ERF of omega-3 fatty acids

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Question

What is the exposure-response function (ERF) of omega-3 fatty acids on several health end points?

Answer

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Rationale

Data

ERF of omega-3 fatty acids(-)
ObsExposure agentResponseExposureExposure unitER functionScalingThresholdERFDescription
1DHALoss in child's IQ pointsMaternal intake through placentamg /kg bw /dayERSBW0-0.07 +- 0.01Cohen et al. 2005; Gradowska 2013; Standard deviation. Negative loss is a benefit.
2DHALoss in child's IQ pointsMaternal intake through placentamg /dayERSNone0-0.0013 (-0.0018 - -0.0008)Cohen et al. 2005; also according to Zeilmaker 2013
3Omega3CHD2 mortalityIngestionmg /dayRRNone00.9999274 (0.9997643 - 1.0000862)Cochrane review 2018 assuming 1000 mg/d of omega3 intake (original RR 0.93, 95% CI 0.79 to 1.09)
4Omega3Coronary heart disease mortalityIngested intake of EPA+DHA from fishmg /dayRRNone00.9980 +- 0.000396Mozaffarian and Rimm 2006; Gradowska 2013 slope = -0.002, SD = exp(-0.002)-exp(-0.002+3.97E-4)
5Omega3CHD arrythmia mortalityIngested intake of EPA+DHA from fishmg /dayRelative HillNone200-0.3Mozaffarian and Rimm 2006
6Omega3CHD2 mortalityIngested intake of EPA+DHA from fishmg /dayRelative HillNone47-0.17 (-0.25 - -0.088)Cohen et al 2005. "antiarrhythmic effect". No-exposure is <1 serving/mo, therefore ED50 = two servings per month = 1400 mg/mo = 47 mg/d
7Omega3CHD3 mortalityIngested intake of EPA+DHA from fishmg /dayRRNone00.99951 (0.99934 - 0.99989)Cohen et al 2005 "antiatherosclerotic effect". 1-0.039*0.01
8Omega3Stroke mortalityIngested intake of EPA+DHA from fishmg /dayRelative HillNone47-0.12 (-0.25 - 0.01)Cohen et al. 2005
9Omega3Stroke mortalityIngested intake of EPA+DHA from fishmg /dayRRNone00.9998 (0.99934 - 1.00027)1-0.02*0.01, Cohen et al 2005: −2.0% 95% CI: +2.7% to −6.6%
10ALACHD2 mortalityIngestionmg /dayRRNone00.9999487 (0.9996715 - 1.0002311)Cochrane review 2018 assuming 1000 mg/d of alpha-linolenic acid intake 0.95 (0.72 - 1.26)
11FishSubclinical brain infarct (one or more) prevalenceIngested intake of tuna/other fish≥3 times/week vs. <1/monthRRNone00.74 (0.54 - 1.01)Virtanen et al. 2008; 95% CI
12FishAny prevalent subclinical brain infarct prevalenceIngested intake of tuna/other fishEach one serving per weekRRNone00.93 (0.88 - 0.994)Virtanen et al. 2008; 95% CI
13FishSubclinical brain infarct (one or more)incidenceIngested intake of tuna/other fish≥3 times/week vs. <1/monthRRNone00.56 (0.30 - 1.07)Virtanen et al. 2008; 95% CI
14FishAny incident subclinical brain infarct incidenceIngested intake of tuna/other fishEach one serving per weekRRNone00.89 (0.78 - 0.993)Virtanen et al. 2008; 95% CI
15FishStatus of cerebral white matter grade scoreIngested intake of tuna/other fishEach one serving per weekERSNone00.038Virtanen et al. 2008; 95% CI
16FishAll-cause mortalityIngestiong /dRRNone00.9978717 (0.9968993 - 0.9987912)RR after 60 g/d fish: 0.88, (95%CI 0.83, 0.93) Zhao et al 2015
17Omega3Breast cancerIngestionmg /dRRNone00.9994872 (0.9989469 - 1.0000000)RR after 0.1 g/d of marine omega3 0.95 (95% CI 0.90, 1.00) Zheng et al 2013
18FishDepressionIngestiong /dRRNone00.9946904 (0.9914339 - 0.9979287)RR for highest to lowest dose assuming 35 g/d vs 0: 0.83 (95% CI 0.74, 0.93), Li et al. 2016
ERF publications

