B
Data Tables
Note: Abbreviations/acronyms included in the following data tables are included in the Glossary (see Appendix A).
Studies on Women, Infants, and Children
TABLE B-1a Studies on Preeclampsia: Effects on Women Who Increase Seafood and/or Omega-3 Fatty Acid Intake
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Sibai, 1998 |
Review |
3 randomized controlled trials |
Fish-oil supplement |
|
Sindelar et al., 2004 |
Randomized Controlled Trial |
Men (n=8) Women (n=4) Mean age of 33 years Lincoln, NE Non-Hispanic White Recruited at YMCA marathon and triathlon training group meetings and word of mouth Exercising regularly as members of a running training group sponsored by the local YMCA No being treated with eating disorders or depression, or those unable to eat eggs, or those using medications known to affect serum lipids |
n-3 PUFA-enriched eggs |
2 weeks baseline period, 4 weeks treatment period (crossover design), 4 weeks washout period between treatments |
Haugen and Helland, 2001 |
Randomized Controlled Trial |
Pregnant women (n=37) Mean age about 27-31 years Oslo, Norway Normotensive without proteinuria, had uncomplicated term pregnancies, randomly taken from another study investigating the influence of omega-3 fatty acids on fetal, neonatal, and child development Another group had moderate preeclampsia |
Cod-liver oil supplement |
16-20 weeks gestation through pregnancy |
Amount |
Results |
Conclusion* |
|
“The beneficial effects of fish oil on the incidence of preeclampsia are supported by observational studies and 1 large, uncontrolled early trial.” Three randomized trials “reveal no reduction in the incidence of preeclampsia in the fish oil group.” |
N |
n-3 PUFA-enriched eggs: flaxseed added to hens’ diet 350 mg n-3 PUFA/60 g egg 0.25 g LA, 0.10 g DHA/60 g egg 1 egg/day for 6 days and no eggs on day 7 Conventional eggs: 60 mg of n-3 PUFA/60 g egg 0.04 g LA, 0.02 g DHA/60 g egg 1 egg/day for 6 days and no eggs on day 7 |
LA, DHA, and total n-3 dietary intake of those randomized to n-3 PUFA-enriched egg treatment were significantly higher than at baseline and compared to the conventional egg treatment (p<0.05). There were no significant differences in serum total cholesterol, LDL-C and HDL-C in physically active adults from baseline to end of treatment or between groups. Serum triglycerides were significantly higher with n-3 PUFA-enriched egg treatment than those from baseline and compared to the conventional egg treatment (p<0.05). |
N/A |
Cod-liver oil group: 10 mL/day Corn oil group: 10 mL/day |
“The pressure increase was significant in both groups, but no significant differences in the constrictory response or in the proportions of preparations displaying dilatatory responses were observed when compared to appropriate control groups.” “Neither preeclampsia nor dietary supplementation with cod-liver oil had any significant effect on the vasoactive response to PGF2α in umbilical cord arteries.” |
N |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Salvig et al., 1996 |
Randomized Controlled Trial |
Pregnant women (n=533) Aged 18-44 years Aarhus, Denmark No history of placental abruption in an earlier pregnancy or a serious bleeding episode in the present pregnancy, no prostaglandin inhibitors regularly, no allergy to fish and regular intake of fish oil |
Fish-oil supplement |
30th week gestation through pregnancy |
Onwude et al., 1995 |
Randomized Controlled Trial |
Pregnant women (n=233) Aged 18-39 years for fish oil group Aged 16-40 for placebo group Leeds, UK Multigravida with a history of one or more small babies, a history of proteinuric or nonproteinuric pregnancy-induced hypertension, or a history of unexplained stillbirth Primigravida with abnormal uterine arcuate artery Doppler blood flow at 24 weeks gestation |
EPA/DHA supplement |
Until 38th week gestation; enrollment time unspecified |
Bulstra-Ramakers, 1995 |
Randomized Controlled Trial |
Pregnant women (n=63) Groningen, Netherlands Birth weight below the 10th percentile in association with pregnancy-induced hypertension or chronic renal disease, or with placenta abnormalities |
EPA supplement |
12-14 weeks gestation until delivery |
Amount |
Results |
Conclusion* |
Fish oil group: 2.7 g/day (4 capsules/day, each capsule contains 32% EPA, 23% DHA, 2 mg tocopherol/ml) Olive oil group: 1 g; 72% oleic acid and 12% LA/capsule 4 capsules/day Control = no capsule |
“Mean blood pressure increased during the course of the 3rd trimester,” but this change was not statistically different among the three groups. “No differences were seen between the groups in proportions of women with a systolic blood pressure above 140 mmHg or a systolic blood pressure above 90 mmHg, although the proportion of women with diastolic above 90 mmHg tended to be lower in the fish oil group compared to the olive oil group (RR=0.48, p=0.07).” |
N |
2.7 g/day (1.62 g/day of EPA) (1.08 g/day of DHA) |
There were no significant differences between the two groups for proteinuric pregnancy-induced hypertension, nonproteinuric pregnancy-induced hypertension, birth weight, gestation length, perinatal death, duration of labor, onset of labor (spontaneous, induced, or prelabor section), or mode of delivery. |
N |
4 capsules 3 times/day (each capsule contains 0.25 mg EPA ) vs. placebo |
“Addition of 3 g/day of EPA to the diet did not result in either a lowering of the incidence of pregnancy induced hypertension or intrauterine growth retardation.” “Birth weight centiles were slightly lower and the recurrence rate of pregnancy-induced hypertension was slightly higher in the EPA group,” compared to the control group, although these differences were not significant. |
N |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Schiff et al., 1993 |
Controlled Trial |
Pregnant women (n=16) Aged 25-34 years Nulliparous Nonsmokers, no history of hypertension, coagulation disorders, thrombocytopenia, or chronic vascular, renal, or other disease |
Fish-oil supplement |
32-34 weeks through the next 21 days |
Olsen and Secher, 1990 |
Randomized Controlled Trial |
Pregnant women (n=5022) Aged 15-44 years London People’s League of Health, 1946 Attending antenatal clinics of 10 hospitals No disease or physical abnormality |
EPA/DHA supplement |
Enrolled at <24 weeks gestation; treatment lasts for <15 weeks (n=288), 16-19 weeks (n=411), 20-23 weeks (n=414), or 24+ weeks (n=417) |
Amount |
Results |
Conclusion* |
6 capsules/day (each capsule contains 1000 mg of concentrated fish oil, 26% of which is n-3 fatty acids) |
“Mean excretion of 11-dehydro-thromboxane B2 before and after 21 days of fish oil consumption was reduced among the fish oil-treated women from 1606±411 pg/mg of creatinine to 779±299 pg/mg after treatment (p<0.0001, paired t test). In all 11 patients the decreased excretion of this metabolite was considerable, ranging from 32% to 71%.” No significant change was detected among the control women. |
B |
0.1 g/day of EPA+DHA from halibut oil in supplement vs. no supplement Supplement includes 0.26 g ferrous iron; 0.26 g calcium; minute quantities of iodine, manganese and copper; 0.60 g thiamin/g; 0.10 g vitamin C; 0.36 g halibut liver oil |
In primiparae, the OR for preeclampsia was significant when comparing the treatment to the control group (OR=0.689, 95% CI 0.50-0.95). In primiparae, the OR for albuminuria was statistically significant when comparing the treatment to the control group (OR=0.717, 95% CI 0.54-0.96). In primiparae, the OR for hypertension was not significant when comparing the treatment to the control group (OR=0.862, 95% CI 0.73-1.02). In multiparae, these statistics were OR=0.677 (95% CI 0.43-1.07), OR=0.675 (95% CI 0.44-1.04), and OR=1.121 (95% CI 0.89-1.42). There were no significant effects on the occurrences of stillbirths, early neonatal deaths (before 8 days), perinatal deaths, sepsis, or the duration of labor. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Clausen et al., 2001 |
Cohort |
Pregnant women (n=3133) Mean age 29.8 years 51.8% nulliparous Representing all socioeconomic classes Aker University Hospital, Oslo, Norway No pregestational diabetes or twin/triplet pregnancies |
Fatty acids from food |
17-19 weeks gestation until after delivery |
Amount |
Results |
Conclusion* |
Tertiles of saturated fatty acids (%energy) Mean = ≤12.0, 12.0-15.0, >15.0 Tertiles of monounsaturated fatty acids (%energy) Mean = ≤10.5, 10.5-13.0, >13.0 Tertiles of polyunsaturated fatty acids (%energy) Mean = ≤5.2, 5.2-7.5, >7.5 Tertiles of omega-3 fatty acids (%energy) Mean = ≤0.9, 0.9-1.6, >1.6 Tertiles of omega-6 fatty acids (%energy) Mean = ≤3.8, 3.8-5.8, >5.8 |
After adjusting for energy, age, smoking, BMI, systolic blood pressure for 20 weeks’ gestation, nullipara and energy: Statistically significant ORs for preeclampsia, comparing the highest group to the lowest group of fatty acid intakes, were observed for polyunsaturated fatty acids (p=0.01) and omega-6 fatty acids (p=0.05); and Statistically nonsignificant ORs for preeclampsia, comparing the highest group to the lowest group of fatty acid intakes, were observed for saturated fat (p=0.10), monounsaturated fat (p=0.59), and omega-3 fatty acids (p=0.06). |
N |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Velzing-Aarts et al., 1999 |
Case-control |
Cases (n=27) = preeclamptic women Controls (n=24) = normotensive, nonproteinuric women Pregnant women Mean age about 27 years Curacao |
Fatty acid composition in maternal and umbilical platelets and umbilical arteries and veins |
During delivery or within 2 hours after birth |
Amount |
Results |
Conclusion* |
Mean fatty acid composition in maternal platelets (in mol%): Controls = 9.66±2.75 LA; 0.27±0.10 ALA; 0.29±0.14 EPA; 2.03±0.62 DHA Cases = 7.0±21.91 LA; 0.22±0.11 ALA; 0.21±0.07 EPA; 2.16±0.93 DHA Mean fatty acid composition in umbilical cord platelets (in mol%): Controls = 3.73±0.76 LA; 0.14±0.10 ALA; 0.16±0.07 EPA; 2.33±0.58 DHA Cases = 4.16±1.51 LA; 0.21±0.11 ALA; 0.17±0.07 EPA; 1.97±0.30 DHA Mean fatty acid composition in umbilical veins (in mol%): Controls = 2.69±0.44 LA; 0.10±0.05 ALA; 0.09±0.04 EPA; 4.26±0.85 DHA Cases = 2.89±0.56 LA; 0.11±0.05 ALA; 0.07±0.02 EPA; 3.35±0.96 DHA Mean fatty acid composition in umbilical arteries (in mol%): Controls = 1.87±0.39 LA; 0.10±0.04 ALA; 0.09±0.03 EPA; 4.83±0.76 DHA Cases = 1.74±0.75 LA; 0.10±0.06 ALA; 0.06±0.03 EPA; 3.73±1.03 DHA |
“Newborns of preeclamptic women had significantly lower birth weights and gestational ages at delivery,” compared to newborns of non-preeclamptic women. Preeclamptic women had significantly lower maternal platelet levels of LA (p<0.001) and EPA (p<0.05) compared to normotensive women. Preeclamptic women had significantly lower umbilical arteries levels of EPA (p<0.01) and DHA (p<0.001) compared to normotensive women. No other significant differences were found for LA, ALA, EPA, or DHA. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Kesmodel et al., 1997 |
Nested case-control |
Cases = women with preeclampsia (n=43), pregnancy-induced hypertension (n=179), intrauterine growth retardation (n=182), delivering preterm (n=153), delivering postterm (n=189) Control = sample from whole cohort (n=256) Pregnant women Aarhus, Denmark |
Seafood and fish-oil supplement |
Between 6 months and 3 1/2 years after delivery |
Williams et al., 1995 |
Case-control |
Cases (n=22) = preeclamptic Controls (n=40) = normotensive Pregnant women Mean age 28.6-31.2 years White (n=17 in preeclamptic group, n=23 in non-preeclamptic group) Seattle, Washington About 21% Medicaid recipient |
Maternal erythrocytes fatty acid profiles |
Day after delivery |
Amount |
Results |
Conclusion* |
Low intake = Maximum of 1 fish snack/week and 1 fish meal/month and no fish oil High intake = Minimum of 4 fish snacks/week or 4 fish meals/month or intake of fish oil during pregnancy Middle intake = Everyone else |
After adjusting for maternal smoking habits, maternal height, maternal weight before pregnancy, parity, maternal social status, and average daily calcium intake: There were no significant ORs of pregnancy-induced hypertension, preeclampsia, intrauterine growth retardation, preterm delivery or postterm delivery for the middle-intake group or the high-intake group compared to the low-intake group. |
N |
Tertiles of EPA: Median = 0.20, 0.26, 0.36 Tertiles of DPA: Median = 1.54, 1.75, 2.02 Tertiles of DHA: Median = 4.38, 5.14, 6.40 Tertiles of total long-chain n-3 fatty acids: Median = 6.23, 7.09, 8.50 |
After adjusting for parity and pre-pregnancy BMI, the OR of preeclampsia for the lowest tertile of EPA, compared to the highest tertile of EPA was 5.54 (95% CI 1.06-28.79). After adjusting for parity and pre-pregnancy BMI, the OR of preeclampsia for the lowest tertile of DPA, compared to the highest tertile of DPA was 3.33 (95% CI 0.65-16.99). After adjusting for parity and pre-pregnancy BMI, the OR of preeclampsia for the lowest tertile of DHA, compared to the highest tertile of DHA was 7.54 (95% CI 1.23-46.22). After adjusting for parity and pre-pregnancy BMI, the OR of preeclampsia for the lowest tertile of the sum of long-chain omega-3 fatty acids, compared to the highest tertile of long-chain omega-3 fatty acids was 7.63 (95% CI 1.43-40.63). |
B |
Amount |
Results |
Conclusion* |
Nonpregnant women (mg/L±SE): 79.51±3.47 total PUFA, 60.79±2.28 LA, 10.99±1.01 AA, 1.88±0.17 ALA, 0.26±0.04 EPA, 5.58±0.60 DHA Normal pregnant women (mg/L±SE): 90.60±6.68 total PUFA, 62.93±4.69 LA, 12.81±0.87 AA, 3.68±0.99 ALA, 1.08±0.33 EPA, 10.40±0.94 DHA Preeclamptic women (mg/L±SE): 67.42±3.88 total PUFA, 45.98±2.80 LA, 11.44±1.00 AA, 1.11±0.25±ALA, 0.11±0.11 EPA, 8.94±0.69 DHA |
Plasma total polyunsaturated fatty acid levels, LA, ALA, and EPA were all significantly higher in the normal pregnant women than in the preeclamptic women (p<0.05, p<0.01, p<0.05, p<0.05, respectively). EPA and DHA were significantly lower in the nonpregnant women compared to the pregnant women (p<0.05 and p<0.01, respectively). No other significant differences between the plasma polyunsaturated fatty acid levels in the three groups were found. “No statistical differences were noted in the five polyunsaturated fatty acid levels between fasting and non-fasting states in both non-pregnant and normal pregnant subjects.” |
B |
TABLE B-1b Studies on Postpartum Depression: Effects on Women Who Increase Seafood and/or Omega-3 Fatty Acid Intake
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Marangell et al., 2004 |
Open trial |
Pregnant women (n=7) Aged 31-42 years Married, Caucasian (except for one married, Hispanic) Baylor College of Medicine History of a depressive episode in the postpartum period, not suffering from a current depressive episode No psychotropic medications within 2 weeks of baseline, history of nonreponse to two or more antidepressants, serious comorbid medical or psychiatric illness, or significant risk of dangerousness to self or others |
Fish-oil supplement |
34-36 weeks gestation until 12 weeks postpartum |
Llorente et al., 2003 |
Randomized Controlled Trial |
Pregnant women (n=89) Aged 18-42 years No chronic medical condition, no dietary supplements other than vitamins, no smoking, who had not been pregnant >5 times Planned to breastfeed infants exclusively for at least 4 months Part of a larger cohort study on effects of DHA on breastfeeding mothers and their infants |
Algae-derived triglyceride supplement |
Within a week of delivery to 4 months after delivery |
Hibbeln and Salem, 1995 |
Review |
Summary of three cohorts |
DHA depletion |
|
Amount |
Results |
Conclusion* |
Fish oil group: 2960 mg fish oil/day 173 mg EPA and 123 mg DHA per day 10 capsules/day |
Trial was terminated because of a high relapse rate observed after enrolling only seven participants. |
N |
Algae-derived triglyceride capsule (about 200 mg DHA/day) vs. placebo |
“Repeated measures analysis of variance, with the use of data only from the women who completed the questionnaires at both baseline and 4 months, showed no difference between the two groups at any time” with regards to postpartum depression. “There were no significant differences between groups in the EPDS and SCID-CV scores, particularly in current or past episodes of depression, as detected by the SCID-CV.” “There were no significant correlations between plasma phospholipid DHA content and BDI, EPDS, or SCID-CV scores.” |
N |
|
“The relative maternal depletion of DHA may be one of the complex factors leading to increased risk of depression in women of childbearing age and in postpartum periods.” |
B |
Amount |
Results |
Conclusion* |
Rare eaters: ≤1 time/month Regular eaters: ≥1 time/week Serving size unspecified |
After adjusting for body mass index, serum total cholesterol level, and socioeconomic situation, women who ate fish rarely had a higher OR for depression, compared to women who ate fish regularly. This statistic was observed by various measurements: Doctor-diagnosis: OR=1.3 (95% CI 0.9-1.9); HSCL-25 <2.01: OR=1.4 (95% CI 1.1-1.9); HSCL-25 <2.01 and doctor-diagnosis: OR=2.6 (95% CI 1.4-5.1). After adjusting for alcohol intake, smoking, physical inactivity, and marital status, women who ate fish rarely had a higher OR for depression, compared to women who ate fish regularly. This statistic was observed by various measurements: Doctor-diagnosis: OR=1.2 (95% CI 0.9-1.6); HSCL-25 <2.01: OR=1.4 (95% CI 1.1-1.8); HSCL-25 <2.01 and doctor-diagnosis: OR=2.4 (95% CI 1.4-4.2). Among men, none of these ORs were significant. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Otto et al., 2003 |
Cohort |
Participated in 2 earlier studies Pregnant women (n=112) Mean age around 30 years Caucasian Southern Limburg, Netherlands Fish intake <2 times/week No metabolic, cardiovascular, neurologic, renal, or psychiatric disorders No medications, except for multivitamins and iron supplements Singleton pregnancy Term delivery No blood transfusions in the perinatal period Gestational age <14 weeks at entry, Caucasian, fish consumption <2 times a week (for Study 2 only) |
Venous (plasma) blood fatty acid composition |
36 weeks gestation, at delivery, and 32 weeks postpartum |
Otto et al., 2001 |
Cohort |
Pregnant women (n=57) Mean age around 30 years Southern Limburg, Netherlands No metabolic, cardiovascular, neurologic, or renal disorders No medications, except multivitamins and iron supplements Singleton pregnancy Term delivery No blood transfusions in the perinatal period |
Diet and venous blood fatty acid profiles |
36-37 weeks gestation; 2-5 days after delivery; 1, 2, 4, 8, 16, 32, 64 weeks postpartum |
Amount |
Results |
Conclusion* |
Absolute amount not specified |
No significant relationship was observed between DHA, n-6DPA, or their ratio and the EPDS scores at delivery or at 32 weeks postpartum. No statistically significant relationships between depression and fatty acid status were observed with DHA or n-6DPA, neither for the levels at delivery, nor for their postpartum changes. “The improvement of the DHA status during the postpartum period, as reflected by the increase of the DHA/n-6DPA ratio during this period, was higher in the non-depressed than in the depressed women (OR=0.90, p=0.04).” Similar results remained after adjusting for Study 1 or 2, parity, education level, maternal age at test moment, breastfeeding, smoking, and alcohol use (OR=0.88, p=0.03). |
N |
Absolute amount not specified |
“After delivery, total fatty acids in plasma phospholipids decreased significantly over time in the lactating and nonlactating women (p<0.0001).” “The amounts of ALA, DHA, and total n-3 fatty acids showed significant downward trends postpartum in both groups, whereas the amounts of EPA and DPA increased significantly after delivery.” |
N/A |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Al et al., 1995 |
Cohort |
Pregnant women (n=110) Aged 19-43 years Maastricht, Netherlands Caucasian Singleton pregnancy DBP <90 mmHg No metabolic, cardiovascular, neurological or renal disorder |
Maternal venous and umbilical vein fatty acid profiles |
10, 14, 18, 22, 26, 30, 32, 34, 36, 38, 40 weeks gestation; after delivery; 6 months after delivery |
Holman, 1991 |
Cohort |
Pregnant women (n=19) Aged 24-36 years Caucasian Normotensive, normal singleton pregnancies Mayo Clinic, Minnesota Controls (n=59) = staff and students from the University of Minnesota, aged 19-48 years |
Blood fatty acid composition |
36 weeks gestation, during labor, 6 weeks postpartum |
Amount |
Results |
Conclusion* |
Absolute amount not specified |
“The average total amount of fatty acid (TF) in maternal venous plasma PL increased significantly (p<0.0001) during pregnancy, but the rise in TF became less pronounced towards the end of gestation (p<0.0001).” “Total fatty acids increased from 1238.11 mg/L at week 10 to 1867.84 mg/L at week 40 of gestation, and all of the fatty acid families showed a similar course.” “The mean amount of total fatty acids in umbilical plasma phospholipids was substantially lower (p<0.0001) than all maternal values” for all fatty acid families. “In contrast to the absolute amounts of AA and DHA, the mean relative amounts of AA and DHA in umbilical plasma phospholipids were significantly (p<0.0001) higher than all maternal values.” |
N/A |
Normal controls of nonpregnant women of childbearing age All in mol%±SEM: 24.1±0.39 LA, 12.5±0.24 AA, 0.22±0.01 ALA, 0.53±0.03 EPA, 1.04±0.04 DPA, 3.71±0.14 DHA |
All individual PUFA were less than normal in pregnant women at 36 weeks of pregnancy than in the nonpregnant women, where EPA was 42% of normal values. “The fatty acid profile of plasma phospholipids during labor was similar to that at 36 weeks except for the subnormal LA and ALA values became significant at p<0.01 and p<0.05, respectively, and the elevated 22:5n-6 became significant at 0.001.” The fatty acid profile of plasma phospholipids for lactating women 6 weeks postpartum was similar to those during pregnancy and labor except that AA status improved, diminished ALA, and increased EPA and DPA toward normal. The fatty acid profile of plasma phospholipids for nonlactating women 6 weeks postpartum was similar to that of the lactating women, expect that abnormalities were less severe or of lower significance. |
N/A |
Amount |
Results |
Conclusion* |
Absolute amount not specified |
“Greater apparent seafood consumption predicted DHA content of mothers’ milk (p<0.006)” and “higher DHA content in mothers’ milk predicted a lower prevalence rate of postpartum depression (p<0.0001).” “Higher national seafood consumption predicted lower prevalence rates of postpartum depression (p<0.0001).” |
B |
TABLE B-1c Studies on Gestation and Birth Weight: Effects on Infants of Mothers Who Increase Seafood and/or Omega-3 Fatty Acid Intake
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
de Groot et al., 2004 |
Randomized Controlled Trial |
Pregnant women (n=79) Mean age of 29-30 years Maternal education about 4 (on an 8-point scale) Maastricht, Heerlen, Sittard, southeastern Netherlands White origin, gestational age <14 weeks, normal health, fish consumption <2 times/week No hypertensive, metabolic, cardiovascular, renal, psychiatric, or neurologic disorder |
ALA-supplemented margarine |
14 weeks gestation until delivery |
Smuts et al., 2003a |
Randomized Controlled Trial |
Pregnant women (n=73) Mainly African-American Aged 16-35 years Reachable by telephone Planned to deliver at the Regional Medical Center in Memphis, TN No more than four pregnancies |
