Introduction

The purpose of this study was to conduct a

systematic review of the scientific medical

literature to identify, appraise, and synthesize the

evidence for the health effects of omega-3 fatty

acids on asthma. 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 Evidencebased Practice Centers (EPCs) currently

investigating the value of omega-3 fatty acid

supplementation across 11 health/disease areas.

The three EPCs are Southern California/RAND,

Tufts-New England Medical Center, and the

University of Ottawa (UO) EPC. To ensure

consistency of approach, the three EPCs

collaborated on selected methodological elements,

including literature search strategies, rating of

evidence, and data table design.

Asthma is a chronic inflammatory disorder of

the airways leading to airways hyperresponsiveness and associated symptoms such as

wheezing and coughing, and is also typically

associated with widespread but variable airflow

obstruction that is often reversible either

spontaneously or with treatment.1 The

inflammatory process is a complex one, involving

a multitude of cell types and activities marking

the early and late phase asthmatic responses.2

There are important issues requiring careful

consideration in diagnosing asthma, including the

need to distinguish it from transient wheezing

disorders in children, especially under the age of 5

years, and also from chronic obstructive

pulmonary disorder, especially in older adults

who are current or ex-smokers.3,4

Various strategies have been developed to

manage asthma. Since airway inflammation is

multifactorial, involving various cell types and

mediators, the drugs used to decrease

inflammation may act at several different steps in

the inflammatory process.1,3 Agents that modify

the asthma process, with some influencing

inflammation, include: beta-2 adrenergic agonists,

corticosteroids, leukotriene modifiers, mast-cell

stabilizing agents, and theophylline. 

Considerable interest in the possible value of

omega-3 fatty acid supplementation in asthma

was sparked by Horrobin’s hypothesis that the low

incidence of asthma in Eskimos stems from their

consumption of large quantities of oily fish, rich

in omega-3 fatty acids.5 Additional impetus for

research came from observations that omega-3

fatty acids’ possible protective, or even

therapeutic, effect might be afforded by their

impact on mediators of inflammation thought to

be related to the pathogenesis of asthma.6

Key Questions

It is from this vantage point that seven

questions were investigated in the present

systematic review:

1. What is the evidence for the efficacy of

omega-3 fatty acids to improve respiratory

outcomes among individuals with asthma?

2. What is the evidence that the possible value

(efficacy/association) of omega-3 fatty acids in

improving respiratory outcomes is dependent

on the:

• Specific type of fatty acid (docosahexaenoic

acid [DHA, 22:6 n-3], eicosapentaenoic

acid [EPA, 20:5 n-3], docosapentaenoic

acid [DPA, 22:5 n-3], alpha linolenic acid

[ALA, 18:3 n-3], fish, fish oil)?

• Specific source (fish, plant, food, dietary

supplement [fish oil, plant oil])? 

Evidence Report/Technology Assessment

Number 91

Health Effects of Omega-3 Fatty Acids on Asthma

Summary

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service

Agency for Healthcare Research and Quality
2

• Its serving size or dose (fish or dietary supplement)? 

• Amount/dose of omega-6 fatty acids given as a

cointervention?

• Ratio of omega-6/omega-3 fatty acids used? 

• Fatty acid content of blood lipid biomarkers? 

• Absolute fatty acid content of the baseline diet? 

• Relative fatty acid content of the baseline diet? 

• Tissue ratios of fatty acid (omega-6/omega-3) during the

investigative period?

• Intervention length? 

• Anti-oxidant use? 

• The manufacturer and its product(s) purity or presence

of other potentially active agents? 

3. What is the evidence that, in individuals with asthma,

omega-3 fatty acids influence mediators of inflammation

which are thought to be related to the pathogenesis of

asthma? 

4. Are omega-3 fatty acids effective in the primary prevention

of asthma? 

5. Among individuals with asthma, do omega-3 fatty acids

alter the progression of asthma (i.e., secondary prevention)? 

