Fish oil administration in older adults: is there potential for adverse events? A systematic review of the literature

There is evidence for benefits of long chain omega-3 (n-3) fatty acids in pathological inflammation [1] including rheumatoid arthritis [2], crohn’s disease [3], ulcerative colitis [4, 5], diabetes mellitus [6], cardiovascular events [7‐9] and cancer cachexia [10]. For this reason, various organizations around the world have established dietary recommendations and guidelines for the intake of n-3 fatty acids (in particular for eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) that are focused primarily on the reduction of cardiovascular disease (CVD) risk [11]. In Australia and New Zealand, the National Health and Medical Research Council (NHMRC) suggest a dietary target for the reduction of chronic disease of 610 and 430 mg/day DHA + EPA for males and females respectively [12, 13]. For the prevention of CVD, the National Heart Foundation (NHF) of Australia recommends a dietary intake of 500 mg/day EPA + DHA, the equivalent of two to three servings (150 grams) of oily fish per week [13]. For adults with diagnosed CVD, a combined dosage of 1000 mg EPA + DHA per day is recommended which is best achieved by fish oil supplementation [13].

Fish oil supplementation has become an established complementary medicine (CM). Data taken from the 2004–05 Australian National Health Survey (NHS) indicated that approximately one-quarter (~1.3 million) of Australian adults affected by chronic illness regularly used some form of CM with users more likely to be ≥60 years and female [14]. Cross-sectional analyses from the Australian Longitudinal Study of Ageing (ALSA) showed that cod liver and fish oils were the most frequently used nutritional supplement (excluding vitamin and mineral supplementation) amongst older adults aged ≥65 years [15].

Despite many reviews concentrating on the efficacy of n-3 fatty acids in various conditions [16‐20], the potential for serious adverse events (SAE) is not well documented, particularly in older adults. The most commonly raised concern for administration of n-3 fatty acids is their potential to increase the risk of serious bleeds through their anti-platelet effects [21‐26]. If there is systematic evidence for serious bleeds or other SAE, the widespread use of n-3 supplementation amongst older adults makes this a public health concern. At the present time, fish oil use as a supplement or CM remains largely unregulated in Australia and currently there are no quantity restrictions of key ingredients or advisory statements concerning these ingredients for labelling purposes [27]. Because many n-3 fatty acid preparations are largely marketed as food supplements, their potential to contribute to SAE is often overlooked.

The aim of this systematic review was to assess published peer reviewed literature of randomized controlled trials (RCTs) to identify the potential for SAE and non-serious adverse events (non-SAE) associated with n-3 supplementation in older adults.

We systematically reviewed the potential for AEs in a population of older adults following an intervention of n-3 fatty acid supplementation versus a placebo. Our results are consistent and in support of current literature showing no evidence of SAE associated with oral n-3 supplementation in older adults at doses ≤1.86 g EPA and/or DHA per day. Although non-SAE related to GI disturbances were observed, these were infrequent and not solely apparent in the n-3 intervention group.

Current literature in support of an association between intake of n-3 fatty acids and SAE in an older adult population is scant. In the present review, Van de Rest et al. 2009 [36‐39] were the only investigators to report on mortality; however this was deemed unrelated to the study design or n-3 intervention. These same investigators also reported one case of a TIA in the placebo arm of the trial, which was high oleic sunflower oil [36‐39]. No studies in the current review reported major bleeds, stroke or bruising. Of clinical importance, 14 of the 17 full-text articles reported positive benefits associated with n-3 supplementation in otherwise healthy older adults; these included reduced symptoms of depression [40], cell-mediated immunity [29, 31, 46], a reduction in oxidative stress [30], relief from osteoarthritic symptoms [42], anti-inflammatory [33, 34, 39], anti-atherogenic [39], increased muscle anabolic signalling [45], cardiovascular benefits [43, 44] and feasibility and acceptability of n-3 fatty acids [41]. With exception to Holguin et al. 2005 [44] who reported a greater prevalence of GI disturbances (eructation and nausea; ~54%) in participants randomized to the n-3 intervention group, the AE rate was relatively low in all other reviewed studies suggesting that the potential benefits associated with moderate-low dose n-3 supplementation exceed the potential for SAE. Moreover, no studies in the current review reported negative outcomes post-intervention.