DHA-enriched egg |
24-28 weeks gestation until delivery |
Smuts et al., 2003b |
Randomized Controlled Trial |
Pregnant women (n=291) Aged 16-36 years Mainly African-descent Plan to deliver at Truman Medical Center in Kansas City, MO Able and willing to consume eggs, access to refrigeration Singleton gestation No weight >240 pounds at baseline, cancer, lupus, hepatitis, infectious disease, diabetes, gestational diabetes, elevated blood pressure at baseline |
DHA-enriched egg |
24-28 weeks gestation until delivery |
Amount |
Results |
Conclusion* |
Experimental group (% total fatty acids): ALA-enriched high-LA margarine 25 g margarine 45.36 LA, 14.18 ALA Control group (% total fatty acids): No ALA high-LA margarine 25 g margarine/day 55.02 LA, 0.17 ALA |
Newborns in the experimental group had a significantly higher mean birth weight than those in the control group (p=0.043). No significant differences in gestational age, APGAR score, or umbilical plasma DHA concentrations in phospholipids were found between the two groups. |
B (birth weight only) |
High-DHA egg group: mean = 183.9±71.4 mg DHA/day ranged from 27.6 to 264.9 mg/day Ordinary egg group: mean = 35.1±13.2 mg DHA/day ranged from 0 to 36 mg/day Low egg intake group: mean = 10.8±4.0 mg DHA/day ranged from 0 to 36 mg/day |
“Mean weight, length, and head circumference of infants in the high-DHA egg group were greater than in the ordinary egg group, and gestation was 5.6 days longer.” |
B |
High-DHA egg group: mean = 133±15 mg DHA/egg ranged from 108 to 165 mg/ egg Ordinary egg group: mean = 33±11 mg DHA/egg ranged from 22 to 51 mg/egg |
After controlling for maternal BMI at enrollment and number of prior pregnancies, the mean difference in gestational age between the two groups was 6.0±2.3 days (p=0.009). After controlling for maternal BMI at enrollment and maternal race, the mean difference in birth weight between the two groups was not significant. |
B (gestation only) |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Haugen and Helland, 2001 |
Randomized Controlled Trial |
Pregnant women (n=37) Mean age about 27-31 years Oslo, Norway Normotensive without proteinuria, had uncomplicated term pregnancies, randomly taken from another study investigating the influence of omega-3 fatty acids on fetal, neonatal, and child development Another group had moderate preeclampsia |
Cod-liver oil supplement |
16-20 weeks gestation through pregnancy |
Helland et al., 2001 |
Randomized Controlled Trial |
Pregnant women (n=590) Aged 19-35 years Oslo, Norway Single pregnancies, Nulli- or primipara Intention to breastfeed No supplement of n-3 LCPUFA earlier during the pregnancy No premature births, birth asphyxia, infections, and anomalies in the infants that required special attention |
Cod-liver oil supplement |
17-19 weeks gestation until 3 months after delivery |
Amount |
Results |
Conclusion* |
Cod-liver oil group: 10 mL/day Corn-oil group: 10 mL/day |
There were no significant differences in gestational age between the four groups (cod-liver oil group, corn oil group, preeclamptic group, and the normotensive group). Birth weight was significantly higher in the corn oil group compared to the cod-liver oil group (p<0.05) and significantly higher in the normotensive group compared to the preeclamptic group (p<0.0001). |
A (birth weight only) |
10 mL/day cod-liver oil vs. corn oil Cod-liver oil group: 803 mg of EPA/10 mL; 1183 mg DHA/10 mL Corn-oil group: 0 mg of EPA/10 mL; 8.3 mg DHA/10 mL |
“There were no significant differences in gestational length or birth weight between the two supplement groups. Birth length, head circumference, and placental weight were also similar in the 2 supplement groups.” |
N |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Olsen et al., 2000 |
Randomized Controlled Trial |
Pregnant women (n=1619) 19 hospitals in Denmark, Scotland, Sweden, England, Italy, Netherlands, Norway, Belgium, and Russia Participated in one of six previous trials (four prophylactic trials and two therapeutic trials) |
Fish-oil supplement |
20 weeks (prophylactic) or 33 weeks (therapeutic) gestation, delivery |
Olsen et al., 1992 |
Randomized Controlled Trial |
Pregnant women (n=533) Mean age 29 years Aarhus, Denmark Main midwife clinic, covers a well-defined geographic area No placental abruption in previous pregnancy or serious bleeding in current pregnancy; no prostaglandin inhibitors regularly No multiple pregnancy, allergy to fish, and regular intake of fish oil |
Fish-oil supplement |
Enrolled at 30 weeks gestation; end time not specified |
Amount |
Results |
Conclusion* |
2.7 g/day fish oil vs. olive oil in the prophylactic trials 6.1 g/day fish oil vs. olive oil in the therapeutic trials |
In the trial of women who experienced preterm delivery in an earlier pregnancy, those randomized to fish oil had statistically significant longer gestation duration (difference = 8.5 days) compared to those randomized to olive oil (p=0.01). In the trial of women who experienced preterm delivery in an earlier pregnancy, those randomized to fish oil had children with a significantly higher mean birth weight (difference = 208.7 g) compared to those randomized to olive oil (p=0.02). In the trial of women with threatening preeclampsia in the current pregnancy, the mean difference of duration until delivery was 8.8 days less for those randomized to fish oil compared to those randomized to olive oil (p=0.19). In the trial of women with suspected intrauterine growth retardation in the current pregnancy, the mean difference of weight for gestational age was 29 g higher in those randomized to fish oil compared to those randomized to olive oil (p=0.75). |
B |
2.7 g/day fish oil vs. olive oil |
The average gestational length for those in the fish-oil group was 4 days longer (95% CI 1.5-6.4, p<0.005) than those in the olive oil group. The average gestational length for those in the fish-oil group was 2.8 days longer (95% CI 0.8-4.8, p<0.01)) than those in the olive-oil and control groups. Birth weight (p=0.07) and length (p=0.1) trended higher in the fish-oil group than in the olive-oil group (3 way ANOVA between fish oil, olive oil, no oil). |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Olsen and Secher, 1990 |
Randomized Controlled Trial |
Pregnant women (n=5022) Aged 15-44 years London People’s League of Health, 1946 Attending antenatal clinics of 10 hospitals No disease or physical abnormality |
EPA/DHA supplement from halibut oil |
Enrolled at <24 weeks gestation; treatment lasts for <15 weeks (n=288), 16-19 weeks (n=411), 20-23 weeks (n=414), or 24+ weeks (n=417) |
People’s League of Health, 1946 |
Randomized Controlled Trial |
Pregnant women (n=5022) London Not beyond the 24th week of pregnancy No physical disease or abnormality |
n-3 supplement |
|
People’s League of Health, 1942 |
Randomized Controlled Trial |
Pregnant women (n=5022) London |
Additional diet, which includes hali-but liver oil |
Enrolled if due date more than 16 weeks away; until delivery |
Amount |
Results |
Conclusion* |
0.1 g/day of EPA+DHA from halibut oil in supplement vs. no supplement Supplement includes 0.26 g ferrous iron; 0.26 g calcium; minute quantities of iodine, manganese, and copper; 0.6 g thiamin/g; 0.1 g vitamin C; 0.36 g halibut liver oil |
“In primiparae, a 19.9% (p=0.012) reduction in the odds of delivering earlier than 40 weeks was seen in the treatment group, whereas in multiparae a reduction of 21.2% (p=0.028) was seen,” compared to the control group. “No significant effects were seen on the odds of delivering after 40 weeks of gestation.” “No significant effects were seen on average birth weight.” |
B (gestation only) |
|
“A smaller incidence of prematurely was revealed among the treated women, and this is particularly significant since about 50% of infant deaths under 1 month are due to prematurely.” |
B |
Weekly intake score for consumption of “the more important foodstuffs” such as milk, butter, wholemeal bread, fresh vegetables, fatty fish, fruit, eggs, etc. Additional diet: 0.26 g ferrous iron; 0.26 g calcium; minute quantities of iodine, manganese, and copper; 1 g adsorbate of vitamin B1; 100 mg vitamin C; 0.36 g halibut liver oil (vitamins A and D) |
Among primigravida women, 20.1±1.10% of those who received additional diet experienced a preterm delivery compared to 23.9±1.10% of those who did not receive additional diet. This difference was statistically significant. Among multiparae women, 20.1±1.33% of those who received additional diet experienced a preterm delivery compared to 24.2±1.33% of those who did not receive additional diet. This difference was statistically significant. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Lucas et al., 2004 |
Cohort |
Postpartum women (n=491) and their infants Mean age of 23.7 years Inuit 14 coastal villages of Nunavik and southern Quebec Delivered at Tulattavik Health Center (Ungava Bay) or Inuulitsivik Health Center (Hudson Bay) |
Cord venous sample |
At delivery |
Amount |
Results |
Conclusion* |
Tertiles of EPA (% of total fatty acids): Tertile 1 = <0.21 Tertile 2 = 0.21-0.39 Tertile 3 = >0.39 Tertiles of DHA (% of total fatty acids): Tertile 1 = <2.99 Tertile 2 = 2.99-4.03 Tertile 3 = >4.03 Tertiles of %n-3 HUFA (% of total HUFA): Tertile 1 = <18.60 Tertile 2 = 18.60-22.96 Tertile 3 = >22.96 |
After adjusting for weight gain during pregnancy, gestational diabetes, cord blood mercury, lead, and PCB congener 153, those in the third tertile of n-3 HUFA (% of total HUFA) had significantly longer gestation (278.4 days) compared to those in the first tertile (273.0 days) (p<0.05). After adjusting for pre-pregnancy weight, weight gain during pregnancy, parity, smoking status during pregnancy, gestational diabetes, age, cord blood mercury, and PCB congener 153, those in the third tertile of n-3 HUFA (% of total HUFA) had babies with a higher birth weight (3551 g) compared to those in the first tertile (3475 g), but this difference was not significant. There were no significant differences in birth weight or gestation based on the tertiles of EPA and DHA in the cord blood. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Oken et al., 2004 |
Cohort |
Pregnant women (n=2109) Aged 14-44 years 16% Black, 7% Hispanic-American, 6% Asian-American Massachusetts Project Viva |
Seafood |
Last menstrual period until enrollment, 3 months prior to 26-28 weeks of gestation, the month prior to delivery |
Olsen and Secher, 2002 |
Cohort |
Pregnant women (n=8729) Aarhus, Denmark Gave birth to singleton, liveborn babies without detected malformations Had not consumed fish-oil supplements |
Seafood |
From when first knew of pregnancy until completion of questionnaires at 16 and 30 weeks gestation |
Amount |
Results |
Conclusion* |
Seafood tertiles: None or <1 serving/month, the remaining subjects were divided into tertiles with the highest intake group used as the referent First trimester quartiles of EPA+DHA: Quartile 1 = 0.00-0.05 Quartile 2 = 0.06-0.12 Quartile 3 = 0.12-0.24 Quartile 4 = 0.24-2.53 Second trimester quartiles of EPA+DHA: Quartile 1 = 0.00-0.05 Quartile 2 = 0.06-0.12 Quartile 3 = 0.12-0.23 Quartile 4 = 0.24-2.71 Third trimester quartiles of EPA+DHA: Quartile 1 and 2 = 0.00-0.06 Quartile 3 = 0.60-0.11 Quartile 4 = 0.11-1.72 |
After adjusting for enrollment site, infant sex, and maternal age, height, intrapartum weight gain, pre-pregnancy BMI, race/ethnicity, smoking during pregnancy, education, and gravidity: Significant negative trends based on EPA+DHA intake were found for the first trimester [birth weight (p=0.01) and fetal growth (p=0.001)], the second trimester [fetal growth (p=0.03)], and the third trimester [birth weight (p=0.001) and fetal growth (p=0.003)]; No other significant trends were observed for change in birth weight, fetal growth or length of gestation with EPA+DHA intake during the three trimesters; Significant negative trends were observed for change in birth weight and fetal growth with seafood consumption, but only during the first trimester (p=0.05 and p=0.08, respectively); and No other significant trends were observed for change in birth weight, fetal growth, or length of gestation with seafood intake during the first two trimesters. |
B |
0.0, 0.5, 2.0, 4.0, 20.0, 28.0 serving/28 days Hot fish meal: 144 g fish/serving 1627 µg n-3 fatty acids/serving Fish sandwich: 29 g fish/serving 431 µg n-3 fatty acids/serving Fish salad: 50 g fish/serving 149 µg n-3 fatty acids/serving |
“Low birth weight, preterm birth, and intrauterine growth retardation all tended to decrease with increasing fish consumption, and mean birth weight, duration of gestation, and birth weight adjusted for gestational age tended to increase with increasing fish consumption.” Low consumption of seafood was a strong risk factor for preterm delivery and low birth weight. The associations were strongest below a daily intake of 0.15 g long change n-3 fatty acids or 15 g fish. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Grandjean et al., 2001 |
Cohort |
Singleton term births (n=182) Faroe Islands Delivered at the National Hospital in Torshavn Birth at >36 weeks of gestation; no congenital neurological disease |
Maternal and cord serum and seafood intake |
Maternal blood taken at week 34, cord blood taken at delivery, questionnaire administered 2 weeks after parturition |
Olsen et al., 1991 |
Cohort |
Mothers of live-born singleton infants (n=99) Mean age about 27 years Faroese (n=62) and Danish women (n=37) Delivered at the Landssjukrahusid and Aarhus Kommenehospital No preeclampsia, rhesus immunization, insulin-dependent diabetes mellitus, or twin pregnancies |
Peripheral venous blood sample |
5-48 hours after delivery |
Amount |
Results |
Conclusion* |
Information on fish species or portion sizes was not collected Fish dinners/week: 0, 1, 2, ≥3 Whale meat dinners/month: 0, 1, ≥2 Whale blubber dinners/month: 0, 1-2, >2 |
Gestational length showed a significant positive association with cord serum DHA concentration (p<0.001) and DTA (p=0.004). After adjusting for nonsmoking, average-height and nulliparous mother with term birth of male baby, birth weight showed a significant positive association with cord serum ETA (p=0.001), EPA (p=0.015), and DPA (p=0.002). After adjusting for gender, parity, gestational length, smoking, and maternal height, birth weight decreases by 246 g for every one unit increase in cord serum EPA concentration (%) (p=0.037). |
B |
Faroese women: Mean of 0.83±0.039% EPA Mean of 2.08±0.059% DPA Mean of 5.87±0.12% DHA Mean of 12.07±0.15% AA Danish women: Mean of 0.61±0.051% EPA Mean of 2.08±0.076% DPA Mean of 4.65±0.159% DHA Mean of 12.07±0.19% AA |
There were no significant differences in gestational age (p=0.3) and birth weight (p=0.1) between the two groups. After controlling for maternal pre-pregnant weight, height, age, parity, marital status, smoking, and employment during pregnancy a significant association was found between the (3/6) ratio from blood and gestational age in the Danish women (p=0.02) but not in the Faroese women (p=0.6). |
N |
Amount |
Results |
Conclusion* |
The Orcandians eat 30% more fish than the Aberdonians, but absolute amount undetermined |
Mean birth weight of the infants born to residents of Orkney Islands was 3521 g and for residents of Aberdeen was 3287 g (p=0.01). Gestational age was 0.36 weeks longer in the Orkney women than in the Aberdeen women (p=0.01). 18.3% of infants born to Orkney women and 10.0% of infants born to Aberdeen women were over the 90th percentile for birth weight (corrected for gestational age and parity) (p=0.01). 4.8% of infants born to Orkney women and 12.2% of infants born to Aberdeen women were below the 10th percentile for birth weight (corrected for gestational age and parity) (p=0.01). Being a resident of Orkney explains a significant proportion of the difference in birth weights between Orkney and Aberdeen women (R2 = 0.489). |
B |
TABLE B-1d Studies on Development (Anthropometry, Visual Acuity, and Cognition): Effects on Infants of Mothers Who Increase Seafood and/or Omega-3 Fatty Acid Intake
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Cohen et al., 2005 |
Review |
Aggregated 8 randomized controlled trials (one study of maternal dietary supplementation and seven studies of formula supplementation) |
DHA supplement |
|
Jensen et al., 2005 |
Randomized Controlled Trial |
Pregnant women (n=114 in DHA group; n=113 in control group) Aged 18-40 years Houston, TX White (75% DHA group; 79% control group) African American (19% DHA group; 13% control group) Gestational age >37 weeks Infant birth weight 2500-4200 g No chronic maternal disorders as well as major congenital anomalies and obvious gastrointestinal or metabolic disorders of the infant |
DHA supplement |
Day 5 after delivery until 4 months postpartum |
Amount |
Results |
Conclusion* |
|
An increase in maternal intake of DHA during pregnancy of 1 g/day will increase child IQ by 0.8-1.8 points. “Prenatal maternal DHA intake increasing the child plasma (RBC) DHA phospholipid fraction by 1% has the same impact on cognitive development as formula DHA supplementation that increases the child’s plasma (RBC) DHA phospholipid fraction by 1%.” “Because typical DHA intake associated with fish consumption is well under 1 g/day, changes in fish consumption will result in IQ effects amounting to a fraction of a point,” but they are not clinically detectable. |
B |
DHA capsule: Algal triacylglycerol 200 mg DHA/day Control capsule: Soy and corn oil |
There were no significant differences in visual acuity (from either the Teller Acuity Card or Sweep VEP) at 4 or 8 months of age between the two groups. There were no significant differences in mean transient VEP latency at 4 and 8 months of age between the two groups; but the transient VEP amplitude was significantly lower in the infants of the DHA group compared to the infants of the control group. There were no significant differences in Gesell Gross Motor Inventory, CAT, CLAMS DQ, or Bayley MDI between the two groups at 12 or 30 months of age; but Bayley PDI at 30 months of age was 8.4 points higher (p=0.005) in infants of the DHA group compared to infants of the control group. |
N |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Dunstan et al., 2004 |
Randomized Controlled Trial |
Pregnant women (n=83) Atopic pregnancies Western Australia History of doctor diagnosed allergic rhinitis and/or asthma One or more positive skin prick test to house mites; grass pollens; molds; cat, dog, or cockroach extracts Nonsmokers No other medical problems, complicated pregnancies, seafood allergy, or >2 fish meals/week Term, healthy infants considered at high risk of allergic disease |
Fish-oil supplement |
20 weeks gestation until delivery |
Jensen et al., 2004 |
Randomized Controlled Trial |
Breast-feeding mothers (n=89 in treatment group; n=85 in placebo group) |
DHA supplement |
Delivery until 4 months postpartum |
Amount |
Results |
Conclusion* |
Fish-oil group: 3.7 g/day fish oil 56% DHA and 27.7% EPA 4 capsules/day Olive-oil group: 66.6% n-9 oleic acid and <1% n-3 PUFA 4 capsules/day |
Breast milk concentrations of DHA, DPA, and EPA were significantly higher (p<0.001) and AA was significantly lower (p=0.045) in fish-oil supplemented mothers compared with controls. “There were no significant differences in the detection or level of free cytokines or IgA between the 2 groups.” |
N/A |
200 mg/day of DHA vs. placebo |
There were no significant differences between the two groups in visual function or neurodevelopment until 30 months of age. At age 30 months, the Bayley PDI of infants whose mothers were randomized to DHA was 0.55 standard deviations higher (p<0.01) than that of infants whose mothers were randomized to the placebo. There were no significant differences between the two groups in visual function; transient VEP; sweep VEP; stereoacuity; and gross and fine motor, executive, perceptual/visual or verbal domains at age 5. At age 5, infants whose mothers were randomized to DHA had significantly higher Sustained Attention Subtest of the Leiter International Performance Scale than those whose mothers were randomized to the placebo (p<0.008). |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Helland et al., 2003 |
Randomized Controlled Trial |
Pregnant women (n=48 in cod-liver oil group; n=36 in corn oil group) Aged 19-35 years Oslo, Norway Healthy women with, singleton pregnancy, nulli- or primiparous, intention to breastfeed No supplement of n-3 LCPUFA earlier during pregnancy, premature births, birth asphyxia, general infections, or anomalies in the infants that required special attention |
Cod-liver oil supplement |
From 18 weeks of pregnancy until 3 months after delivery |
Amount |
Results |
Conclusion* |
Cod-liver oil: 10 mL/day 1183 mg DHA, 803 mg EPA Corn oil: 10 mL/day 4747 mg LA, 92 mg ALA |
K-ABC scores were significantly higher for the subset MPCOMP among children from the cod-liver oil group compared to the corn oil group (p=0.049). The scores for the other subtests (SEQPROC, SIMPROC, NONVERB) were also higher in the cod-liver oil group compared to the corn oil group, but they were not significant. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Auestad et al., 2001 |
Randomized Controlled Trial |
Infants (n=294 formula fed; n=165 breastfed) Kansas City, MO; Little Rock, AR; Pittsburgh, PA; Tucson, AZ Good health, term status, either ≤9 days of age (formula group) or ≤11 days of age and currently breastfeeding (breastfeeding group), birth weight ≥2500 g, 5-minute APGAR score ≥7, ability to tolerate milk-based formula or breast milk, guardian or parent agreement to feed the assigned study formula ad libitum according to the study design No evidence of significant cardiac, respiratory, ophthalmologic, gastrointestinal, hematologic, or metabolic disease; milk-protein allergy; or a maternal medical history known to have proven adverse effects on the fetus, tuberculosis, HIV, perinatal infections, or substance abuse 61-74% European American 60-80% mothers married Mean mother’s age about 29 years Mean mother’s education about 14 years |
Fish oil/fungal oil and egg-derived triglyceride supplemented formulas |
9-11 days after birth until 12 months of age |
Amount |
Results |
Conclusion* |
Fish oil and fungal oil supplemented preterm formula: 0.46 g AA/100 g total fatty acids ≤0.04 g EPA/100 g total fatty acids 0.13 g DHA/100 g total fatty acids Egg-derived triglyceride supplemented preterm formula: 0.45 g AA/100 g total fatty acids No detected EPA 0.14 g DHA/100 g total fatty acids Control formula: No detected AA, EPA, DHA |
The vocabulary expression score at 14 months was significantly higher in the fish/fungal group than in the egg-TG group (p<0.05). Smiling and laughter was significantly higher in the control group than in the egg-TG group (p=0.05). No other development, cognition, vocabulary, or temperament outcomes presented were significantly difference between the formula groups. No significant differences were found between groups for weight, length, and head circumference or visual acuity. |
N |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Helland et al., 2001 |
Randomized Controlled Trial |
Pregnant women (n=590) Aged 19-35 years Oslo, Norway Single pregnancies, nulli-or primipara Intention to breastfeed No supplement of n-3 LCPUFA earlier during the pregnancy No premature births, birth asphyxia, infections, and anomalies in the infants that required special attention |