6. What is the evidence for adverse events, side effects, or

counter-indications associated with omega-3 fatty acid use

to treat or prevent asthma (DHA, EPA, DPA, ALA, fish

oil, fish)? 

7. What is the evidence that omega-3 fatty acids are

associated with adverse events in specific subpopulations of

asthmatic individual such as diabetics? 

Methods

A Technical Expert Panel (TEP) consisting of six members

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

A comprehensive search for citations was conducted using

six databases (MEDLINE®, PreMEDLINE®, EMBASE,

Cochrane Central Register of Controlled Trials,

Commonwealth Agricultural Bureau Health, and Dissertation

Abstracts). Searches were not restricted by language of

publication, publication type, or study design except with 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®; fish oil); and,

relevant population terms (e.g., asthma; inflammation).

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 1,010 unique references was identified and posted to

the UO EPC’s Internet-based software system for review.

Studies were considered relevant if they described human

populations of any age, involved any type of study design, and

investigated the use of any foods or extracts known to contain

omega-3 fatty acids as a treatment, primary, or secondary

prevention. Populations in treatment or secondary prevention

studies had to have received a diagnosis of asthma, whereas

those in primary prevention studies could be either at elevated

risk for asthma or healthy (i.e., without asthma). Ineligible for

treatment studies or secondary prevention studies were

populations exclusively exhibiting a subset of the symptoms or

signs of asthma (e.g., wheeze), that is, without a clearly stated

diagnosis of asthma. In primary prevention studies, methods

had to have been employed to identify asthma as well as the

omega-3 fatty acids exposure. Studies investigating

polyunsaturated fatty acids were included if an explicit

evaluation was also made of their omega-3 fatty acid content.

Studies where an asthmatic response was experimentally

induced in nonasthmatic populations were excluded. A

treatment study could assess a respiratory outcome, mediators

of inflammation, or safety. A primary prevention study needed

to estimate asthma prevalence or incidence, although casecontrol studies employing outcomes pertinent to this question

were also acceptable. A secondary prevention study required a

long-term assessment of respiratory function to permit, for

example, the observation of a maintained decrement in the

need for medication in response to asthma exacerbations.

Two levels of screening for relevance, and two reviewers per

level, were employed (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.7

Disagreements were resolved by forced consensus and, if

necessary, third party intervention. 

Data Abstraction 

Following a calibration exercise, three reviewers

independently abstracted the contents of each included study

using an electronic Data Abstraction form. A second reviewer

checked all abstracted data. Data included the characteristics of

the report (e.g., publication status), study (e.g., research

design), population (e.g., diagnosis description),

intervention/exposure (e.g., omega-3 fatty acid type) and

comparator(s) (i.e., comparison group[s]), cointerventions (e.g.,

asthma medications), withdrawals and dropouts, and outcomes

(i.e., respiratory, mediators of inflammation, safety). 

After calibration exercises, each study’s quality (internal

validity) and applicability (external validity) were rated

independently by two assessors. Disagreements were resolved by

forced consensus and, if necessary, third party intervention.

Randomized controlled trials’ (RCTs’) reporting of
randomization, double blinding, withdrawals and dropouts,

and the concealment of allocation, were evaluated using Jadad’s8

and Schulz’s validated instruments.9 Five items selected from

Downs and Black’s 27-item validated instrument were used to

rate the study quality of all other study designs, including a

clear description of the study hypothesis or objective, study

participants, characteristics of participants lost to followup, the

interventions/exposures of interest, and, whether the outcome

measures were valid and reliable.10 One applicability index for

treatment and secondary prevention studies, and another for

primary prevention studies, were constructed without rigorous

validation. Applicability for treatment or secondary prevention

studies was defined as the degree to which a given study’s

sample population was representative of a “typical” North

American population of asthmatics. The reference standard for

primary prevention studies was the “typical” healthy North

American or one at risk for asthma. 

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 and applicability ratings.

