lowcock EC, Zhang L, 

Sampson M, Morrison A, Tran K, Miguelez M, Lewin G

Agency for Healthcare Research and Quality

Advancing Excellence in Health Care • www.ahrq.gov

Agency for Healthcare Research and Quality Evidence-Based

Practice
2

reduce pressure-induced retinal damage in monkeys.10 It is

against this backdrop that the key 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. 

Degenerative diseases of the retina—macular

degeneration:

• What is the evidence for efficacy of omega-3 fatty acids in

preventing ARMD and slowing the progression of

ARMD? 

• What is the evidence that omega-3 fatty acids decrease

the rate of progression to advanced forms of macular

degeneration in all patients, diabetics, and patients with

cataracts? 

• What is the evidence that omega-3 fatty acids decrease

the rate of progression of advanced forms of macular

degeneration in all patients, diabetics, and patients with

cataracts?

Degenerative diseases of the retina—retinitis

pigmentosa:

• What is the evidence for efficacy of omega-3 fatty acids in

slowing the progression of RP (i.e., an inherited retinal

dystrophy)?

Vascular diseases of the retina—retinal vein or retinal

artery occlusions:

• What is the evidence for efficacy of omega-3 fatty acids in

preventing retinal vein occlusion and retinal artery

occlusion? 

• What is the evidence for efficacy of omega-3 fatty acids in

slowing the progression of retinal vein occlusion and

retinal artery occlusion? 

Vascular diseases of the retina in diabetics:

• What is the evidence for efficacy of omega-3 fatty acids in

preventing proliferative retinopathy in diabetics? 

• What is the evidence for efficacy of omega-3 fatty acids in

slowing the progression of proliferative retinopathy in

diabetics? 

• What is the evidence for efficacy of omega-3 fatty acids in

preventing clinically significant macular edema in patients

with diabetic retinopathy? 

• What is the evidence for efficacy of omega-3 fatty acids in

slowing the progression of clinically significant macular

edema in patients with diabetic retinopathy? 

Cataracts:

• What is the evidence for efficacy of omega-3 fatty acids in

preventing age-related cataracts? 

• What is the evidence for efficacy of omega-3 fatty acids in

slowing the rate of progression of age-related cataracts in

all patients, diabetics, and patients with ARMD?

• What is the evidence that omega-3 fatty acids decrease

the rate of cataract surgery in aging populations? 

Adverse events:

• What is the evidence for the risk of short- and long-term

adverse events related to the intake of omega-3 fatty

acids?

Methods

A Technical Expert Panel was convened to provide advisory

support to the project, including refining the questions and

highlighting key variables requiring consideration in the

evidence synthesis. 

Study Identification

Several electronic databases were searched: MEDLINE®

(1966–November Week 2 2003 and updated to February

Week 1 2004), PreMEDLINE® (May 4, 2004), EMBASE

(1980 to 2003 Week 48 and updated to 2004 Week 7), the

Cochrane Library including the Cochrane Central Register of

Controlled Trials (3rd Quarter 2003), and CAB Health

(1973–Dec 2003). Searches were not restricted by language of

publication, publication type, or study design, except with

respect to the MeSH® term “dietary fats,” which was limited

by study design to increase its specificity. Search elements

included: scientific terms, with acronyms, as well as generic

and trade names relating to the exposure and its sources (e.g.,

eicosapentaenoic acid (EPA); omega-3 fatty acids; MaxEPA®);

and, relevant population terms (e.g., macular degeneration).

Additional published or unpublished literature was sought

through manual searches of reference lists of included studies

and key review articles, and from the files of content experts. A
final set of 507 unique references was identified and posted to

an Internet-based software system for review.

Studies were considered relevant if they described live

human populations of any age, investigated the use of any

source, type, dose, or method to deliver omega-3 fatty acids as

primary or secondary prevention for any of the above-noted

eye health conditions in any of the populations or

subpopulations of interest (e.g., diabetics), and investigated at

least one pertinent clinical outcome (e.g., prevalence,

incidence; change in clinical status; need for cataract surgery).

No restrictions were placed on the requisite levels of evidence

(i.e., study designs) given the expected dearth of studies. As

markers of omega-3 fatty acid metabolism, the following fatty

acid compositions or concentrations, from any source (e.g., red

blood cell membranes, plasma phospholipids), were considered

relevant: EPA, DHA, arachidonic acid (AA)/EPA, AA/DHA,

and AA/EPA+DHA. 

Two initial levels of screening for relevance, and two

reviewers per level, were employed (directed at bibliographic

records, then full articles). Calibration exercises preceded each

step of the screening process. Excluded studies were noted as

to the reason for their ineligibility using a modified

QUOROM format.11 Disagreements were resolved by forced

consensus and, if necessary, third party intervention. 

Data Abstraction

Following a calibration exercise, two reviewers

independently abstracted the contents of included studies

using an electronic Data Abstraction form developed especially

for this review. A third reviewer then verified the data. Data

abstracted included characteristics of the following: 

• Report (e.g., publication status, language of publication,

year of publication).

• Study (e.g., sample size, research design, number of study

arms/groups).

• Population (e.g., age; diagnosis, including severity,

duration, and comorbidity).

• Intervention/exposure (e.g., omega-3 fatty acid types,

sources, doses, and intervention/exposure length), and

comparator(s).

• Cointerventions (e.g., concurrent treatments/medications,

omega-6 fatty acid use). 

• Withdrawals and dropouts, including reasons.

• Clinical outcomes.

• Fatty acid content of biomarkers. 

• Adverse events (e.g., side effects).

Data Synthesis

A summary table provided a question-specific overview of

included studies’ relevant data presented in greater detail in

evidence tables. A question-specific summary matrix situated

each study in terms of its quality (i.e., internal validity) and

applicability ratings (i.e., generalizability to the North

American population). Question-specific qualitative syntheses

of the evidence were derived. While no restrictions were placed

on study designs, greater interpretative weight was given to

prospective and controlled designs. Given the paucity of

relevant studies addressing any given question, as well as the

variability in the research designs, definitions of the study

populations, exposures/interventions or clinical outcomes

employed to investigate it, meta-analysis was deemed

impossible or inappropriate with respect to each of the

questions.

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

3
4

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 linoleic acid (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, electroretinogram 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. Crosssectional 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 shortor 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 the 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 Evidencebased Practice Center under Contract No. 290-02-0021. It is

expected to be available in July 2005. At that time, 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. In addition, Internet users will be able to access the

report and this summary online through AHRQ’s Web site at

www.ahrq.gov.

Suggested Citation

Hodge W, Barnes D, Schachter HM, Pan Y, Lowcock EC,

Zhang L, Sampson M, Morrison A, Tran K, Miguelez M,

Lewin G. Effects of Omega-3 Fatty Acids on Eye Health.

Summary, Evidence Report/Technology Assessment No. 117.

(Prepared by the University of Ottawa Evidence-based Practice

Center under Contract No. 290-02-0021.) AHRQ Publication

No. 05-E008-1. Rockville, MD: Agency for Healthcare

Research and Quality. July 2005.

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ISSN 1530-440X