Cod-liver oil supplement |
17-19 weeks gestation until 3 months after delivery |
McCann and Ames, 2005 |
Review |
Summary of observational, RCTs, other experimental and animal studies |
LCPUFA supplement |
|
Amount |
Results |
Conclusion* |
10 mL/day cod-liver oil vs. corn oil Cod-liver oil: 803 mg of EPA/10 mL; 1183 mg DHA/10 mL Corn oil: 0 mg of EPA/10 mL; 8.3 mg DHA/10 mL |
“There were no significant differences in gestational length or birth weight between the 2 supplement groups. Birth length, head circumference, and placental weight were also similar in the 2 supplement groups.” |
N |
|
“Evidence from chronic dietary restriction rodent studies … shows that the addition of DHA to diets of animals whose brain concentration of DHA have been severely reduced restored control performance levels.” “Formula comparison and maternal supplementation studies in humans and ALA dietary restriction studies in nonhuman primates both link the availability of n-3 LCPUFAs to the development of visual attention” and higher DHA status to enhanced neuromotor development. RCTs in humans have often shown no effect of “LCPUFA supplementation on cognitive or behavioral performance and some reviewers have considered that, overall, the evidence was insufficient to conclude that LCPUFA supplementation benefited development.” |
B |
Amount |
Results |
Conclusion* |
|
“Breastfeeding, which supplies preformed LCPUFA, is the preferred method of feeding for healthy infants and is strongly supported.” “Infant formulas should contain at least 0.2% of total fatty acids as DHA and 0.35% as AA; formulas for preterm infants should include at least 0.35% DHA and 0.4% AA.” There is an absence of published studies showing direct functional benefits of supplementation of LCPUFA and studies to determine if the variability in LCPUFA status among pregnant women is related to functions in either the mother or infant. “It seems prudent for pregnant and lactating women to include some food sources of DHA in their diet.” |
B |
|
“There appears to be no detectable reduction in plasma n-3 LCPUFA concentrations during pregnancy, whereas there is a clear decline during the early postpartum period.” “Results of randomized clinical studies suggest that n-3 LCPUFA supplementation during pregnancy does not affect the incidences of pregnancy-induced hypertension and preeclampsia without edema.” “n-3 LCPUFA supplementation may cause modest increases in the duration of gestation, birth weight, or both.” “To date there is little evidence of harm as a result of n-3 LCPUFA supplementation during either pregnancy or lactation.” |
B |
Amount |
Results |
Conclusion* |
Carbohydrate (g) 182-218, 218-258, >258 Protein (g) 55-66, 66-79, >79 Total fat (g) 55-68, 68-84, >84 Saturated fat (g) 21-27, 27-35, >35 Polyunsaturated fat (g) 9-12, 12-16, >16 Monounsaturated fat (g) 19-24, 24-30, >30 Calcium (mg) 759-938, 939-1127, >1127 Potassium (mg) 2177-2582, 2583-3021, >3021 Magnesium (mg) 207-254, 255-308, >308 Protein/carbohydrate 0.26-0.30, 0.31-0.35, >0.35 Animal protein (g) 35-44, 44-53, >53 Omega-3 fatty acids (g) 0.03-0.09, 0.10-0.27, >0.27 |
After adjusting for sex, child’s age for blood pressure, and maternal pregnancy energy intake, a significant inverse association was found between omega-3 fatty acids and offspring blood pressure at age 7.5 years (p=0.04). After adjusting for sex, child’s age for blood pressure, and maternal pregnancy energy intake, there were no significant differences in offspring blood pressure at age 7.5 years based on maternal intake of carbohydrate, protein, total fat, saturated fat, polyunsaturated fat, monounsaturated fat, calcium, potassium, magnesium, protein/carbohydrate or animal protein. After adjusting for measurement factors, current anthropometry, maternal and social factors, birth weight, and gestation, there was a significant positive association found between maternal intake of carbohydrates and offspring blood pressure at 7.5 years (p=0.04). After adjusting for measurement factors, current anthropometry, maternal and social factors, birth weight, and gestation, there were no significant differences between the tertiles of maternal intake of protein, total fat, saturated fat, polyunsaturated fat, monounsaturated fat, calcium, potassium, magnesium, protein/carbohydrate, animal protein, or omega-3 fatty acid and offsprings’ systolic blood pressure at age 7.5 years. |
N |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Oken et al., 2005 |
Cohort |
Mother-infant pairs (n=135) Aged <30 years (n=16) Aged 30-34 years (n=53) Aged ≥35 years (n=31) 82% White; 18% non-White 80% college or graduate degree Massachusetts Singleton pregnancy, were able to complete forms in English, did not plan to move out of the study area before delivery Project Viva |
Seafood |
Second trimester of pregnancy |
Colombo et al., 2004 |
Cohort |
Infants (n=70) Mean gestation 39.29 weeks Mean birth weight 3248.57 g Mean APGAR score (1 min) 7.94 Mean APGAR score (5 min) 8.80 Mean education (11.77 years for mother and 11.88 for father) 77% African American 21% Caucasian 1% Hispanic Kansas |
DHA-enriched egg |
24-28 weeks gestation until delivery |
Amount |
Results |
Conclusion* |
Number of servings/week: Canned tuna fish (3-4 oz/serving) Shrimp/lobster/scallop/clam (1 serving) Dark meat fish (3-5 oz/serving) Other fish (3-5 oz/serving) 6 responses from never or less than 1/month to 1 or more servings/day |
After controlling for maternal hair mercury level, age, race/ethnicity, education, marital status, infant sex, gestational age at birth, birth weight for gestational age, breast-feeding duration and age at cognitive testing: Each 1 serving/week increase of fish intake increases the VRM score by 4 points (%novelty preference; 95% CI 1.3-6.7). After controlling for maternal seafood intake, age, race/ethnicity, education, marital status, infant sex, gestational age at birth, birth weight for gestational age, breast-feeding duration, and age at cognitive testing: Each 1 ppm increase in maternal hair mercury levels decreases the VRM score by 7.5 points (%novelty preference; 95% CI −13.7 to −1.2). |
B |
This study is a follow-up to an RCT High-DHA eggs: 135 mg DHA/egg Ordinary eggs: 35 mg DHA/egg |
“Infant red blood cell DHA level was unrelated to subsequent attentional measures, but maternal red blood cell DHA was consistently predictive of later attentional outcomes.” “Infants whose mothers had higher levels of DHA at birth showed accelerated developmental courses in attention across the 1st year.” Percent of time spent looking in orienting increased over time in both the high- and low-DHA groups, but it was larger in the high-DHA group compared to the low-DHA group at 4, 6, and 8 months. Percent of time spent looking in sustained attention declined over time in both groups, but it was smaller in the high-DHA group compared to the low-DHA group at 4, 6, and 8 months. Percent of time spent looking in attention termination was larger at 4 months in the low-DHA group compared to the high-DHA group, and then declined and leveled off at 6 months in both groups. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Daniels et al., 2004 |
Cohort |
Infants (n=1054) Mothers’ mean age = 29 years Majority of mothers with at least an O (moderate) level education Bristol, UK Singleton, term births Avon Longitudinal Study of Parents and Children (ALSPAC) |
Seafood |
Maternal fish intake: 32 weeks of gestation Breastfeeding practices: 15 months after birth Infant fish intake: 6 and 12 months after birth Total mercury concentration: Cord blood at birth |
Sakamoto et al., 2004 |
Cohort |
Pregnant women (n=63) Aged 21-41 years Japan Planning to deliver at Munakata Suikokai General Hospital, Fukuoka Healthy |
Maternal blood and umbilical cord blood lipids |
Umbilical cord blood at birth and maternal blood 1 day after parturition before breakfast |
Amount |
Results |
Conclusion* |
Maternal fish intake categories (during pregnancy): 1 = Rarely/never 2 = 1 meal/2 weeks 3 = 1-3 meals/week 4 = 4+ meals/week Child fish intake categories (6 months of age): 1 = Rarely/never 2 = 1+ meal/week Child fish intake categories (12 months of age): 1 = Rarely/never 2 = 1+ meal/week |
Children whose mothers ate 1-3 fish meals/week and 4+ fish meals/week had significantly lower odds of low MCDI scores for social activity (OR=0.6, 95% CI 0.5-0.8 and OR=0.7, 95% CI 0.5-0.9, respectively) than the children whose mothers rarely or never ate fish during pregnancy. Children whose mothers ate 1-3 fish meals/week and 4+ fish meals/week had significantly lower odds of low DDST scores for language (OR=0.7, 95% CI 0.5-0.9 and OR=0.7, 95% CI 0.5-0.9, respectively) than the children whose mothers rarely or never ate fish during pregnancy. Children who ate 1+ fish meals/week had significantly lower odds of low MCDI scores for vocabulary comprehension (OR=0.7, 95% CI 0.5-0.8) and social activity (OR=0.7, 95% CI 0.6-0.9) and total DDST scores (OR=0.8, 95% CI 0.6-0.9). All other odds ratios presented were nonsignificant. |
B |
Unspecified |
In all cases, fetal RBC-Hg levels (13.4 ng/g) were statistically higher than maternal RBC-Hg levels (8.41 ng/g) (p<0.01). “A strong correlation was observed in RBC-Hg between mothers and fetuses (r=0.92, p<0.001).” “Maternal RBC-Hg concentrations showed significant correlation coefficients with maternal plasma EPA (r=0.36, p<0.001) and DHA (r=0.33, p<0.005) concentrations.” “Fetal RBC-Hg concentrations showed a significant positive correlation with fetal plasma EPA (r=0.32, p<0.05) and DHA (r=0.35, p<0.01).” |
N/A |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Willatts et al., 2003 |
Cohort |
Mother and infant pairs (n=96) Term pregnancy and infant birth weight >2499 g Dundee |
DHA and AA content in maternal red blood cells |
34-36 weeks gestation |
Cheruku et al., 2002 |
Cohort |
Pregnant women (n=17) Men aged 29 years in the high-DHA group Men aged 24 years in the low-DHA group White (n=14) Hispanic (n=3) Windham, CT ≥4 hours of crib time in the first and second days postpartum No history of chronic hypertension, hyperlipidemia, renal or liver disease, heart disease, thyroid disorders, multiple gestations, or pregnancy-induced complications No drugs that affect the respiration of newborns, such as magnesium sulfate and butorphanol |
Maternal plasma DHA |
Day 1 and day 2 postpartum |
Amount |
Results |
Conclusion* |
Absolute DHA and AA levels in blood unspecified |
After adjusting for maternal education, social class, birth weight, gestation, type of feeding at birth, and infant age at time of assessment: “There was a significant negative relation between maternal DHA and peak look duration (p<0.05), and a significant positive relation between maternal DHA and visual acuity (p<0.01)” at 4 months of age. The relation between AA and peak look duration and visual acuity at 4 months of age were not significant. “These results suggest that higher maternal DHA status is related to more efficient information processing and improved visual acuity development in 4-month-old infants.” |
B |
High-DHA group (maternal plasma): >3.0% by weight of total fatty acids Low-DHA group (maternal plasma): ≤3.0% by weight of total fatty acids |
On day 2 postpartum, the low-DHA group had significantly higher sleep-wake transition (% of time in crib) and less wakefulness (% time in crib) than the high-DHA group (p<0.05). There was a significant group effect for active sleep time (p=0.004) and active:quick sleep time (p=0.001), these times being shorter in the high-DHA group than in the low-DHA group. “Differences in the prenatal supply of LCPUFAs, especially DHA, may modify brain phospholipids and affect neural function.” |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Haggerty et al., 2002 |
Cohort |
Mothers, smokers (n=11) Mothers, nonsmokers (n=13) Aberdeen, Scotland Uncomplicated, full-term pregnancies Perfusion on term placentas delivered vaginally or by elective Caesarean section from otherwise uncomplicated pregnancies |
Placental tissue lipids |
Within 20 minutes of delivery |
Innis et al., 2001 |
Cohort |
Infants (n=83) Term Birth weight 2500-4500 g Mean mother’s age of 32 years British Colombia Intend to breast-feed for 3 months, no solid foods for at least the first 4 months after birth No mothers with substance abuse, communicable diseases, metabolic or physiologic problems, infections likely to influence fetal growth, or multiple births No infants with evidence of metabolic or physical abnormalities |
Fatty acids in blood from infants and milk from mothers |
2 months of age |
Amount |
Results |
Conclusion* |
Unspecified |
The rates of transfer of LA and AA per perfused area were not different between the groups; “neither was the rate of placental transfer of ALA and DHA affected by smoking during pregnancy.” “In the non-smoking control group the placenta selectively transferred polyunsaturated fatty acids to the fetus in the order DHA > AA > ALA > LA. The order of selectivity was unaltered in placentas from smokers, but the addition of ethanol to the perfusion medium altered the order of selectivity to AA > ALA > LA > DHA.” “The presence of ethanol in the perfusate at a concentration of 2 mg/ml significantly reduced (p<0.01) the absolute rate of transfer of ALA and DHA.” |
N/A |
Infant DHA: (g/100 g fatty acids) Plasma phospholipids = 2.2-8.0 RBC PE = 6.3-13.0 PC = 1.4-4.6 Infant AA: (g/100 g fatty acids) Plasma phospholipids = 8.1-15.8 RBC PE = 20.2-27.8 PC = 5.6-9.7 Mother’s milk: (g/100 g milk fatty acids) DHA = 0.10-2.50 AA = 0.20-0.81 LA = 6.30-21.50 LNA = 0.50-4.10 |
“The ability to correctly discriminate a retroflex compared with dental phonetic contrast at 9 months of age was positively correlated with the plasma phospholipid DHA (p<0.02) and the RBC PE at 2 months of age (p=0.02).” “There were no significant correlations between the infants’ AA status and the ability to discriminate the native or nonnative language contrasts.” “There were no significant correlations between the infant DHA or AA status at 2 months of age and test scores for novelty preference, or the job search task, with adjustments for covariates included in the model.” |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Otto et al., 2001 |
Cohort |
Pregnant women (n=57) Mean age around 30 years Southern Limburg, Netherlands No metabolic, cardiovascular, neurologic, or renal disorders No medications, except multivitamins and iron supplements Singleton pregnancy Term delivery No blood transfusions in the perinatal period |
Plasma phospholipids |
36-37 weeks gestation; 2-5 days after delivery; 1, 2, 4, 8, 16, 32, 64 weeks postpartum |
Williams et al., 2001 |
Cohort |
Boys and girls (n=435) Mean age of 3.5 years Born in last 6 months of the Avon Longitudinal Study of Parents and Children (ALSPAC) enrollment period Healthy term infants |
Seafood |
During pregnancy for the mothers and at 4 weeks, 4 months, and 6 months for the infants |
Amount |
Results |
Conclusion* |
Absolute amount not specified |
“After delivery, total fatty acids in plasma phospholipids decreased significantly over time in the lactating and nonlactating women (p<0.0001).” “The amounts of ALA, DHA, and total n-3 fatty acids showed significant downward trends postpartum in both groups, whereas the amounts of EPA and DPA increased significantly after delivery.” |
N/A |
Oily fish consumption categories: 1 = Never or rarely 2 = Once every 2 weeks 3 = More than once every 2 weeks White fish = cod, haddock, plaice, and fish fingers Oily fish = pilchards, sardines, mackerel, tuna, herring, kippers, trout, and salmon |
After adjusting for breastfeeding, sex, maternal education, maternal age, housing tenure, financial difficulties, maternal smoking, number of older siblings in household, child care, maternal job status, mother is a vegetarian, mother’s fish eating habits: “Mothers who ate oily fish at least once every 2 weeks during pregnancy were more likely to have children who achieved foveal steroacuity than were the mothers who never ate oily fish (OR=1.57, 95% CI 1.00-2.45),” but this was not significant. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Haggerty et al., 1999 |
Cohort |
Pregnant women (n=10) Mean age of 31.3 years In last trimester of pregnancy 31-38 weeks gestational age Aberdeen, Scotland Healthy |
Fatty acid composition of maternal perfusate |
31-38 weeks gestation |
Haggerty et al., 1997 |
Cohort |
Term placentae (n=9) Mean weight of 566 g Delivered vaginally or by elective caesarean section Uncomplicated pregnancies Nonsmokers |
Placental tissue lipids |
Within 20 minutes of delivery |
Al et al., 1995 |
Cohort |
Pregnant women (n=110) Aged 19-43 years Maastricht, Netherlands Caucasian Singleton pregnancy DBP <90 mmHg No metabolic, cardiovascular, neurological or renal disorder |
Maternal venous and umbilical vein fatty acid profiles |
10, 14, 18, 22, 26, 30, 32, 34, 36, 38, 40 weeks gestation; after delivery; 6 months after delivery |
Amount |
Results |
Conclusion* |
Unspecified |
“When perfused with fatty acids in the ratios found in maternal circulating triglyceride, the human placenta selectively transfers PUFA to the fetus in the order: DHA > ALA > LA > AA.” “The ultimate source of fatty acids for the placenta is important for estimates of the likely supply of individual PUFA/LCPUFA to the fetus in utero.” “The biggest determinant of transfer of individual fatty acids from the mother to fetus is the supply of fatty acids available in the maternal circulation.” |
N/A |
Unspecified |
“The order of selectivity for placental transfer to the fetal circulation was DHA > ALA > LA > oleic acid, whilst the proportion of AA transferred was actually lower than that for oleic acid.” “There was no evidence of chain elongation of LA or ALA to any LCPUFA of the n-6 or n-3 series in the perfused placenta.” |
N/A |
Absolute amount not specified |
“The average amount of total fatty acid in maternal venous plasma phospholipids increased significantly (p<0.0001) during pregnancy, but the rise in total fatty acids became less pronounced towards the end of gestation (p<0.0001).” Total fatty acids increased from 1238.11 mg/L at week 10 to 1867.84 mg/L at week 40 of gestation, and all of the fatty acid families showed a similar course. “The mean amount of total fatty acids in umbilical plasma phospholipids was substantially lower (p<0.0001) than all maternal values” for all fatty acid families. “In contrast to the absolute amounts of AA and DHA, the mean relative amounts of AA and DHA in umbilical plasma phospholipids were significantly (p<0.0001) higher than all maternal values.” |
N/A |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Clandinin et al., 1980b |
Cohort |
Male infants (n=14) Female infants (n=7) Died within 3 days of birth Toronto, Canada Infants died from intrapartum asphyxia, congenital heart disease, sudden infant death syndrome, diaphragmatic hernia, and accidental causes Infants were of normal body weight and weight for length, with the exception of two infant males; infants had normal head circumference, with the exception of one infant male No infections or gastrointestinal disorders, apparently normally nourished, and growing reasonably well until the time of death |
Tissue fatty acid content from frontal and occipital brain lobes and cerebellum |
16 hours postmortem |
Bjerve et al., 1993 |
Case-control |
Cases = adults (n=156) Controls = normal human serum stored at −80 degrees C Aged >40 years Nord-Trondelag, Norway Previously undiagnosed diabetic patients Preterm infants (n=21) Very low birth weight, with birth weight <1500 g seen consecutively at the Department of Pediatrics |
Seafood and dietary DHA and AA intake |
10 weeks for adults and 1 year for the preterms |
Amount |
Results |
Conclusion* |
|
“Postnatal brain growth, expressed as wet weight of brain tissue, increased during the postpartum period, but was not as rapid as intrauterine brain growth.” “In contrast to the fatty acid components, postpartum levels of LA increased 4-fold relative to prenatal levels; postpartum brain levels of AA do not differ from those observed in brain during the third trimester.” “Chain elongation-desaturation of AA and LA to longer-chain homologues does not occur at maximal rates for several weeks postnatally or, alternatively, that these long-chain homologues if synthesized in extracerebral tissues may not be directed into synthesis of brain tissue during this early period of infant development.” |
N/A |
Number of fish meals per week: <2, 2, 3, and ≥4 Mean AA intake of these groups: (g/day) 1.22, 1.19, 1.31, 1.59 |
“After controlling for age, gender, BMI, alcohol intake, and smoking, there was a statistically significant positive correlation based on individual observations between increasing number of fish meals and the concentration of plasma phospholipid EPA (p<0.001) and DHA (p<0.001).” After controlling for APGAR score and weight at 1 year, 82% of the variance in MDI was explained by a model including the inverse of both DHA and EPA (p=0.0001). After controlling for weight at 1 year, 64% of the variance in PDI was explained by a model including the inverse of DHA (p=0.0001). |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Uauy et al., 1990 |
Case-control |
Case = infants fed formula by day 10 (n=32) Control = infants fed their own mother’s milk from birth (n=10) Birth weight appropriate for gestational age, able to receive enteral feedings, free of major neonatal morbidity by day 10 |
Human milk and milk formula |
Day 10 until 36 weeks old |
Makrides et al., 1994 |
Cross-sectional |
Male infants (n=16) Female infants (n=19) Died between weeks 2 and 48 South Australia All but two born at term |
Human milk and milk formula |
Within 48 weeks of birth |
Amount |
Results |
Conclusion* |
Human milk: 12.7 g/100 g AA, 1.5 g/100 g n-6 > C18, 0.8 g/100 g ALA, 0.5 g/100 g n-3>C18 Formula A: 24.2 g/100 g AA, 0.0 g/100 g n-6 > C18, 0.5 g/100 g ALA, 0.0 g/100 g n-3>C18 Formula B: 20.8 g/100 g AA, 0.0 g/100 g n-6 > C18, 2.7 g/100 g ALA, 0.0 g/100 g n-3>C18 Formula C: 20.4 g/100 g AA, 0.1 g/100 g n-6 > C18, 1.4 g/100 g ALA, 1.0 g/100 g n-3>C18 |
“Group C was comparable to the human milk-fed group, but Group A had lower DHA and n-3 LCPUFA in plasma and RBC membranes.” “Cone function was not affected by dietary essential fatty acids.” “Rod electroretinogram thresholds were significantly higher for Group A relative to the human milk-fed infants and Group C and significantly correlated with RBC n-3 LCPUFA (p<0.0001).” “Rod electroretinogram amplitude was significantly lower for Group A relative to the human milk-fed infants and Group C and related to plasma DHA and total n-3 LCPUFA (p<0.0001).” |
N/A |
Breast-feeding index = length of breastfeeding as a % of age at death: Breast-fed: ≥85% Formula fed: <30% LA in formula ranged from 12.0% to 15.0% and ALA in formula ranged from 1.0% to 1.6% |
Erythrocyte fatty acid composition of tissues were significantly lower in total saturated fatty acids (p<0.05), AA (p<0.05), and DHA (p<0.05) and significantly higher in DGLA (p<0.05), EPA (p<0.05), and DPA (p<0.05) for infants fed formula compared to those fed from the breast. Cortex fatty acid composition of tissues were significantly higher in 22:4n-6 (p<0.05), 22:5n-6 (p<0.05), and total n-6 (p<0.005) and lower in DHA (p<0.005) and total n-3 (p<0.005) for infants fed formula compared to those fed from the breast. There were no significant differences in retina fatty acid composition of tissues between the formula-fed and breast-fed infants. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Farquharson et al., 1992 |
