Health Benefits Associated with Nutrients in Seafood
This chapter reviews the evidence for benefits derived from nutrients in seafood or from dietary supplementation with nutrients derived from seafood. The review of evidence related specifically to the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from seafood is presented in two parts: Part I addresses the impact of EPA/DHA on maternal, infant, and child health outcomes and Part II addresses the impact on chronic disease, particularly coronary heart disease, in adults. The discussions that follow include a review of the literature and evaluation of the quality of the evidence for benefits.
The committee considered a broad range of evidence on potential benefits associated with nutrients from seafood and reviewed evidence from other systematic reviews, i.e., the Agency for Health Research and Quality (AHRQ) reviews (Balk et al., 2004; Schachter et al., 2004, 2005; Wang et al., 2004) and other published reports of evidence associating nutrients from seafood with specific health outcomes. In cases where benefits were not supported or were poorly supported by the literature, a statement is made to that effect.
Scientific evidence to support benefits associated with seafood intake on cardiovascular risk reduction through prevention of disease development consists mainly of observational studies of seafood consumption among the general population. Recommendations to the general population are inferred from these findings despite the fact that they have not been tested by trials in this population. Fish-oil supplementation, on the other hand, has been used in secondary prevention trials in high cardiovascular-risk
populations or populations with established disease to examine its role in preventing recurrence of cardiovascular events.
Given the potential for different outcomes in general compared to high-risk populations, the committee also considered best practice guidelines for both, which take into account currently available evidence. The conclusions drawn from the evidence reviewed were the basis for decision-making about seafood selections discussed in later chapters. The literature reviewed in the chapter is summarized in tables included in Appendix B.
Seafood is a food source comparable to other animal protein foods in nutrient composition (see Chapter 2). In addition, seafood is an important contributor of selenium to the American diet and is unique among animal protein foods as a rich source for the omega-3 fatty acids EPA and DHA, although the roles of these fatty acids in maintaining health and preventing certain chronic diseases have not been completely elucidated (IOM, 2002/2005).
Benefits to the General Population Associated with Nutrients in Seafood
As noted in Chapter 1, the US Dietary Guidelines for Americans (DGA) provides science-based advice to promote health and reduce risk for chronic diseases through diet and physical activity. The guidelines are targeted to the general public over 2 years of age living in the United States. But as noted in Chapter 2, general adherence to the DGA is low among the US population.
Seafood provides an array of nutrients that may have beneficial effects on health (see Chapter 2). While protein is an important macronutrient in the diet, most Americans already consume enough protein and do not need to increase their intake. Fats and oils are also part of a healthful diet, but the type of fat can be important, for example, with regard to heart disease. Many Americans consume greater than recommended amounts of saturated fat from high-fat animal protein foods such as beef and pork as well as trans fat from processed foods (Capps et al., 2002). A diet high in fat (greater than 35 percent of calories), particularly animal fat, may increase saturated fat intake, add excess calories, and increase risk for coronary heart disease. Many seafood selections, depending upon preparation method, are lower in total and saturated fat and cholesterol than some more frequently selected animal protein foods, including both lean and fatty cuts of beef, pork, and poultry (Table 3-1). By substituting seafood more often for other animal foods, consumers can decrease their overall intake of total and saturated fats while retaining the nutritional quality of other protein food choices.
TABLE 3-1 Differences in Saturated Fat Content Between Commonly Consumed Animal Food Products
Portion Size (ounces)
Saturated Fat (grams)
Regular cheddar cheese
Low-fat cheddar cheese
Regular ground beef (25% fat)
Extra lean ground beef (5% fat)
Fried chicken (with skin)
Roasted chicken (no skin)
Fried fish (catfish)
Baked fish (catfish)
SOURCE: USDA, Release 18.
The 1994–1996 Continuing Survey of Food Intake by Individuals (CSFII) identified several micronutrients that were consumed at levels below the Recommended Dietary Allowance (RDA), including vitamins E and B-6, calcium, iron, magnesium, and zinc. Seafood is a good source of zinc and some calcium, e.g., from canned salmon or other fish with bones, which may contribute to the total intake of these nutrients when substituted for other animal food products. For example, a 3-ounce cooked serving of beef, lamb, chicken, or pork contains approximately 10–20 mg of calcium, whereas a 3-ounce serving of canned salmon with bones contains approximately 240 mg. (Source: http://www.nal.usda.gov/fnic/foodcomp/Data/SR18/sr18.html.)
Nutritional Benefits Associated with Omega-3 Fatty Acids
Optimal Intake Levels for EPA and DHA
There are insufficient data on the distribution of requirements to set an Estimated Average Requirement (EAR) for alpha-linolenic acid (ALA), so an Adequate Intake (AI) was set instead, at approximately the level of current intakes (IOM, 2002/2005). Given that ALA conversion to EPA and DHA is low and variable (Burdge, 2004), intakes of the preformed omega-3 fatty acids may be less than desired under certain physiologic circumstances (see Chapter 2). Despite the number of studies conducted over the past two decades to assess the impact of omega-3 fatty acids in general on health outcomes, optimal intake levels for EPA and DHA are still not defined. The Dietary Reference Intakes (IOM, 2002/2005) did not establish a require-
ment for any omega-3 fatty acids; rather, an estimate of adequacy, the AI, was derived from the highest median intake of ALA in the United States.
Target intake goals for seafood consumption for the general population and recommended EPA/DHA intake levels for specific population subgroups have been put forward by both public agencies and private organizations (reviewed in Chapter 1). Whether there are benefits to the general population that are related specifically to EPA/DHA obtained from consuming seafood is not clear from the available evidence. A low-saturated-fat, nutrient-dense protein food such as seafood does represent a good food choice for the general population and this is reflected in the recommendations of the Dietary Guidelines for Americans to choose low-fat foods from among protein sources that include fish (see Chapter 1). The evidence in support of recommendations to increase EPA/DHA intake, whether from seafood or fish-oil supplements, among the population groups that would most benefit is presented in the following discussions.
It should, however, be kept in mind that the benefits of seafood consumption for health may not be limited to intake of EPA/DHA. Other nutrients present in seafood may provide specific health benefits or even facilitate the action of EPA/DHA. Additionally, substitution of seafood for other food sources may decrease exposure to nutrients that are shown to increase health risks, such as saturated fats. On the other hand, some contaminants or toxins present in seafood may decrease or negate the benefit of EPA/DHA, as illustrated by the dilemma in making recommendations for seafood consumption in pregnant women, considering the potential benefits of EPA/DHA compared to potential risks of methylmercury exposure to the fetus. Therefore, when assessing the question of benefits of seafood consumption, seafood should not be considered as equivalent to EPA/DHA. This differentiation may explain some of the inconsistencies in the findings described below. In other words, demonstrated benefits of EPA/DHA do not necessarily mean benefits of seafood, and lack of benefit from EPA/DHA does not necessarily mean lack of benefit from seafood.
Part I: Benefits to Women, Infants, and Young Children Associated with Omega-3 Fatty Acids
BENEFITS TO WOMEN DURING AND AFTER PREGNANCY
An array of studies based on supplemental intake of EPA/DHA or biochemical indicators of EPA/DHA levels has been carried out to determine whether there is an association between increased intake or blood levels of EPA/DHA and decreased incidence of or risk for preeclampsia (Olsen and Secher, 1990; Schiff et al., 1993; Williams et al., 1995; Velzing-Aarts et al., 1999; Clausen et al., 2001). Because these and other studies, including randomized clinical trials (Bultra-Ramakers et al., 1995; Onwude et al., 1995; Salvig et al., 1996) or reviews of trials (Sibai, 1998) did not show clear evidence of a beneficial effect of a broad range of intake (or biochemical indicators) of EPA/DHA levels, it does not appear likely that increased seafood intake or fish-oil supplementation will reduce the incidence of preeclampsia among US women (see Appendix Table B-1a).
During pregnancy and lactation there is a correspondent transfer of DHA from the mother to the fetus or infant (Holman et al., 1991; Al et al., 1995). Following pregnancy and lactation, maternal DHA blood levels may require many months for recovery to pre-pregnancy levels (Otto et al., 2001). Although prior depressive illness is the best predictor of higher risk for postpartum depression, it has been proposed that low DHA levels in the brain in late pregnancy and early postpartum period may contribute to the emergence of postpartum depression (Hibbeln and Salem, 1995). Further, it has been hypothesized that increased EPA/DHA intake during pregnancy could reduce the risk for postpartum depression. To date, however, there have been no randomized controlled trials or controlled clinical studies testing whether increased omega-3 fatty acid intake by pregnant women could reduce the risk for postpartum depression.
Hibbeln (2002) conducted a cross-cultural review of 41 studies and concluded that there is an association between increased seafood consumption and higher maternal milk DHA levels (p<0.006) and that this was associated with a lower prevalence of postpartum depression (p<0.0001). Timonen et
al. (2004) followed up the Northern Finland 1966 Birth Cohort prospectively from pregnancy to 31 years of age. Members of the cohort were sent questionnaires, invited to undergo a clinical examination to assess indices of depression, and asked to estimate seafood consumption in the previous six months (presumably related to the lifetime pattern of seafood consumption). The study found that females who rarely consumed fish showed greater incidences of life-time depression than regular consumers of fish, based on the Hopkins Symptom Check List (HSCL-25) depression subscale alone (cutoff-point 2.01) (OR=1.4; 95% confidence interval [CI] 1.1-1.9) and the HSCL-25 depression subscale (cutoff-point 2.01) with a doctor diagnosis (OR=2.6; 95% CI 1.4-5.1), but not based on doctor diagnosis alone (OR=1.3; 95% CI 0.9-1.9) or suicidal ideation. This study, however, did not show causation and did not address postpartum depression specifically.
Otto et al. (2003) investigated the relationship between postpartum depression and changes in maternal plasma phospholipid-associated fatty acid (DHA and docosapentaenoic acid [DPA]) status by measurement at 36 weeks of pregnancy, at delivery, and 32 weeks postpartum in women in the Netherlands. Postpartum depression was assessed using the Edinburgh Postnatal Depression Scale (EPDS), developed as a screening and monitoring tool for postpartum depression (Cox et al., 1987). Only relative plasma fatty acid levels (percent of total fatty acids, wt/wt) were reported because total absolute amounts of plasma phospholipid-associated fatty acids at delivery and changes that occurred postpartum were not significantly different between the “possibly depressed” and “non-depressed” groups. The conclusion from this study was that the ratio of 22:6 n-3 (DHA) to 22:5 n-6 (DPA) becomes reduced during pregnancy and the difference is significant (p<0.04) compared to increased EPDS scores, while DHA status at delivery did not correlate with depressive symptoms (p=0.563) (Otto et al., 2003).
In contrast to the above-mentioned studies, Llorente et al. (2003) examined a cohort of 44 women who consumed 200 mg of DHA per day during the first 4 months of lactation compared to a placebo control group (n=45) for indices of postpartum depression and information processing (cognition). Both groups were analyzed for symptoms of depression using a self-rating questionnaire, the Beck Depression Inventory (BDI). Additionally, a subgroup of the population was administered the EPDS and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I Disorders—Clinical Version. A positive and statistically significant correlation was found between the BDI questionnaire at 4 months and the EPDS scores at 18 months (p<0.0001), which validated use of the BDI for assessment of symptoms. However, no difference was found between the supplemented and control groups for diagnostic measures of postpartum depression or information processing (see Appendix Table B-1b).
