Summary of Published Research on the Beneficial Effects of Fish Consumption and Omega-3 Fatty Acids for Certain Neurodevelopmental and Cardiovascular Endpoints
This report serves as a companion document to the Food and Drug Administration (FDA) draft report entitled "Report of Quantitative Risk and Benefit Assessment of Commercial Fish, Focusing on Fetal Neurodevelopmental Effects (Measured by Verbal Development in Children) and on Coronary Heart Disease and Stroke in the General Population." The information contained in this document represents an in-depth overview of the scientific literature regarding the health effects of fish and of the long chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid on cardiovascular disease and neurodevelopment.
Fish provide a source of easily digestible protein of high biological value, micronutrients including vitamins A and D, the minerals iodine and selenium, and high levels of the amino acids taurine, arginine and glutamine (EFSA 2005; He and Daviglus 2005). Additionally, many fish provide a uniquely rich food source of long chain omega-3 fatty acids (also called n-3) long-chain polyunsaturated fatty acids (n-3 LC PUFA), most notably docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).
A number of research studies have reported associations between consumption of fish, fish oil, or n-3 LC PUFA and reduced risk of cardiovascular events such as heart attack and stroke (Kris-Etherton et al., 2002). Moreover, the n-3 LC PUFA, docosahexaenoic acid, has been shown to be essential for development of the central nervous system (EFSA 2005, page 30). Consequently, there is considerable interest in whether there is an association between fetal, infant or child neurodevelopment and maternal intake of fish or n-3 LC PUFA during pregnancy and lactation (SACN 2004).
There are a number of original (or primary) scientific studies on the health effects associated with consumption of fish or n-3 LC PUFA. The primary studies most relevant to the evaluation of the risks and benefits of fish consumption have been summarized and evaluated previously in a number of recent scientific reports and review articles (or secondary sources). Thus, the approach used to develop this document was primarily to inventory these secondary sources and to highlight any findings related to the health effects of fish consumption and of the n-3 LC PUFA found in fish on cardiovascular disease and neurodevelopment. Research has addressed the possible association of fish or of n-3 LC PUFA consumption with numerous other health outcomes, including neuropsychiatric disorders (including depression and psychotic disorders), cognitive decline and Alzheimer's Disease, neurodegenerative disorders, cancer risk reduction, and reduced risk of chronic degenerative diseases related to immune and auto-immune or musculo-skeletal function, acute macular degeneration and other visual impairments, although consideration of these outcomes is beyond the scope of this document. When available, the document also identifies reports of quantitative dose-response relationships which may be used in risk and benefit assessment modeling.
Summary of Scientific Information in Section A: Effect of Fish Consumption and Omage-3-Fatty Acids on Cardiovascular Disease
Published reports have made conclusions about the relationship between fish or n-3 LC PUFA consumption and coronary heart disease (CHD) risk:
- Primary and secondary prevention, randomized clinical trial of fish oil consumption. The recently published large-scale clinical trial called the Japan EPA Lipid Intervention Study (JELIS) from Japan included over 18,000 men and women (Yokoyama et al., 2007). Almost 15,000 participants had no record of coronary artery disease (primary prevention). Results showed a 19 percent decrease in major coronary events (fatal plus nonfatal) for all subjects, a 19 percent decrease for secondary prevention subjects and an 18 percent decrease for primary prevention subjects. The decrease in risk was similar in magnitude for primary and secondary prevention, but was not statistically significant for primary prevention alone (p = 0.13). For the full study and for both subgroups, there was no significant decrease in sudden cardiac death or coronary death alone, probably reflecting that the high baseline fish intake in Japan is above a possible threshold for effect on risk of sudden death or CHD death.
- Secondary prevention, randomized clinical trials of fish or fish oil consumption. The large, well-conducted secondary prevention trial, GISSI, included over 10,000 men and found a 15 percent decrease in all deaths plus nonfatal heart attacks and strokes, a 26 percent decrease in cardiovascular deaths plus nonfatal heart attacks and strokes and a 45 percent decrease in sudden death, all significant (1999; Marchioli et al., 2002) Results of the DART1 study were consistent with GISSI, but results differed for the poor quality DART2 study (Burr et al., 2003; Burr et al., 1989).
- Meta-analyses of randomized controlled trials of fish or fish oil consumption. Mozaffarian and Rimm (Mozaffarian and Rimm 2006) conducted a meta-analysis including five randomized controlled trials and 15 prospective cohort studies of fish or fish oil intake and CHD death among >300,000 subjects. There was a significant, 17 percent decrease in total CHD mortality. A total 36 percent reduction in risk was estimated for intakes of 250 mg/day EPA/DHA.