Cochrane review 2018 https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD003177.pub4/full . Strangely enough, the dose characterisation is unclear, but the summary talks about "typical" dose of 1 g/d. In the case of alpha-linolenic acid, the dose probably does not contain the other fatty acids (EPA, DHA), but in the case of "fish oils", this probably covers all three. Which of the 25 high-quality studies had which is not described in the summary. See sections "Subgroup analysis and investigation of heterogeneity" vs. "Included studies".

Li et al. reported reduced risk of depression in a meta-analysis[1]. The article does not directly tell the dose, but the studies typically compared groups with less than 1 fish meal per week vs 1-5 (often 2) fish meals per week. Therefore, we assume here that the contrast is 0 g/d vs 2 meals/week / 7 days/week * 120 g/meal = 35 g/d.

Zhao et al. reported reduction in all-cause mortality in a meta-analysis[2]. In their dose-response analysis, they found that the dose-response function is fairly linear up to 60 g/d and then levels off. Therefore, we used linear assumption and scaled the ERF to 1 g/d.

ERF data as described in original articles
Exposure agent Trait Response metric Exposure route Exposure metric Exposure unit ERF parameter Threshold ERF Description
DHA Child´s IQ Change in IQ points Placenta Maternal intake mg/kg bw/day ERS 0 0.07(±0.01) Cohen et al. 2005; Gradowska 2013
Omega3 CHD Δlog(CHD mortality rate) Ingestion Intake from fish mg/day EPA+DHA ERS 0 -0.002 (±3.97E-4) Mozaffarian and Rimm 2006; Gradowska 2013
DHA and EPA Stroke Incidence Ingestion Dietary intake of EPA+DHA 520 mg /day vs. 148 mg /day RR 0 0.72 (0.54-0.96) Multivariable- and PCB-adjusted RR (95% CI) Bergkvist et al. 2014
Fish Subclinical brain infarct (one or more) Prevalence Ingestion Intake of tuna/other fish =3 times/week vs. <1/month RR 0 0.74(0.54-1.01) Virtanen et al. 2008
Fish Any prevalent subclinical brain infarct Prevalence Ingestion Intake of tuna/other fish Each one serving per week Decrease in RR % 0 7(0.6-12) Virtanen et al. 2008
Fish Subclinical brain infarct (one or more) Incidence Ingestion Intake of tuna/other fish =3 times/week vs. <1/month RR 0 0.56(0.30-1.07) Virtanen et al. 2008
Fish Any incident subclinical brain infarct Incidence Ingestion Intake of tuna/other fish Each one serving per week Decrease in RR % 0 11(0.7-22) Virtanen et al. 2008
Fish Status of cerebral white matter Grade score Ingestion Intake of tuna/other fish Each one serving per week Increase in grade score % 0 3.8 Virtanen et al. 2008
Fish Cerebrovascular disease Incidence Ingestion Intake of fish 2-4 versus ≤1 servings a week RR 0 0.94 (0.90-0.98) 95% CI, Meta-analysis based on 18 and eight studies Chowdhury et al,. 2012
Fish Cerebrovascular disease Incidence Ingestion Intake of fish ≥5 versus ≤1 servings a week RR 0 0.88 (0.81-0.96) 95% CI, Meta-analysis based on 18 and eight studies Chowdhury et al,. 2012
Fish Cerebrovascular disease Incidence Ingestion Intake of fish Increment of two servings per week Reduced risk 0 0.04 (0.01-0.07) 95% CI, Meta-analysis based on 18 and eight studies Chowdhury et al,. 2012
Fish thrombotic infarction Incidence Ingestion Intake of fish 2 or more times per week vs. <1 serving per month RR 0 0.49 (0.26-0.93) 95% CI, Iso et al. 2001

