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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



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Seafood Choices: Balancing Benefits and Risks 3 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

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Seafood Choices: Balancing Benefits and Risks 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. INTRODUCTION 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.

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Seafood Choices: Balancing Benefits and Risks TABLE 3-1 Differences in Saturated Fat Content Between Commonly Consumed Animal Food Products Food Category Portion Size (ounces) Saturated Fat (grams) Calories (kcal) Cheese       Regular cheddar cheese 1 6.0 114 Low-fat cheddar cheese 1 1.2 49 Ground beef       Regular ground beef (25% fat) 3 (cooked) 6.1 236 Extra lean ground beef (5% fat) 3 (cooked) 2.5 145 Chicken       Fried chicken (with skin) 3 3.4 229 Roasted chicken (no skin) 3 0.9 130 Fish       Fried fish (catfish) 3 2.8 195 Baked fish (catfish) 3 1.5 129 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-

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Seafood Choices: Balancing Benefits and Risks 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.

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Seafood Choices: Balancing Benefits and Risks Part I: Benefits to Women, Infants, and Young Children Associated with Omega-3 Fatty Acids BENEFITS TO WOMEN DURING AND AFTER PREGNANCY Preeclampsia 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). Postpartum Depression 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

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Seafood Choices: Balancing Benefits and Risks 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).

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Seafood Choices: Balancing Benefits and Risks 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

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Seafood Choices: Balancing Benefits and Risks growth retardation (van Wassenaer, 2005), and preterm delivery (Hediger et al., 2002) are associated with poor developmental outcomes. Fish-Oil Supplementation 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-

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Seafood Choices: Balancing Benefits and Risks 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

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Seafood Choices: Balancing Benefits and Risks (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). 1 Examining the blood remaining in the umbilical cord after birth, though it is not precisely identical to that in the infant bloodstream, provides a noninvasive way to approximate the infant’s blood profile.

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Seafood Choices: Balancing Benefits and Risks 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-

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