- Observational studies of blood levels of n-3 LC PUFA and CHD risk. As summarized by (SACN 2004) and others, additional evidence for the cardiovascular benefits of fish and fish oil consumption is provided by several cohort or case control studies that found decreased CHD risk associated with higher blood levels of DHA and EPA. SACN stated that, "Taken together, these data support the hypothesis that n-3 LC PUFA are responsible for the observed inverse association between fish consumption and sudden cardiac death."
- Meta-analyses of observational studies of fish consumption and risk of cardiovascular disease. There are several meta-analyses of observational studies of fish consumption and risk of CHD or stroke with fairly consistent results among the meta-analyses. The prospective studies of CHD death included more than 200,000 men and women and the prospective studies of stroke also included more than 200,000 men and women. For example, the meta-analyses of He et al (He et al., 2004a; He et al., 2004b) found a 15 percent decreased risk of CHD death and a 13 percent decreased risk of stroke associated with fish intake once per week compared with less than once per month.
- A meta-analysis (Studer et al., 2005) of 97 studies, with 137,140 individuals in intervention and 138,976 individuals indicted that the benefits of n-3 LC PUFAS were comparable to (or greater) than the benefits of statins for overall mortality.
In 2002, FDA reviewed the credible scientific evidence available at that time to support a qualified health claim for the labeling of foods. The Agency concluded that supportive but not conclusive research showed that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease.
Summary of Scientific Information in Section B: Effect of Fish Consumption and Omega-3 Fatty Acids on Neurodevelopmental Outcomes
This section summarizes recent reports and review articles and presents an overview of current scientific information on the association of maternal fish consumption with infants' and children's visual and cognitive neurodevelopment.
Randomized trials of maternal supplementation in pregnancy and lactation: Among the few available studies of maternal supplementation, women in the Helland et al. (Helland et al., 2003) study were supplemented with fish or fish oil providing 1.2 grams of DHA per day during pregnancy and lactation and increased infant DHA blood levels were demonstrated biochemically (Eilander et al., 2007). Limitations included uncertain effect of the corn oil control supplement, the small subset of the population that received follow up IQ testing at age four years, and uncertain differences in background n-3 LC PUFA intake between Norwegian and U.S. women. However, the 4.1 point higher average K-ABC Mental Processing IQ scores of the children of fish oil supplemented mothers supports the plausibility of measurable neurodevelopmental benefits of maternal seafood consumption and gives one example of magnitude of dose-response. Additional maternal supplementation trials would be helpful to replicate this result, and to add features such as detailed background n-3 LC PUFA status, supplementation in pregnancy alone or including lactation, various levels of fish oil supplement dose, and several years of complete, planned follow up testing.
Randomized trials of infant formula supplementation: The complexity and inconsistency of the literature on supplementation of infant formula with DHA is a barrier to demonstrating the plausibility of measurable neurodevelopmental benefits for infants and children. The potential for estimating a quantitative dose-response from these data is limited. Among the factors that differed across the randomized trials were: infant population (preterm or term birth), timing of supplementation (beginning at birth or after period of breastfeeding; duration of a few months to one year), test formula composition (presence of arachidonic acid (AA); levels of DHA, AA and ALA), additional breastfed comparison group, neurodevelopment outcome (vision, cognitive, general development, other), visual acuity testing (behavioral or electrophysiologic), neurodevelopment testing (global or targeted assessment), age at testing (early infancy to three years or older). Systematic reviews and meta-analyses evaluated the randomized trials in subgroups according to various study conditions, and generally found the evidence for neurodevelopmental benefit of DHA supplemented formula to be inconsistent and inconclusive (Lewin et al., 2005; Simmer 2001; Simmer and Patole 2004; Simmer et al., 2008a; Simmer et al., 2008b; Smithers et al., 2008). Studies were grouped differently in different systematic reviews, and newer studies were available for more recent reviews, making comparisons difficult across reviews.
The analysis of Lauritzen et al. (Lauritzen et al., 2001) concentrated on a single age at testing (four months) and identified formula composition and visual acuity method as likely sources of heterogeneity among trials. These authors recommended that future trials use conditions from previous positive trials, including DHA as 0.36 percent of lipids in test formula and electrophysiologic method for visual acuity testing. The meta-regression of Uauy et al (Uauy et al 2003) quantified the dose-response for DHA equivalents in 12 comparisons from seven controlled trials of term infant visual acuity at four months of age (Table 3). Morale et al. (2005) analyzed visual acuity at age 12 months in studies from a single laboratory and found a linear dose-response for duration of supply of LC PUFA from formula supplemented with DHA as 0.36 percent of lipids, breastfeeding, or both (Table 12). Birch et al. (2005) designed a trial to carry out the Lauritzen et al. recommendations regarding DHA level in test formula and electrophysiological visual acuity as well as adequate sample size (greater than 20 per group). Supplemented infants had significantly better visual acuity at six, 17, 39 and 52 weeks of age and better stereoacuity at 17 weeks.