EFSA recommends (as reference intake RI) 100 mg/d of DHA to children below two years of age, and 250 mg/d of EPA+DHA to everyone above two years of age; pregnant and lactating women should take extra 100-200 mg/d of DHA to ensure proper DHA intake if the fetus and infant.[3]

Exposure-response of fish oil intake for MI risk in adults is indexed by variable age. It applies to age categories > 18 years.

Elizabeth Pennisi reports several studies about genetic variation of fatty acid metabolism and links to cardiovascular risk[4]. The overall conclusion is that although these issues are not well understood, there seem to be genetic variation about the health benefits of omega-3 fatty acids.

Aung et al. have conducted a meta-analysis of omega-3 supplement trials with more than 77000 individuals[5]. They found only weak, border-marginal cardiovascular benefits and concluded that the study did not support the use of dietary omega-3 supplements.

The US NCCIH says more about these studies and also: "Moderate evidence has emerged about the health benefits of eating seafood. The health benefits of omega-3 dietary supplements are unclear"[6]

Lauritzen et al. made a review on docosahexaenoic acid (DHA) and concluded that it is especially important for the developing brain during fetal period and infancy, although there may be variation in intrinsic production and therefore in the need of DHA from food. [7]

EFSA also has looked at the safety of omega-3 fatty acids and concluded that daily supplemental intakes of 5g of long-chain omega-3 fatty acids raise no safety concerns for adults[8]

The study by Cohen et al. 2005 [9] estimates that increasing maternal docosahexaenoic acid (DHA) intake by 100 mg/day increases child's IQ by 0.13 points D↷. This value represents central estimate while the upper and lower bound for this ERF is 0.08 and 0.18. Triangular distribution is used.

In a cohort study, 3660 over 65-year-old individuals were monitored for five years, and the change in small brain infarctions was observed by magnetic resonance imageing. The infaction risk was 25 % lower in those who ate at least three portions of omega-3-rich fish meals per week, and 13 % lower in those who ate one meal per week. [10]

Fernandez-Jarne et al. [11] examined the relationship between intake of fish and n-3 PUFA and the risk of first acute myocardial infarction (AMI) in a low risk population from Navarre (Spain). They found that the n-3 PUFA intake has a protective effect on AMI. The adjusted odds ratio (OR) for the second and third tertile of n-3 PUFA intake were 0.44 (95% Cl, 0.21-0.91) and 0.47 (95% Cl, 0.22-1.00), respectively. The trend test was not statistically significant. D↷

Mozaffarian and Rimm [12] estimated that at intakes between 0 and 250 mg/d, the relative risk of coronary heart disease (CHD) death is lower by 14.6% (95% CI: 8% to 21%) per each 100 mg/d of EPA and DHA intake and that at higher intakes ( > 250 mg/d) the risk reduction is 0.0% (95% CI: -0.9% to 0.8%) per each 100 mg/d.

The ERF of omega-3 fatty acids (DHA+EPA) intake from fish (in unit of mg/kg bw-day) on the CHD mortality is estimated based on information provided in [12]. First, the central estimate and the 95% CI for the change (in this case decrease) in natural logarithm of relative risk (RR) of CHD mortality per unit change in omega-3 fatty acids intake (in unit of mg/day) in both intake intervals were derived. In general, the relationship between the percent change in RR (%RR) associated with c-unit increase in omega-3 fatty acids intake and the incremental change in lnRR (beta) per unit change in omega-3 fatty acids intake is beta = (1/c)*ln((%RR/100)+1). Normal distribution was chosen to describe the uncertainty in the parameter of the log-linear model for RR in each intake interval. For intake of EPA+DHA between 0 and 250 mg/day the mean and the standard deviation of parameter distribution are -0.0016 and 0.0004, for higher intakes 0 and 0.0005. Then, the distribution of ERF of omega-3 fatty acids intake from fish in units of mg/kg bw-day was obtained by multiplying ERFs of omega-3 fatty acids intake measured in mg/day by the body weight of adult.