Summary of Evidence
Based solely on these studies, the committee cannot draw a conclusion about the effect of increased EPA/DHA on postpartum depression. Thus, there is not sufficient evidence to conclude that the health of pregnant or lactating women will benefit directly from an increase in seafood intake.
BENEFITS TO INFANTS AND CHILDREN ASSOCIATED WITH PRENATAL OMEGA-3 FATTY ACID INTAKE
Transfer of Maternal DHA to the Fetus or Breastfeeding Infant
The level of maternal DHA intake influences DHA levels in both maternal blood and milk. Blood DHA levels increase by about 50 percent in pregnancy (Al et al., 1995) and decline dramatically by 6 weeks after parturition, especially with lactation (Makrides and Gibson, 2000; Otto et al., 2001). DHA transport across the placenta is increased with higher compared to lower maternal blood DHA concentration and, compared with other fatty acids in maternal blood, DHA is selectively transferred across the placenta (Haggerty et al., 1997, 1999, 2002). Thus, increased maternal blood DHA levels in pregnancy may enhance DHA availability for placental transfer to the fetus.
Maternal DHA status could influence the DHA supply available to the fetal brain as well as other organs and tissues (Clandinin et al., 1980a). Brain DHA accumulates rapidly from approximately 22 weeks gestation until at least 2 years after birth (Clandinin et al., 1980b; Martinez, 1992). Studies that examined autopsy tissue from a limited number (n = 5) of both preterm and term infants reported that tissue from infants who consumed breast milk after birth showed greater cortical accumulation of DHA than those fed formulas that did not contain DHA, and the differences increased with duration of feeding (Farquharson et al., 1992; Makrides et al., 1994).
Duration of Gestation and Birth Weight
Infant birth weight is the result of a complex interaction involving many factors, including both biological and social mechanisms. Biological mechanisms are also variable and complex but appear to be linked to duration of gestation and fetal growth, conditional on duration of gestation (Ghosh and Daga, 1967; Villar and Belizan, 1982; Alberman et al., 1992). Higher birth weight is positively associated with cognitive ability among full-term infants in the normal birth weight range (Matte et al., 2001; Richards et al., 2001) as well as some preterm infants (Hediger et al., 2002). Low infant birth weight (less than 2500 grams or 5.2 pounds) (Juneja and Ramji, 2005), fetal
growth retardation (van Wassenaer, 2005), and preterm delivery (Hediger et al., 2002) are associated with poor developmental outcomes.
Observational and experimental studies have been carried out to determine if there is a relationship between DHA intake and increased gestation duration or birth weight. Both observational and experimental studies suggest that increased seafood consumption or DHA intake from supplements can increase gestation duration or birth weight. Any outcome correlated with a variable in an observational study can only suggest an association. In the case of the observational studies cited here showing relationships between EPA/DHA or seafood intake, the effect may be explained by these variables or by other variables that accompany diets higher in EPA/DHA or seafood intake. The People’s League of Health trial (reviewed in Olsen, 2006) showed that deliveries before 40 weeks were reduced by 20.4 percent in the group that received a fish-oil/vitamin supplement compared to the group that was not supplemented (p<0.0008) (Olsen and Secher, 1990).
Several randomized controlled trials (RCT) have tested for an association between dietary supplementation with fish oil or the omega-3 fatty acids from fish oil (i.e., either DHA alone or EPA and DHA) and longer duration gestation. Olsen et al. (1992) conducted an RCT that administered 2.7 g/day of a fish-oil supplement beginning in the 30th week of pregnancy in a Danish cohort. The study found an average increase in gestation of 2.8 days in subjects from the fish-oil treatment group compared with control groups receiving an olive oil supplement or no supplement (p<0.01). In a similar study, Olsen et al. (2000) found among women who had a previous preterm delivery (delivery at <37 weeks) a significantly decreased risk for recurrent preterm delivery, a mean increase in gestation of 8.5 days (p=0.01), and an increase in birth weight of 209 g (p=0.02) in the fish oil compared to the olive-oil treatment group. In this study, however, prophylactic trials using fish-oil supplementation did not increase gestation duration and birth weight in pregnancies with intrauterine growth retardation, twins, or pregnancy-induced hypertension.
In contrast to these studies, a randomized trial conducted in Norwegian women (Helland et al., 2001) found no increase in either gestation duration or birth weight with a supplement of 2 g/day of EPA and DHA from cod-liver oil during the last two trimesters of pregnancy. However, a post hoc analysis found an increase in length of gestation of 7 days in infants in the highest quartile for plasma phospholipid DHA compared to those in the lowest quartile (Helland et al., 2001). Similarly, a post hoc analysis of results from the previously mentioned Danish trial (Olsen et al., 1992) found an increase in gestation duration of 5.7 days associated with fish-oil supple-
mentation in a group of women who had the lowest 20 percent of seafood consumption at study entry (p<0.05), compared to a 2.8-day increase in gestation associated with fish-oil supplementation in all women.
The committee found that compared to women in Denmark and Norway, US women have been shown to consume less omega-3 long-chain polyunsaturated fatty acids and have lower levels of DHA in breast milk (Jensen et al., 1995). They also have, on average, shorter gestation durations and smaller infants (Smuts et al., 2003 a,b; Olsen et al., 1992; Helland et al., 2001). Birth weight depends on both length of gestation and intrauterine growth. Problematically high birth weight is not due to excessive gestation but rather to excessive intrauterine growth. No experimental trials have been conducted in the United States in which fish-oil supplements were evaluated for increasing gestation duration.
EPA/DHA Intake from Seafood and Other Food Sources
In a randomized controlled trial, Smuts et al. (2003b) evaluated the effect of feeding DHA-fortified eggs (mean 133 mg DHA/egg) to pregnant women in the United States, beginning at 24–28 weeks gestation. They reported a significant increase in gestation of 6 days among women consuming the high-DHA eggs compared to women receiving unfortified eggs (mean 33 mg DHA/egg). There was no significant increase in birth weight (p=0.184), birth length (p=0.061), or head circumference (p=0.081) among infants of mothers consuming high-DHA eggs. Although birth weight is frequently used as a marker for infant growth, head circumference and birth length are likely better indicators of positive pregnancy outcome.
An observational study examining an association between seafood consumption and gestational duration was conducted in a cohort of women in the Orkney Islands and Aberdeen, Scotland. This study identified a significant association between the 30 percent greater amount of seafood consumed by Orkney Island women over that consumed by women in Aberdeen, Scotland, and an increase in gestational duration of 2.5 days (p=0.01) (Harper et al., 1991).
Olsen et al. (1991) examined whether there was a difference in the ratio of the long-chain polyunsaturated fatty acids (LCPUFA) EPA, DPA, and DHA to arachidonic acid (AA) measured in erythrocytes obtained within 2 days of delivery between Faroese and mainland Danish women and whether there was a correlation between the LCPUFA levels and gestational duration in these populations. Among the Faroese subjects, significantly higher percentages of blood EPA and DHA were detected compared to Danish subjects, whereas DPA and AA values in both groups were similar. The Faroese subjects were found to have a gestational duration an average of 2 days longer (p=0.3) and a corresponding higher birth weight of 140 g
(p=0.1) compared to the Danish subjects, but these differences were not significant. After making allowance for seven potential confounders, an increase in duration of gestation of 5.7 days was found for each 20 percent increase in the ratio of erythrocyte EPA and DHA to AA in the Danish women (95% CI 1.4-10.1 days; p=0.02), but not in Faroese women (95% CI −2.0 to 3.3; p=0.6).
Increased gestational duration has also been investigated using observational studies of women who consumed seafood in geographical locations where there was higher exposure to environmental contaminants. Grandjean et al. (2001) examined a birth cohort from the Faroe Islands whose mothers consumed the meat and blubber from pilot whales in addition to regional fish. In a questionnaire, the women reported that they consumed, on average, 72 g of fish, 12 g of whale meat, and 7 g of whale blubber per day (Grandjean et al., 2001). The estimated intake of polychlorinated biphenyls (PCBs) for these women was 30 µg/g of blubber, and of mercury was 2 µg/g of whale meat (Grandjean et al., 2001). In addition to the increase in contaminant concentrations, there was an approximate 10-fold molar excess of selenium over mercury in serum samples from the subjects. The concentration of EPA in the cord1 serum from the infants of Faroese subjects was strongly associated with a maternal diet rich in marine fats. Gestational length showed a strong positive association with cord serum DHA concentration. Each 1 percent increase in the relative DHA concentration in cord serum phospholipids was associated with an increased duration of 1.5 days (95% CI 0.70-2.22), supporting the hypothesis that increased seafood intake may prolong gestation.
Lucas et al. (2004) concluded from an observational study that infants of the Inuit in Nunavik, Canada, had 2.2-fold higher omega-3 fatty acid (p<0.0001), 18.6-fold higher mercury (p<0.0001), 2.4-fold higher lead (presumably related to maternal smoking as ~85 percent of pregnant Inuit women studied smoked) (p<0.0001), and 3.6-fold higher PCB congener 153 cord blood levels (p<0.0001) compared to levels from infants in southern Québec. Despite the association of seafood intake with environmental contaminants, however, the Nunavik women whose infants were in the third compared to the first tertile of percentage of omega-3 fatty acid out of total highly unsaturated fatty acid (HUFA) cord blood values still had a mean 5.4-day longer gestation duration (95% CI 0.7-10.1; p<0.05). This study also showed a nonsignificant increase in mean adjusted birth weight in the third, compared to the first, tertile among Inuit (difference = 77 g, 95% CI −64 to 217).
Infants born preterm are at higher risk for neonatal complications and developmental delay. A reduction in the incidence of preterm birth (birth at <37 weeks) is desirable and could be associated with an increase in gestation duration among this at-risk population. Olsen and Secher (2002) evaluated the risk of preterm birth in relation to seafood intake in a prospective cohort study in Denmark. A questionnaire was used to evaluate intake of seafood, including roe, prawn, crab, and mussels, as well as fish-oil supplements, among participants. Quantification of fish consumption and EPA/DHA intakes was based on assumptions about the type and amount of fish reported in the questionnaire. Results of the analysis were based on seafood consumption only, since very few of the subjects took fish-oil supplements. Among the respondents, there was a trend of decreasing incidence of low birth weight, preterm birth, and intrauterine growth retardation with increasing fish consumption and increasing mean birth weight and duration of gestation among subjects. Women who were not smokers, primiparous women, teenagers, and women who had low weight, short stature, and without a high school education and cohabitant tended to fall into the low exposure group. This group had 3.57 (95% CI 1.14-11.14) times the risk of preterm birth and 3.60 (95% CI 1.15-11.20) times the risk of low birth weight (< 2500 g) delivery compared to women who consumed the highest amount of seafood. This study could be interpreted to suggest that a relatively low threshold intake of seafood EPA and DHA may increase gestation duration. However, Oken et al. (2004) found no relationship between seafood EPA and DHA intake and duration of gestation or risk of preterm birth in US women from Massachusetts.