Cross-sectional |
Term infants (n=20) Preterm infants (n=2) Greater Glasgow Health Board area Died within 43 weeks of birth Previously well infants who died suddenly in the home, “cot deaths” |
Human milk and milk formula |
Within 43 weeks of birth |
Martinez, 1992 |
Cross-sectional |
Infants born at different gestational ages and died soon after birth of acute causes that were not related to the central nervous system Not fed but mothers well-nourished Infants nourished in utero and after birth |
PUFA supplementation and PUFA-enriched formula |
After infant died (they died shortly after birth) |
Amount |
Results |
Conclusion* |
Breast milk or the formula milks SMA Gold Cap and/or White Cap, Cow and Gate Premium, or Osterfeed |
“Breast fed infants had greater concentrations of DHA in their cerebral cortex phospholipids than either the mixed fed group or the older SMA and CGOST groups.” “No significant differences in phospholipid fatty acid content of cerebral cortex were found between the age-comparable SMA and CGOST groups.” |
N/A |
Prenatal fatty acid amounts not specified |
“Long-chain fatty acids accumulate in the human brain during the brain’s growth spurt unless a serious imbalance in the supply of LA and ALA occurs.” “The active formation of synaptic structures and dendritic arborizations increases significantly between 31 weeks of gestation and term.” “It seems highly desirable to enrich parenteral lipids and milk formulas with DHA to provide between 0.5% and 1% of total fatty acids similar to those in human milk.” “A total n-6/n-3 fatty acid ratio between 5 and 7 seems appropriate according to our analysis of human milk from others consuming complete, balanced Mediterranean diets rich in fish.” |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Kodas et al., 2004 |
Animal |
2 generations of female Wistar rats |
ALA-deficient diet |
Control group: Control diet at birth to 60 days after birth Deficient group: Deficient diet at birth to 60 days after birth Diet reversed group 1: Control diet at day of birth until 60 days after birth Diet reversed group 2: Deficient diet until day 7 of life and then control diet from day 7 to day 60 of life Diet reversed group 3: Deficient diet until day 14 of life and then control diet from day 14 to day 60 of life Diet reversed group 4: Deficient diet until day 21 of life and then control diet from day 21 to day 60 of life |
Amount |
Results |
Conclusion* |
ALA-deficient diet: 6% fat African peanut oil <6 mg ALA/100 g diet 1200 mg LA/100 g diet Control diet: 60% peanut oil, 40% rapeseed oil 200 mg ALA/100 g diet 1200 mg LA/100 g diet |
The fatty acid composition of phosphatidylcholine in the hippocampus of 2-month-old rats was as follows: AA was not significantly different among the different diet groups; DHA was significantly higher in the control group and all diet reversed groups compared to the deficient group (p<0.05); n-6:n-3 was significantly lower in the control group and all diet reversed groups compared to the deficient group (p<0.05); these differences were not significant between the control group and the diet reversed groups. The fatty acid composition of phosphatidylethanolamine in the hippocampus of 2-month-old rats was as follows: AA was significantly lower in the control group and all diet reversed groups compared to the deficient group (p<0.05); DHA was significantly higher in the control group and all diet reversed groups compared to the deficient group (p<0.05); n-6:n-3 was significantly lower in the control group and all diet reversed groups compared to the deficient group (p<0.05); these differences were not significant between the control group and the diet reversed groups. The fatty acid composition of phosphatidylserine in the hippocampus of 2-month-old rats was as follows: AA was not significantly different among the different diet groups; DHA was significantly higher in the control group and all diet reversed groups compared to the deficient group (p<0.05); n-6:n-3 was significantly lower in the control group and all diet reversed groups compared to the deficient group (p<0.05); these differences were not significant between the control group and the diet reversed groups; and Basal 5-HT levels were significantly higher in the deficient group compared with the control group (p<0.05); there were no significant differences in basal 5-HT levels between the diet reversed groups 1, 2, and 3 and the control group; there were no significant differences in basal 5-HT levels between the diet reversed group 4 and the control group, deficient group, and all other diet reversed groups. |
B |
Amount |
Results |
Conclusion* |
n-6:n-3 diet (in mol%): 7.0% soybean oil 56.0% LA, 6.2% ALA, 9.0% n-6:n-3 n-3 diet (in mol%): 7.0% linseed oil 14.0% LA, 33.0% ALA, 0.4% n-6:n-3 n-6 diet (in mol%): 7.0% sunflower oil 65.0% LA, 0.3% ALA, 216.0% n-6:n-3 |
In the pups not exposed to ovalbumin: Delayed-type hypersensitivity responses against ovalbumin, as well as against human serum ovalbumin were not significantly different between the dietary groups; IgG anti-avalbumin and IgG anti-human serum ovalbumin antibodies were not significant different between the three diet groups; IgM anti-ovalbumin antibodies in the n-3 diet group are significantly higher than those in the n-6:n-3 diet group (p<0.05); and IgM anti-human serum ovalbumin antibodies in the n-3 diet group are significantly higher that those in the n-6: n-3 diet group (p<0.05). In the pups exposed to ovalbumin: Delayed-hypersensitivity responses against ovalbumin were significantly higher in the n-6:n-3 diet group compared to the n-3 diet group and the n-6 diet group, while delayed-hypersensitivity responses to human serum ovalbumin were significantly higher in the n-6:n-3 diet group compared to the n-3 diet group (p<0.05); IgG anti-human serum ovalbumin antibodies were significantly higher in the n-6:n-3 diet group than those in the n-3 diet group (p<0.05); and IgM anti-human serum ovalbumin antibodies in the n-3 diet group are significantly lower than those in the n-6: n-3 diet group and the n-6 diet group (p<0.05). Those in the n-3 diet group exposed to ovalbumin have significantly lower IgG ovalbumin, IgG anti-human serum ovalbumin, IgM anti-ovalbumin, and IgM anti-human serum ovalbumin antibodies than those not exposed to ovalbumin (p<0.05). Those in the n-6 diet group exposed to ovalbumin have significantly lower IgG ovalbumin and IgM anti-ovalbumin antibodies than those not exposed to ovalbumin (p<0.05). |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Levant et al., 2004 |
Animal |
Adult female Long-Evans rats |
LCPUFA-deficient diet |
Control diet: Day 1 of pregnancy until end of study Deficient diet: Day 1 of pregnancy until postnatal day 21. Postnatal day 21, half on deficient diet were changed to remediation diet and half stayed on deficient diet |
Amount |
Results |
Conclusion* |
Control diet: 0.35 kg/5 kg diet from soybean oil; no detected AA, EPA, DPA, or DHA Deficient diet: 0.35 kg/5 kg diet from sunflower oil; no detected AA, EPA, DPA, or DHA Remediation diet: 0.3275 kg/5 kg diet from sunflower oil and 0.0225 kg/5 kg diet from fish oil 0.1 g/100 g fatty acids AA, 1.6 g/100 g fatty acids EPA, 0.4 g/100 g fatty acids DPA, 3.5 g/100 g fatty acids DHA |
“Rats raised on the deficient diet exhibited a decrease in brain DHA content to 80% of control animals at maturity (p<0.05)” and an “increase in DPA content to 575% of control animals at maturity (p<0.001).” The remediation diet restored brain DHA and DPA content to levels similar to those on the control diet. Catalepsy score was significantly lower in the deficient diet group compared to the control group (p<0.05) and the remediation diet group (p<0.05). In a test of locomotor activity in a novel environment, the deficient diet group exhibited 187% of the activity of the control diet group during the 2-hour observation (p<0.05); results were similar between the deficient diet group and the remediation diet group. In the test of amphetamine-stimulated locomotor activity, the deficient diet group exhibited 144% of the activity of the control group (p<0.05). |
A |
Amount |
Results |
Conclusion* |
Semipurified diet: Deficient in n-3 fatty acids Safflower oil was sole fat source High n-6:n-3 ratio Controls: Soybean oil was sole fat source High in LA |
At all ages, animals of the “deficient group had considerably lower levels of n-3 fatty acids in tissue phospholipids than their controls.” Based on the occipital cortex, perinatal 22:5n-6 (p<0.01) and total n-6 (p<0.05) were significantly higher and perinatal DHA (p<0.01) and total n-3 (p<0.01) were significantly lower in the deficient group compared to the control group. Based on the occipital cortex, 22:4n-6 (p<0.01), 22:5n-6 (p<0.01), and total n-6 (p<0.01) at 22 months were significantly higher and DHA (p<0.01) and total n-3 (p<0.01) at 22 months were significantly lower in the deficient group compared to the control group. Based on the frontal cortex, perinatal 22:5n-6 (p<0.01) was significantly higher and perinatal DHA (p<0.01) and total n-3 (p<0.01) were significantly lower in the deficient group compared to the control group. Based on the frontal cortex, 22:5n-6 (p<0.01) and total n-6 (p<0.01) at 22 months were significant higher and DHA (p<0.01) and total n-3 (p<0.01) at 22 months were significantly lower in the deficient group compared to the control group. |
N/A |
TABLE B-1e Studies on Allergies: Effects on Infants and Children of Mothers Who Increase Seafood and/or Omega-3 Fatty Acid Intake
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Denburg et al., 2005 |
Randomized Controlled Trial |
Pregnant women (n=83) Booked for delivery at St. John of God Hospital Subiaco, Western Australia With confirmed allergy No smoking, other medical problems, complicated pregnancies, seafood allergy; normal dietary intake did not exceed two meals of fish per week |
Fish-oil supplement |
20 weeks of pregnancy until delivery |
Amount |
Results |
Conclusion* |
Fish oil group: 3.7 g of n-3 PUFA 56.0% as DHA and 27.7% as EPA Placebo group: 2.6 g olive oil 26 g/day oleic acid |
Infants of those in the fish oil group had a significantly higher %CD34 expression than infants of those in the placebo group (p<0.002). There was no significant difference between the two groups with respect to expression of all cytokine and chemokine receptors. There was a significant association found between CD34+ in cord blood and AEDS (OR=3.93; 95% CI 1.05-14.64, p=0.042) at one year of age; however, there were no significant associations found for food allergy, moderate severe AEDS, asthma, chronic cough, or recurrent wheeze. There were significant associations found between cord blood progenitor responsiveness to IL-5 and AEDS (OR=1.09, 95% CI 1.00-1.18, p=0.039) and recurrent wheeze (OR=1.11, 95% CI 1.02-1.21, p=0.022) at one year of age; however, there were no significant associations found for food allergy, moderate severe AEDS, asthma, or chronic cough. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Dunstan et al., 2003a |
Randomized Controlled Trial |
Pregnant women (n=83) Atopic women Booked for delivery at St. John of God Hospital Subiaco, Western Australia Physician-diagnosed allergic rhinitis and/or asthma Allergic to house dust mites, grass pollens, molds, cat, dog, feathers, and cockroach and/or asthma No medical problems, no smoking, no complicated pregnancies, no seafood allergy; normal diet did not exceed two meals of fish per week |
Fish-oil supplement |
20 weeks of pregnancy until delivery |
Dunstan et al., 2003b |
Randomized Controlled Trial |
Pregnant women (n=83) Atopic women Booked for delivery at St. John of God Hospital Subiaco, Western Australia Physician-diagnosed allergic rhinitis and/or asthma Allergic to house dust mites, grasses, molds, cat, dog, feathers, and cockroach and/or asthma No medical problems, no smoking, no complicated pregnancies, no seafood allergy; normal diet did not exceed two meals of fish per week; no preterm deliveries |
Fish-oil supplement |
20 weeks of pregnancy until delivery |
Amount |
Results |
Conclusion* |
Fish oil group: Four 1 g fish oil capsules/day 3.7 g of n-3 PUFA 56.0% as DHA and 27.7% as EPA Placebo group: Four 1 g olive oil capsules/day 66.6% n-9 oleic acid and <1.0% n-3 PUFA |
Neonatal in vitro IL-10 response to cat allergen was significantly lower in the fish oil group than in the placebo group (p=0.046). At birth, no significant differences were found in the neonates’ cytokine response to allergens and mitogens in the two groups at birth. IFN-γ responses to OVA were detected more frequently in the control group than in the fish oil group (p=0.009). There were no significant differences found in the frequency of detectable IL-5, IL-10, or IL-13 responses between the two groups. “The detection of a lymphoproliferative response to allergens also tended to be lower in the fish oil group compared with the control group,” although this difference was not always significant (OR=4.48, 95% CI 0.87-23.07 for response to OVA allergen and OR=2.02, 95% CI 0.69-5.88 for response to cat). |
B |
Fish oil group: Four 1 g fish oil capsules/day 3.7 g of n-3 PUFA 56.0% as DHA and 27.7% as EPA Placebo group: Four 1 g olive oil capsules/day 66.6% n-9 oleic acid and <1.0% n-3 PUFA |
IL-13 levels were significantly lower (p=0.025) in neonates whose mothers received fish-oil supplements in pregnancy compared to the placebo group. There were no significant differences in IFN-γ levels in cord plasmas or in IgE in plasma between the two groups. There were no significant differences in the frequency of lymphocyte subsets for total T cells, T helper cells, T suppressor cells, NK cells, and B cells between the two groups. After adjusting for parity, gender, and delivery method, there were significant associations between cord plasma IL-13 levels and neonatal red cell membrane DHA levels (β=−0.25, 95% CI −0.49 to −0.01) and total n-3 fatty acid levels (β=−2.70, 95% CI −5.35 to −0.05). |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Hawkes et al., 2002 |
Randomized Controlled Trial |
Women (n=120) Aged 20-42 years, mean about 30 years Delivered full-term singleton infants, intended to breast-feed ≥12 weeks Adelaide, South Australia No known history of inflammatory disorders, not currently taking anti-inflammatory medication or fish-oil supplements Excluded women who had ceased lactating by 4 weeks postpartum |
DHA supplement |
Day 3-week 12 postpartum |
Amount |
Results |
Conclusion* |
Asked to limit fish and seafood intake to a maximum of 1 meal/week Placebo: 500 mg placebo oil Low-DHA capsule group: 70 mg EPA/day, 300 mg DHA/day High-DHA capsule group: 140 mg EPA/day, 600 mg DHA/day |
“There was no significant difference between the dietary groups in mean rank concentrations of IL-6 or TNF-α in the aqueous phase of milk” at 4 weeks postpartum. “There was no significant difference in mean rank concentrations between the dietary groups for any of the cytokines produced by cells isolated from human milk or peripheral blood after in vitro stimulation with lipopolysaccharide or in the absence of stimulation” at 4 weeks postpartum. |
N |
Amount |
Results |
Conclusion* |
Omega-3 diet group: Canola oil and canola-based margarines and salad dressings to replace usual oils and margarines Supplement capsules = 0.18 g EPA and 0.12 g DHA/capsule 4 capsules/day = 1.20 g omega-3/day Omega-6 diet group: Sunflower oil and sunflower oil-based margarines and salad dressings to replace usual oils and margarines Supplement capsules = 0.45 g safflower oil, 0.45 g palm oil, 0.10 g olive oil/capsule No EPA or DHA |
“There was no significant change in spirometric function, dose-response ratio to histamine or asthma severity score at either 3 or 6 months in either group.” |
N |
Amount |
Results |
Conclusion* |
Cord blood (percentages of total red blood cell membrane phospholipid): Medians: 0.02 ALA, 0.11 EPA, 0.22 DPA, 2.00 DHA, 4.65 LA, and 7.80 AA Maternal blood (percentages of total red blood cell membrane phospholipid): Medians: 0.14 ALA, 0.23 EPA, 0.60 DPA, 2.02 DHA, 11.46 LA, and 5.88 AA |
After controlling for sex, gestational age at birth, birth weight, mother’s age, education level, housing tenure, parity, ethnicity, smoking in pregnancy, maternal atopic disease, child’s head circumference at birth, child’s crown to heel length at birth, mother’s BMI, breastfeeding in first 6 months, and day care use in first 6 months: All associations between fatty acid exposure (based on cord blood levels and maternal blood levels) and eczema at 18 to 30 months were found to be nonsignificant; All associations between fatty acid exposure (based on both cord blood levels and maternal blood levels) and wheezing at 30 to 42 months of age were found to be nonsignificant; LA:ALA levels in cord blood were significantly associated with later-onset wheeze (OR=1.30, 95% CI 1.04-1.61), as was the ratio of ALA:sum of n-3 products (OR=0.86, 95% CI 0.75-0.99); and No other significant associations were found between fatty acid exposure and transient infant wheeze, later-onset wheeze, or persistent wheeze. |
N |
TABLE B-1f Studies on Visual Acuity: Effects on Infants Supplemented with Omega-3 Fatty Acids in Formula
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Simmer, 2005 |
Cochrane Review |
9 Randomized Controlled Trials |
LCPUFA-supplemented formula |
|
Gibson et al., 2001 |
Review |
Randomized Controlled Trials (11 on preterm and 10 on term infants) Involving healthy preterm infants fed preterm formula Involving healthy term infants fed formulas from near birth Systematic literature review |
DHA-supplemented formula |
|
Uauy et al., 2001 |
Review |
Summary of Randomized Controlled Trials on preterm and term infants |
LCPUFA-supplemented formula |
|
Amount |
Results |
Conclusion* |
|
“There is little evidence from randomized trials of LCPUFA supplementation to support the hypothesis that LCPUFA supplementation confers a benefit for visual or general development of term infants.” “Minor effects on VEP acuity have been suggested, but appear unlikely when all studies are reviewed.” |
N |
|
“Benefits of adding DHA to formulas (with or without AA) on VEP acuity have been reported in some studies, whereas other studies have failed to detect a benefit of LC-PUFA supplementation.” |
B |
|
There is evidence supporting “the view that dietary essential fatty acid supply affects visual development of preterm and term infants.” |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
SanGiovanni et al., 2000a |
Meta-analysis |
Studies done in industrialized countries Healthy, term infants Randomized studies: DHA supplemented (n=114) DHA-free (n=87) Nonrandomized studies: Milk-fed/behavioral-based (n=117 at 2 months; n=148 at 4 months) Milk-fed/electrophysiological tasks (n=146 at 4 months) DHA-free/behavioral-based (n=174 at 2 months; n=113 at 4 months) DHA-free/electrophysiological tasks (n=108 at 4 months) All study designs: DHA-supplemented/behavioral-based at 2 months (n=219) DHA-supplemented/electrophysiological tasks at 4 months (n=265) DHA-free/behavioral-based at 2 months (n=86) DHA-free/electrophysiological tasks at 4 months (n=109) |
DHA-supplemented formula |
|
Amount |
Results |
Conclusion* |
|
Based on behavioral tests of visual acuity, the randomized studies showed a significant difference in the estimates for those fed DHA-supplemented formula vs. those fed unsupplemented formula at 2 months of age (p≤0.0005). This difference was not significant at any other age presented. Based on behavioral tests of visual acuity, the non-randomized studies showed a significant difference in the estimates for those fed human milk vs. those fed unsupplemented formula at 2 months of age (p≤0.0005) and 4 months of age (p≤0.05). This difference was not significant at any other age presented. Based on electrophysiological tests of visual acuity, the randomized studies showed a significant difference in the estimates for those fed (DHA-supplemented) formula vs. those fed unsupplemented formula at 7 months of age (p≤0.05). This difference was not significant at any other age presented. Based on electrophysiological tests of visual acuity, the nonrandomized studies showed a significant difference in the estimates for those fed human milk vs. those fed unsupplemented formula at 4 months of age (p≤0.0005), 5 months of age (p≤0.05), and 7 months of age (p≤0.05). This difference was not significant at any other age presented. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
SanGiovanni et al., 2000b |
Meta-analysis |
5 original papers (4 prospective trials) 4 review chapters Preterm infants Randomized studies: DHA-supplemented/behavioral-based (n=48 at 2 months; n=70 at 4 months) DHA-supplemented/VEP at 4 months (n=13) DHA-free/behavioral-based (n=49 at 2 months; n=56 at 4 months) DHA-free/VEP at 4 months (n=28) All study designs: DHA-supplemented/behavioral-based at 4 months (n=80) DHA-supplemented/VEP at 4 months (n=37) DHA-free/behavioral-based at 4 months (n=87) DHA-free/VEP at 4 months (n=43) |
DHA-supplemented formula |
|
Amount |
Results |
Conclusion* |
|
Based on behavioral tests of visual acuity, the randomized comparisons (between those fed DHA-supplemented formula and those fed unsupplemented formula) showed significant differences at 2 and 4 months of age (p≤0.001). This difference was not significant at any other age presented. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Hoffman et al., 2003 |
Randomized Controlled Trial |
Infants (n=61) Healthy, term, singleton infants Birth weight appropriate for gestational age Breast-fed to 4-6 months North Dallas area, TX 95% White No family history of milk protein allergy; genetic or familial eye disease; vegetarian or vegan maternal dietary patterns; maternal metabolic disease, anemia, or infection; presence of a congenital malformation or infection; jaundice; perinatal asphyxia; meconium aspiration; or any perinatal event that resulted in placement in the neonatal intensive care unit |
AA/DHA-supplemented formula |
Enrolled at 6.5 weeks of age until 12 months of age (during time of weaning) |
Amount |
Results |
Conclusion* |
Commercial formula (Enfamil with iron) or commercial formula supplemented with 0.36% of total fatty acids as DHA and 0.72% as AA |
There were no significant differences in VEP acuity before weaning in the two groups, but at 12 months the supplemented group had significantly better VEP acuity than infants in the commercial formula group (p<0.0005). There was a trend of better stereoacuity in the supplemented group compared to the commercial group at 9 months (p=0.12) and 12 months (p=0.13). |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Birch et al., 2002 |
Randomized Controlled Trial |
Infants (n=65) Healthy, term, singleton births Birth weight appropriate for gestational age Weaned from breastfeeding at 6 weeks of age Dallas area, TX Mean maternal age about 30 years 75-78% White Majority of mothers with at least a college degree No family history of milk protein allergy; genetic or familial eye disease; vegetarian or vegan maternal dietary patterns; maternal metabolic disease, anemia, or infection; presence of a congenital malformation or infection; jaundice; perinatal asphyxia; meconium aspiration; or any perinatal event that resulted in placement in the neonatal intensive care unit |