In cohort studies comparing categories of fish intake the pooled relative risk for cerebrovascular disease was demonstrated based ob 26 prospective cohort studies and 12 randomised controlled trials with aggregate data on 794 000 non-overlapping people and 34 817 cerebrovascular outcomes by a review by Chowdhury et al. 2012 [13]. He and coworkers found protective effect of fish intake against stroke[14] and coronary heart disease mortality[15].

In a study by Iso et al. 2001 [16] a significant inverse associations between fish intake and age- and smoking-adjusted risk of total stroke, ischemic stroke, and thrombotic infarction, specifically lacunar infarction was found. After further adjustment for other cardiovascular and selected dietary variables, the inverse remained significant for thrombotic infarction and lacunar infarction, with a reduced risk of these stroke subtypes among women who ate fish 2 or more times per week. The multivariate RRs were 0.49 (95% CI, 0.26-0.93; P = .03), and 0.28 (95% CI, 0.12-0.67; P = .004), respectively. We found no excess risk of hemorrhagic stroke, either intraparenchymal or subarachnoid hemorrhage, among women who ate fish frequently.

Marckmann and Grønbaek [17] made a systematic review of eleven prospective cohort studies in 1999. The cohorts counted a total of 116764 individuals. Of four studies judged to be of high quality, the two largest (n = 44895 and 20051) were performed in populations at low risk of coronary heart disease. They found no protective effect of fish consumption. The other two high-quality studies were relatively small (n = 852 and 1822) and included individuals at higher risk. They both found an inverse relationship between fish consumption and coronary heart disease death, suggesting that 40-60 g fish per day (containing 0.6-0.9 g/d of omega-3) is optimal and associated with a risk reduction of 40-60%. Results of four studies of intermediate quality support that fish consumption is inversely associated with coronary heart disease mortality in high-risk populations only.

Secondary prevention trials were reviewed by Din et al. in 2004[18].

A large part of omega-3 benefit literature is based on studies on cardiac patients, and there is uncertainty about how well this can be extrapolated to the general population.

Hu et al. (2003) [19] examined prospectively the association between intake of fish and omega-3 fatty acids and risk of CHD and total mortality among 5103 female nurses with diagnosed type 2 diabetes but free of cardiovascular disease or cancer at baseline. Compared with women who seldom consumed fish (<1 serving/mo), the relative risks (RRs) (95% CI) of CHD adjusted for age, smoking, and other established coronary risk factors were 0.70 (0.48 to 1.03) for fish consumption 1 to 3 times per month, 0.60 (0.42 to 0.85) for once per week, 0.64 (0.42 to 0.99) for 2 to 4 times per week, and 0.36 (0.20 to 0.66) for 5 or more times per week (P for trend=0.002). Higher consumption of fish was also associated with a significantly lower total mortality (multivariate RR=0.48 [0.29 to 0.80] for > or =5 times per week [P for trend=0.005]). Higher consumption of long-chain omega-3 fatty acids was associated with a trend toward lower incidence of CHD (RR=0.69 [95% CI 0.47 to 1.03], P for trend=0.10) and total mortality (RR=0.63 [95% CI, 0.45 to 0.88], P for trend=0.02). ----#: . Not in the tables --Arja (talk) 08:17, 20 October 2016 (UTC) (type: truth; paradigms: science: comment)