Summary of Evidence
In summary, observational studies suggest and several experimental studies support that EPA/DHA supplementation or higher seafood intake is associated with an increased duration of gestation. In trials that show longer gestation duration, the populations studied varied markedly in both baseline EPA and DHA blood levels and in estimated amounts of EPA and DHA provided from supplements (see Appendix Table B-1c). The clinical significance of increased duration of gestation is not clear. In general, health professionals consider that the fetus benefits from a longer time in utero up to the point that the fetus is >4500 g, although the advantage remains theoretical.
Development in Infants and Children
During pregnancy, AA and DHA are delivered to the fetus via the placenta (Crawford et al., 1997). Hornstra et al. (1995) found that maternal essential fatty acid status progressively declines during pregnancy. There ap-
pears to be a greater transplacental gradient in proportions of AA and DHA at term than midterm. Such a difference is consistent with the decline in plasma concentration of DHA between the beginning and end of pregnancy and suggests that the placenta is progressively depleting maternal DHA as the fetus grows (Crawford, 2000). Although the mechanism of transport for AA and DHA has not been elucidated, Campbell et al. (1998) proposed and Larque et al. (2003) identified a fatty acid binding protein, p-FABPpm, in placental tissue that showed a higher binding capacity for DHA and AA than linoleic acid (LA) and oleic acid (OA).
Visual Acuity and Sensory-Motor Development
Because lower visual acuity was observed in rhesus monkeys with lower brain DHA (p<0.001) (Neuringer et al., 1984), this outcome has been the most studied in human infants relative to DHA intake. The first experimental studies that provided DHA, AA, and EPA to preterm infants demonstrated an increase in blood lipid content of these fatty acids as well as increases in visual acuity (Uauy et al., 1990; Carlson et al., 1993). Subsequently, DHA in cord blood and infant blood lipids has been used as an indicator of DHA exposure of the fetus or infant.
DHA status in infants is determined using blood as a biomarker because levels of DHA in the brain correlate with those in erythrocytes (Makrides et al., 1994). Previous studies have identified a correlation between dietary intake of AA, DHA, and other LCPUFAs; their respective levels in blood and erythrocyte phospholipids; and performance on tests of visual acuity and sensory-motor development in preterm infants (Uauy et al., 1990; Bjerve et al., 1993; Carlson et al., 1993). Observational studies that associate higher maternal EPA or DHA intake with higher stereoacuity or visual acuity in their infants are discussed below. Subsequently, maternal EPA/DHA supplementation or biochemical markers for their intake have been assessed as indicators of an association between increased intake levels of EPA/DHA and improved sensory-motor development in infants and young children.
Williams et al. (2001) observed that stereoacuity at 3.5 years of age in a subset of 435 healthy full-term children from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort was associated with breastfeeding, greater maternal age, and maternal antenatal consumption of fatty fish. After multiple logistic regression, only breastfeeding and maternal consumption of fatty fish at least once every 2 weeks remained significant predictors of higher stereoacuity (foveal acuity) in the children. Among 4733 women in the main ALSPAC cohort for whom both dietary intake and red blood cell DHA percentage were available, only intake of fatty fish was associated with higher red blood cell DHA levels, an indicator of higher maternal DHA status. Higher maternal DHA intake is also known to
increase human milk DHA (Jensen et al., 2005). Therefore, both variables associated with significantly higher stereoacuity are themselves influenced by maternal DHA intake, and both could be expected to result in increased DHA exposure of the fetus or infant.
Innis et al. (2001) conducted a prospective observational study of 83 infants who were breastfed at least 3 months. Blood and plasma fatty acid status were determined at 2 months; visual acuity at 2, 4, 6, and 12 months; and speech perception and object search at 9 months. Maternal milk DHA content was measured as an indicator of maternal DHA status, and this was linked with higher visual acuity (p<0.01) and higher ability to discriminate nonnative retroflex and phonetic contrasts (p<0.02) in infants at 2 months of age (see Appendix Table B-1d). Both of these tasks suggest more mature sensory development; however, additional measures would be required to make a definitive determination. Placement in front of the Teller Acuity Cards (the technique employed to measure visual acuity) does not require motor development such as head turning, but it is required on the infants’ performance on head-turning in response to sound. Thus, associations of DHA with motor function cannot be ruled out, particularly for the task related to hearing. Differences in cognitive development (discussed in the next section) also cannot be ruled out as a possible explanation for the association. However, factors that have been associated with cognitive development in infancy include speed, attention, and memory (Jacobson et al., 1992; Rose et al., 2004).
Cognitive developmental outcome has been assessed in a single randomized controlled trial in children born to women supplemented with EPA and DHA during pregnancy (see Appendix Table B-1d). Helland et al. (2001, 2003) evaluated children whose mothers consumed 2 g/day of DHA and EPA from cod liver oil for the last two trimesters of pregnancy compared with children of those receiving a corn oil supplement as control and found significantly higher Mental Processing Composite scores at 4 years of age in the children of supplemented mothers (p=0.049). Women continued to consume the cod-liver oil supplements or the control oil during lactation, most of the infants were breastfed, and infants from both groups began to receive a fish-oil supplement at ~1 month of age. The analysis of results suggested that all of the increase in IQ at 4 years of age was attributed to prenatal rather than postnatal exposure to EPA and DHA. The trial was conducted in Norwegian woman, whose seafood consumption considerably exceeds that of US women.
Auestad et al. (2001) found that breast milk DHA levels between Norwegian women in the control group was 0.51 percent compared to DHA
levels of 0.12 percent reported in breast milk of US women. Although the results of this study suggest that provision of EPA and DHA to neonates through supplemented formula might be greater than can be easily achieved through the diet, other investigators have reported higher levels of DHA in human milk than those reported by Auestad et al. (2001). Birch et al. (1998) compared visual acuity among infants who were fed DHA- and/or AA-supplemented formula with infants fed unsupplemented formula and breastfed infants. In comparing the red blood cell content of DHA among the infant groups, there was no significant difference in DHA level between the DHA-supplemented group and the breastfed group at week 0 and at week 52. However, there was a significant difference at week 17. In addition, a significant difference in the red blood cell AA concentration was found between the DHA-supplemented and breastfed groups only at week 17. As with the findings of Auestad et al. (2001), Birch et al. found that dietary supply of DHA is associated with optimal visual acuity.
Jensen and co-workers (2005) hypothesized that DHA supplementation of breastfeeding women would increase the DHA content of plasma lipids and improve visual and neuropsychological development in their infants. Women who planned to breastfeed were randomly assigned in a double-blinded manner to receive either a 200-mg algal DHA supplement or a control mixture of 50:50 soy and corn oil for the first 4 postnatal months. The results showed an increase in milk lipid and plasma phospholipid DHA levels of 75 and 35 percent, respectively, in the DHA-supplemented compared to control groups at 4 months. No differences were seen between supplemented and unsupplemented groups in either developmental indexes at 12 months or in visual acuity at 4 or 8 months. DHA-supplemented children subsequently showed higher Bayley Psychomotor Development scores at 30 months of age (p=0.005); and, in an earlier report, longer sustained attention at 5 years of age (Jensen et al., 2005). These outcomes suggest that 4 months of postnatal DHA supplementation via mother’s milk is associated with long-term motor and cognitive development as defined by the Bayley Psychomotor Development score in US children. Because neither the experimental trial by Helland et al. (2003) nor that by Jensen et al. (2005) found benefits in infancy from maternal DHA supplementation, but both found benefits in early childhood, these trials suggest that studies that stopped developmental follow-up in infancy may have missed benefits to children of improving maternal omega-3 fatty acid intake. These findings also suggest that the benefit of perinatal DHA intake may only be manifested after a latency period.
Oken et al. (2005) in a prospective observational cohort study of pregnant women from Massachusetts, Project VIVA (see Box 3-1), examined associations of maternal fish intake during pregnancy and maternal hair mercury at delivery with infant cognition in a subset for which these data
Longitudinal Studies of Beneficial Outcomes to Women and Children from Seafood Consumption
Project Viva is a longitudinal study of women and their children, investigating the “effects of mother’s diet and other factors during pregnancy on her health and the health of her child.”
From 1999 to 2002, more than 2600 pregnant women were enrolled from eight different Harvard Vanguard Medical Associate sites in the greater Boston area. Participating expectant mothers completed standardized interviews (on diet, exercise, medical history, stress, societal factors, and financial support) and provided blood samples several times during and after their pregnancies.
Participating mothers were also asked to enroll their babies in the study. Research assistants interviewed the mothers and measured the newborns’ body size and blood pressure in the first few days after birth (1703 women and 1203 newborns) and 6 months later (1266 mothers and 1210 babies). Hair samples from 210 women and umbilical cord blood from 1022 participants were also collected at delivery, and developmental tests were performed on the infants at 6 months of age.
At the child’s first, second, and fourth birthdays, the mothers were sent a questionnaire asking about their child’s health, diet, and environment, and at their third birthday, research assistants measured body size and blood pressure and performed additional developmental tests. The mother and child were also asked for another blood sample.
The Project Viva investigators hope to follow the Viva children throughout their lives, and are currently pursuing additional funding opportunities. The information provided here, along with updates, articles, facts, etc., can be accessed at http://www.dacp.org/viva/index.html [accessed November 2, 2005].
Avon Longitudinal Study of Parents and Children (ALSPAC)
“The Avon Longitudinal Study of Parents and Children (ALSPAC) also known as ‘Children of the 90s’ is aimed at identifying ways in which to optimize the health and development of children. The main goal is to understand the ways in which the physical and social environments interact, over time, with the genetic inheritance to affect the child’s health, behavior and development.”
Over 14,500 pregnant women, resident in Avon, UK, were enrolled in this study, along with almost 14,000 of their children. Throughout their pregnancies, expectant mothers (and sometimes their partners) received various questionnaires to identify features of the early environment that might affect the fetus and to acquire information on the mother’s
demographic characteristics; past medical, social, and environmental history; and attitudes, activities, and emotional well-being. Maternal blood and urine samples were also obtained when the mothers gave routine samples at their respective clinics.
During delivery, cord blood and umbilical cord samples were collected, along with the placentas from births at two major hospitals. After delivery, further questionnaires were distributed to both the mothers from 4 weeks and throughout the next 9.5 years and to the children from 65 months until 9.5 years of age. During these years, samples of the child’s hair and nail clippings, primary teeth, blood, and urine were also collected. For a complete list of topics covered on all questionnaires, see the ALSPAC website (http://www.ich.bristol.ac.uk/protocol/section3.htm).
“ALSPAC has the long-term aim of following the children into adulthood and thus will be set to answer questions related to prenatal and postnatal factors associated, for example, with schizophrenia, delinquency, and reproductive failure on the one hand, and realisation of full educational potential, health and happiness on the other.” The information provided here, along with updates, articles, facts, etc., can be accessed at http://www.ich.bristol.ac.uk/welcome/index.shtml [accessed May 30, 2006].
were available. After adjusting for participant characteristics with linear regression, higher cognitive performance was associated with higher seafood intake. Each additional serving of fish per week was associated with a 4-point higher visual recognition memory (VRM) score at 6 months of age (95% CI 1.3-6.7), although an increase of 1 ppm in mercury was associated with a decrement in the VRM score of 7.5 (95% CI −13.7 to −1.2). VRM scores were highest among infants of women who consumed more than 2 servings of fish per week and had hair mercury levels less than or equal to 1.2 ppm. The study concluded that higher fish consumption was associated with better infant cognition but higher mercury levels were associated with lower cognition.