AA/DHA-supplemented formula |
6 weeks of age to 52 weeks of age |
Amount |
Results |
Conclusion* |
Commercial formula (Enfamil with iron) or commercial formula supplemented with 0.36% of total fatty acids as DHA and 0.72% as AA |
There were no significant differences in VEP acuity at age 6 weeks between the two groups. The control group had significantly poorer visual acuity at week 17 (p<0.003), week 26 (p<0.001), and week 52 (p<0.001) compared to the supplemented group. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Innis et al., 2002 |
Randomized Controlled Trial |
Infants (n=194) Premature Healthy, very low birth weight infants (846-1560 g), formula-fed Multi-center study (16 neonatal centers in North America) Not small for gestational age or >24 days postnatal age when full enteral feeds ≥375 kJ/kg/day were achieved No necrotizing enterocolitis or other gastrointestinal disease, impaired visual or ocular status, or a history of underlying disease or congenital malformation that could interfere with growth Reference group = term infants whose mothers anticipated breastfeeding for at least 4 months |
AA/DHA-supplemented formula |
Preterm formulas: At least 28 days after enteral intake of 375 kJ/kg/day reached Term formulas: After hospital discharge until 57 weeks of age |
Amount |
Results |
Conclusion* |
Preterm formula 1 = Control formula (no AA or DHA) Preterm formula 2 = DHA formula (0.34% fatty acids as DHA) Preterm formula 3 = DHA+AA formula (0.33% fatty acids as DHA, 0.60% fatty acids as AA) Term formula = no AA or DHA Breast-fed term infants = no solid foods during the study unless otherwise instructed by their physicians |
At 57 weeks, visual acuity of the breast-fed term infants was significantly higher than in the premature infants, but not at 48 weeks; at 48 or 57 weeks, visual acuity was not significantly different among the premature infant groups. |
N |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Van Wezel-Meijler et al., 2002 |
Randomized Controlled Trial |
Infants (n=42) Preterm, admitted to neonatal intensive- or high-care unit of hospital Birth weight <1750 g Leiden, Netherlands Mothers not breast-feeding Normal neurological examination throughout the neonatal period Repeated ultrasound of the brain being normal or showing, at most, minor abnormalities No abnormalities of the central nervous system; abnormal neurological examination or occurrence of seizures; any systemic disease with potential negative influence on future growth or development; serious nutritional or gastrointestinal problems preventing initiation of enteral feeding after the first week postpartum or complete enteral feeding after the third week postpartum; retinopathy of prematurity grade 3 or more |
AA/DHA-supplemented formula |
2-3 weeks after birth until weighing 3000 g |
Amount |
Results |
Conclusion* |
Supplemented preterm formula: 4.4 g fat/100 mL 0.015 g/100 mL of added DHA (microalgae) 0.031 g/100 mL of added AA (fungi) Control formula: 4.4 g fat/100 mL No addition of AA and DHA |
There were no significant differences found in Flash VEP at 3 and 12 months between the two groups. There were no significant differences found in visual acuity at 3, 6, 12, or 24 months between the two groups. |
N |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Makrides et al., 2000 |
Randomized Controlled Trial |
Infants (n=73 in formula groups; n=63 in breastfed group) White Full-term and appropriate weight for gestational age Mean mothers’ education was mid-secondary school level for formula-fed infants and completion of secondary school for breastfed infants No congenital disease or complications during pregnancy |
AA/DHA-supplemented formula |
Age at entry not specified, up to 34 weeks of age |
Bougle et al., 1999 |
Randomized Controlled Trial |
Infants (n=40) Mean age about 33 weeks Enrolled the 2nd day of enteral feeding Healthy, appropriate weight for gestational age Premature Free of respiratory, metabolic or neurological disease; malformations; infections; intrauterine asphyxia Fed by digestive route within the first 7 days of life |
LCPUFA-supplemented formula |
Within the first 2 days of enteral feeding, then for 30 days |
Amount |
Results |
Conclusion* |
Placebo formula (% total fatty acids): 16.8% LA, 1.5% ALA DHA formula (% total fatty acids): 16.80% LA, 1.20% ALA, 0.10% EPA, 0.35% DHA DHA+AA formula (% total fatty acids): 16.60% LA, 0.34% AA, 1.00% ALA, 0.34% DHA Breast milk (% total fatty acids, mean±SE): 13.40±2.90% LA, 0.39±0.07% AA, 0.95±0.32% ALA, 0.09±0.03% EPA, 0.20±0.07% DHA |
After adjusting for gender, postconceptional age, birth weight, and maternal smoking, there were no significant differences in VEP between any of the groups at 16 or 34 weeks of age. |
N |
Breast milk (% total fatty acids, mean±SE): 14.1±2.0% LA, 0.4±0.2% GLA, 0.9±0.2% AA, 0.5±0.1% ALA, 0.5±0.1% DHA Formula A (% total fatty acids): 14.1% LA, 1.3% ALA Formula B (% total fatty acids): 17.7% LA, 0.4% GLA, 0.1% AA, 1.2% ALA, 0.1% EPA, 0.6% DHA |
There were no significant differences between the groups based on electrophysiological data, except that the maturation of the motor nerve conduction was significantly slower in the Formula B group than in the breast milk group and the Formula A group (p<0.05). |
N |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Carlson et al., 1999 |
Randomized Controlled Trial |
Infants (n=119) |
AA/DHA-supplemented formula |
<8 days of age until about 12 months of age Infants fed supplemented formula near birth received commercial formula from term less 3 months until 12 months of age; infants fed supplemented formula near term received commercial formula from term less 3 months to term less 1 month, and then supplemented formula until 12 months of age |
Amount |
Results |
Conclusion* |
Commercially available standard formula contained no EPA or DHA Supplemented formula 0.13% DHA and 0.40% AA from egg phospholipids |
Compared to the infants not supplemented, “only those supplemented near birth had higher acuity at 2 months (p<0.02) and a trend toward higher acuity at 6 months (p<0.07).” Infants supplemented at birth “also had higher acuity than those supplemented at term at 2 months (p<0.05).” “First year acuity continued to increase (p<0.05) between consecutive ages until 6 months” in those supplemented at birth and 9 months in those unsupplemented and supplemented at term. “All groups had similar acuity at 9 and 12 months.” |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Birch et al., 1998 |
Randomized Controlled Trial |
Infants (n=108) Healthy, term, birth weight appropriate for gestational age Singleton births Dallas, TX 75% White, 12% Black, 12% Hispanic, 1% other Mean maternal age 29 years 67.6% mothers completed at least 2 years of college No family history of milk protein allergy; genetic or familial eye disease; vegetarian or vegan maternal dietary patterns; maternal metabolic disease, anemia, or infection; presence of a congenital malformation or infection; jaundice; perinatal asphyxia; meconium aspiration; or any perinatal event that resulted in placement in the neonatal intensive care unit |
AA/DHA-enriched formula |
0-4 days postpartum through 17 weeks of age |
Carlson et al., 1996a |
Randomized Controlled Trial |
Infants (n=58) Born at term (37-43 weeks) Birth weight 747-1275 g Memphis, TN Predominantly Black No growth retardation in utero and no medical problems likely to influence long-term growth and development Mothers education mean of about 12 years |
DHA-supplemented formula |
24 hours after birth; end point not specified |
Amount |
Results |
Conclusion* |
Enfamil + iron Enfamil + iron + 0.35% DHA Enfamil + iron + 0.36% DHA + 0.72% AA |
Visual acuity was significantly poorer in the control group than in the DHA or DHA+AA groups and the breast-fed group. At 6, 17, 26, and 52 weeks the association between RBC AA and sweep VEP was not statistically significant. The association was also nonsignificant for RBC EPA. At 6, 17, 26, and 52 weeks, the association between RBC DHA was significantly associated with lower sweep VEP (p<0.001, p=0.01, p=0.05, p<0.001, respectively). At 6, 17, and 52 weeks, the association between RBC n-3:n-6 was significantly associated with lower sweep VEP (p<0.001, p=0.03, p<0.001, respectively); the association was not statistically significant at 26 weeks. |
B |
Formula with AA+DHA = 2 g AA/100 g total fatty acids; 0.1 g DHA/100 g total fatty acids Formula without DHA = 2.2 g ALA/100 g total fatty acids |
“Term infants fed formulas with added AA and DHA had higher grating acuity at 2 months of age but not at 4, 6, 9, or 12 months of age compared with infants fed an unsupplemented formula.” |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Carlson et al., 1996b |
Randomized Controlled Trial |
Infants (n=59) Memphis, TN Maternal mean age about 22.5 year No intraventricular or periventricular hemorrhage > grade 2; a history of maternal cocaine or alcohol abuse; congenital anomalies likely to affect long-term growth and development; or intrauterine growth retardation Full enteral feeding of 418 kJ/kg/day by 6 weeks of age and tolerated enteral feeding thereafter |
EPA/DHA-supplemented formula (marine oil) |
Between 3-5 days postpartum until 2 months from expected term of 48±1 week post-menstrual age |
Carlson et al., 1993 |
Randomized Controlled Trial |
Infants (n=67) Birth weight 748-1398 g Mean gestational age 29 weeks Memphis, TN Did not require mechanical ventilation; have intraventricular hemorrhage > grade 2; have retinopathy of prematurity > stage 2; require surgical intervention for necrotizing enterocolitis; have severe intrauterine growth retardation; or a history of maternal substance abuse Predominantly Black and from lower socioeconomic groups Maternal age about 23 years |
EPA/DHA-supplemented formula (marine oil) |
Preterm formula from when infant tolerated enteral intakes >462 kJ/kg body weight/day for 5-7 days (≈3 weeks of age) until discharge Term formula from discharge until 9 months |
Amount |
Results |
Conclusion* |
Standard preterm formula = LA at 2.5% of total fatty acid Marine-oil supplemented formula = 0.20% DHA and 0.06% EPA of total fatty acids |
“Visual acuity improved significantly between successive ages of 0 and 2 months, 2 and 4 months … Between 6 and 12 months visual acuity plateaued.” |
B |
Commercially available standard formula contained no EPA or DHA Marine-oil supplemented formula contained 0.2% DHA and 0.3% EPA of total fatty acids |
Visual acuity development was significantly higher in the marine-oil group compared to the control group at 2 months (p<0.014) and 4 months (p<0.002). There were no significant differences found at the other ages reported. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Birch et al., 1992 |
Randomized Controlled Trial |
Male infants (n=32) Female infants (n=41) Born 27-33 weeks gestation Birth weight 1000-1500 g No respirator treatment for more than 7 days or congenital infections; gross congenital malformations; retinopathy of prematurity; or grade III or IV intracranial hemorrhages |
EPA/DHA-supplemented formula (soy/ marine oil) |
10 days of age until 6 months of age |
Lauritzen et al., 2001 |
Review |
Summary of the literature (animal, observational, RCTs) |
DHA-supplemented formula |
|
Amount |
Results |
Conclusion* |
Soy/marine oil-supplemented formula (preterm/follow-up formula, g/100 g lipids): LA = 20.4/18.1 ALA = 1.4/1.4 EPA+DHA = 1.0/0.9 Corn oil-based formula (preterm/follow-up formula, g/100 g lipids): LA = 24.2/21.1 ALA = 0.5/0.5 EPA+DHA = 0.0/0.0 Soy oil-based formula (preterm/follow-up formula, g/100 g lipids): LA = 20.8/20.3 ALA = 2.7/2.8 EPA+DHA = 0.0/0.1 |
There were significant differences in VEP acuity for the different formula groups (p<0.025), with the corn oil group having poorer VEP acuity than the soy/marine oil group (p<0.05) at 36 weeks. The corn oil group (p<0.05) and the soy oil group (p<0.05) had significantly poorer VEP acuity than the soy/marine oil group at 57 weeks. |
B |
|
“Observational studies in general show better retinal function in breast-fed infants than in infants fed formula without DHA, but approximately half of the intervention studies show no effect.” Animal studies do offer evidence that DHA plays a role in retinal function, but these results cannot easily be extrapolated to humans. 4 RCTs with “preterm infants have all shown a positive effect of dietary DHA on visual development;” the results from term infants are not as conclusive. More data is needed to see if the “variation in DHA content of human milk has a functional effect.” |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Williams et al., 2001 |
Cohort |
Boys and girls (n=435) Mean age of 3.5 years Born in last 6 months of the Avon Longitudinal Study of Parents and Children (ALSPAC) enrollment period Healthy term infants |
Seafood (mother) and breast milk (child) |
Seafood = during pregnancy (mother) Breast milk = until 4 months of age (child) |
Amount |
Results |
Conclusion* |
Oily fish consumption categories: 1 = Never or rarely 2 = Once every 2 weeks 3 = More than once every 2 weeks White fish = cod, haddock, plaice, and “fish fingers” Oily fish = pilchards, sardines, mackerel, tuna, herring, kippers, trout, and salmon |
After adjusting for breast-feeding, sex, maternal education, maternal age, housing tenure, financial difficulties, maternal smoking, number of older siblings in household, child care, maternal job status, mother being vegetarian, mother’s fish-eating habits: “Mothers who ate oily fish at least once every 2 weeks during pregnancy were more likely to have children who achieved foveal stereoacuity than were the mothers who never ate oily fish (OR=1.57, 95% CI 1.00-2.45),” but this was not significant; and “The results of this study suggest that for full-term infants, breast-feeding is associated with enhanced stereopsis at age 3.5 years, as is a maternal DHA-rich antenatal diet, irrespective of later infant feeding practice.” |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Carlson et al., 1986 |
Cohort |
Infants (n=27) Born on or before 32 weeks gestation (range 24-32 weeks) University of Mississippi Medical Center Weighed <1500 g at birth and were on full feedings of at least 60 kcal/kg without intravenous supplementation Free of major congenital malformations and did not have any ongoing major disease process Discharged at about 1800 g |
Human milk and milk formula |
Delivery to an average of 7 weeks later |
Amount |
Results |
Conclusion* |
Expressed, previously frozen milk produced by their own mothers or formula Infants fed formula started with enteral feeding with Portagen and then Enfamil Premature and Similac Special Care as tolerated. Those followed after discharge were fed term formulas also produced by Enfamil and Similac Human milk (in mol%, mean±SE): LA = 16.00±1.30, AA = 0.59±0.04, ALA = 0.62±0.04, EPA = 0.03±0.00, DPA = 0.09±0.03, DHA = 0.19±0.03 Portagen (in mol%, mean±SE): LA = 8.1, AA = None, ALA = Trace, EPA = None, DPA = None, DHA = None Enfamil Premature (in mol%, mean±SE): LA = 22.4, AA = None, ALA = 0.6, EPA = None, DPA = None, DHA = None Similac Special Care (in mol%, mean±SE): LA = 17.4, AA = None, ALA = 0.9, EPA = None, DPA = None, DHA = None |
Based on phosphatidylethanolamine composition of fatty acids (in mol%): EPA was significantly lower (p<0.005) in those breast-fed after the feedings than in the pre-study samples; LA and DPA were significantly higher (p<0.001) and DHA was significantly lower (p<0.005) in those breast-fed after the feedings than in the preterm cord blood; LA was significantly higher (p<0.005) and EPA was significantly lower (p<0.005) in those formula-fed after the feedings than in the pre-study samples; LA was significantly higher (p<0.005) and DHA was significantly lower (p<0.001) in those formula-fed compared to those breast-fed; LA (p<0.005) and DPA (p<0.001) were significantly higher and AA (p<0.005) and DHA (p<0.001) were significantly lower in those formula-fed after the feedings than in the preterm cord blood; LA was significantly higher (p<0.005) and EPA was significantly lower (p<0.005) in those formula-fed after the feedings than in the pre-study samples. Based on phosphatidylcholine composition of fatty acids (in mol%): LA was significantly higher (p<0.005) in those breast-fed after the feedings than in the pre-study samples; LA was significantly higher (p<0.005) and AA (p<0.001) and DHA (p<0.005) were significantly lower in those breast-fed after the feedings than in the preterm cord blood; LA was significantly higher (p<0.001) and AA was significantly lower (p<0.001) in those formula-fed after the feedings than in the pre-study samples; LA was significantly higher (p<0.005) and AA and DHA were significantly lower (p<0.001) in those formula-fed compared to those breast-fed; LA was significantly higher (p<0.005) and AA and DHA were significantly lower (p<0.001) in those formula-fed after the feedings than in the preterm cord blood. Based on phosphatidylserine composition of fatty acids (in mol%): LA and DHA were significantly higher (p<0.005) in those breast-fed after the feedings than in the preterm cord blood; AA was significantly lower (p<0.005) in those breast-fed after the feedings than in the pre-study samples; LA and DHA were significantly higher (p<0.005) in those formula-fed after the feedings than in the pre-study samples; AA was significantly lower (p<0.005) and DHA was significantly higher (p<0.025) in those formula-fed after the feedings than in the pre-study samples. |
N/A |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Putnam et al., 1982 |
Cohort |
Infants (n=40) Enrolled at birth Well-baby clinic at the University of South Florida Medical Clinics At least 90% of energy from human milk or formula before sample collection |
Human milk and milk formula |
3 weeks of age to 6 months of age Breast milk collected at 8 weeks and infants’ blood drawn between 4.5 and 6 months of age |
Amount |
Results |
Conclusion* |
Mothers were encouraged to follow the recommendations of the American Academy of Pediatrics Committee on Nutrition (food other than human milk or humanized formula be omitted from infant’s diet until he/she was 4-6 months of age) Human milk (% of total, mean): 15.80±0.61 LA, 0.60±0.03 AA, 0.80±0.09 ALA, 0.10±0.03 EPA, 0.10±0.01 DPA, 0.10±0.01 DHA Enfamil + iron (% of total, mean): 45.1 LA, No AA, 5.0 ALA, No EPA, No DPA, No DHA SMA formula (% of total, mean): 14.0 LA, No AA, 1.2 ALA, No EPA, No DPA, No DHA |
“Human milk-fed infants had lower concentrations of membrane LA than SMA-fed infants despite the equivalent relative intakes of dietary LA.” “These diets did not influence the relative contributions of PE, PC, Sp, and PS to erythrocyte membrane phospholipid nor did they influence the lipid phosphorous/cholesterol ratio.” Significant differences in fatty acid composition of infant erythrocyte ethanolamine are as follows (weight % of total fatty acid methyl esters): Infants fed human milk had significantly higher AA (p<0.05), DPA (p<0.05), and DHA (p<0.001) than those fed SMA formula; and Infants fed human milk had significantly higher AA (p<0.01) and significantly lower LA (p<0.001), ALA (p<0.001), EPA (p<0.05), and DHA (p<0.001) than those fed Enfamil formula with iron. |
N/A |
Amount |
Results |
Conclusion* |
Breast milk (% total fatty acids, mean±SE): LA = 6.90±0.81, ALA = 0.80±0.05, EPA = 0.20±0.08, DPA = 0.52±0.27, DHA = 0.59±0.23 Milk formula (% total fatty acids, mean): LA = 1.60, ALA = 0.70, EPA = 0.08, DPA = 0.11, DHA = 0.02 |
LA, AA, DHA are significantly lower in the formula-fed infants than in the breast-fed infants (p<0.01, p<0.05, p<0.01, respectively). EPA and DPA are significantly higher in the formula-fed infants than in the breast-fed infants (p<0.05). “The minimum requirement of the young infant for LA is substantially less than 1% of the dietary energy, the value most widely quoted.” |
N/A |
Experimental group: Semipurified diet deficient in n-3 fatty acids Safflower oil sole fat source 76.0% LA, 0.3% GLA, 0.2% DGLA, 0.3% ALA, 225.0% n-6:n-3 of total fatty acids Control group: Soy bean oil sole fat source 53.1% LA, 0.0% GLA, 0.3% DGLA, 7.7% ALA, 7.0% n-6:n-3 of total fatty acids |
AA and total n-6 fatty acids were significantly higher in the experimental group infants compared to the control group infants (p<0.005). ALA, EPA, DPA, DHA and total n-3 fatty acids are all significantly lower in the experimental group infants compared to the control group infants (p<0.001). At 4, 8, and 12 weeks, the visual acuity threshold in the experimental group was significantly lower than in the control group (p<0.05, p<0.0005, p<0.005, respectively). |
B |
TABLE B-1g Studies on Cognitive and Motor Development: Effects on Infants Supplemented with Omega-3 Fatty Acids in Formula
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Cohen et al., 2005 |
Review |
Aggregated 8 randomized controlled trials (1 study of maternal dietary supplementation and 7 studies of formula supplementation) |
n-3 supplement |
|
Simmer and Patole, 2005 |
Cochrane Review |
11 randomized controlled trials |
LCPUFA-supplemented formula |
|
Simmer, 2005 |
Cochrane Review |
9 randomized controlled trials |
LCPUFA-supplemented formula |
|
Amount |
Results |
Conclusion* |
|
An increase in maternal intake of DHA during pregnancy of 1 g/day will increase child IQ by 0.8-1.8 points. “Prenatal maternal DHA intake increasing the child plasma (RBC) DHA phospholipid fraction by 1% has the same impact on cognitive development as formula DHA supplementation that increases the child’s plasma (RBC) DHA phospholipid fraction by 1%.” “Because typical DHA intake associated with fish consumption is well under 1 g/day, changes in fish consumption will result in IQ effects amounting to a fraction of a point,” but they are not clinically detectable. |
B |
|
“No long-term benefits were demonstrated for infants receiving formula supplemented with LCPUFA. There was no evidence that supplementation of formula with n-3 and n-6 LCPUFA impaired the growth of preterm infants.” |
N |
|
“There is little evidence from randomized trials of LCPUFA supplementation to support the hypothesis that LCPUFA supplementation confers a benefit for visual or general development of term infants.” “Minor effects on VEP acuity have been suggested, but appear unlikely when all studies are reviewed.” |
N |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Gibson et al., 2001 |
Review |
Randomized controlled trials (11 on preterm and 10 on term infants) Involving healthy preterm infants fed preterm formula Involving healthy term infants fed formulas from near birth Systematic literature review |
LCPUFA-supplemented formula |
|
Uauy et al., 2001 |
Review |
Summary of randomized controlled trials on preterm and term infants |
AA/DHA-supplemented formula |
|
Carlson and Neuringer, 1999 |
Review |
Summary of animal studies and randomized controlled trials Based on a session from the AOCS 1996 meeting: PUFA in Infant Nutrition: Consensus and Controversies |
Neural DHA accumulation |
|
Amount |
Results |
Conclusion* |
|