A meta-analysis was performed by Chen et al. (2016) [20] to evaluate the associations of dietary or circulating n-3 long-chain polyunsaturated fatty acids (LCPUFA) with risk of all-cause mortality. Potentially eligible studies were identified by searching PubMed and EMBASE databases. The summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated using the random-effects model. Eleven prospective studies involving 371 965 participants from general populations and 31 185 death events were included. The summary RR of all-cause mortality for high-versus-low n-3 LCPUFA intake was 0.91 (95% CI: 0.84-0.98). The summary RR for eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intake was 0.83 (95% CI: 0.75-0.92) and 0.81 (95% CI: 0.74-0.95), respectively. In the dose-response analysis, each 0.3 g/d increment in n-3 LCPUFA intake was associated with 6% lower risk of all-cause mortality (RR = 0.94, 95% CI: 0.89-0.99); and each 1% increment in the proportions of circulating EPA and DHA in total fatty acids in blood was associated with 20% (RR = 0.80, 95% CI: 0.65-0.98) and 21% (RR = 0.79, 95% CI: 0.63-0.99) decreased risk of all-cause mortality, respectively. Moderate to high heterogeneity was observed across our anlayses. Our findings suggest that both dietary and circulating LCPUFA are inversely associated with all-cause mortality. ----#: . Not in the tables yet --Arja (talk) 08:17, 20 October 2016 (UTC) (type: truth; paradigms: science: comment)

Larsson et al. (2012) [21] conducted a meta-analysis of prospective studies to summarize available evidence regarding the relation between long-chain omega-3 PUFA intake and stroke. Prospective studies that provided relative risks (RRs) with 95 % confidence intervals (CIs) for the association between dietary long-chain omega-3 PUFA intake and stroke were eligible. A random-effects model was used to combine study-specific results. Eight prospective studies, with 5238 stroke events among 242,076 participants, were included in the meta-analysis. The combined RR of total stroke was 0.90 (95 % CI, 0.81-1.01) for the highest versus lowest category of long-chain omega-3 PUFA intake, without heterogeneity among studies (P = 0.32). Results were similar for ischemic (RR, 0.82; 95 % CI, 0.71-0.94) and hemorrhagic stroke (RR, 0.80; 95 % CI, 0.55-1.15). A statistically significant reduction in total stroke risk was observed in women (RR, 0.80; 95 % CI, 0.65-0.99). This meta-analysis showed no overall association between omega-3 PUFA intake and stroke, but suggests that women might benefit from a higher intake of these PUFAs. ----#: . Not in the tables yet --Arja (talk) 08:17, 20 October 2016 (UTC) (type: truth; paradigms: science: comment)

The association between intake of fish and n-3 polyunsaturated fatty acids (n-3 PUFA) and the risk of breast cancer was investigated in a meta-analysis and systematic review of prospective cohort studies by Zheng at al. (2013) [22]. Twenty six publications, including 20,905 cases of breast cancer and 883,585 participants from 21 independent prospective cohort studies were eligible. Eleven articles (13,323 breast cancer events and 687,770 participants) investigated fish intake, 17 articles investigated marine n-3 PUFA (16,178 breast cancer events and 527,392 participants), and 12 articles investigated alpha linolenic acid (14,284 breast cancer events and 405,592 participants). Marine n-3 PUFA was associated with 14% reduction of risk of breast cancer (relative risk for highest v lowest category 0.86 (95% confidence interval 0.78 to 0.94), I(2)=54), and the relative risk remained similar whether marine n-3 PUFA was measured as dietary intake (0.85, 0.76 to 0.96, I(2)=67%) or as tissue biomarkers (0.86, 0.71 to 1.03, I(2)=8%). Subgroup analyses also indicated that the inverse association between marine n-3 PUFA and risk was more evident in studies that did not adjust for body mass index (BMI) (0.74, 0.64 to 0.86, I(2)=0) than in studies that did adjust for BMI (0.90, 0.80 to 1.01, I(2)=63.2%). Dose-response analysis indicated that risk of breast cancer was reduced by 5% per 0.1g/day (0.95, 0.90 to 1.00, I(2)=52%) or 0.1% energy/day (0.95, 0.90 to 1.00, I(2)=79%) increment of dietary marine n-3 PUFA intake. No significant association was observed for fish intake or exposure to alpha linolenic acid. ----#: . Not in the tables yet --Arja (talk) 08:17, 20 October 2016 (UTC) (type: truth; paradigms: science: comment)

The importance of omega-3 fatty acids, especially DHA, has been studied during pregnancy and early life[23][24].