Daniels et al. (2004) studied a subset of 1054 children from the British ALSPAC cohort (see Box 3-1) for associations between maternal fish intake during pregnancy and infant development of language and communication skills in relation to mercury exposure. This study found an association between maternal fish intake during pregnancy and comprehension on the MacArthur Communicative Development Inventory (MCDI) (consumption of 1–3 or 4+ fish meals/week decreased odds of a low MCDI score, p<0.05) and the Denver Developmental Screening Test (DDST) (consumption of 1–3
or 4+ fish meals/week decreased odds of a low DDST score, p<0.05) at 15 and 18 months, respectively. In this cohort, mercury levels were low and not associated with measures of neurodevelopment. Similar findings of association between maternal DHA status and more mature attentional development in infancy (Willatts et al., 2003b; Colombo et al., 2004) and lower distractibility among toddlers (Colombo et al., 2004) were reported.
Some animal studies suggest that low brain DHA early in development produces adverse effects on behavior that are not reversible even when brain DHA content is returned to normal (Kodas et al., 2004; Levant et al., 2004). No studies have been designed to address possible programming of development in human infants, but the animal work suggests that timing of brain DHA accumulation should be considered as a variable in human studies.
Cheruku et al. (2002) investigated whether central nervous system integrity in newborns, measured with sleep recordings, was associated with maternal DHA status. Plasma phospholipid fatty acids, including DHA, were measured in 17 women at parturition, and infant body movement and respiratory patterns were measured on postpartum days 1 and 2. Infants born to mothers in the high-DHA group had significantly lower ratios of active compared to quiet sleep patterns and less total active sleep compared to infants of low-DHA mothers. The conclusion from this study is that infants born to mothers with higher plasma DHA had more mature sleep patterns (p<0.05) compared to infants of mothers with lower plasma DHA levels (see Appendix Table B-1d).
Infant and Child Allergy
Few studies have been carried out to examine whether supplementation with fish oil is associated with reducing the inflammatory responses to allergens. Hodge et al. (1998) assessed the clinical and biochemical effects in asthmatic children of fish-oil supplementation and a diet that increases omega-3 and reduces omega-6 fatty acids. Although the supplemented group had higher plasma levels of omega-3 fatty acids and lower stimulated tumor necrosis factor-α production, there was no effect of the intervention on the clinical severity of asthma in the children. Dunstan et al. (2003) examined associations between fish-oil supplementation and levels of immune factors (cytokines and IgE) in a randomized, double-blind, placebo-controlled trial. No significant differences were found in interleukin (IL-13) (p=0.025) and cytokine levels within the treatment group, except that neonates of supplemented mothers had significantly lower levels of IL-13. In a subset of children from the ALSPAC cohort, Newson et al. (2004) found no relationship
between cord and maternal red blood cell EPA/DHA and either eczema at 18 to 30 months (p>0.05) or wheezing at 30 to 42 months (p>0.05). These findings do not provide strong support for the hypothesis that exposure to omega-3 fatty acids from fish oil in utero or through breast milk could decrease the incidence of wheezing and atopic disease in early childhood (see Appendix Table B-1e).
Summary of Evidence
The strongest evidence of benefit for higher maternal seafood or EPA/ DHA intake is an increase in gestation duration, with anticipated benefits to the newborn. Populations or subgroups within populations who have the lowest baseline consumption of seafood may show the greatest benefit in duration of gestation with higher EPA/DHA intake. Observational and experimental studies offer evidence that maternal DHA intake can benefit development of the offspring; however, there are large gaps in knowledge that need to be filled by experimental studies.
The average EPA/DHA intake among US women is considerably below that of most other populations in the world and the majority of the data on benefits to infants and children from increased DHA levels comes from populations outside the United States and/or from studies using supplementation rather than seafood consumption.
BENEFITS TO INFANTS FROM POSTNATAL SUPPLEMENTATION THROUGH FORMULA
Although the focus of this report is seafood intake, the committee reviewed evidence for benefits associated with DHA-supplemented infant formulas to consider whether this data supports the previously discussed findings on benefits associated with seafood consumption or fish-oil supplementation in pregnant and lactating women. Formula-fed infants have much lower red blood cell phospholipid DHA levels than breastfed infants (Putnam et al., 1982; Carlson et al., 1986; Sanders and Naismith, 1979). DHA supplementation may increase brain DHA levels and improve visual acuity and various behavioral domains that are dependent upon brain function. Since 2002, infant formulas supplemented with DHA from algal oil in combination with a fungal source of AA have been commercially available in the United States. Randomized clinical trials have been conducted using a variety of sources of EPA/DHA including fish oil, tuna eye socket oil, egg phospholipid, total egg lipids, and algal oils to test for associations between DHA supplementation and improved developmental outcomes in formula-fed infants.
Studies by Carlson et al. (1993; 1996a,b; 1999) have tested the effect of DHA-supplemented formula on infant visual acuity using the Teller Acuity Card (TAC) procedure. The TAC procedure is subjective because it assesses an integrated behavioral response and may be influenced by nonvisual factors such as alertness, attention, and motor control (Lauritzen et al., 2001). Studies using the TAC procedure found significantly higher visual acuity in the groups receiving supplemented formula; higher visual acuity was found throughout infancy in trials that employed the sweep visual evoked potential (VEP) acuity procedure (Birch et al., 1992, p<0.025; 1998, p<0.05). VEP measures involve placing electrodes over the visual cortex to measure responses to different grating stimuli. This is not a subjective measure of visual acuity and also is more sensitive at detecting the threshold of visual acuity.
Higher VEP acuity was also found in studies on term infants that used formulas supplemented with both DHA and AA after weaning from breast milk (Hoffman et al., 2003, p<0.0005; Birch et al., 2002, p<0.003). Two trials that measured VEP acuity in preterm (Bougle et al., 1999) and term infants (Makrides et al., 2000) did not find any association between infant visual acuity and DHA-supplemented formula. However, these studies measured acuity using a flash of light rather than a sweep of high-contrast bands of graded spatial frequencies.
With the exception of Bougle et al. (1999), all of the previously discussed preterm infant trials and about half of the term infant trials that measured visual acuity have found higher visual acuity at some age. Uauy et al. (2001) in a review and San Giovanni et al. (2000a,b) in meta-analyses of previous studies concluded that DHA supplementation of infant formula was beneficial to visual acuity development in both preterm and term infants. A Cochrane systematic review of nine randomized controlled trials, however, concluded that there was no association between DHA supplementation and increased visual acuity or general development in term infants (Simmer, 2005) (see Appendix B-1f).
Cognitive and Motor Development
Many of the experimental trials that have studied postnatal DHA supplementation have also measured nonvisual developmental outcomes, most commonly global scales of development such as the Bayley Scales of Infant Mental Development Index (MDI) and Psychomotor Developmental Index (PDI) or a related test, Brunet-Lezine’s developmental quotient (see Appendix Table B-1g). The majority of the extant published trials were reviewed by Gibson et al. (2001) and Uauy et al. (2001). Two trials in term infants found
higher apparent motor development in infancy with DHA supplementation, as tested by the motor aspect of the Brunet-Lezine (p<0.05) (Agostoni et al., 1995) or general movement assessment (p=0.032) (Bouwstra et al., 2003). However, neither study found any benefit for movement or psychomotor development when the infants were tested again at 18 months of age. Birch et al. (2000) found higher (by 7 points) Bayley MDI scores at 18 months of age in term infants who consumed a formula supplemented with DHA and AA, compared to those who consumed the control formula (p<0.05), whereas Lucas et al. (1999) found no benefit of DHA and AA on either the Bayley MDI or PDI of term infants at 18 months of age.
It has been hypothesized that preterm infants may benefit more than term infants from DHA supplementation. Fewtrell et al. (2002, 2004) found no effect of supplementation on Bayley MDI of preterm infants in two other larger longitudinal studies.
Among smaller studies in preterm infants, however, Clandinin et al. (2005) in a randomized controlled trial found significant increases in both the Bayley MDI and PDI in preterm infants given DHA- and AA-supplemented formula (p<0.05) whereas van Wezel-Meijler et al. (2002) did not; Carlson et al. found higher Bayley MDI but not PDI at 12 months in only one of two preterm trial (Carlson et al., 1994, 1997).
Global tests such as the Bayley Scales of Infant Development and the Brunet-Lezine administered in infancy may be less related to performance on cognitive tests in childhood than more specific tests of attention and problem-solving (Carlson and Neuringer, 1999; Jacobson, 1999). While there is limited evidence from global tests of infant development (e.g., higher Bayley MDI scores in properly powered trials) to conclude there may be cognitive benefits of DHA supplementation for either preterm or term infants, evidence in support of benefits associated with DHA supplementation from specific tests in infancy that are more strongly related to several developmental parameters is mixed. O’Connor et al. (2001) assessed, among other measures, developmental outcomes in infants who received DHA- and AA-supplemented formula compared to controls. No differences were found in the Bayley MDI at 12 months, although the motor development index scores were higher among the supplemented infants who weighed less than 1250 g at birth compared to the nonsupplemented controls (p=0.007). When Spanish-speaking and twin infants were excluded from the analyses scores for the MacArthur Communicative Development Inventories, the supplemented infants had higher vocabulary comprehension at 14 months (p=0.01 for the egg triglyceride/fish group; p=0.04 for the fish/fungal group).
While there is limited evidence from global tests of infant development (e.g., higher Bayley MDI scores in properly powered trials) to conclude there may be cognitive benefits of DHA supplementation for either preterm or term infants, there is collective evidence of benefits associated with
supplementation from specific tests in infancy that are better related to later cognitive function, e.g., higher novelty preference (O’Connor et al., 2001, p=0.02); duration of looking (Carlson and Werkman, 1996, p<0.05; Werkman and Carlson, 1996, p<0.05); and problem-solving (Willatts et al., 1998a, p=0.021; 1998b, p<0.02); although, excepting Willatts et al., these benefits have been found in preterm infants. Infants who received the supplemented formula had significantly more intentional solutions than infants who received the control formula (median 2 vs. 0; p=0.021). Intention scores (median 14.0 vs. 11.5; p=0.035) were also increased in this group (Willatts et al., 1998a).
Among studies assessing postnatal DHA supplementation, Willatts et al. (2003a) identified a long-term cognitive benefit, specifically, higher scores and speed on the matching familiar figures test (MFFT) at school age, in children provided DHA formula supplementation compared to unsupplemented formula as infants. Cognitive benefits reported at school age after postnatal supplementation are longer sustained attention at 5 years (Jensen et al., 2004) and higher IQ at 4 years of age noted in children exposed to higher DHA through maternal supplementation (Helland et al., 2003).
Language is highly associated with IQ, and studies that have assessed some aspect of early language are included here under the general topic of cognitive function. Scott et al. (1998) reported lower vocabulary comprehension (p=0.17) and production scores (p=0.027) with the MacArthur Communicative Development Inventories in term infants supplemented with formula containing DHA compared to control and DHA+AA formula groups, but not the human milk group. No effects of early DHA feeding on language were apparent at three years of age when children were tested again (Auestad et al., 2003). In a term study supported by Ross Laboratories, Auestad et al. (2001) found, in a randomized controlled trial among term infants, significantly higher vocabulary production in those fed DHA and AA from fish and fungal sources compared to DHA and AA from egg triglyceride (p<0.05). Neither group differed, however, from controls on this or any other MacArthur subscore.