Question-specific qualitative syntheses of the evidence were

derived. In consultation with our TEP, forced expiratory

volume in one second (FEV1) was selected as the primary

outcome, given its status as a gold standard index of pulmonary

function. Problems and limitations of available studies made it

inappropriate to conduct meta-analysis of RCT evidence for

any question (see Discussion). For the purposes of interpreting

the results, a greater emphasis was placed on RCT evidence

given its status as the gold standard by which an

intervention/exposure’s efficacy or effectiveness is investigated.11

Results

Literature Search

Of 1,010 records entered into the initial screening for

relevance, 851 were excluded. All but five of the remaining 159

reports were then retrieved, and subjected to a more detailed

relevance assessment.12-16 The second relevance screening then

excluded 122 reports. In total, 31 reports, describing 26 unique

studies, were deemed relevant for the systematic review, with

five studies each described by two reports. To simplify matters,

only one report per study is referred to in this summary. Yet,

data from all of the study documents were included in the

qualitative synthesis. Some information regarding the study

parameters of an RCT exclusively described by an abstract17

were taken from a Cochrane review,18 which had obtained

additional details from a source unavailable to the present

review team.

Of the included studies, two were abstracts and the rest were

published articles in scientific journals. One relevant, published

report was identified by manual search. Five reports required

translation,19-23 although one was not translated in time to

include its data in the synthesis.23 Question-specific synopses

follow.

Question 1 (Impact on Respiratory Outcomes) 

Ten RCTs and nine studies employing other designs (i.e.,

non-randomized controlled trials [non-RCTs]; noncomparative

case series) addressed Question 1. Of the RCTs, two exclusively

randomized children,24,25 one included both older adolescents

and adults,26 one did not report any age data,27 and six focused

on adults.17,28-32 Two non-RCTs focused on children22,33 and

seven other studies enrolled adults.19,21,34-38 Of the latter, one was

a non-RCT21 and six involved noncomparative case series.19,34-38

Given the largely inconsistent picture of efficacy within and

across respiratory outcomes, it is impossible to conclude one

way or the other whether omega-3 fatty acids are an efficacious

adjuvant or monotherapy in improving respiratory outcomes in

adults or children. This view is perhaps best illustrated by what

was observed with respect to the primary outcome, FEV1. 

Adult RCTs revealed a somewhat contradictory picture of

efficacy with respect to FEV1. One very small adult study (n =

14) that employed uncontrolled dosing of perilla seed oil and

corn oil (control) over a short intervention period (n = 4 wk)

reported a significant effect. However, two RCTs each observed

no benefit relating to an omega-3 fatty acid intervention. One

compared high and low doses of EPA ethyl ester31 over 16

weeks in a small study (n = 12), whereas the second

investigated the benefit of low-dose EPA/DHA (versus olive oil)

over 10 weeks in the systematic review’s highest quality RCT.32

The latter included one of the largest sample populations (n =

46) included in the evidence review. Emelyanov et al. also

demonstrated good control of three confounding factors, while

providing one of the most rigorous methods to select its asthma

population.32 No studies of adults using other research designs

investigated this outcome. With regard to studies of children,

one RCT25 and a non-RCT22 observed no benefit in terms of

FEV1. The fact that there were few studies to consider makes

the most balanced understanding one that suggests more

research is needed before anything definitive can be concluded

about the impact of omega-3 fatty acids on FEV1. A similar

picture characterized the other respiratory outcomes. 

The inconsistency among study results may be attributable

to the heterogeneity in definitions of the:

• Settings (e.g., hospital versus outpatient; countries). 

• Populations (e.g., age; gender; clinical picture of asthma,

including its severity and concomitants, or triggers with the

potential to impact asthma control). 

• Interventions and their contrasts with comparators (e.g.,

different types and amounts of oil and omega-3 fatty acid

contents; controlled versus uncontrolled dosing). 

• Cointerventions (e.g., asthma medication with varying

capacities to control asthma in the short term or long

term). 

3
4

This observation applies to all patterns of results relating to

Questions 1, 2, 3, and 4. 