“Although there are still some concerns on safety issues regarding the addition of LCPUFA to preterm infant formula, the evidence in support of a beneficial effect of such supplementation on visual function is relatively compelling.” “It seems that the possible negative effects of n-3 LCPUFA on growth of preterm infants have been overcome through improved study design and/or the addition of a balance of n-6 and n-3 LCPUFA.” “There is also mixed evidence for the support of an effect of dietary LCPUFA on more global measures of development (Bayley’s Scales of Infant Development or Brunet-Lezine test).” |
B |
|
“Evidence for a beneficial effect of AA+DHA supplementation on CNS development is strong.” “The preliminary information on cognitive development is insufficient to fully establish a relationship between LCPUFA and mental development.” |
B |
|
Studies in deficient monkeys suggest that “lower brain accumulation of DHA may influence neural domains such as sensation, motivation or temperament, but not cognition.” “The most consistent effect identified to date in human and animal studies has been that of look duration and tests of visual attention.” “A limited number of behavioral studies in animals and humans address the question of neural DHA accumulation and developmental measures other than vision.” |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Bouwstra et al., 2005 |
Randomized Controlled Trial |
Infants (n=256 to 446, depending on assessment) Term, healthy Groningen, Netherlands University and Martini Hospitals in Groningen and at midwife clinics No congenital disorders that interfered with adequate functioning in daily life; infants from multiple births; infants whose mothers did not have mastery of the Dutch language or suffered from significant illness or disability; adopted or foster infants; or formula-fed infants who had received human milk >5 days |
LCPUFA-supplemented formula |
Birth to 2 months of age |
Amount |
Results |
Conclusion* |
Control formula (in mol%): 11.56 LA, 1.27 ALA Supplemented formula (in mol%): 11.00 LA, 0.18 GLA, 0.03 DGLA, 0.39 AA, 1.30 ALA, 0.06 EPA, 0.23 DHA Breastfed (in mol%, mean±SE): 13.62±4.24 LA, 0.11±0.03 GLA, 0.34±0.06 DGLA, 0.34±0.06 AA, 1.11±0.35 ALA, 0.06±0.04 EPA, 0.19±0.11 DHA |
“The groups did not show statistically significant differences in clinical neurological condition, neurological optimality score, fluency score, and the psychomotor and mental development indices at 18 months.” |
N |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Clandinin et al., 2005 |
Randomized Controlled Trial |
Infants (n=361) Preterm Multi-site study First phase: Gestational age ≤35 weeks postmenstrual age <10 total days of enteral feeding of >30 mL/kg/day No congenital abnormalities of the gastrointestinal tract, hepatitis, hepatic or biliary pathology, necrotizing enterocolitis confirmed before enrollment, or history of underlying disease or congenital malformations likely to interfere with evaluation Second phase: Successful completion of the first phase, ≥80% of enteral intake from study formula during hospitalization, and 100% caloric intake from study formula at completion of the first phase |
Algal-DHA- and fish-DHA-supplemented formulas, human milk |
Premature formula: ≥14 days of age until at/near hospital discharge (40 weeks of age) Discharge formula: 40 weeks until 53 weeks post-menstrual age Term formula: 53 weeks until 92 weeks post-menstrual age |
Amount |
Results |
Conclusion* |
Control formula: No DHA or AA Algal-DHA formula: 17 mg DHA/100 kcal from algal oil, 34 mg AA/100 kcal from fungal oil 0.3% fatty acids from DHA, 0.6% fatty acids from AA Fish-DHA formula: 17 mg DHA/100 kcal from tuna fish oil, 34 mg AA/100 kcal from fungal oil 0.3% fatty acids from DHA, 0.6% fatty acids from AA Worldwide human milk: 0.3% DHA and 0.6% AA (weight of fatty acids) |
At 118 weeks, breast-fed term infants had significantly higher MDI and PDI scores compared to the control formula group, the algal-DHA formula group, and the fish-DHA formula group (p<0.05). At 118 weeks, the algal-DHA formula group had a higher MDI score (p=0.056), although it was not significant, and a significantly higher PDI score (p<0.05) compared to the control formula group. At 118 weeks, the fish-DHA formula group had significantly higher MDI and PDI scores (p<0.05) compared to the control formula group. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Jensen et al., 2005 |
Randomized Controlled Trial |
Pregnant women (n=227) Aged 18-40 years Houston, TX White (75% DHA group; 79% control group) African American (19% DHA group; 13% control group) Women plan to breastfeed exclusively for ≥4 months Infant gestational age >37 weeks Infant birth weight 2500-4200 g No chronic maternal disorders; major congenital anomalies and obvious gastrointestinal or metabolic disorders of the infant |
DHA supplement |
Within 5 days after delivery until 4 months postpartum |
Fewtrell et al., 2004 |
Randomized Controlled Trial |
Infants (n=238) Preterm Glasgow, UK Birth weight ≤2000 g Mean maternal age about 29 years Social class 1 or 2 (18% in controls; 27% in LCPUFA group) Mothers with degree or higher (2% in controls; 7% in LCPUFA group) |
LCPUFA-supplemented formula |
Preterm formulas: when pediatrician decided that preterm formula should be started, to discharge Discharge formulas: from discharge until 9 months after term |
Amount |
Results |
Conclusion* |
High-DHA capsule (algal triacylglycerol): 0.8% LA and 41.7% DHA by weight 200 mg DHA/day Control capsule (soy and corn oil): 56.3% LA, 3.9% ALA by weight |
There were no significant differences in visual acuity from the Teller Acuity Card at 4 or 8 months of age or from the Sweep VEP at 4 months of age between the two groups. There were no significant differences in mean transient VEP latency at 4 and 8 months of age between the two groups; but the transient VEP amplitude was significantly lower in the infants of the high-DHA capsule group compared to the infants of the control capsule group (p<0.03). There were no significant differences in Gesell Gross Motor, CAT, or CLAMS DQ scores at 12 and 30 months of age or in Bayley MDI at 30 months of age between the two groups; but Bayley PDI at 30 months of age was 8.4 points higher in infants of the high-DHA capsule group compared to infants of the control capsule group. |
N |
LCPUFA-supplemented formulas (g/100 g fat): 12.30 LA, 0.04 AA, 1.50 ALA, 0.10 EPA, 0.50 DHA Control formulas (g/100 g fat): 11.5 LA, 1.6 ALA, no AA, EPA, or DHA |
At 18 months of age, the Bayley MDI and PDI scores did not differ significantly between the groups. At 9 months of age, overall development scores and individual subscale scores did not differ significantly between the groups. |
N |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Bouwstra et al., 2003 |
Randomized Controlled Trial |
Infants (n=397) Term, healthy Groningen, Netherlands University and Martini Hospitals in Groningen and at midwife clinics No congenital disorders that interfered with adequate functioning in daily life; infants from multiple births; infants whose mothers did not have mastery of the Dutch language or suffered from significant illness or disability; adopted or foster infants; or formula-fed infants who had received human milk >5 days |
LCPUFA-supplemented formula |
Birth to 2 months of age |
Amount |
Results |
Conclusion* |
Control formula (in mol%): 11.56 LA, 1.27 ALA Supplemented formula (in mol%): 11.00 LA, 0.18 GLA, 0.03 DGLA, 0.39 AA, 1.30 ALA, 0.06 EPA, 0.23 DHA Breast-fed (in mol%, mean±SE): 13.62±4.24 LA, 0.11±0.03 GLA, 0.34±0.06 DGLA, 0.34±0.06 AA, 1.11±0.35 ALA, 0.06±0.04 EPA, 0.19±0.11 DHA |
After controlling for profession of mother’s partner requiring a university or vocational-college education, Obstetrical Optimality Score, and age at assessment: The control formula group had a significantly lower OR of occurrence of normal-optimal general movements at age 3 months when compared to the breastfed infants (OR=0.55; p=0.038); and Those in the supplemented formula group had a significantly lower OR of occurrence of normal-optimal general movements at age 3 months when compared to the breast-fed infants (OR=0.42; p=0.006), but the OR was not significant when compared to the control formula group (OR=0.77; p=0.41). After controlling for marital status, family history of diabetes, gestational age at birth, condition of perineum, and age at assessment: The control formula group had a significantly higher OR of mildly abnormal general movements at age 3 months when compared to the breast-fed infants (OR=2.03; p=0.039); and The supplemented formula group had a significantly lower OR of mildly abnormal general movements at age 3 months when compared to the control formula group (OR=0.49; p=0.032), but the OR was not significant when compared to the breast-fed infants (OR=0.94; p=0.87). |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Helland et al., 2003 |
Randomized Controlled Trial |
Pregnant women (n=48 in cod-liver oil group; n=36 in corn oil group) Aged 19-35 years Oslo, Norway Healthy women with, singleton pregnancy, nulli- or primiparous, intention to breast-feed No supplement of n-3 LCPUFA earlier during pregnancy, premature births, birth asphyxia, general infections, or anomalies in the infants that required special attention |
Cod-liver oil supplement |
From 18 weeks of pregnancy until 3 months after delivery |
Fewtrell et al., 2002 |
Randomized Controlled Trial |
Infants (n=195 formula-fed; n=88 breast-fed) Preterm Birth weight <1750 g Nottingham and Leicester, UK No congenital malformation known to affect neurodevelopment Mothers decided not to breast-feed by 10 days of age; tolerated enteral feeds at that time (for randomized groups) Social class 1 or 2 (19% in controls; 26% in LCPUFA group; 33% in breast-fed group) |
LCPUFA-supplemented formula |
10 days of age until discharge |
Amount |
Results |
Conclusion* |
Cod-liver oil: 10 mL/day 1183 mg DHA, 803 mg EPA Corn oil: 10 mL/day 4747 mg LA, 92 mg ALA |
K-ABC scores were significantly higher for the subset MPCOMP among children from the cod-liver oil group compared to the corn oil group (p=0.049). The scores for the other subtests (SEQPROC, SIMPROC, NONVERB) were also higher in the cod-liver oil group compared to the corn oil group, but they were not significant. |
B |
LCPUFA-supplemented formula (g/100 g fat): 12.00 LA, 0.31 AA, 0.60 ALA, 0.04 EPA, 0.17 DHA Control formula (g/100 g fat): 10.6 LA, 0.7 ALA, no detected AA, EPA, DHA |
There were no significant differences in KPS quotients at 9 months of age and neurological status at 9 or 18 months of age between the two formula groups. There were no significant differences found in Bayley MDI or PDI at 18 months of age between the two formula groups. Breast-fed infants had significantly higher KPS quotients (overall, adaptive, gross motor, fine motor, and personal-social) at 9 months of age (p<0.005) and significantly higher Bayley MDI and PDI at 18 months of age (p<0.005) compared to the control formula-fed infants. Breast-fed infants had significantly higher KPS quotients (overall, adaptive, gross motor, fine motor, and personal-social) at 9 months of age (p<0.005; p<0.05 for gross motor quotient) and significantly higher Bayley MDI and PDI at 18 months of age (p<0.005) compared to the LCPUFA-supplemented formula infants. |
N |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Van Wezel-Meijler et al., 2002 |
Randomized Controlled Trial |
Infants (n=42) Preterm, admitted to neonatal intensive-or high-care unit of hospital Birth weight <1750 g Leiden, Netherlands Mothers not breast-feeding Normal neurological examination throughout the neonatal period Repeated ultrasound of the brain being normal or showing, at most, minor abnormalities No abnormalities of the central nervous system; abnormal neurological examination or occurrence of seizures; any systemic disease with potential negative influence on future growth or development; serious nutritional or gastrointestinal problems preventing initiation of enteral feeding after the first week postpartum or complete enteral feeding after the third week postpartum; retinopathy of prematurity grade 3 or more |
AA/DHA-supplemented formula |
2-3 weeks after birth until weighing 3000 g |
Amount |
Results |
Conclusion* |
Supplemented preterm formula: 4.4 g fat/100 mL 0.015 g/100 mL of added DHA (microalgae) 0.031 g/100 mL of added AA (fungi) Control formula: 4.4 g fat/100 mL No addition of DHA and AA |
There were no significant differences found in Bayley MDI and PDI at 3, 6, 12, or 24 months between the two groups. There were no significant differences found in myelination at 3 and 12 months between the two groups. |
N |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Auestad et al., 2001 |
Randomized Controlled Trial |
Infants (n=294 formulafed; n=165 breast-fed) Kansas City, MO; Little Rock, AR; Pittsburgh, PA; Tucson, AZ Good health, term status, either ≤9 days of age (formula group) or ≤11 days of age and currently breast-feeding (breast-feeding group), birth weight ≥2500 g, 5-minute APGAR score ≥7, ability to tolerate milk-based formula or breast milk, guardian or parent agreement to feed the assigned study formula ad libitum according to the study design No evidence of significant cardiac, respiratory, ophthalmologic, gastrointestinal, hematologic, or metabolic disease; milk-protein allergy; or a maternal medical history known to have proven adverse effects on the fetus, tuberculosis, HIV, perinatal infections, or substance abuse 61-74% European American 60-80% mothers married Mean mothers’ age about 29 years Mean mothers’ education about 14 years |
Fish oil/fungal oil and egg-derived triglyceridesupplemented formulas |
9-11 days after birth until 12 months of age |
Amount |
Results |
Conclusion* |
Fish oil and fungal oil-supplemented preterm formula: 0.46 g AA/100 g total fatty acids ≤0.04 g EPA/100 g total fatty acids 0.13 g DHA/100 g total fatty acids Egg-derived triglyceride-supplemented preterm formula: 0.45 g AA/100 g total fatty acids No detected EPA 0.14 g DHA/100 g total fatty acids Control formula: No detected AA, EPA, DHA |
The vocabulary expression score at 14 months was significantly higher in the fish/fungal group than in the egg-TG group (p<0.05). Smiling and laughter was significantly higher in the control group than in the egg-TG group (p=0.05). No other development, cognition, vocabulary, or temperament outcomes presented were significantly different between the formula groups. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
O’Connor et al., 2001 |
Randomized Controlled Trial |
Infants (n=470) Preterm Birth weight 750-1800 g Cleveland, OH; Kansas City, MO; Little Rock, AR; Nottingham and Leeds, UK; Louisville, KY; Portland, OR; New York, NY; Santiago, Chile White (n=81 controls; n=80 fish/fungal; n=85 egg-TG) No serious congenital abnormalities that could affect growth and development; major surgery before randomization; periventricular/intra-ventricular hemorrhage greater than grade II; maternal incapacity; liquid ventilation; asphyxia resulting in severe and permanent neurologic damage; or uncontrolled systemic infection at the time of enrollment |
Fish oil/fungal oil and egg-derived triglyceride/fish oil-supplemented formulas |
In hospital formula from within 72 hours of first enteral feeding until term-corrected age Post-discharge formula from term-corrected age until 12 months of age |
Amount |
Results |
Conclusion* |
All in g/100 g total fatty acids (mean±SE) In-hospital control: 16.0±0.9 LA, 2.4±0.1 ALA, no AA, EPA, DHA In-hospital AA+DHA (fish/fungal oil): 16.80±1.00 LA, 2.60±0.30 ALA, 0.43±0.02 AA, 0.08±0.01 EPA, 0.27±0.04 DHA In-hospital AA+DHA (egg-TG/fish oil): 17.50±0.90 LA, 2.50±0.30 ALA, 0.41±0.00 AA, no EPA, 0.24±0.01 DHA Post-discharge control: 19.1±1.1 LA, 2.4±0.2 ALA, no AA, EPA, DHA Post-discharge AA+DHA (fish/fungal oil): 19.50±0.70 LA, 2.40±0.20 ALA, 0.43±0.01 AA, no EPA, 0.16±0.01 DHA Post-discharge AA+DHA (egg-TG/ fish oil): 20.30±0.40 LA, 2.40±0.20 ALA, 0.41±0.02 AA, no EPA, 0.15±0.02 DHA |
The mean novelty preference of the egg-TG/fish oil formula group was significantly greater than the control group (p=0.02) and the fish/fungal formula group (p=0.003) at 6 months corrected age. Using a Bonferroni adjusted alpha level of 0.0083, the difference between the fish/fungal formula group and the egg-TG/fish formula group was statistically significant. “Vocabulary comprehension did not differ among the 3 study formula groups at either 9 or 14 months corrected age in either the intent-to-treat or subgroup analysis.” |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Birch et al., 2000 |
Randomized Controlled Trial |
Infants (n=56) Healthy, term, birth weight appropriate for gestational age Singleton births Dallas, TX Predominantly White About 65% mothers had a college or postgraduate education No family history of milk protein allergy; genetic or familial eye disease; vegetarian or vegan maternal dietary patterns; maternal metabolic disease, anemia; or infection; presence of a congenital malformation or infection; jaundice; perinatal asphyxia; meconium aspiration; or any perinatal event that resulted in placement in the neonatal intensive care unit |
AA-enriched formula |
0-4 days of age to 17 weeks of age |
Lucas et al., 1999 |
Randomized Controlled Trial |
Infants (n=309 formula-fed; n=138 breast-fed) Healthy, term, singleton pregnancies, appropriate size for gestational age Nottingham and Leicester, UK Mean maternal age about 27 years 93.5% married About 70% with no higher school qualifications |
LCPUFA-supplemented formula |
Birth until 6 months of age |
Amount |
Results |
Conclusion* |
Enfamil + iron Enfamil + iron + 0.35% DHA Enfamil + iron + 0.36% DHA + 0.72% AA |
The mean Bayley MDI score at 18 months was significantly higher in the DHA/AA-supplemented formula group than in the control formula group (p<0.05). The mean Bayley PDI score at 18 months was not statistically different among the three groups (p=0.13). The mean Behavioral Rating Scale score at 18 months was not statistically different among the three groups (p=0.30). |
B |
LCPUFA-supplemented formula: 15.90% LA, 0.30% AA, 1.40% ALA, 0.01% EPA, 0.32% DHA Control formula: 12.4% LA, 1.1% ALA |
There were no significant differences in Bayley MDI and PDI at 18 months or in Knobloch, Passamanick, and Sherrard’s test at 9 months between the two formula groups. There were no significant differences in stools to 6 months, crying time (minutes/day) to 6 months, or formula intake to 6 months between the two formula groups. There were no significant differences in the OR of infection-related outcomes or the prescription of antibiotics at 9 months between the two formula groups. |
N |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Scott et al., 1998 |
Randomized Controlled Trial |
Infants (n=274) Healthy, full-term Kansas, MO; Portland, OR; Seattle, WA No prematurity, intrauterine growth retardation, congenital anomalies, 5-minute APGAR score <7, or other significant perinatal medical complications |
AA/DHA-supplemented formula |
Those randomized, formula from first week after delivery Those exclusively breastfeeding, breast milk for first 3 months and then supplementation with Similac + iron Solid food supplementation at 4 months |
Willatts et al., 1998a |
Randomized Controlled Trial |
Infants (n=44) Term UK Mothers from a single maternity hospital |
LCPUFA-supplemented formula |
Birth to 4 months of age |
Amount |
Results |
Conclusion* |
Control formula: No added LCPUFA DHA formula group (fish oil): 0.2wt% DHA DHA+AA formula group (egg yolk phospholipid): 0.12wt% DHA, 0.43wt% AA |
There were no significant differences in Bayley scores among the groups for either the Mental Index or the Motor Index. After controlling for maternal education and site, when comparing all four groups, the vocabulary comprehension score at 14 months was significantly lower in the DHA formula group compared to the breast-feeding group (p=0.017). After controlling for maternal education and site, when comparing only the three formula groups, the vocabulary production score at 14 months was significantly lower in the DHA formula group compared to the control formula group (p=0.027). No other reported associations between MacArthur Communicative Development Inventories at 14 months and the formula groups and those breast-feeding were found to be significant. |
A |
Unsupplemented formula (g/100 g fat): 11.40 LA, 0.70 ALA, <0.10 AA, no DHA LCPUFA-supplemented formula (g/100 g fat): 11.50-12.80 LA, 0.60-0.65 ALA, 0.30-0.40 AA, 0.15-0.25 DHA |
The median quartiles for entire problem intention score (p=0.035) and the cover step intention score (p=0.032) were significantly higher in the LCPUFA-supplemented group compared to the unsupplemented group. The median quartiles for entire problem intentional solutions score (p=0.021) and cover step intentional solutions (p=0.005) were significantly higher in the LCPUFA-supplemented group compared to the unsupplemented group. There were no significant differences in the median quartiles for the barrier step or cloth step for either the intention score or the intentional solutions score. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Willatts et al., 1998b |
Randomized Controlled Trial |
Infants (n=40) Term Birth weight 2500-4000 g Dundee, UK Mean maternal age about 27 years Mean maternal education about 17 years Demonstrated either an early or late peak fixation on the habituation assessment undertaken at 3 months of age |
LCPUFA-supplemented formula |
Birth to 4 months of age |
Carlson and Werkman, 1996 |
Randomized Controlled Trial |
Infants (n=59) Mean gestational age about 28 weeks Birth weight 747-1275 g Predominantly Black Memphis, TN Mean mothers’ education about 12 years No need for mechanical ventilation at that time; intraventricular hemorrhage > grade 2; retinopathy of prematurity > stage 2; surgery for necrotizing enterocolitis; weight < the fifth percentile for gestational age; history of maternal substance abuse |
DHA-supplemented formula |
Preterm formula from 3 days to 2 months of age Term formula from 2 months to 12 months of age |
Amount |
Results |
Conclusion* |
Unsupplemented formula (g/100 g fat): 11.40 LA, 0.70 ALA, <0.10 AA, no DHA LCPUFA-supplemented formula (g/100 g fat): 11.50-12.80 LA, 0.60-0.65 ALA, 0.30-0.40 AA, 0.15-0.25 DHA |
There were no significant differences in 9-month problem-solving scores (intention score and number of solutions) between the two groups. For those who had an early peak fixation at 3 months, there were no significant differences in 9-month problem-solving score (intention score or intentional solutions) between the two groups (p=0.18). For those who had a late peak fixation at 3 months, the number of intentional solutions was significantly higher in the LCPUFA-supplemented group compared to the unsupplemented group (p<0.02). |
B |
All in g/100 g total fatty acids Preterm control formula: 21.20 LA, 2.40 ALA, no EPA or DHA Preterm DHAsupplemented formula: 21.20 LA, 2.40 ALA, 0.06 EPA, 0.20 DHA Term formula: 34.30 LA, 4.80 ALA, no EPA or DHA |
At 12 months of age, the DHA-supplemented group had statistically more number of looks to familiar (p<0.05) and less seconds of time/novel looks (p<0.05) compared to the controls. No other statistically significant results were reported on visual attention. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Werkman and Carlson, 1996 |
Randomized Controlled Trial |