At most, specific outcomes have been measured in only one or two individual trials and these have been measured at different ages. Even though numerous developmental outcomes have been identified that collectively suggest there are benefits associated with EPA/DHA supplementation, it is difficult to subject the studies in total to a systematic review, because of the differences in experimental design among the studies. The benefits of postnatal DHA supplementation for cognitive development need further study because of the heavy reliance on global assessments as outcomes and the limited employment of more specific developmental outcomes. Furthermore, the majority of trials stopped looking at development well before children
reached school age, when more sophisticated measures of cognitive function may be employed.
Allergy and Immunity
Reviews of the effects of fatty acid supplementation on immune function in the neonate have not provided strong support for beneficial effects (Calder et al., 2001; Field et al., 2001) (see Appendix Table B-1h). One human study showed positive effects of human milk and formulas containing DHA and AA compared to formulas without DHA and AA in the form of lower CD4RO+ immune cells and IL-10 cytokine production (Field et al., 2000). However, experimental studies of DHA-supplemented lactating women have not found any effect of supplementation on milk cytokines at intakes as high as 140 mg/day EPA and 600 mg/day DHA (Hawkes et al., 2002) or 3.7 g EPA/DHA from fish oil (28 percent EPA and 56 percent DHA) in a group selected to be at high risk for allergic disease (Denburg et al., 2005).
Summary of Evidence
The strongest evidence of benefit for postnatal DHA supplementation in formula-fed preterm and term infants is higher visual acuity, an outcome that has been measured repeatedly in clinical trials. In addition, some positive effects have been found on cognitive function in infancy and childhood in both experimental and observational studies and in relation to both pre- and postnatal DHA intake. Reviews that take into account all lines of evidence have concluded that omega-3 fatty acids can be beneficial to cognitive development (Cohen et al., 2005; McCann and Ames, 2005), whereas reviews that rely strictly on published results from experimental trials limited to global assessments of cognitive development, e.g., the MDI, do not offer strong support (Simmer, 2005; Simmer and Patole, 2005).
Results of some experimental trials suggest that postnatal DHA infant formula supplementation benefits cognitive function as well. Specific behavioral domains such as novelty preference and duration of looking are more related to later function than global tests of development (Carlson and Neuringer, 1999; Jacobson, 1999). Bryan et al. (2004) and Cheatham et al. (2006) postulate that benefits associated with postnatal infant formula supplementation may have been underestimated as a result of the emphasis on global tests of infant development as well as the paucity of outcomes measured in childhood.
Results from animal studies indicate a possible role for the timing of exposure to DHA in development. These studies testing variable levels of brain DHA on neurotransmitters such as dopamine and serotonin (Delion et al., 1996; de la Presa Owens and Innis, 1999; Chalon et al., 2001; Kodas et al., 2004) and responses of these neurotransmitter systems in rodent and pig models suggest there is a critical window for brain DHA accumulation for some aspects of development and that behavior remains abnormal even when brain DHA is remediated well before testing (Kodas et al., 2004; Levant et al., 2004). These animal studies, although not the subject of this review, provide suggestive evidence that the presence of DHA could be critical during early periods of human brain development.
BENEFITS TO CHILDREN
The few studies that exist of EPA/DHA supplementation in children have focused on the potential for EPA/DHA to modify diseases, i.e., they have not been designed to evaluate if DHA is needed in healthy children after infancy for optimal neurological development or physiological function. The majority of studies in children relate to diseases and disorders that involve brain and behavior, especially attention deficit hyperactivity disorder (ADHD) or dyslexia, though one experimental study evaluated possible effects of supplementation on symptoms of allergy. Few randomized trials have been carried out to test whether EPA/DHA supplementation in children reduced symptoms of ADHD, and there is little evidence for benefits. Neither can any conclusions yet be drawn about the possible role of seafood or EPA/DHA supplementation in the prevention of asthma. There is interest in the clinical benefits of EPA/DHA in certain childhood diseases and it is being actively studied, but such therapeutic interventions are beyond the scope of this report (see Appendix Table B-1i and B-1j).
Seafood is a nutrient-rich food that makes a positive contribution to a healthful diet. It is a good source of protein, and relative to other protein foods, e.g., meat, poultry, and eggs, is generally lower in saturated fatty acids and higher in the omega-3 fatty acids EPA and DHA as well as selenium;
The evidence to support benefits to pregnancy outcome in females who consume seafood or fish-oil supplements as part of their diet during pregnancy is derived largely from observational studies. Clinical trials and epidemiological studies have also shown an association between increased duration of gestation and intake of seafood or fish-oil supplements. Evidence
that the infants and children of mothers who consume seafood or EPA/DHA supplements during pregnancy and/or lactation may have improved developmental outcomes is also supported largely by observational studies;
Increased EPA/DHA intake by pregnant and lactating women is associated with increased transfer to the fetus and breastfed infant.
A number of observational studies show a positive association between maternal blood or breast milk DHA levels and a range of developmental outcomes in infants and children.
Two experimental studies of maternal EPA/DHA supplementation found cognitive benefits for the children when they were 4 or 5 years of age.
Because these two studies differed dramatically in timing of EPA/DHA supplementation (pre- and postnatally or postnatally), source (cod-liver oil or algal DHA), and amount (2 g or 200 mg EPA/DHA) and, likely, in usual seafood intake (Norway or US residents), insufficient data are available to define an ideal level of EPA/DHA intake from seafood in pregnant and lactating women;
A large number of experimental trials have provided DHA directly to human infants through infant formula and have found benefits for infant and child neurological development. These trials offer the best evidence that infants/children would benefit from increased DHA in breast milk and increased maternal seafood intake.
Visual acuity has been measured in the most trials and is increased by DHA supplementation, with preterm infants more likely to benefit than term infants.
Cognitive benefits of postnatal DHA supplementation with formula have also been found in infancy and early childhood. However, the number of trials has been limited and the specific outcomes varied, precluding a systematic review;
At present there is no convincing evidence that ADHD, other behavioral disorders, and asthma in children can be prevented or treated with seafood or EPA/DHA consumption.
Part II: Benefits for Prevention of Adult Chronic Disease
CARDIOVASCULAR DISEASE, CARDIOVASCULAR MORTALITY, AND ALL-CAUSE MORBIDITY AND MORTALITY
Most evidence for benefits of seafood consumption and EPA/DHA supplementation associated with coronary heart disease (CHD) mortality is inferred from interventional studies of populations at risk, observational studies in the general population, and mechanistic studies. Early investigations of the association between diet and cardiovascular disease led to the recommendations to restrict dietary fat and cholesterol as a public health intervention to prevent CHD. However, subsequent observations suggest a more complex association between dietary fat intake and cardiovascular pathophysiology (Howard et al., 2006).
Cardiovascular Benefits to Specific Population Groups
Certain populations in the Mediterranean region consuming a diet relatively high in monounsaturated fat from olive oil enjoyed some of the lowest cardiovascular disease rates in the world. Another intriguing observation came from the comparison of Greenland Eskimo populations that had low mortality rates from CHD compared to the mainland Danish population, despite having a diet rich in fat (Bang et al., 1971). Bang et al. (1971) hypothesized that genetics, lifestyle, and the high content of EPA/DHA in the diet (which consisted primarily of fish, sea birds, seal, and whale) may account for the low cardiovascular mortality rate observed in this population. Plasma lipid patterns examined in this study showed that most types of lipids were decreased compared to a Danish cohort control and Eskimos living in Denmark (p<0.001). Remarkably, the levels of pre-β lipoprotein (p<0.001) and, consequently, plasma triglycerides (p<0.001) were much lower among the Greenland Eskimos than the Danish controls. As a result of this and related studies, seafood consumption, including or even especially of seafood rich in fat, has received increased attention as a public health means to decrease the burden of cardiovascular disease.
Several observational studies have shown an inverse association between seafood consumption and the risk of cardiovascular disease, most probably due to reductions of sudden death (reviewed in Wang et al., 2006). Some studies, however, have not found a significant association between seafood consumption and cardiovascular disease. These discrepancies may be due to
differences among study populations and the type, amount, or preparation method of seafood consumed. For example, among studies reviewed, it has been hypothesized that the benefit of greater amounts of seafood may be more apparent in populations that have low seafood intakes and are at higher risk for cardiovascular disease (Marckmann and Gronbaek, 1999). Although initial studies suggested an optimal level of seafood consumption, more recent analyses have brought this observation into question and have suggested a more continuous association between seafood consumption and prevention of cardiovascular disease (p for trend = 0.03) (He et al., 2004b).
The possible mechanisms by which seafood or EPA/DHA supplements are cardioprotective include demonstrated antiarrhythmic, antithrombotic, antiatherosclerotic, and anti-inflammatory effects. Ismail (2005) and Calder (2004) linked the consumption of EPA/DHA to improved endothelial function, lower blood pressure, and lower fasting and postprandial triglyceride concentrations. Furthermore, populations and individuals who consume large amounts of seafood also tend to consume smaller amounts of alternative protein sources, such as beef, that are rich in saturated fats that are known to increase blood cholesterol levels and to elicit a proinflammatory state (Weisberger, 1997; Baer et al., 2004; Miller, 2005). Any one or a combination of these effects may explain the association between seafood intake and cardiovascular protection observed in some studies.
It is important to note that supplementation trials have been mostly conducted in individuals with existing cardiovascular disease for secondary prevention. Therefore, these findings are relevant to the progression of existing cardiovascular disease, but may not be relevant to the development of new cardiovascular disease in the general population, as these two processes may have different biological determinants. On the other hand, many observational studies of seafood consumption have been conducted in the general population and are relevant to primary prevention and the development of cardiovascular disease in the first place. Again, as determinants of cardiovascular disease development may be different from those of disease progression, the pertinence of these observational studies to secondary prevention is limited. These studies are, however, more informative than supplementation studies to assess the role of seafood in a healthy diet. The committee has tried to clearly differentiate these two types of studies and the conclusions that can be derived from them in the discussions that follow.
Seafood or Omega-3 Fatty Acid Consumption and Coronary Heart Disease
Randomized Controlled Trials in High Risk Populations
No randomized controlled trials have been carried out on subjects representative of the general population, as the small expected number of
cardiovascular events would require large and perhaps impractical sample sizes and/or follow-up periods. In an early randomized trial of men who had already experienced a myocardial infarction (MI), Burr et al. (1989) reported that dietary advice, including advice to increase consumption of seafood, was associated with a significant reduction (29 percent) in 2-year all-cause mortality (p<0.05). An extended follow-up of these subjects, however, did not suggest any substantial long-term survival benefit (Ness et al., 2002). In contrast, in a separate study of male subjects over age 70 with stable angina, Burr et al. (2003) reported higher, and not lower, cardiovascular mortality in the group assigned to receive advice to consume seafood or n-3 fatty acid supplements (p=0.02). The reports by Burr et al. (2003) and Ness et al. (2002) seemed to some researchers a serious challenge to the idea that patients with coronary artery disease (CAD) and those at increased risk for heart disease should be advised to increase consumption of seafood rich in EPA/DHA or to take fish-oil supplements (Marckmann, 2003). A more detailed review of the literature considered by the committee is provided in Appendix B-2.