Even though study quality, as operationally defined in the

present review, was not an obvious shortcoming of the 20

included treatment studies, the very limited generalizability

potential for all but two of them31,36 can be taken to suggest that

answering Question 1 requires more research conducted with

North American samples. The prominent limitation for the

RCTs was limited blinding, and the key limitation for the

studies using designs other than an RCT was the poor

description of study participants.

Question 2 (Impact of Effect Modifiers)

Given the inappropriateness of conducting meta-analysis, an

informal assessment was undertaken looking at the possible

consistent or exclusive relationship between significant clinical

effects and specific definitions, or levels, of variables with the

potential to account for these effects (e.g., high-dose

supplementation). These variables are the predefined covariates,

as well as any study-defined ones (e.g., type, source, or dose of

omega-3 fatty acids). To be eligible, an outcome required results

provided by at least two studies, with at least one of them

noting a significant clinical effect in favor of the omega-3 fatty

acids exposure. Question 2 involved data from 12 of the 19

studies addressing Question 1, including eight RCTs17,26-32 and

four noncomparative case series.19,35,37,38 None of the studies

included children, since the pediatric studies did not meet the

criteria established with respect to this question. The assessment

did highlight one exposure potentially worth exploring in

future empirical investigations of the health effects of omega-3

fatty acids in asthma. It was noted that perilla seed oil

supplementation, provided in an uncontrolled fashion to

adults, was the only exposure that was exclusively associated

with significant clinical effects (12/12) in favor of the omega-3

fatty acids exposure.28,34,38 Yet, even this observation is likely

unreliable. Without the option of meta-analysis, it is difficult to

respond adequately to Question 2. It must be concluded that,

at present, it is impossible to identify effect modifiers

responsible for any significant asthma-related benefits accruing

to omega-3 fatty acids supplementation. This exploration was

complicated by the fact that few significant effects were found.

Question 3 (Impact on Mediators of Inflammation)

It is likewise unfeasible to conclude one way or the other

that omega-3 fatty acids positively influence the lipid mediators

of inflammation in adult studies in ways congruent with the

biological model implicating the lipoxygenase and

cyclooxygenase pathways in asthma. Moreover, virtually no

other mediators of inflammation were investigated (e.g., TNFa).25 Question 3 was addressed by 11 studies, including five

RCTs, one non-RCT, and four noncomparative case series. Of

the RCTs, one involved children25 and four included

adults.26,28,30,31 All of the studies using designs other than an

RCT enrolled adults.19,20,34,36-38

The only consistent impacts of omega-3 fatty acids on

mediators of inflammation involved the suppression of

leukotriene C4

28,34,38 and of polymorphonuclear leukocyte

chemotaxis in response to various stimuli.26,31 However, all of

the results must be interpreted with caution given the small

sample sizes, as well as the fact that the findings of significant

effects for the same outcome involved different interventioncomparator contrasts and varying doses of omega-3 fatty acids.

As with the evidence regarding Question 1, considerable

clinical heterogeneity characterizes these studies. Their average

study quality was good, and their applicability was restricted. 

Question 4 (Impact on Primary Prevention)

Six studies investigated Question 4. Of these, one was an

RCT looking at the impact of omega-3 fatty acids on

neonates39 and five were observational studies that focused on

adults,40 adolescents,41 young children and adolescents,42 and

children.43,44 Dietary fish consumption, including oily fish

intake, assessed primarily through a retrospective foodfrequency questionnaire, appeared to serve as primary

prevention for asthma in two pediatric populations.43,44

However, asthma prevalence and fish, or oily fish, intake were

significantly and positively related in studies that included

adolescents from Asia,41,42 with one of these studies also

including some children.42 In a prospective study of nurses, no

association was found between adult asthma onset and dietary

fish intake.40

Mihrshahi et al.’s factorial RCT is, in large part, a study

evaluating the impact of an omega-3 fatty acid regimen (versus

placebo), initiated prebirth, on neonates at risk for asthma,

given that at least one parent or sibling had received this

diagnosis.39 Their interim results indicated little benefit accruing

to the omega-3 fatty acid exposure, yet 18 months is likely too

early in life to reliably identify asthma. Final followup at 5 years

of age should provide a clearer picture of the value of omega-3

fatty acids as primary prevention. Study quality was better, on

average, for the observational studies than for the single RCT;

and, as with treatment studies, almost no studies even remotely

resembled the North American population standard established

in this review. 