Infants (n=67) Mean gestational age 29 weeks Birth weight 748-1398 g Can tolerate enteral; intakes >462 kJ/kg body weight/day for 5-7 days Predominantly Black Memphis, TN Mean maternal age 23 years Mean mothers’ education about 11.5 years No need for mechanical ventilation at that time; intraventricular hemorrhage > grade 2; retinopathy of prematurity > stage 2; surgery for necrotizing enterocolitis; weight < the fifth percentile for gestational age; history of maternal substance abuse |
DHA-supplemented formula |
Preterm formula until discharge Term formula from discharge until 9 months past term Other foods gradually added to diet at about 4 months past term Mixed diet, including whole cow’s milk from 9 to 12 months |
Agostoni et al., 1995 |
Randomized Controlled Trial |
Infants (n=86) Mothers’ mean age = about 30 years Gestational age between 37-42 weeks, weight at birth appropriate for gestational age Milan, Italy APGAR score better than 7 at 5 minutes, absence of disease |
LCPUFA-supplemented formula |
Within 3 days until 4 months of age |
Amount |
Results |
Conclusion* |
All in g/100 g total fatty acids Preterm control formula: 19.1 LA, 3.0 ALA, no EPA or DHA Preterm DHA-supplemented formula: 18.7 LA, 3.1 ALA, 0.3 EPA, 0.2 DHA Term control formula: 33.2 LA, 4.8 ALA, no EPA or DHA Term DHA-supplemented formula: 32.6 LA, 4.9 ALA, 0.3 EPA, 0.2 DHA |
“Diet did not significantly influence look duration during familiarization, but there was a trend toward shorter look duration in DHA-supplemented infants compared to the controls.” At 6.5 months of age, the DHA-supplemented group had a statistically higher number of total looks (p<0.01), number of looks to novel (p<0.01), and number of looks to familiar (p<0.05) compared to the controls. At 9 months of age, the DHA-supplemented group had a statistically higher number of total looks (p<0.01), number of looks to novel (p<0.01), number of looks to familiar (p<0.05), and less seconds for average time/look (p<0.05) compared to the controls. At 12 months, the DHA-supplemented group had a statistically shorter novel time as a percentage of total time (p<0.05), more seconds of time to familiar (p<0.05), and a higher number of total looks (p<0.01), number of looks to novel (p<0.05), and number of looks to familiar (p<0.05) compared to the controls. No other significant results were reported for visual attention. |
B |
Supplemented formula (g/100 g fat): 10.80 LA, 0.30 GLA, 0.73 ALA, 0.44 AA, 0.05 EPA, 0.30 DHA Standard formula (g/100 g fat): 11.10 LA, 0.70 ALA Human milk (g/100 g fat): 6.9-16.4 LA, 0.1-0.9 GLA, 0.7-1.3 ALA, 0.2-1.2 AA, 0.0-0.6 EPA, 0.1-0.6 DHA |
The mean developmental quotient (DQ) at 4 months for those in the standard formula group was statistically lower from the DQ in the supplemented formula group (p<0.05) and the breast-feeding group (p<0.05). There was no statistical difference between the mean DQ at 4 months of the supplemented formula group and the breast-feeding group. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
McCann and Ames, 2005 |
Review |
Summary of observational, RCTs, other experimental and animal studies |
DHA status and LCPUFA-supplemented formula |
|
Bryan et al., 2004 |
Review |
Summary of the literature (all designs) |
PUFA from breast milk or formula |
|
Jacobson, 1999 |
Review |
Mostly 2 prospective longitudinal studies Detroit study on effects of prenatal exposure to alcohol Michigan study of effects of pre- and postnatal exposure to PCBs |
LCPUFA-supplemented formula |
|
Amount |
Results |
Conclusion* |
|
“Evidence from chronic dietary restriction rodent studies … shows that the addition of DHA to diets of animals whose brain concentration of DHA have been severely reduced restored control performance levels.” “Formula comparison and maternal supplementation studies in humans and ALA dietary restriction studies in nonhuman primates both link the availability of n-3 LCPUFAs to the development of visual attention” and higher DHA status to enhanced neuromotor development. RCTs in humans have often shown no effect of “LCPUFA supplementation on cognitive or behavioral performance and some reviewers have considered that, overall, the evidence was insufficient to conclude that LCPUFA supplementation benefited development.” |
B |
|
“There is moderate evidence that PUFAs, and long-chain omega-3 PUFAs in particular, from either breast milk or supplemented infant formula, are beneficial in the development of visual acuity and cognitive performance in infants.” “There is very limited empirical evidence, due to the small number of extant studies, for the beneficial effects of PUFAs, and omega-3 PUFAs in particular, on cognitive performance in older children.” “Evidence suggest that omega-3 PUFAs may have a role in the control of the symptoms of neurological disorders such as ADHD and dyslexia.” |
B |
|
“Any comparisons between breastfed and supplemented groups should include measures of maternal IQ and quality of parenting on which these groups tend to differ.” “Animal and human studies indicating a relation between LCPUFA supplementation and enhanced visual acuity and shorter visual fixations may, in fact, represent relatively independent effects of supplementation on both acuity and cognitive processing speed.” |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Daniels et al., 2004 |
Cohort |
Infants (n=1054) Mothers’ mean age = 29 years Majority of mothers with at least an O level (moderate) education Bristol, UK Singleton, term births Avon Longitudinal Study of Parents and Children (ALSPAC) |
Seafood |
Maternal fish intake: 32 weeks of gestation Breast-feeding practices: 15 months after birth Infant fish intake: 6 and 12 months after birth Total mercury concentration: Cord blood at birth |
Innis et al., 2001 |
Cohort |
Infants (n=83) Term Birth weight 2500-4500 g Mean mothers’ age 32 years British Columbia Intend to breast-feed for 3 months, no solid foods for at least the first 4 months after birth No mothers with substance abuse, communicable diseases, metabolic or physiologic problems, infections likely to influence fetal growth, or multiple births No infants with evidence of metabolic or physical abnormalities |
Fatty acids in blood from infants and milk from mothers |
2 months of age |
Amount |
Results |
Conclusion* |
Maternal fish intake categories (during pregnancy): 1 = Rarely/never 2 = 1 meal/2 weeks 3 = 1-3 meals/week 4 = 4+ meals/week Child fish intake categories (6 months of age): 1 = Rarely/never 2 = 1+ meal/week Child fish intake categories (12 months of age): 1 = Rarely/never 2 = 1+ meal/week |
Children whose mothers ate 1-3 fish meals/week and 4+ fish meals/week had significantly lower odds of low MCDI scores for social activity (OR=0.6, 95% CI 0.5-0.8 and OR=0.7, 95% CI 0.5-0.9, respectively) than the children whose mothers rarely or never ate fish during pregnancy. Children whose mothers ate 1-3 fish meals/week and 4+ fish meals/week had significantly lower odds of low DDST scores for language (OR=0.7, 95% CI 0.5-0.9 and OR=0.7, 95% CI 0.5-0.9, respectively) than the children whose mothers rarely or never ate fish during pregnancy. Children who ate 1+ fish meals/week had significantly lower odds of low MCDI scores for vocabulary comprehension (OR=0.7, 95% CI 0.5-0.8) and social activity (OR=0.7, 95% CI 0.6-0.9) and total DDST score (OR=0.8, 95% CI 0.6-0.9). All other odds ratios presented were nonsignificant. |
B |
Infant DHA: (g/100 g fatty acids) Plasma phospholipids = 2.2-8.0 RBC PE = 6.3-13.0 PC = 1.4-4.6 Infant AA: (g/100 g fatty acids) Plasma phospholipids = 8.1-15.8 RBC PE = 20.2-27.8 PC = 5.6-9.7 Mother’s milk: (g/100 g milk fatty acids) DHA = 0.10-2.50 AA = 0.20-0.81 LA = 6.30-21.50 LNA = 0.50-4.10 |
“The ability to correctly discriminate a retroflex compared with dental phonetic contrast at 9 months of age was positively correlated with the plasma phospholipid DHA (p<0.02) and the RBC PE at 2 months of age (p=0.02).” “There were no significant correlations between the infants’ AA status and the ability to discriminate the native or nonnative language contrasts.” “There were no significant correlations between the infant DHA or AA status at 2 months of age and test scores for novelty preference, or the job search task, with adjustments for covariates included in the model.” |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Kodas et al., 2004 |
Animal |
2 generations of female Wistar rats |
ALA-deficient diet |
Control group: Control diet at birth to 60 days after birth Deficient group: Deficient diet at birth to 60 days after birth Diet reversed group 1: Control diet at day of birth until 60 days after birth Diet reversed group 2: Deficient diet until day 7 postpartum and then control diet from day 7 to day 60 postpartum Diet reversed group 3: Deficient diet until day 14 postpartum and then control diet from day 14 to day 60 postpartum Diet reversed group 4: Deficient diet until day 21 postpartum and then control diet from day 21 to day 60 postpartum |
Amount |
Results |
Conclusion* |
ALA-deficient diet: 6% fat African peanut oil <6 mg ALA/100 g of diet 1200 mg LA/100 g of diet Control diet: 60% peanut oil, 40% rapeseed oil 200 mg ALA/100 g of diet 1200 mg LA/100 g of diet |
The fatty acid composition of phosphatidylcholine in the hippocampus of 2-month-old rats was as follows: AA was not significantly different among the different diet groups; DHA was significantly higher in the control group and all diet reversed groups compared to the deficient group (p<0.05); n-6:n-3 was significantly lower in the control group and all diet reversed groups compared to the deficient group (p<0.05). These differences were not significant between the control group and the diet reversed groups. The fatty acid composition of phosphatidylethanolamine in the hippocampus of 2-month-old rats was as follows: AA was significantly lower in the control group and all diet reversed groups compared to the deficient group (p<0.05); DHA was significantly higher in the control group and all diet reversed groups compared to the deficient group (p<0.05); n-6:n-3 was significantly lower in the control group and all diet reversed groups compared to the deficient group (p<0.05). These differences were not significant between the control group and the diet reversed groups. The fatty acid composition of phosphatidylserine in the hippocampus of 2-month-old rats was as follows: AA was not significantly different among the different diet groups; DHA was significantly higher in the control group and all diet reversed groups compared to the deficient group (p<0.05); n-6:n-3 was significantly lower in the control group and all diet reversed groups compared to the deficient group (p<0.05). These differences were not significant between the control group and the diet reversed groups. Basal 5-HT levels were significantly higher in the deficient group compared with the control group (p<0.05); there were no significant differences in basal 5-HT levels between the diet reversed groups 1, 2, and 3 and the control group; there were no significant differences in basal 5-HT levels between the diet reversed group 4 and the control group, deficient group, and all other diet reversed groups. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Levant et al., 2004 |
Animal |
Adult female Long-Evans rats |
AA/EPA/DPA/DHA-deficient diet |
Control diet: Day 1 of pregnancy until end of study Deficient diet: Day 1 of pregnancy until postnatal day 21. Postnatal day 21, half on deficient diet were changed to remediation diet and half stayed on deficient diet |
Chalon et al., 2001 |
Animal |
Male rats 2-3 months old |
ALA-deficient diet |
2-3 months of age |
Amount |
Results |
Conclusion* |
Control diet: 0.35 kg/5 kg diet from soybean oil; no detected AA, EPA, DPA, or DHA Deficient diet: 0.35 kg/5 kg diet from sunflower oil; no detected AA, EPA, DPA, or DHA Remediation diet: 0.3275 kg/5 kg diet from sunflower oil and 0.0225 kg/5 kg diet from fish oil AA = 0.1 g/100 g fatty acids EPA = 1.6 g/100 g fatty acids DPA = 0.4 g/100 g fatty acids DHA = 3.5 g/100 g fatty acids |
“Rats raised on the deficient diet exhibited a decrease in brain DHA content to 80% of control animals at maturity (p<0.05)” and an “increase in DPA content to 575% of control animals at maturity (p<0.001).” The remediation diet restored brain DHA and DPA content to levels similar to those on the control diet. Catalepsy score was significantly lower in the deficient diet group compared to the control group (p<0.05) and the remediation diet group (p<0.05). In a test of locomotor activity in a novel environment, the deficient diet group exhibited 187% of the activity of the control diet group during the 2-hour observation (p<0.05); results were similar between the deficient diet group and the remediation diet group. In the test of amphetamine-stimulated locomotor activity, the deficient diet group exhibited 144% of the activity of the control group (p<0.05). |
A |
ALA-deficient diet: 1200 mg LA/100 g diet, <6 mg ALA/100 g diet African peanut oil Diet balanced in n-6 and n-3 PUFA: 1200 mg LA/100 g diet, 200 mg ALA/100 g African peanut oil and rapeseed oil |
“Intake of PUFA constitutes an environmental factor able to act on the central nervous system function.” “Chronic dietary deficiency in ALA in rats induces abnormalities in several parameters of the mesocortical and mesolimbic dopaminergic systems.” “It is proposed that strong links exist among PUFA status, neurotransmission processes, and behavioral disorders in humans.” |
B |
Amount |
Results |
Conclusion* |
4 formula diets (all in g/100 g): Diet 1 (Diet D-): 1.6 LA, 0.1 ALA, no GLA, AA, or DHA Diet 2 (Diet D+): 1.9 LA, 0.1 GLA, 0.4 AA, 0.1 ALA, 0.3 DHA Diet 3 (Diet C-): 15.6 LA, 1.5 ALA, no GLA, AA, or DHA Diet 4 (Diet C+): 16.4 LA, 0.1 GLA, 0.4 AA, 1.6 ALA, 0.3 DHA |
There were no significant differences in brain weight, brain protein, DNA, cholesterol or phospholipid concentrations, or CNPase activity among the different diet groups. Piglets fed formulas with AA and DHA had significantly higher frontal cortex dopamine, HVA, norepinephrine, tryptophan and serotonin concentrations than piglets fed formulas without AA and DHA. The concentrations of all frontal cortex monoamines and metabolites in piglets fed Diet 2 formula were not different from those of piglets fed Diets 3 and 4. The inclusion of AA and DHA in Diet 4 had no significant effect on any of the frontal cortex monoamines or metabolites measured, compared to Diet 3. |
B |
ALA-deficient diet: 6% fat as peanut oil 6 mg ALA/100 g diet 1200 mg LA/100 g diet Control diet: 60% peanut oil, 40% rapeseed oil 200 mg ALA/100 g diet 1200 mg LA/100 g diet |
In the control diet group, n-3 (mostly DHA) levels reached a maximum in the stratium and a minimum in the frontal cortex at 12 months of age and remained unchanged during aging in the cerebellum. “In the deficient diet group, DHA content considerably reduced as compared with controls.” No specific effects of the deficient diet were found on the proportion of any phospholipid classes. In the control diet group, dopamine levels reached a maximum at 6 months of age, were decreased up to 12 months of age, and then stabilized in the stratium and frontal cortex. However, “the levels were not diet related in the stratium but were dramatically reduced in the frontal cortex of deficient rats and remained unchanged throughout all ages.” In the control diet group, 5-HT levels increased between 2 and 6 months of age in the stratium and then stabilized; they did not change in the frontal cortex or cerebellum during aging. |
N |
TABLE B-1h Studies on Allergies: Effects on Infants Supplemented with Omega-3 Fatty Acids in Formula
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Calder, 2001 |
Review |
Summary of animal studies and human trials |
Fish-oil supplement |
|
Field et al., 2001 |
Review |
Summary of animal studies and human trials |
AA/DHA-supplemented formula |
|
Amount |
Results |
Conclusion* |
|
“Animal studies have shown that dietary fish oil results in altered lymphocyte function and in suppressed production of proinflammatory cytokines by macrophages.” “Clinical studies have reported that fish-oil supplementation has beneficial effects in rheumatoid arthritis, inflammatory bowel disease, and among some asthmatics.” “The effect of fatty acids during pregnancy upon the maternal immune system and upon that of the infant are not known.” |
B |
|
“Recent research has been directed at the neurological, retinal, and membrane benefits of adding AA and DHA to infant formula. In adults and animals, feeding DHA affects T-cell function. However, the effect of these lipids on the development and function of the infant’s immune system is not known.” “The addition of small amounts of DHA and AA (at levels similar to that in human milk) to preterm infant formula can influence the concentration, proportion, maturation, and cytokine production of peripheral blood lymphocytes.” |
N |
Amount |
Results |
Conclusion* |
Standard commercial preterm formula group (% weight of total fatty acids): 12.8 LA, 1.4 ALA, no AA or DHA Supplemented preterm formula group (% weight of total fatty acids): 12.10 LA, 1.50 ALA, 0.49 AA, 0.35 DHA |
At 14 days postpartum, infants in the supplemented formula group had significantly higher hematocrit (L/L) concentrations compared to those in the human milk group (p<0.05). At 14 days postpartum, infants in the human milk group had significantly higher monocytes compared to both the standard formula group and the supplemented formula group (p<0.05). At 42 days postpartum, infants in the standard formula group had significantly higher T helper phenotypes and CD4/CD8 phenotypes compared to both the supplemented formula group and the human milk group (p<0.05). At 42 days postpartum, infants in the standard formula group had significantly lower monocytes compared to the human milk group (p<0.05). At 42 days postpartum, infants in the human milk group had significantly higher B cells compared to those in both formula groups (p<0.05). At 42 days postpartum, infants in the standard formula group had significantly higher sIL-2R production compared to the supplemented formula group (p<0.05) and significantly lower IL-10 production compared to the human milk group (p<0.05). No other reported results were found to be significant. |
B |
TABLE B-1i Studies on ADHD: Effects on Children Supplemented with Omega-3 Fatty Acids in Foods Other Than Exclusively Breast Milk or Infant Formula Experimental Studies in Humans
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Richardson, 2004 |
Review |
Summary of RCTs |
HUFA supplement |
|
Hirayama et al., 2004* |
Randomized Controlled Trial |
Children (n=40) Aged 6-12 years Recruited from a summer camp for children with psychiatric disorders Diagnosed or suspected as ADHD |
DHA supplement |
2 months |
Amount |
Results |
Conclusion** |
|
Omega-3 fatty acids, particularly EPA, may be beneficial in the management of dyslexia, dyspraxia, and ADHD. There is no evidence that omega-6 fatty acids are beneficial in the management of dyslexia, dyspraxia, and ADHD, but positive results have been found using an omega-3:omega-6 combination for both ADHD and dyslexia. |
B |
DHA group: Fermented soybean milk 3 times/week (600 mg DHA/125 mL) Bread rolls 2 times/week (300 mg DHA/45 g) Steamed bread 2 times/week (600 mg DHA/60 g) Total = 3600 mg DHA, 700 mg EPA/week Control group: Placebo food containing olive oil instead of DHA-rich fish oil |
Short-term visual memory was significantly improved in the control group from baseline until the end of the study (p=0.02), but not in the DHA group. The short-term visual memory was significantly better in the control group than in the DHA group (p=0.02). The number of errors of omission and commission were significantly improved in the continuous performance test in the control group from baseline until the end of the study (p=0.02 and p=0.01, respectively). The number of errors of commission were significantly higher in the DHA group than in the control group (p=0.001). |
A |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Harding et al., 2003* |
Trial |
Boys and girls (n=20) Aged 7-12 years Diagnosed with ADHD No other medication or treatment, street drugs, other nutritional or botanical supplements, comorbid disorders |
Multivitamin, multiple mineral, phytonutrients, essential fatty acid supplements |
4 weeks |
Stevens et al., 2003* |
Randomized Controlled Trial |
Boys and girls (n=47) Aged 6-13 Central Indiana = 100-mile radius of West Lafayette Those with diagnosed ADHD and those without ADHD No chronic health problems Presence of 1+ severe symptoms or several mild symptoms |
PUFA supplement |
4 months |
Amount |
Results |
Conclusion** |
Groups determined by parental choice Ritalin group: 5-15 mg Ritalin 2-3 times daily Supplement group: A multivitamin, multi-mineral, phytonutrients, essential fatty acids (180 mg EPA and 120 mg DHA from salmon oil and 45 mg GLA from borage oil) and phospholipids (soy lecithin), probiotics, and amino acids |
Both the Ritalin group and the supplement group showed significant gains in the Full Scale Response Control Quotient and the Full Scale Attention Control Quotient scores (p≤0.01 and p≤0.001, respectively). There were no significant differences in improvement between the two groups. |
B |
PUFA group: 8 capsules of PUFA/day 60 mg DHA, 10 mg EPA, 5 mg AA, 12 mg GLA, 3 mg vitamin E/capsule Placebo group: 8 capsules of placebo/day 0.8 g olive oil/capsule |
Based on those who completed the intervention, the change in teacher hit reaction time (measured both in ms and T-score) was significantly greater in the PUFA group than in the placebo group (p=0.05 and p=0.02, respectively) at 4 months. At baseline, there were no significant differences in parents’ DBD and teachers’ DBD scores between the two groups; after 4 months of treatment the number of children who improved on the parents’ DBD attention and oppositional/defiant disorder scales was significantly higher in the PUFA group than in the placebo group (p=0.09 and p=0.02, respectively). No other significant differences were found between the two groups. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Richardson and Puri, 2002* |
Randomized Controlled Trial |
Boys and girls (n=41) Aged 8-12 years Northern Ireland Referred to a school for children with specific literacy problems No official diagnosis of ADHD or any other psychiatric disorder; use of fatty acid supplements in last 6 months; consumption of oily fish >2 times/week; history of any other neurological or major psychiatric disorder or other significant medical problems; not in treatment for ADHD |
HUFA supplement |
12 weeks |
Amount |
Results |
Conclusion** |
Supplement group: 186 mg EPA/day, 480 mg DHA/day, 96 mg GLA/day, 60 IU vitamin E/day, 864 mg LA/day, 42 mg AA/day, 8 mg thyme oil/day Placebo: Olive oil |
At 3 months, the mean psychosomatic ADHD subscale, mean Conners’ ADHD index score, and mean DSM inattention score were significantly lower in the supplemented group than in the placebo group (p=0.05, p=0.03, p=0.05, respectively). At 12 weeks, the improvements were significantly greater for the supplemented group compared to the placebo group for the cognitive problems (p=0.01), the anxious/shy subscales (p=0.04), and the Conners’ index global scale (p=0.02). |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Brue et al., 2001 |
Randomized Controlled Trial |
Boys and girls (n=51) Aged 4-12 years Referred by parents, pediatricians, psychologists, psychiatrists, and educators ADHD diagnosed by a physician or psychologist No serious and preexisting medical or psychological condition or taking a stimulant medication other than Ritalin |