The potential for undesirable anticoagulant effects with the concurrent use of fish oil and anticoagulant or antiplatelet medications have previously been highlighted [25, 26]. It is speculated that older adults in particular may have an increased risk of major bleeding due to increased sensitivity to anticoagulation, multiple comorbidites and polypharmacy [25]. However, evaluation of the evidence concerning the safety considerations associated with n-3 supplementation shows little support of an increase risk in bleeding with n-3 intake, even when concurrently administered with anticoagulant agents [24]. Despite this Bays 2007 [24] suggested it would be prudent to discontinue high doses of n-3 fatty acid supplementation in the days prior to invasive surgical procedures or in patients at high risk for haemorrhagic stroke. Expert opinion by Harris 2007 [47] was also in agreement suggesting that n-3 fatty acid supplementation does not increase the risk for clinically significant bleeding with the proposed cardiovascular benefits outweighing the theoretical risks for increased bleeding. In the present review only four of ten studies excluded participants at study entry medicated with oral anticoagulant or antiplatelets despite the theoretical potential for anticoagulation of n-3 fatty acids. Regardless of the previous speculation, current evidence has shown that n-3 supplementation at doses ≤4 g per day, even when concurrently administered with antiplatelet or anticoagulant medications, are safe for general consumption [21, 48]. However, the doses of n-3 fatty acids in the present review were considerably smaller compared with those previously reported suggesting caution may need to be applied when administering higher doses until further evidence is obtained. Although the majority of studies in the present review (8/10 studies) indicated compliance toward the n-3 intervention, a dose–response relationship between n-3 intake and the potential for AE is unclear given the uncertainty associated with the exact quantity of EPA/DHA ingested in the majority of studies.

Despite the lack of evidence supporting previous recommendations concerning cessation of n-3 supplementation, we recognize that the population group in the present review are non-surgical, older adults free from CVD or CVD risk factors and are therefore unlikely to possess the same theoretical complications associated with bleeding tendency as those with a diagnosis of CVD or with CVD risk factors. Furthermore, it must also be noted that while our findings demonstrated no significant differences in the total AE rate between groups, this was based only on a small number of studies (n = 10) of variable quality. Of further importance was the general lack of consistency in the systematic approach for the recording of all AEs in each of the individual studies. Recognizing this as a potential limitation, the authors of the present review attempted to address this by email correspondence to each corresponding author, however much of the AE data reported in the present review and documented in each of the studies are mainly qualitative and therefore may underestimate nor appropriately describe all potential AEs associated with n-3 supplementation. For example, there are some concerns raised over the potential adverse effect on LDL-cholesterol and the subsequent increased susceptibility to oxidation following n-3 supplementation [49‐52]. Additionally, despite certain types of large predatory fish including shark, swordfish and king mackerel containing higher sources of methyl mercury, fish oil preparations supplemented in smaller doses (1-3 g/d) are unlikely to pose SAE related to methyl mercury and/or other contaminants including dioxins and polychlorinated biphenyls (PCBs) [24, 50, 53]. Moreover, the level of mercury and other environmental toxins present in commercially available fish oil preparations are likely to be negligible given the extensive purification process to remove these [24, 53]. However, the potential harm from methyl mercury and/or other environmental contaminants subsequent to long-term exposure at higher doses is less well understood.

Minor intolerances to fish oil are not unusual with symptoms including eructation, nausea, aversion to odour and diarrhoea commonly reported [16, 24, 54, 55]. In keeping with this, our review showed that in an older adult population non-SAE related to GI disturbances were the most commonly reported. Despite this, we observed no significant differences in the frequency of reported GI disturbances between groups, suggesting that the fatty acid composition of fish oil (i.e. EPA and DHA) is unlikely to be the contributing factor for non-SAE. Furthermore, the main placebo(s) used in each of the reviewed studies were typically sunflower or corn oil (n-6 fatty acids) which have both previously demonstrated similar non-SAE as described in the present review [56, 57]. Results from a recent palatability study in older adults ≥60 years showed that an association between reported non-SAE and n-3 fatty acid supplementation was unlikely [58]. Using various doses of liquid fish oil (10%, 40% and 100%; containing 5.2 g EPA and 3.6 g DHA at 100% concentrations) Yaxley et al. 2011 [58] reported that older adults were unable to distinguish between varying doses of liquid fish oil and most would not cease consumption if non-SAE such as GI disturbances were experienced.

Fish oils are naturally highly unstable, making them susceptible to oxidation and rancidity [24]. For this reason, many individuals are concerned about taking fish oils as they fear unwanted side effects such as eructation and diarrhoea. Episodes of GI disturbances may be minimized by avoiding aerated drinks at the time of ingestion and by consuming fish oil immediately before meals without further (excessive) fluid consumption [54]. Moreover, tolerance can be improved by refrigerating fish oil supplements (particularly liquid fish oil) once opened [24, 54]. Results from the present review suggest that it is feasible that non-SAE relating to taste and smell are associated with personal taste and perception, rather than a physiological rationale. Further improvement in the development and manufacturing of fish oil supplements may improve patient tolerance and perception.

The potential for AEs related to n-3 supplementation in older adults appear mild-moderate at worst, and not of clinical importance. No reports of SAE including bleeding, stroke or bruising were observed. Non-SAE related to GI disturbances were the most commonly reported however these were infrequent and not significantly different when compared against the placebo group. However this review also highlights that well-documented data describing the potential for SAE following n-3 supplementation are limited nor adequately reported to draw definitive conclusions concerning the safety associated with n-3 supplementation. Although these results suggest that a low-moderate intake of EPA/DHA appear safe and acceptable for use in otherwise healthy older adults, caution should be applied when administering larger doses until further evidence is positioned. Our review further highlights that a more rigorous and systematic approach for monitoring and recording AE data in clinical settings that involve the use n-3 supplementation is required.