Question 5 (Impact on Secondary Prevention)

Question 5 could not be addressed since this review failed to

identify any secondary prevention studies. 

Question 6 (Impact on Safety)

Eight RCTs and two studies employing other designs

provided safety data addressing Question 6. No safety profile

relating to omega-3 fatty acids as an exposure was observed for

primary prevention studies and, on balance, the evidence

suggests that the safety profile in the treatment studies was

good. Most of the adverse events were related to the capsule

delivery of oils, rather than to the oils per se.17,24,26,29 On several

occasions, an inability to swallow capsules led to a withdrawal.
Other participants may have had difficulties taking 18 capsules

a day of oil in two specific RCTs, yet these difficulties were not

reported.26,29 The one moderately serious reaction was an

undefined number of episodes of nausea and vomiting after

ingesting fish oil capsules, and led to a withdrawal.29

Unspecified numbers of children and adults experienced some

(e.g., mild gastrointestinal) discomfort, but not all individuals

had been receiving the omega-3 fatty acid exposure.25 Fishy

hiccups or burping were a rare complaint. By far the most

serious event linked to a treatment study involved severe apnea

associated with repeated allergen challenge.21 The omega-3 fatty

acid exposure had not yet begun.

Question 7 (Impact on Safety in Subpopulations)

Question 7 could not be evaluated since no study reported

adverse events associated with a specific subpopulation (e.g.,

diabetics). 

Discussion

Twenty-six studies, described by 31 reports, investigated five

of the seven questions posed in this systematic review of the

evidence concerning the health effects of omega-3 fatty acids in

asthma. The questions of secondary prevention and of safety

related to omega-3 fatty acid use in subpopulations of

asthmatics could not be addressed due to a lack of studies.

Eleven RCTs (ten treatment, one primary prevention) and 15

studies using other designs (ten treatment, five primary

prevention) were included. Three of the former and six of the

latter involved children or adolescents exclusively. It is likely

that, other than Ashida et al.’s noncomparative case series

lasting 2 weeks, 38 all treatment studies lasted long enough to

demonstrate that a difference could be found in terms of

respiratory outcomes and mediators of inflammation. Relevant

studies could only be synthesized qualitatively according to the

question(s) they addressed. 

The present findings suggest that, with omega-3 fatty acid

supplementation intended to influence asthma, there is little

probability of harm beyond occasional mild discomfort. The

most frequent troublesome events were produced by the

delivery of the oils in large numbers and sizes of capsules. On

the other hand, the lack of sufficiently consistent evidence, as

well as a paucity of evidence from well-designed, wellconducted, and adequately powered studies, suggests that no

definitive conclusion can yet be drawn regarding the efficacy of

omega-3 fatty acid supplementation as a treatment for asthma

in children and adults. Likewise, nothing specific can be

concluded regarding the role of specific sources, types, or doses

of omega-3 fatty acid content in producing significant clinical

effects. One possible explanation for the inconsistent findings is

the heterogeneity in definitions of settings, populations,

interventions/exposures, and the types and doses of asthma

medication. 

Having too few well-designed studies with which to

adequately address this question means that nothing definitive

can be said about the influence of omega-3 fatty acids on those

mediators of inflammation thought to be implicated in the

pathogenesis of asthma, or, about the actual role played by

these mediators in asthma. More research is required. 