Unit
lnRR/ 1 (mg/kg bw-day) change in EPA+DHA intake from fish
Beneris distributions
For intakes of EPA+DHA from fish between 0 and 250 mg/day: N(-0.0016,0.0004)*BW
For intakes of EPA+DHA from fish higher than 250 mg/day: N(0,0.0005)*BW
Summary of dose–response relationships[25]
Health effect Relationship Central estimate Uncertainty
Fish consumption and CHD mortality ΔRR for some fish consumption vs no fish consumption (<1 serving/month) −17% 95% CI a: −8.8% to −25%
ΔRR per additional serving/week −3.9% 95% CI a: −1.1% to −6.6%
Fish consumption and stroke incidence ΔRR for some fish consumption vs no fish consumption (<1 serving/month) −12% 95% CI a: +1.0% to −25%
ΔRR per additional serving/week −2.0% 95% CI a: +2.7% to −6.6%
MeHg exposure and cognitive development ΔIQ per μg/g total Hg in maternal hair −0.7 pts Bounds: 0 to 1.5 pts
DHA intake and cognitive development ΔIQ per g/day maternal intake of DHA 1.3 pts Bounds: 0.8 to 1.8 pts

a 95% CI is based on the distribution for this coefficient calculated from the regression analysis used to develop the dose–response relationship for CHD or stroke. CHD, coronary heart disease; CI, confidence interval; DHA, docosahexaenoic acid; MeHg, methyl mercury; pts, points; RR, relative risk. Serving size was 100 g.

Here we need to convert the serving size to omega-3 intake. It depends on the average omega-3 content in the diets of the patients in the studies, and it is not known to us. Therefore, we may assume that it is higher than in lean fish (0 - 0.5 %) and lower than in fatty fish (1-2 %), i.e. say 0.7 % or 700 mg per serving. Therefore, the published RR changes (per servings/week) must be multiplied by 1 per (servings * 700 mg/serving / (week * 7 d/week) = 0.01 * RR changes per mg/d. CHD2 is used as the trait to prevent double counting with the other ERFs based on Mozaffarian and Rimm.

In addition, Cohen[25] concluded that the ERFs for CHD and stroke are non-linear with a larger reduction in risk between non-consumers and some-consumers (the limit defined as 1 serving per month). In addition, a linear incremental benefit was estimated for intakes more than 1 serving per week. This results in two independent ERFs where the low-dose "antiarrhythmic" effect follows Relative Hill function and the high-dose "antiatherosclerotic" effect follows RR function. Cohen assumed a negative correlation between these, but this is not easy to implement with the current HIA ovariables and therefore we ignore the correlation; this results in an increase of the estimated uncertainty in the model.

In a recent large cohort study by Engeset et al. (2015) [26] no associations were seen for consumption of total fish, lean, or fatty fish and either total mortality or cause-specific mortality among men; broadly similar results were obtained for women. The statistically significant associations found in the non-calibrated analyses disappeared in the calibrated analyses and bootstrap analyses.

⇤--arg9436: . Check these articles and documents about omega-3. --Jouni (talk) 07:53, 7 June 2019 (UTC) (type: truth; paradigms: science: attack)

For discussion about interaction of omega-3 fatty acids and methylmercury, see ERF of methylmercury#Methylmercury and omega-3 interaction.