The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI-Prevenzione) trial (GISSI Prevenzione Investigators, 1999) examined associations between dietary supplementation with EPA/DHA from fish oil, vitamin E, or combined treatment, and incidence of a second MI. From October 1993 to September 1995, 11,324 Italian patients surviving recent (≤ 3 months) MI were randomly assigned supplements of EPA/ DHA (1 g daily, n=2836), vitamin E (300 mg daily, n=2830), both (n=2830), or none (control, n=2828) for 3.5 years. The primary combined efficacy measurement endpoints of death, nonfatal MI, and nonfatal stroke were significantly reduced by EPA/DHA treatment; the relative risk reduction (RRR) was 15 percent for death, nonfatal MI, or nonfatal stroke (RR=0.85; 95% CI 0.74-0.98). Intention-to-treat analyses were done according to a (two-way) factorial design and by a (four-way) treatment group.
Results showed that EPA/DHA, but not vitamin E supplementation, significantly reduced risk of death, nonfatal MI, and nonfatal stroke (RR=0.90, 95% CI 0.82-0.99, two-way analysis; RR=0.85, 95% CI 0.74-0.98, four-way analysis). A decrease was found in the risk of all-cause mortality (14 percent [95% CI 3-24] two-way, 20 percent [95% CI 6-33] four-way) and cardiovascular death (17 percent [95% CI 3-29] two-way, 30 percent [95% CI 13-44] four-way). There was no significant effect between the combined treatment and EPA/DHA for the primary endpoints listed above. This study showed that dietary supplementation with fish oil as a source of EPA/DHA led to a statistically significant benefit in people with a history of MI; however, effects on fatal cardiovascular events require further exploration.
The percentage of patients who experienced at least one cardiac event (cardiac death, resuscitation, recurrent MI, or unstable angina) was 28 in
the EPA/DHA group and 24 in the corn oil (control) group. There was no significant difference in prognosis between the groups for either single or combined cardiac events. Total cholesterol concentrations decreased in both groups, although intergroup differences were not significant. On average, high density lipoprotein (HDL) cholesterol increased by 1.1 percent in the EPA/DHA group and by 0.55 percent in the corn oil group (p=0.0016) per month. In the same time period, triacylglycerol concentrations decreased by 1.3 percent in the EPA/DHA group, whereas they increased by 0.35 percent in the corn oil group per month (p<0.0001). Thus, no clear clinical benefit of a high-dose concentrate of EPA/DHA acids compared with corn oil was shown, despite a favorable effect on serum lipids.
In addition to the randomized clinical trials described above, another commonly cited study in support of the benefits of fish oil consumption comes from the Indian Study on Infarct Survival. This was reported by Singh et al. (1997) as a randomized, placebo-controlled study of 360 Indian patients enrolled within 1 day after MI into one of three groups: a group receiving fish oil (1.08 g/day EPA and 0.72 g/day DHA), a group receiving mustard seed oil (20.0 g/day, ALA content 2.9 g/day), and a placebo (control) group receiving aluminum hydroxide (100 mg/day). The combined primary end point was total cardiac events (sudden cardiac death plus total cardiac deaths plus nonfatal reinfarction). According to the authors, the fish oil group had a 30 percent lower risk in total cardiac events after 1 year, compared to the placebo group (RR=0.70; 95% CI 0.29-0.90). However, serious concerns have been raised about the performance and conclusions of this trial and other related publications from this investigator (White, 2005; Al-Marzouki et al., 2005) and therefore, based on these caveats, the evidence in support of EPA/DHA consumption should be considered after exclusion of this widely used report.
Taken together, these randomized trials showed conflicting results for an effect of EPA/DHA on cardiovascular events and no long-term protective effect of seafood intake in subjects with a previous history of CHD. These findings are consistent with a systematic Cochrane review that concluded that “It is not clear that dietary or supplemental omega-3 fats alter total mortality, combined cardiovascular events, or cancers in people with, or at high risk of, cardiovascular disease or in the general population” (Hooper et al., 2005) and with the more recent work of Hooper et al. (2006).
Observational Studies of Seafood or EPA/DHA Intake in the General Population
Several studies have addressed a possible association of seafood or EPA/ DHA intake with cardiovascular deaths or events in the general population, including individuals with a previous history of CHD. Whelton et al. (2004)
conducted a meta-analysis of observational studies to determine if seafood consumption was associated with lower fatal and total CHD in people with and without a history of heart disease. The analysis included English-language articles published before May 2003. A total of 19 observational studies (14 cohort and 5 case-control) met the prestated inclusion criteria that the studies were conducted in adult humans, used an observational case-control or cohort design, compared a group that consumed seafood regularly with one that did not, used CHD as an outcome, and reported an association as a relative risk (RR), hazard ratio (HR), or odds ratio (OR) of CHD by category of seafood consumption. A random effects model was used to pool data from each study. The analysis found that regular fish consumption compared to little to no fish consumption was associated with a relative risk of 0.83 (95% CI 0.76-0.90; p<0.005) for fatal CHD and 0.86 (95% CI 0.81-0.92; p<0.005) for total CHD.
He et al. (2004b) also examined associations between seafood consumption and CHD mortality in people with or without a history of heart disease using a meta-analysis design. A database was developed based on 11 eligible studies that included 13 cohorts consisting of a total of 222,364 individuals and an average follow-up of 11.8 years. Pooled RR and 95 percent CI for CHD mortality were calculated by using both fixed-effect and random-effect models. Possible dose-response relationships were assessed using a linear regression analysis of the log RR weighted by the inverse of variance. The results of the analysis found a consistent inverse association between seafood consumption and CHD mortality rates and suggested a dose-response association. The pooled multivariate RRs for CHD mortality, compared to seafood intake less than once per month, were 0.89 (95% CI 0.79-1.01) for seafood intake one to three times per month, 0.85 (95% CI 0.76-0.96) for once per week, 0.77 (95% CI 0.66-0.89) for two to four times per week, and 0.62 (95% CI 0.46-0.82) for five or more times per week.
Each 20 g/day increase in seafood intake lowered the risk of CHD mortality by 7 percent (p for trend = 0.03). These results indicate that mortality from CHD may be significantly reduced by eating seafood as infrequently as once per week, with increasing benefit with increasing intake. This meta-analysis does not provide subgroup analyses and does not include case-control studies.
The most recent meta-analysis by König et al. (2005) provides another quantitative assessment of the association between seafood consumption and CHD. In this meta-analysis, all studies identified of primary prevention, i.e., incidence of CHD in people without a history of CHD, were observational studies that assessed seafood intake, while all studies of secondary prevention, i.e., in people with a history of CHD, were randomized trials using EPA/DHA supplements at doses difficult to achieve with seafood consumption. The authors of this meta-analysis were able to provide a
quantitative assessment of the association of seafood consumption with CHD mortality and nonfatal MI in people without a history of CHD, but concluded that insufficient evidence supported a quantitative assessment of seafood consumption for secondary prevention. From this study, it was estimated that, compared to not eating seafood, eating a small amount of seafood—as little as half a serving per week—was associated with a reduction in risk of cardiovascular death of 17 percent (95% CI 8.8-25.0) and a reduction in risk of nonfatal MI of 27 percent (95% CI 21-34). Each additional weekly serving of seafood was associated with a further decrease in the risk of cardiovascular death of 3.9 percent (95% CI 1.1-6.6), but no additional benefit was statistically significant for the risk of nonfatal MI. The Agency for Healthcare Research and Quality (AHRQ) reviews are systematic reviews that synthesize observational and experimental studies in a qualitative way (see Appendix B). The conclusions of the AHRQ reviews are also based on intervention studies in groups at risk. In contrast, the studies by Whelton et al., He et al., and Konig et al. are meta-analyses that quantitatively combined observational studies. Meta-analyses are usually considered stronger evidence than systematic reviews.
Taken together, these meta-analyses of observational studies suggest a negative association between seafood consumption and CHD or death, particularly in individuals without a prior history of CHD. Recent data suggest that even small amounts of seafood consumption may be associated with a decreased risk for CHD or death (Schmidt et al., 2005a,b). These results should, however, be interpreted with caution, as they are based on observational studies and are thus subject to residual confounding. In other words, based on observational studies only, it is difficult to exclude the possibility that seafood intake may just be a marker for healthier lifestyle, and that no causal association exists between seafood consumption and cardiovascular protection (see Appendix Tables B-2a and B-2b).
The only reported studies of the association between seafood consumption and stroke have been observational (see Appendix Table B-2b). He et al. (2004a) quantitatively assessed the relationship between seafood consumption and risk of stroke using a meta-analysis of nine cohorts from eight studies. Pooled RR and 95 percent CI of risk for stroke were estimated by variance-based meta-analysis. These results demonstrated that consumption of seafood was inversely related to stroke risk, particularly ischemic stroke. Even infrequent seafood consumption (as seldom as 1 to 3 times per month) may be protective against the incidence of ischemic stroke compared to seafood consumption less than once per month. The pooled RRs for all stroke, compared to individuals who consumed seafood less than once a month,
were 0.91 (95% CI 0.79-1.06) for individuals with seafood intake one to three times/month, 0.87 (95% CI 0.77-0.98) for once/week, 0.82 (95% CI 0.72-0.94) for two to four times/week; and 0.69 (95% CI 0.54-0.88) for five or more times/week (p for trend = 0.06).
Three large cohort studies with data on stroke subtypes were used in a stratified meta-analysis to determine pooled RRs across five categories of seafood intake for ischemic stroke. Compared to individuals who consumed seafood less than once a month, the RRs were 0.69 (95% CI 0.48-0.99) for individuals with seafood intake one to three times/month, 0.68 (95% CI 0.52-0.88) for once/week, 0.66 (95% CI 0.51-0.87) for two to four times/week; and 0.65 (95% CI 0.46-0.93) for five or more times/week (p for trend = 0.24) (He et al., 2004a).
For hemorrhagic stroke, compared to individuals who consumed seafood less than once a month, the RRs were 1.47 (95% CI 0.81-2.69) for individuals with seafood intake one to three times/month, 1.21 (95% CI 0.78-1.85) for once/week, 0.89 (95% CI 0.56-1.40) for two to four times/ week, and 0.80 (95% CI 0.44-1.47) for five or more times/week (p for trend = 0.31) (He et al., 2004a). In a separate recent meta-analysis, Bouzan et al. (2005) quantified the association of seafood consumption with stroke risk, based on five cohort studies and one case-control study. Although a decrease of 12 percent in the risk of both ischemic and hemorrhagic strokes was observed with a small amount of seafood consumption compared to no seafood consumption, this result was not statistically significant (95%CI: increased risk of 1 percent to decreased risk of 25 percent). Furthermore, there was no evidence for further decrease in the risk of strokes with increasing seafood intake above a small amount: 2 percent decrease in risk per serving per week (95%CI: increased risk of 2.7 percent to decreased risk of 6.6 percent).