No studies were identified which investigated the potential

of omega-3 fatty acids as secondary prevention. Primary

prevention attempts were found, yet they lacked unanimity in

their findings. While two studies of children outside North

America noted a protective effect of dietary fish intake for

asthma,43,44 one American survey, discovered after the present

qualitative synthesis was completed, reported no benefit.45

Moreover, studies outside North America, and primarily

including adolescents, found that dietary fish intake actually

increased the risk of asthma.41,42 The only study involving adults

found no relationship between these variables.40 However, many

of these studies employed different sampling methods and

varying definitions of both the frequency of fish intake and fish

types. Likely the most promising attempt to use omega-3 fatty

acids as primary prevention involves a large, ongoing RCT of

expectant mothers whose children at risk for asthma are being

followed for 5 years.39 To date, 18-month, interim analysis data

are too unreliable given the difficulties in diagnosing asthma in

children this young.

At this point in time, aside from an acceptable safety profile,

it is impossible to definitively conclude anything with respect to

the value of using omega-3 fatty acid supplementation in

asthma for adults or children either in or beyond North

America. Recommendations for future research follow directly

from observations of the problems and limitations in the

included studies. Flawed or problematic designs need to be

avoided in any further attempts to assess the clinical utility of

omega-3 fatty acids in asthma. These requirements include

better control of factors with the potential to confound the

interpretation of results. For example, failing to assure that the

delivery of the supplementation is controlled, and hence

definable as the “intervention,” yields results difficult to

interpret. Likewise, failing to assure that there is not an uneven

distribution of corticosteroid users or doses across study

arms/cohorts can restrict the ability to meaningfully attribute a

significant or null effect to the actions of the omega-3 fatty acid

supplementation. Asthma medications’ capacity to improve

asthma symptoms can mask the benefits linked to use of

omega-3 fatty acid supplementation. 

Poor reporting practices, which led to an inability to know

whether, and how, these or other confounders might have

influenced individual treatment RCT results, together with the

lack of comparability in many of the RCTs’ parameters (e.g.,

intervention-comparator contrasts), led to the decision to

forego meta-analysis. Any pooled estimates would have been

derived within a context instilling as little confidence in the

appropriateness of the extrapolations of results as in the validity

of the results themselves. 

The present review highlighted some of the methodological

issues worth considering in treatment RCTs. As carefully as it

5
6

chooses a high quality design, future research likely needs to

judiciously select the dose(s), while assuring the identity and

purity of the exposure. It should also involve North American

samples if there is any belief that omega-3 fatty acid

supplementation may be helpful in asthma for North

Americans. The need to study this population stems from a

paucity of research investigations with this focus; and, possibly

because North Americans’ high omega-6/omega-3 fatty acid

intake ratio may make it less likely that data obtained from

populations (e.g., Japanese) with a substantially lower intake

ratio (associated with a much higher consumption of omega-3

fatty acids) can be generalized to North Americans. 

A potentially interesting hypothesis requiring investigation

relates to the possible asthma-related benefits associated with

actively and markedly decreasing levels of omega-6 fatty acid

intake concurrent with increasing the intake of omega-3 fatty

acids. At the same time, given that the present collection of

evidence does not constitute the best test of the overarching

hypothesis that omega-3 fatty acid supplementation alone can

foster asthma-related benefits, more research is likely needed to

adequately answer the questions posed in the present systematic

review.

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 Evidence-based

Practice Center, Ottawa, Canada, under Contract No. 290-02-

0021. It is expected to be available in March 2004. 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. 91, Health Effects of Omega-3 Fatty Acids on

Asthma. 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

Schachter HM, Reisman J, Tran K, Dales B, Kourad K,

Barnes D, Sampson M, Morrison A, Gaboury I, Blackman J.

Health Effects of Omega-3 Fatty Acids on Asthma. Summary,

Evidence Report/Technology Assessment No. 91. (Prepared by

the University of Ottawa Evidence-based Practice Center,

Ottawa, Canada.) AHRQ Publication No. 04-E013-1.

Rockville, MD: Agency for Healthcare Research and Quality.

March 2004.

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March 2004

ISSN 1530-440X