Calculations

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See also

Benefit-risk assessment on farmed salmon: To the assessment page | To the Analytica model
Decision variables:

Variable:Recommendation for consumption of farmed salmon | Variable:Pollutant concentration limits for fish feed

Indicators:

Variable:Pollutant health risk due to the consumption of salmon | Variable:Net health effects due to the consumption of salmon

Other variables:

Variable:Persistent pollutant concentrations in fish feed | Variable:Persistent pollutant concentrations in salmon | Variable:Salmon intake in the population of the Western Europe | Variable:Exposure to persistent pollutants due to salmon in the population of the Western Europe | Variable:Dose-response function of persistent pollutants | Variable:Omega-3 content in salmon | Variable:Omega-3 intake due to salmon in the population of the Western Europe | Variable:Dose-response function of cardiovascular effects of omega-3 fatty acids | Variable:Total mortality in the Western Europe | Variable:Cardiovascular mortality in the Western Europe | Variable:Cardiovascular effects of omega-3 in salmon in the Western Europe

References

  1. ↑ Li F, Liu X, Zhang D. Fish consumption and risk of depression: a meta-analysis. J Epidemiol Community Health 2016;70:299-304 http://dx.doi.org/10.1136/jech-2015-206278
  2. ↑ Zhao L-G, Sun J-W, Yang Y, Ma X, Wang Y-Y, Xiang Y-B. Fish consumption and all-cause mortality: a meta-analysis of cohort studies. European Journal of Clinical Nutrition (2015) 70: 155–161. https://doi.org/10.1038/ejcn.2015.72
  3. ↑ EFSA. (2017) Dietary Reference Values for nutrients. Summary report. https://doi.org/10.2903/sp.efsa.2017.e15121
  4. ↑ Pennisi E. Is fish oil good for you? Depends on your DNA. Science 17 September 2015 [1]
  5. ↑ Aung T, Halsey J, Kromhout D, et al. Cardiovascular Disease Risks. Meta-analysis of 10 Trials Involving 77 917 Individuals. JAMA Cardiol. 2018;3(3):225-233. doi:10.1001/jamacardio.2017.5205 [2]
  6. ↑ National Center for Complementary and Integrative Health. (2018) Omega-3 supplements in depth. Website edited May 2018. [3] Accessed 2 July 2019.
  7. ↑ Lotte Lauritzen, Paolo Brambilla, Alessandra Mazzocchi, Laurine B. S. Harsløf, Valentina Ciappolino and Carlo Agostoni. (2016) DHA Effects in Brain Development and Function. Nutrients 2016, 8(1), 6. doi:10.3390/nu8010006 [4]
  8. ↑ EFSA. Scientific Opinion on the Tolerable Upper Intake Level of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and docosapentaenoic acid (DPA). EFSA Journal 2012;10(7):2815. doi:10.2903/j.efsa.2012.2815 [5]
  9. ↑ Cohen, J.T., PhD, Bellinger, D.C, PhD, W.E., MD, Bennett A., and Shaywitz B.A. 2005b. A Quantitative Analysis of Prenatal Intake of n-3 Polyunsaturated Fatty Acids and Cognitive Development. American Journal of Preventive Medicine 2005;29(4):366–374).
  10. ↑ Fish consumption and risk of subclinical brain abnormalities on MRI in older adults Jyrki K. Virtanen, David S. Siscovick, Will T. Longstreth, Lewis H. Kuller, Dariush Mozaffarian Neurology 2008;71:439–446.
  11. ↑ Fernandez-Jarne E, Garrido FA, Gutierrez AA, Arrillaga CDF, Martinez-Gonzales MA. Dietary intake of n-3 fatty acids and the risk of acute myocardial infarction: a case-control study. (In Spanish) 2002;118:121–5.