Skerrett and Hannekens (2003) reviewed ecologic/cross-sectional and case-control studies of associations between consumption of seafood or EPA/DHA and stroke risk. Five prospective studies showed inconsistent results: no association, a possible inverse association, and three significant inverse associations. In the most recent Nurses’ Health Study, the relative risk for total stroke was somewhat lower among women who regularly ate seafood compared to those who did not, although there was no significant difference. After adjusting for age, smoking, and other cardiovascular risk factors, a significant decrease in the risk for thrombotic stroke was observed among women who ate seafood at least two times per week compared with those who ate seafood less than once per month (RR=0.49; 95% CI 0.26-0.93). The decrease observed among women in the highest quintile of EPA/ DHA intake was not significant nor was an association observed between consumption of seafood or fish oil and hemorrhagic stroke.
Data from Mozaffarian et al. (2005) suggest that the type of seafood
meal may be an influential variable. Mozaffarian and collaborators investigated the association between seafood consumption and stroke risk in the Cardiovascular Health Study, an older population in whom the disease burden is high. Dietary intakes were assessed in 4775 adults aged ≥65 years (range, 65–98 years) and free of known cerebrovascular disease at baseline in 1989–1990 using a food frequency questionnaire. In a subset of this population, consumption of tuna or other broiled or baked seafood, but not fried seafood or fish sandwiches (fish burgers), correlated with plasma phospholipid long-chain omega-3 fatty acid levels. During 12 years of follow-up, participants experienced 626 incident strokes, of which 529 were ischemic strokes. Tuna/other seafood consumption was associated with a 27 percent lower risk of ischemic stroke when consumed one to four times per week (HR=0.73; 95% CI 0.55-0.98), and with a 30 percent lower risk when consumed five or more times per week (HR=0.70, 95% CI 0.50-0.99) compared with consumption of less than once per month.
Conversely, consumption of fried fish/fish sandwiches was associated with a 44 percent higher risk of ischemic stroke when consumed once per week compared with less than once per month (HR=1.44; 95% CI 1.12-1.85). Seafood consumption was not associated with hemorrhagic stroke. Consumption of tuna or other broiled or baked seafood was associated with lower risk of ischemic stroke while intake of fried seafood/fish sandwiches was associated with higher risk among elderly individuals.
Taken together, these observational studies provided inconclusive results for an association between seafood intake and stroke. These results suggest that seafood consumption may influence stroke risk; however, identification of mechanisms or alternate explanations for the results requires further study. The type of seafood meal, particularly the method of preparation, is not recorded in most observational studies but may be a major effect modifier.
The effects of seafood or EPA/DHA on serum lipid profiles have been extensively studied to determine if intake influences indicators of cardiovascular disease risk (see Appendix Table B-2c). In AHRQ Evidence Report/ Technology Assessment No. 93 (2004), Balk et al. showed that with few exceptions, serum triglyceride levels were found to decrease with increasing intake of EPA/DHA, and this change was statistically and biologically significant. Moreover, the effect appears to be dose-dependent regardless of the EPA/DHA source. Most of the studies reviewed reported net decreases of approximately 10–33 percent in triglyceride levels. Effects were dose-dependent among subjects that were healthy, had cardiovascular disease, or
were at increased risk for cardiovascular disease or dyslipidemia, and were greatest among subjects who had higher mean baseline triglyceride levels.
EPA/DHA intake was only weakly associated with levels of other serum lipids, including total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol and lipoprotein (a) (Lp(a)). Balk et al. (2004) reviewed 65 randomized controlled trials and found a wide range of effects of EPA/DHA on total cholesterol. Most studies achieved a small net effect and the trend was towards increased total cholesterol; however, the direction of the effect was not consistent across studies. For example, two studies (Hanninen et al., 1989; Mori et al., 1994) used seafood-based diets as part of the intervention protocol, and neither of them reported significant effects of seafood consumption on total cholesterol levels. Further, Mori et al. (1994) found that LDL cholesterol levels were not changed in subjects consuming EPA/DHA-enriched diets. No significant differences were found in men who consumed various doses of EPA and DHA either from seafood or fish oil.
Balk et al. (2004) reviewed 19 reports of effects of EPA/DHA on HDL cholesterol. Most studies reported small increases in HDL cholesterol, and in about one-third of the studies, the effects were statistically significant. One study conducted in men using intervention with a seafood-enriched diet (Mori et al., 1994) found no difference among those consuming various doses of EPA and DHA either as supplements or from seafood in a diet regimen. In a randomized controlled trial, Vandongen et al. (1993) found that the effect of EPA/DHA on HDL cholesterol was independent of the source of the EPA/DHA.
Consistent effects of EPA/DHA on Lp(a) levels have not been found (Balk et al., 2004). In approximately one-third of the 14 studies reviewed, EPA/DHA intakes were associated with a net increase in Lp(a) compared to controls. In the remaining studies reviewed, the net decrease in Lp(a) level was generally small and nonsignificant. Only two studies (Eritsland et al., 1995; Luo et al., 1998) reported a statistically significant difference between the effect of EPA/DHA intake and control. Both found a net decrease in Lp(a) (p=0.023; only for those with a baseline Lp(a) of ≥20 mg d/l). However, the large interindividual variability in Lp(a) levels resulted in wide confidence intervals in all studies reviewed by Balk et al. (2004). One study examined a diet enriched with seafood, but found no significant effect on Lp(a) levels (Schaefer et al., 1996).
Increased consumption of seafood is one of several dietary recommendations in studies examining dietary effects on blood pressure. Thus, the
effect of EPA/DHA from seafood is difficult to isolate from benefits provided by other dietary changes.
Randomized Controlled Trials
The effect of fish-oil supplementation has been studied in a meta-analysis of experimental studies (Geleijnse et al., 2002). The overall results of 36 trials examined indicate that the mean adjusted net reduction in systolic and diastolic blood pressure was −2.1 mmHg (95% CI −3.2 to −1.0), and −1.6 mmHg (95% CI −2.2 to −1.0), respectively. Moreover, systolic and diastolic blood pressure reductions were significantly greater in older (mean age ≥45 years) than younger populations, and in hypertensive (blood pressure ≥140/90 mmHg) compared to normotensive populations. Inconsistent results among studies in women precluded adequate analysis based on sex. Body mass index, trial duration, and seafood dose did not affect the blood pressure response noted with fish-oil supplementation. Studies conducted in diabetic patients were not included in the meta-analysis. The review by Balk et al. (2004) found only small and inconsistent net effects of EPA/DHA on blood pressure levels of diabetic patients.
A single RCT with advice to increase seafood intake has been reported. The Diet and Reinfarction Trial (DART) examined the effect of advice to consume seafood on blood pressure outcomes at 6 and 24 months in over 2000 men with a history of MI (Ness et al., 1999). The average intake of the group advised to consume fish was 330 mg of EPA compared to 100 mg in the control group. There were no significant differences in blood pressure detected between the groups at either 6 or 24 months.
Appleby et al. (2002) examined the effect of diet and lifestyle factors on differences between meat eaters, seafood eaters, vegetarians, and vegans on the prevalence of self-reported hypertension, and mean systolic and diastolic blood pressure. Data for the analysis was obtained from the Oxford cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Oxford). More than 11,000 adult men and women were classified into the four diet groups for analysis. Results showed that age-adjusted prevalence of self-reported hypertension in men was 15 percent in meat eaters, 9.8 percent in both seafood eaters and vegetarians, and 5.8 percent in vegans. In women, the prevalence was 12.1, 9.6, 8.9, and 7.7 percent in the respective diet groups. After adjustment for body mass index (BMI), the group differences decreased in both men and women. When seafood eaters were compared to vegetarians, no benefit was seen that could be attributed to seafood consumption per se.
Dewailly et al. (2001) examined the relationship between plasma phospholipid concentrations of EPA/DHA and various cardiovascular disease risk factors among the Inuit of Nunavik, Canada, whose traditional high-seafood diet contains very large amounts of EPA/DHA. Over 400 Inuit adults participated in a health survey that included home interviews and clinical visits. Plasma samples were obtained from participants and analyzed for phospholipid fatty acid composition. No association was found between phospholipid content of EPA/DHA and blood pressure in this population of high seafood consumers.
It is unclear from these studies whether seafood consumption, in the range consumed by most Americans, is an effective means to reduce blood pressure (see Appendix Table B-2d). Further, it is not known if the association between EPA/DHA consumption and blood pressure is linear or if there is a threshold below which no benefit is detectable.
Leaf et al. (2003) reviewed studies of prevention of arrhythmic deaths correlated with EPA/DHA intake, summarizing clinical evidence for the antiarrhythmic effect of EPA/DHA and reviewing possible mechanisms of action through modulation of ion channels in cardiomyocytes. Based on the evidence from human and experimental data (see Appendix B-2e) the authors suggest that in the presence of family history of sudden cardiac death, supplementation with EPA and DHA should be of 1 to 2 grams/day.
Christensen et al. (1999) examined the effect of EPA/DHA on heart rate variability in healthy subjects by randomized controlled trial. Treatment groups received either low- or high-dose EPA/DHA from fish-oil supplements and control groups received olive oil for 12 weeks. No significant effect of the fish-oil supplements was found on heart rate variability. In an earlier study, Christensen et al. (1996) examined the effect of EPA/DHA supplementation on subjects who had a recent MI and found significant improvement in heart rate variability among the fish-oil supplemented group (p=0.04); however, when those subjects were segregated by level of seafood consumption (Christensen, 1997), the groups who consumed one or more seafood meals per week had somewhat higher heart rate variability that was not statistically significant.
More recently, Frost and Vestergaard (2005) examined the association between consumption of EPA/DHA from fish and risk of atrial fibrillation or flutter on the prospective cohort study of 47,949 participants (mean age: 56 years) in the Danish Diet, Cancer, and Health Study. During a follow-up of 5.7 years, atrial fibrillation or flutter had developed in 556 subjects (374 men and 182 women). Using the lowest quintile of omega-3 fatty acid intake from fish as a reference, the unadjusted hazard rate ratios in quintiles 2–5
were 0.93 (95% CI 0.70-1.23), 1.11 (95% CI 0.85-1.46), 1.10 (95% CI 0.84-1.45), and 1.44 (95% CI 1.12-1.86), respectively (p for trend=0.001). The corresponding adjusted hazard rate ratios were 0.86 (95% CI 0.65-1.15), 1.08 (95% CI 0.82-1.42), 1.01 (95% CI 0.77-1.34), and 1.34 (95% CI 1.02-1.76) (p for trend = 0.006). In conclusion, there was no association between n-3 fatty acid intake from fish and a reduction in risk of atrial fibrillation or flutter. Surprisingly, the risk was significantly higher at increased EPA/DHA intake. The authors, however, were unable to exclude the possibility of residual confounding caused by a lack of information on intake of fish-oil supplements.
Other Cardiovascular Indicators
Balk et al. (2004) found no consistent effect of EPA/DHA on fibrinogen levels, and the studies reviewed were equally divided among those showing increases, no change, or decreases in fibrinogen levels compared to controls. Most of the study results were not significant. However, for those that did show statistically significant differences between omega-3 treatment and controls, three showed decreases ranging from 5–20 percent, and one showed an increase of 11 percent in fibrinogen levels. Cobiac et al. (1991) reported that seafood consumption may be associated with a small decrease in fibrinogen level (change = 0.15±0.12), which was significantly different than the change in the controls (p<0.05). Overall, however, no significant differences in effect of EPA/DHA on fibrinogen level have been shown (see Appendix Table B-2f).