Most studies showed little evidence of a positive effect of supplemented formula on infant neurodevelopment using global tests, such as the Bayley scales. A few studies reported positive effects using more specific, focused developmental assessments, but these assessment methods were not adopted by other research groups (Willatts et al., 1998). The study of Birch et al. (Birch et al., 1998) did find a positive effect of supplemented formula for four months using Bayley's MDI at 18 months of age. In a follow up at four years of age, infants supplemented with DHA plus AA had mean Wechsler Performance, Verbal and Full Scale IQ scores that were 4.4, 5.7 and 6.5 points higher, respectively, than scores of control infants (Birch et al., 2007). However, the statistical significance of this comparison was not tested directly but in a research design including a breastfed group and a DHA (with no AA) supplemented group. A secondary analysis of the IQ comparison for DHA plus AA supplemented and control infants from Birch et al. (Birch et al., 2007) would show whether the result is statistically significant and if not significant, what sample size would be needed to replicate the results with adequate power.
Cohen et al (Cohen et al., 2005a; Cohen et al., 2005c) pooled the results of nine unique trials of supplemented formula and neurodevelopmental outcomes. Based on the average DHA level in supplemented formulas, the authors estimated an effect size of 4.6 IQ points for each one percent DHA (as percent of lipids) in infant formula (Table 9). In the supplemented formula of Birch et al. (2007), the DHA level was 0.36 percent, giving a Full Scale IQ effect size of 18 points (6.5/0.36) per one percent DHA in formula, considerably larger than the 4.6 point effect size of Cohen et al. (2005a, 2005c) Cohen and coauthors reported only a point estimate and did not state whether their result was significantly different from no effect.
Observational studies: Observational studies, such as prospective cohort studies, consider outcomes related to participants' actual diets. In a project on the Risks and Benefits of Seafood, maternal fish consumption, rather than infant or maternal fish oil supplementation, is the actual exposure most relevant to assessing potential health benefits for infant and child neurodevelopment. Although an observational study cannot conclusively demonstrate a cause and effect relationship, possible confounding variables that are known and measured can be adjusted for in the statistical analysis.
In three cohort studies, children's visual function (Williams et al., 2001) and neurodevelopment (Daniels et al., 2004; Oken et al., 2005) were positively associated with mother's fish intake during pregnancy, with adjustment for covariates. The association with visual function is consistent with certain analyses of supplemented infant formula (Birch et al., 2005; Lauritzen et al., 2001; Morale et al., 2005; Uauy et al., 2003). Recent results estimated a positive, quantitative association between maternal fish consumption and children's developmental scores in Project Viva in the United States at three years of age (Oken et al 2008a) and in the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort in the United Kingdom at eight years of age (Hibbeln et al., 2007a, 2007b) (Table 14). The magnitude of the quantitative estimates from observational studies is considerably larger than estimates based on infant supplementation studies and a series of assumptions (Cohen et al., 2005a, 2005c).
In both observational cohorts, the positive association of neurodevelopment with mothers' fish intake was stronger with additional adjustment for maternal mercury exposure. Independent, negative associations of neurodevelopment with maternal mercury exposure were also observed, but these were smaller than the independent, positive associations with maternal fish intake (Hibbeln et al., 2007a; Hibbeln et al., 2007b; Oken et al., 2008a). This was in contrast to the Cohen et al. (Cohen et al., 2005a) risk benefit assessment, which used different types of data and evidence for DHA benefits of fish intake (Cohen et al., 2005a) and for risks of mercury (Cohen et al 2005c). As discussed in the FDA draft risk and benefit assessment report, Cohen et al. (2005c) may have overestimated the dose-response for the risks of maternal methylmercury exposure. However, a possible underestimate of the dose-response for the benefits of maternal DHA intake in Cohen et al. (2005b) should not be overlooked. The quantitative estimates of neurodevelopmental DHA benefits of Cohen et al. (2005a, 2005b) have been used in other analyses (Guevel et al., 2008), but should be viewed with caution because of their inconsistency with the cohort studies.
The identification of independent neurodevelopmental benefits of maternal seafood intake and risks of maternal mercury exposure in Project Viva and the ALSPAC cohort are consistent with recent data from established cohort studies of maternal mercury exposure and children's neurodevelopment. Structural equation modeling of neurodevelopmental test data at seven and 14 years of age from the Faroe Islands showed that, after mutual adjustment for both variables, there was an independent, positive association with maternal fish intake as well as a negative association with maternal mercury exposure (Budtz-Jorgensen et al., 2007). Preliminary results from the Seychelles nutrition cohort suggested that children's developmental tests were positively associated with maternal n-3 LC PUFA blood levels and negatively associated with maternal hair mercury (Myers et al., 2007). These associations were stronger when mutually adjusted for the other variable.