  12. ↑ 12.0 12.1 Mozaffarian D., Rimm E.B., Fish intake, contaminants, and human health. Evaluating the risks and the benefits. (Reprinted) JAMA, 2006. Vol 296, No. 15
  13. ↑ Chowdhury Rajiv, Stevens Sarah, Gorman Donal, Pan An, Warnakula Samantha, Chowdhury Susmita et al. Association between fish consumption, long chain omega 3 fatty acids, and risk of cerebrovascular disease: systematic review and meta-analysis BMJ 2012; 345 :e6698 https://doi.org/10.1136/bmj.e6698
  14. ↑ P Xun, B Qin, Y Song, Y Nakamura, T Kurth, S Yaemsiri, L Djousse & K He. (2012) Fish consumption and risk of stroke and its subtypes: accumulative evidence from a meta-analysis of prospective cohort studies. European Journal of Clinical Nutrition volume 66, pages 1199–1207. https://doi.org/10.1038/ejcn.2012.133
  15. ↑ Ka He, Yiqing Song, Martha L. Daviglus, Kiang Liu, Linda Van Horn, Alan R. Dyer, and Philip Greenland. Accumulated Evidence on Fish Consumption and Coronary Heart Disease Mortality. A Meta-Analysis of Cohort Studies. Circulation. 2004;109:2705–2711. https://doi.org/10.1161/01.CIR.0000132503.19410.6B
  16. ↑ Iso et al. 2001. Intake of fish and omega-3 fatty acids and risk of stroke in women. JAMA. 2001;285(3):304-312. doi:10.1001/jama.285.3.304. [6]
  17. ↑ Marckmann P, Gronbaek M. (1999). Fish consumption and coronary heart disease mortality. A systematic review of prospective cohort studies. European Journal of Clinical Nutrition; 53(8):585-590.
  18. ↑ Din JN, Newby DE, Flapan AD. Science, medicine, and the future - Omega 3 fatty acids and cardiovascular disease - fishing for a natural treatment. British Medical Journal 2004; 328(7430):30-35. Intranet file
  19. ↑ Hu FB, Cho E, Rexrode KM, Albert CM, Manson JE (2003). Fish and long-chain omega-3 fatty acid intake and risk of coronary heart disease and total mortality in diabetic women. Circulation 107(14):1852-7.
  20. ↑ Chen GC, Yang J, Eggersdorfer M, Zhang W, Qin LQ. (2016). N-3 long-chain polyunsaturated fatty acids and risk of all-cause mortality among general populations: a meta-analysis. Sci Rep. 6:28165. doi: 10.1038/srep28165.
  21. ↑ Larsson SC, Orsini N, Wolk A. (2012). Long-chain omega-3 polyunsaturated fatty acids and risk of stroke: a meta-analysis. Eur J Epidemiol. 27(12):895-901. doi: 10.1007/s10654-012-9748-9.
  22. ↑ Zheng JS, Hu XJ, Zhao YM, Yang J, Li D. (2013). Intake of fish and marine n-3 polyunsaturated fatty acids and risk of breast cancer: meta-analysis of data from 21 independent prospective cohort studies. BMJ 27;346. doi: 10.1136/bmj.f3706.
  23. ↑ Ann Reynolds. (2001) Breastfeeding and Brain Development. Pediatric Clinics of North America 48(1)159-171. https://doi.org/10.1016/S0031-3955(05)70291-1
  24. ↑ Carlo Agostoni. (2008) Role of Long-chain Polyunsaturated Fatty Acids in the First Year of Life. Journal of Pediatric Gastroenterology and Nutrition. 47():S41–S44. DOI: 10.1097/01.mpg.0000338811.52062.b2
  25. ↑ 25.0 25.1 Cohen JT, Bellinger DC, Shaywitz BA. A quantitative analysis of prenatal methyl mercury exposure and cognitive development. Am J Prev Med. 2005 Nov;29(4):353-65. [7]
  26. ↑ Engeset et al. 2014: Fish consumption and mortality in the European Prospective Investigation into Cancer and Nutrition cohort [8]
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