Most studies reviewed by Balk et al. (2004) found a net decrease in von Willebrand factor with increased EPA/DHA intake. However, only one study reported statistical significance in the association. None of the studies reviewed examined the effects of regular consumption of seafood meals on von Willebrand factor levels.
Other clotting factors were also reviewed by Balk et al. (2004). Factor VII showed no consistency in effects across studies, with equal numbers of subjects reporting increases and decreases of factor VII activity in relation to EPA/DHA intake. Agren et al. (1997) reported that the effects of EPA/DHA levels from seafood consumption were not significant and were similar to those observed for fish-oil supplementation and an algal source of DHA oil supplementation in the same study. Findings from studies on EPA/DHA on factor VIII are similar to those for factor VII with some studies showing
a net increase and others a net decrease. None of the studies investigated specify the effect of increased seafood consumption on factor VIII levels (Balk et al., 2004) (see Appendix Table B-2f).
Platelet aggregation is a very complex measurement, depending on the aggregating agent, the dose of the agent, and the measurement metric used. As a result, findings of studies on the effects of EPA/DHA on platelet aggregation are inconsistent and difficult to interpret (Balk et al., 2004). Agren et al. (1997) examined the effects of a seafood-based diet, fish-oil supplementation, and algal DHA oil on platelet aggregation and showed that collagen aggregation was reduced more in subjects on both the seafood diet and fish-oil supplementation regimens, but not the algal DHA oil treatment, compared to the controls (p<0.05). No significant association was found for EPA/DHA impairment of platelet aggregation, although algal DHA oil is less potent than either fish oil or seafood (which are sources of both EPA and DHA) (see Appendix Table B-2f).
Indicators of Glucose Tolerance in Diabetes
Although EPA/DHA consumption has been shown to improve lipid profiles and other indicators of cardiovascular risk in those with type II diabetes, there is currently no evidence that intakes of 2–4 g/day of EPA/ DHA can improve glycemic control (Grundt et al., 1995; Sirtori et al., 1998; Kesavulu et al., 2002). Consistent with this finding, a review (Balk et al., 2004) concluded that there was no clear evidence that EPA/DHA had an effect on moderating glucose tolerance or hemoglobin A1c levels, fasting blood sugar, and fasting insulin levels (see Appendix Table B-2g).
Allergy and Asthma
The Nurses’ Health Study’s prospective cohort was evaluated by Troisi et al. (1995) for a possible association of risk for adult-onset asthma and frequency of intake of various types of food. A semi-quantitative food frequency questionnaire was employed to index food intake over the previous year (e.g., “dark meat” seafood vs. other seafood). Over 1200 cases of adult-onset asthma were identified. Data from this study showed that the 6-year risk of adult-onset asthma was unrelated to the frequency of intake of dark meat seafood, tuna, or shrimp. This nonsignificant association was maintained when results were adjusted for age and smoking status, and also when other factors (body mass index, residential area, number of physician visits, and energy intake) were adjusted for (see Appendix Table B-2h; see also Schachter et al., 2004, AHRQ Report No. 91).
The biological functions associated with consumption of omega-3 fatty acids suggest that it may have some impact on cancer risk (Larsson, 2004). Available evidence comes primarily from observational studies rather than randomized controlled trials (Terry, 2003; MacLean, 2006) (see Appendix Table B-2i; see also MacLean et al., 2005b, AHRQ Report No. 113). A small number of these studies show some protection for certain types of cancer (i.e., breast, colorectal, and lung), whereas others support an increase in risk (e.g., breast). The majority of the studies, however, conclude there is no significant effect on risk for cancer associated with seafood consumption or intake of other sources of EPA/DHA. Overall, the consumption of seafood, ALA, or EPA/DHA from all sources does not appear to decrease cancer risk (MacLean, 2006).
Aging and Other Neurological Outcomes
Consumption of EPA/DHA, specifically from seafood consumption, may provide some protection in terms of age-related cognitive decline as well as risk for Alzheimer’s and other neurological diseases (Kalmijn et al., 1997; Gharirian et al., 1998; Barberger-Gateau et al., 2002; Morris et al., 2003). It should be noted that, as discussed above for cancer, evidence for reduced risk for these diseases comes primarily from observational studies. The beneficial effects appear to be more closely related to the consumption of seafood and/or global intake of DHA rather than EPA or ALA. Overall, the evidence is tenuous and counterbalanced by a number of studies that did not find significant benefits (see Appendix Table B-2j; see also MacLean et al., 2005a, AHRQ Report No. 114).
Summary of Evidence
Results from individual studies are not consistent and results from critical reviews are not clearly supportive of a cardioprotective effect of EPA/DHA. Furthermore, evidence for an effect on other adult chronic disease is controversial. Tables that summarize the committee’s assessment of levels of evidence and reports from individual studies are shown in Table 3-2 and Appendix Tables B-1 through B-2. The level of evidence identified as “Contradictory or insufficient evidence to base recommendations” includes outcomes where a large body of literature exist, but leads to contradictory conclusions, as well as outcomes where the body of literature is too small to lead to recommendations. The committee’s assessment of level of evidence summarized in Table 3-2 has its limitations. The Oxford Centre for Evidence-based Medicine’s levels of evidence may not be ideal to assess nutrition studies. The quality of the various studies cannot be summarized
TABLE 3-2 Level of Evidence for Benefits of Increasing Seafood or EPA/ DHA Intake in the General Populationa and Specific Subgroups Reviewed
Level of Evidenceb
Higher Seafood Intake
Increase in EPA/DHA Intake
Meta-analyses of randomized controlled trials
Randomized controlled trial(s)
Meta-analyses of observational studies
Contradictory evidence or insufficient evidence on which to base recommendations
aUnless otherwise noted.
bThe level of evidence is based on the Oxford Centre for Evidence-based Medicine’s Levels of Evidence (http://www.cebm.net/levels_of_evidence.asp#top). When several levels of evidence existed, only the highest level of evidence was reported.
using this approach, but is described in more detail in the preceding discussions. Furthermore, the committee’s selection of studies reflects its subjective assessment of quality and importance, and is therefore subject to limitations. Only the highest level of evidence is provided in the table, and studies with a lower level of evidence are omitted. For an alternative approach to the assessment and synthesis of evidence, refer to the recent and comprehensive
AHRQ systematic reviews addressing these questions (Balk et al., 2004, AHRQ Report No. 93; Jordan et al., 2004, AHRQ Report No. 92; MacLean et al., 2004, AHRQ Report No. 89; Schachter et al., 2004, AHRQ Report No. 91; Wang et al., 2004, AHRQ Report No. 94; MacLean et al., 2005b, AHRQ Report No. 113; MacLean et al., 2005a, AHRQ Report No. 114.)
Observational evidence suggests that increased seafood consumption is associated with a decreased risk of cardiovascular deaths and cardiovascular events in the general population. Evidence is insufficient to assess if this association is mediated through an increase in EPA and DHA consumption and/or a decrease in saturated fat consumption and/or other correlates of seafood consumption.
Experimental studies of the effect of EPA/DHA supplements on cardiovascular mortality or cardiovascular disease have not been conducted in the general population.
There is mixed evidence suggesting that consumption of fish-oil supplements for individuals with a history of MI will protect them from further coronary events. Meta-analyses have also led to mixed conclusions, with most recent analyses suggesting no benefits. Experimental evidence from in vitro and other types of mechanistic studies suggests that EPA/DHA intake should be associated with positive cardiovascular outcomes. However, this prediction has not been borne out in results of human studies.
In the general population, the effect from increased seafood consumption on the lipid profile is unclear. However, experimental studies of EPA/ DHA supplementation at levels >1 g per day showed decreased triglyceride levels; the effect on other components of the lipid profile is less clear.
Evidence is inconsistent for protection against further cardiovascular events in individuals with a history of myocardial infarction from consumption of EPA/DHA-containing seafood or fish-oil supplements. The protection evidenced by population (observational) studies has not been consistently observed in randomized clinical trials.
Evidence for a benefit associated with seafood consumption or fish-oil supplements on blood pressure, stroke, cancer, asthma, type II diabetes, or Alzheimer’s disease is inconclusive. Whereas observational studies have suggested a protective role of EPA/DHA for each of these diseases, supportive evidence from randomized clinical trials is either nonexistent or inconclusive.
Based on the three recent meta-analyses of observational studies (Table 3-2), there appears to be a linear association between seafood consumption and primary prevention of cardiovascular disease; the committee did not find strong scientific evidence to suggest a threshold of consumption,
such as two servings per week, below which seafood consumption provides no benefit and above which increasing consumption provides no additional benefits.
Recommendation 1: Dietary advice to the general population from federal agencies should emphasize that seafood is a component of a healthy diet, particularly as it can displace other protein sources higher in saturated fat. Seafood can favorably substitute for other high biologic value protein sources while often improving the overall nutrient profile of the diet.
Recommendation 2: Although advice from federal agencies should also support inclusion of seafood in the diets of pregnant females or those who may become pregnant, any consumption advice should stay within federal advisories for specific seafood types and state advisories for locally caught fish.
Pregnant and Lactating Women
Recommendation 1: Better data are needed to determine if outcomes of increasing consumption of seafood or increasing EPA/DHA intake levels in US women would be comparable to outcomes of populations in other countries. Such studies should be encouraged to include populations of high fish-consumers outside the United States to determine if there are differences in risks for these populations compared to US populations.
Recommendation 2: Dose-response studies of EPA/DHA in pregnant and lactating women are needed. This information will help determine if higher intakes can further increase gestation duration, reduce premature births, and benefit infant development. Other studies should include assessing whether DHA alone can act independently of EPA to increase duration of gestation.
Infants and Toddlers
Recommendation 3: Research is needed to determine if cognitive and developmental outcomes in infants are correlated with performance later in childhood. This should include:
Evaluating preschool and school-age children exposed to EPA/ DHA in utero and postnatally, at ages beginning around 4 years when executive function is more developed, and;
Evaluating development of school-age children exposed to variable EPA/DHA levels in utero and postnatally with measures of distractibility, disruptive behavior, and oppositional defiant behavior, as well as more commonly assessed cognitive outcomes and more sophisticated tests of visual function.
Recommendation 4: Additional data is needed to better define optimum intake levels of EPA/DHA for infants and toddlers.
Recommendation 5: Better-designed studies about EPA/DHA supplementation in children with behavioral disorders are needed.
Adults at Risk for Chronic Disease
Recommendation 6: In the absence of meta-analyses that systematically combine quantitative data from multiple studies, further meta-analyses and larger randomized trials are needed to assess outcomes other than cardiovascular, in particular total mortality, in order to explore possible adverse health effects of EPA/DHA supplementation.
Recommendation 7: Additional clinical research is needed to assess a potential effect of seafood consumption and/or EPA/DHA supplementation on stroke, cancer, Alzheimer’s disease, and depression.
Recommendation 8: Future epidemiological studies should assess intake of specific species of seafood and/or biomarkers, in order to differentiate the health effects of EPA/DHA from those of contaminants, such as methylmercury.
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