Essential fatty acid supplement |
Two 12-week trials |
Amount |
Results |
Conclusion** |
Trial 1: Treatment Group and Ritalin + Treatment Group: 10 mg Ginkgo biloba, 200 mg Melissa officinalis, 30 mg Grapine, 35 mg dimethylaminoethanol, 100 mg 1-glutamine Placebo Group and Ritalin + Placebo Group: 200 mg Slippery elm supplement Trial 2: Double Treatment Group and Ritalin + Double Treatment Group: 20 mg Ginkgo biloba, 400 mg Melissa officinalis, 60 mg Grapine, 70 mg dimethylaminoethanol, 200 mg 1-glutamine Double Treatment + EFA Group and Ritalin + Double Treatment + EFA Group: 20 mg Ginkgo biloba, 400 mg Melissa officinalis, 60 mg Grapine, 70 mg dimethylaminoethanol, 200 mg 1-glutamine, 1000 mg flaxseed |
Based on parent and teacher reports from Trial 1, there were no significant differences in inattentiveness or hyperactive-impulsive subscales between any of the treatment groups and their respective controls. Based on parent reports from Trial 2, those in the double treatment + EFA group had a significantly lower hyperactive-impulsive subscale score than the double treatment group (p=0.03). Based on teacher reports from Trial 2, those in the Ritalin + double treatment + EFA group had a significantly higher inattentive subscale score than the Ritalin + double treatment group (p=0.04). Based on teacher reports from Trial 2, those in the double treatment + EFA group had a significantly higher hyperactive-impulsive subscale score than the double treatment group (p=0.04). |
N |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Voigt et al., 2001* |
Randomized Controlled Trial |
Boys and girls (n=63) Aged 6-12 years 100% White in DHA group; 85% White in placebo group Texas No ineffective treatment with stimulant medication; treatment with other psychotropic medications; previous diagnosis of other childhood psychiatric disorders; use of dietary supplements; occurrence of a significant life event within 6 months; history of head injury or seizures; receipt of special education services for mental retardation or a pervasive developmental disorder; premature birth; exposure to tobacco, alcohol, or other drugs in utero; diagnosis of a disorder of lipid metabolism or other chronic medical condition Previous diagnosis of ADHD Being treated successfully with stimulant medication |
Algae-derived triglyceride supplement |
4 months |
Amount |
Results |
Conclusion** |
Algae-derived TG capsule: 345 mg DHA/day |
Between baseline and 4 months, TOVA errors of omission significantly increased (p=0.03-0.01) and color trails 1 (p=0.03-0.01) and color trails 2 (p=0.001) significantly decreased for the supplemented group. Between baseline and 4 months, TOVA errors of commission (p<0.0003) and color trails 2 (p<0.0003) significantly decreased and TOVA total response time (p=0.03-0.01) significantly increased for the placebo group. “There were no differences between groups at any time on any behavior measure by the parental Conners’ Rating Scales.” |
N |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Stevens et al., 1995* |
Case-control |
Cases = boys with ADHD (n=53) Control = healthy boys (n=43) Aged 6-12 years North central Indiana Primarily White |
Plasma fatty acid analysis |
At time of visit |
Mitchell et al., 1987* |
Case-control |
Cases = hyperactive children (n=48) Controls = from two local primary schools (n=49) Boys and girls Mean age about 9 years 92% European About 95% mothers in top three socioeconomic groups Auckland, New Zealand |
Serum fatty acid levels |
At time of visit |
Mitchell et al., 1983* |
Case-control |
Cases = from a residential school for “maladjusted” children (n=23) Controls = from a normal intermediate school (n=20) Boys and girls Aged 10-13 years for controls Aged 7.5-13 years for cases Auckland, New Zealand |
Level of red blood cell essential fatty acids |
At time of visit |
*Included in Schachter HM, Kourad K, Merali Z, Lumb A, Tran K, Miguelez M. 2005. Effects of Omega-3 Fatty Acids on Mental Health. Summary, Evidence Report/Technology Assessment No. 116 (Prepared by the University of Ottawa Evidence-based Practice Center under Contract No. 290-02-0021). Rockville, MD: Agency for Healthcare Research and Quality. **B = Evidence of a benefit; A = Evidence of an adverse effect; N = Evidence of no association or no clear association. |
Amount |
Results |
Conclusion** |
Omega-3 fatty acids as continuous variables |
Boys with ADHD had significantly lower mean levels of plasma AA, EPA, and DHA than the controls (p<0.02, p<0.02, p<0.03, respectively). Boys with ADHD had significantly lower mean levels of red blood cell AA (p<0.02), 22:4n-6 (p<0.03), and DHA (p<0.06), and significantly higher mean levels of red blood cell 22:5n-6 (p<0.05) compared to the controls. |
B |
Omega-3 fatty acids as continuous variables |
The mean level of DHA from nonfasting blood samples was significantly lower in the hyperactive children than in the controls (p=0.045). The mean levels of DGLA and AA from nonfasting blood samples were significantly lower in the hyperactive children than in the controls (p=0.007 and p=0.027, respectively). No significant differences in blood serum n-3 or n-6 fatty acids were found. |
B |
Omega-3 fatty acids as continuous variables |
The mean levels of LA, DGLA, and AA from fasting blood samples were lower in the “maladjusted” children than in the normal children (0.05<p<0.01), although the differences were not significant. The mean level of 22:5n-6 from fasting blood samples was higher in the “maladjusted” children than in the normal children (0.05<p<0.1), although this difference was not significant. No other significant differences were found between the two groups in terms of fatty acid levels in fasting blood samples. |
N |
TABLE B-1j Studies on Allergies and Asthma: Effects on Children Supplemented with Omega-3 Fatty Acids in Foods Other Than Exclusively Breast Milk or Infant Formula
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Peat et al., 2004 |
Randomized Controlled Trial |
Pregnant women (n=616) Mean age about 29 years About 47% tertiary educated Sydney, Australia At least one parent or sibling with current asthma or frequent wheeze; fluency in English; a telephone at home; residence within 30 km of the recruitment center No pet at home; vegetarian diet; multiple births; or less than 36 weeks gestation The Childhood Asthma Prevention Study (CAPS) |
Tuna-fish oil supplement |
Child’s age of 6 months to 3 years |
Hodge et al., 1998* |
Randomized Controlled Trial |
Boys and girls (n=39) Aged 8-12 years Sydney, Australia Asthmatic with a history of episodic wheeze in the last 12 months and airway hyperresponsiveness to histamine No other significant diseases; taking regular oral corticosteroids or with known aspirin or dietary salicylate sensitivity |
EPA/DHA supplement |
6 months |
Amount |
Results |
Conclusion** |
Intervention group: 500 mg/day tuna fish oil 184 mg omega-3 fatty acids Placebo group: Sunola oil 83% monounsaturated oil |
At 3 years of age, there were no significant differences in prevalence of asthma, wheezing, eczema, and atopy between the intervention group and the placebo group. However, those in the intervention group had significantly lower prevalence of mild or moderate coughing (p=0.03) and atopic coughing (p=0.003) than the placebo group. |
N |
Omega-3 group: 0.18 g EPA and 0.12 g DHA/capsule 4 capsules/day = 1.2 g omega-3/day Omega-6 group: 0.45 g safflower oil, 0.45 g palm oil, 0.10 g olive oil/capsule No EPA or DHA |
“There was no significant change in spirometric function, dose response ratio to histamine or asthma severity score at either 3 or 6 months in either group.” “There were no significant differences between groups in TNFα production over time (p=0.22).” “Dietary enrichment of omega-3 fatty acids over 6 months increased plasma levels of these fatty acids, reduced stimulated tumour necrosis factor α production, but had no effect on the clinical severity of asthma in these children.” |
N |
Amount |
Results |
Conclusion** |
|
“Very few studies investigated the effects of polyunsaturated fatty acids (PUFAs) on chronic obstructive pulmonary disease (COPD) and asthma, and the results of those that were found showed conflicting results.” “It is very difficult to draw any conclusions on the true impact of dietary PUFA intake on respiratory health.” “The evidence in this review suggests that diet does play a role in asthma and COPD, but the causality of association cannot be confirmed because of the observational nature of most of the studies.” |
N |
|
“The findings of several large studies in adults suggest that high fish intake has beneficial effects on lung function.” “The relationship between fish intake and respiratory symptoms and clinical disease is less evident.” |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Peat et al., 1998* |
Review |
Longitudinal cohort studies and cross-sectional studies |
Diet |
|
Amount |
Results |
Conclusion** |
|
In cross-sectional studies, the risk factors for presence in:
In longitudinal studies, the risk factors for ongoing conditions from:
Important future longitudinal studies will be those that divide the broad spectrum of asthma into phenotypic groups. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Takemura et al., 2002* |
Case-control |
Cases = currently asthmatic students (n=1673) Controls = students who were never asthmatic (n=22,109) Boys and girls Elementary and junior high school students Aged 6-15 years, Tokorozawa City, Japan Tokorozawa Childhood Asthma and Pollinosis Study |
Seafood |
|
Amount |
Results |
Conclusion** |
Fish intake categories: 1 = Almost none 2 = 1-2 times/month 3 = 1-2 times/week 4 = ≥3-4 times/week Serving size unspecified; cited that “most of the variation is explained by frequency of use rather than differences in serving sizes” |
After adjusting for age, gender, parental history of asthma: The OR for current asthma was slightly significantly higher for those who ate fish 1-2 times/week compared to those who ate fish 1-2 times/month (OR=1.133, 95% CI 1.021-1.258); and Although the ORs for current asthma were not significant for those who ate fish almost never (OR=0.957, 95% CI 0.725-1.263) and ≥3-4 times/week (OR=1.334, 95% CI 0.907-1.963) compared to those who ate fish 1-2 times/month, there was a significant positive trend with an increase of fish consumption (p for trend = 0.0078). After adjusting for age, gender, parental history of asthma, and vegetable and fruit intake: The OR for current asthma was slightly significantly higher for those who ate fish 1-2 times/week compared to those who ate fish 1-2 times/month (OR=1.117, 95% CI 1.005-1.241); and Although the ORs for current asthma were not significant for those who ate fish almost never (OR=1.039, 95% CI 0.785-1.376) and ≥3-4 times/week (OR=1.319, 95% CI 0.896-1.943) compared to those who ate fish 1-2 times/month, there was a significant positive trend with an increase of fish consumption (p for trend = 0.0349). |
A |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Hodge et al., 1996* |
Case-control |
Boys and girls (n=468) Aged 8-11 Sydney, Australia With airway hyperresponsiveness, wheeze in the last 12 months, and 3-in-5 sample of children with no airway hyperresponsiveness or wheeze in the last 12 months |
Seafood |
In the past year |
Ellwood et al., 2001 |
Ecological |
Children Aged 6-7 and 13-14 years 53 countries The International Study of Asthma and Allergies in Childhood (ISAAC) Data from FAO Food Balance Sheet |
PUFA and seafood intake |
|
Amount |
Results |
Conclusion** |
Total fish intake/week Ever eat fresh fish, fresh oily fish, or fresh non-oily fish |
There were no significant differences in total fish intake between children with normal airways (1.2 servings, 95% CI 1.0-1.3), airway hyperresponsiveness (1.2 servings, 95% CI 0.9-1.5), wheeze (1.2 servings, 95% CI 0.8-1.5) and current asthma (1.0 servings, 95% CI 0.8-1.2). Significantly fewer children with asthma ever ate oil fish compared to children with normal airways (p<0.05); however, there was no significant difference between those with current asthma and normal children who ate exclusively oily fish. After adjusting for atopy, parental asthma, parental smoking, ethnicity, country of birth, early respiratory illness, and sex: Children who ate oily fish had a significantly lower OR of current asthma when compared to children who did not eat oily fish (OR=0.26, 95% CI 0.09-0.72); and There were no other significant associations found between type of fish (fresh fish, oily fish, non-oily fish) and airway hyperresponsiveness, wheeze, or current asthma. |
B |
Percentage of total energy consumed as PUFA: 3%-12% Range of fish intake not reported |
There were no significant associations found between total PUFA intake (% of total fat) for current wheezing, severe wheezing, allergic rhinoconjunctivitis, and atopic eczema. There was a significant inverse association found between all fish (fresh and frozen) consumption and asthma, allergic rhinoconjunctivitis, and atopic eczema, for the 13- to 14-year-old age group; the same inverse association remained for the 6- to 7-year-old age group, but the association was weaker. |
B |
Author |
Study Type |
Subjects |
Exposure |
Timing of Exposure |
Satomi et al., 1994* |
Ecological |
Boys and girls (n=7742) Aged 6-11 years Japan 1st-, 3rd-, 5th-grade students Coastal schools = fish harvest and consumption are high Inland schools = located far from sea but close to the coast school district |
Seafood |
|
*Included in Schachter HM, Reisman J, Tran K, Dales B, Kourad K, Barnes D, Sampson M, Morrison A, Gaboury I, Blackman J. 2004. Health Effects of Omega-3 Fatty Acids on Asthma. Summary, Evidence Report/Technology Assessment No. 91 (Prepared by the University of Ottawa Evidence-based Practice Center under Contract No. 290-02-0021). AHRQ Publication No. 04-E013-2. Rockville, MD: Agency for Healthcare Research and Quality. **N = Evidence of no association or no clear association; B = Evidence of a benefit; A = Evidence of an adverse effect. |
Amount |
Results |
Conclusion** |
Fish consumption categories: Very often = ≥4-5 times/week Relatively often = 2-3 times/week Often = 1 time/week Infrequently = 1-2 times/month Seldom = <1 time/month |
Coastal school children who ate reddish fish (sardine, mackerel, pike) very often had a significantly lower prevalence of history of asthma than those who seldom ate reddish fish (p<0.01). There were no other significant differences for these children based on consumption of pale fish, shellfish, fish-paste, seaweed, and dried fish. Inland school children who ate pale fish (flatfish, sea bream, turbot) and seaweed very often had significantly higher prevalence of history of asthma than those who seldom ate pale fish and seaweed (p<0.01; 0.01<p<0.05, respectively). There were no other significant differences for these children based on reddish fish, shellfish, fish-paste, and dried fish. |
B |
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Studies on Adult Chronic Diseases
TABLE B-2a Secondary Prevention Studies with Cardiovascular Outcomes
Author |
Study Type |
Subjects |
Exposure |
Hooper et al., 2006 |
Meta-analysis |
48 randomized controlled trials 41 cohorts Omega-3 intake for ≥6 months in adults Primary and secondary prevention |
n-3 supplement |
Amount |
Results |
Conclusion** |
High omega-3 fat vs. low omega-3 fat/control Intake differed by 0.1-0.6 g omega-3/day among the two groups (absolute levels not specified) |
Based on RCTs, no significant differences were found between the high omega-3 fat group and the low omega-3 fat/control group with regards to risk of mortality (n=15 RCTs; RR=0.87, 95% CI 0.73-1.03), cardiovascular events (n=18 RCTs; RR=0.95, 95% CI 0.82-1.12), cancer or death from cancer (n=10 RCTs; RR=1.07, 95% CI 0.88-1.30), or stroke (n=9 RCTs; RR=1.17, 95% CI 0.91-1.51). Based on cohorts, no significant differences were found between the high omega-3 fat group and the low omega-3 fat/control group with regards to risk of cardiovascular events (n=7 cohorts; RR=0.91, 95% CI 0.73-1.13), cancer or death from cancer (n=7 cohorts; RR=1.02, 95% CI 0.87-1.19), or stroke (n=4 cohorts; RR=0.87, 95% CI 0.72-1.04). Based on three cohorts, those in the low omega-3 fat/control group had a significantly higher risk of mortality compared to those in the high omega-3 fat group (RR=0.65, 95% CI 0.48-0.88). |
N |
Amount |
Results |
Conclusion** |
|
Based on RCTs, no significant differences were found between those randomized to n-3 supplementation or advice and those not randomized to n-3 supplementation or advice with regards to total mortality (n=44 RCTs; RR=0.87, 95% CI 0.73-1.03), combined cardiovascular events (n=31 RCTs; RR=0.95, 95% CI 0.82-1.12), cancers (n=10 RCTs; RR=1.07, 95% CI 0.88-1.30), cardiovascular deaths (n=44 RCTs; RR=0.85, 95% CI 0.68-1.06), fatal myocardial infarction (n=38 RCTs; RR=0.86, 95% CI 0.60-1.25), non-fatal myocardial infarction (n=26 RCTs; RR=1.03, 95% CI 0.70-1.50), sudden death (n=37 RCTs; RR=0.85, 95% CI 0.49-1.48), angina (n=25 RCTs; RR=0.78, 95% CI 0.59-1.02), stroke (n=26 RCTs; RR=1.17, 95% CI 0.91-1.51), heart failure (n=20 RCTs; RR=0.51, 95% CI 0.31-0.85), peripheral vascular events (n=17 RCTs; RR=0.26, 95% CI 0.07-1.06), and re-vascularization (n=23 RCTs; RR=1.05, 95% CI 0.97-1.12). Based on cohort studies, no significant differences were found between those randomized to n-3 supplementation or advice and those not randomized to n-3 supplementation or advice with regards to combined cardiovascular events (n=7 cohorts; RR=0.91, 95% CI 0.73-1.13), cancers (n=10 cohorts; RR=1.02, 95% CI 0.87-1.19), nonfatal myocardial infarction (n=4 cohorts; RR=0.93, 95% CI 0.69-1.26), stroke (n=4 cohorts; RR=0.87, 95% CI 0.72-1.04), peripheral vascular events (n=1 cohort; RR=0.94, 95% CI 0.84-1.04), and revascularization (n=2 cohorts; RR=1.07, 95% CI 0.76-1.50). Based on cohort studies, significant differences were found between those randomized to n-3 supplementation or advice and those not randomized to n-3 supplementation or advice with regards to total mortality (n=3 cohorts; RR=0.65, 95% CI 0.48-0.88), cardiovascular deaths (n=11 cohorts; RR=0.79, 95% CI 0.63-0.99), fatal myocardial infarction (n=2 cohorts; RR=0.42, 95% CI 0.21-0.82), and sudden death (n=1 cohort; RR=0.44, 95% CI 0.21-0.91). |
N |
Author |
Study Type |
Subjects |
Exposure |
Konig et al., 2005 |
Meta-analysis |
7 observational studies (primary prevention) 4 RCTs (secondary prevention) |
Seafood |
Burr et al., 2005 |
Review |
Review of two randomized controlled trials (Burr et al., 1989, 2003 below) Secondary prevention |
Dietary advice |
Harper and Jacobson, 2005 |
Review |
Systematic literature review of 14 randomized controlled trials Northern Europe, Southern Europe, India Excluded if trial involved >1 intervention unless in a prospective 2×2 design Patients followed for ≥1 year Secondary prevention |
6 on fish oil 2 on fish 5 on ALA suppl. 2 on ALA-enriched diets |
Amount |
Results |
Conclusion** |
Servings/week, a continuous number 1 serving = 100 g |
Among those with no preexisting CHD (from observational studies), the linear regression model showed that each one serving increase in fish consumption per week reduces one’s risk of CHD death by 0.039 (95% CI −0.066 to −0.011) but does not significantly change one’s risk of nonfatal MI by (ΔRR=0.0083, 95% CI −0.012 to 0.028) “The information available is insufficient for the purposes of quantitatively analyzing the impact of fish consumption on CHD risk for individuals with preexisting CHD” (from RCTs). |
B |
See Burr et al., 1989, 2003 below |
“It appeared that fish oil, which protected post-MI male patients in DART, increased the risk of cardiac death in men with angina, being particularly associated with sudden death.” “The apparently conflicting findings may be attributable to the different clinical conditions of the subjects … together with different effects of dietary fish and fish oil.” |
N |
|
“The evidence supports a role for fish oil (EPA or DHA) or fish in secondary prevention, because the clinical trials have demonstrated a reduction in total mortality, CHD death, and sudden death.” “Evidence from these trials had indicated that EPA plus DHA supplementation in the range of 0.5-1.8 g/day provides significant benefit.” “The data on the plant-based n-3 PUFA, ALA, is very promising. However, the existing studies were small, and a large randomized controlled trial is needed before recommendations can be definitely made for CHD prevention.” “The data for ALA show possible reductions in sudden death and nonfatal myocardial infarction, suggesting other potential cardioprotective mechanisms other than a predominately antiarrhythmic role.” |
B |
Author |
Study Type |
Subjects |
Exposure |
Leaf et al., 2005 |
Randomized Controlled Trial |
Men and women (n=402) Mean age about 65 years 18 US centers Had a cardioverter defibrillator implanted because of a history of cardiac arrest, sustained ventricular tachycardia, or syncope with inductive, sustained ventricular tachycardia or ventricular fibrillation during electrophysiologic studies Follow-up of 12 months Secondary prevention |
n-3 supplement |
Amount |
Results |
Conclusion** |
Treatment: Four 1 g gelatin capsules of an ethyl ester concentrate of n-3 fatty acids (2.6 g EPA+DHA) Placebo: Four 1 g capsules of olive oil |
After controlling for sex, left ventricular ejection fraction (continuous), New York Heart Association class III congestive heart failure, history of myocardial infarction, history of prior defibrillator therapies for ventricular tachycardia or ventricular fibrillation, time from implanted cardioverter/defibrillator implant (continuous), and sustained ventricular tachycardia as the indication for the implanted cardioverter defibrillator: The intent-to-treat analysis provided a significant relative risk of time to first event of 0.67 (95% CI 0.47-0.95, p=0.024) for all confirmed events among those in the treatment group compared to the placebo group; The on-treatment analysis (for all who had taken any of their prescribed supplements) provided a significant relative risk of time to first event of 0.67 (95% CI 0.46-0.98, p=0.037) for all confirmed events among those in the treatment group compared to the placebo group; and The on-treatment analysis (for all on-treatment at least 11 months) provided a significant relative risk of time to first event of 0.52 (95% CI 0.32-0.83, p=0.0060) for all confirmed events among those in the treatment group compared to the placebo group. Similar results were found when probable events were also included. |
B |
Author |
Study Type |
Subjects |
Exposure |
Raitt et al., 2005 |
Randomized Controlled Trial |
Men and women (n=200) Mean age about 62 Patients at six medical centers in the United States Receiving an implantable cardioverter defibrillator for an electrocardiogram-documented episode of sustained ventricular tachycardia or ventricular fibrillation that was not the result of acute myocardial infarction or a revisible cause or who had a preexisting implantable cardioverter defibrillator and had received implantable cardioverter/defibrillator therapy for an electrocardiogram-documented episode of sustained ventricular tachycardia or ventricular fibrillation within the last 3 months No class I or class II antiarrhythmic medications; ≥1 fatty fish meal/week; flaxseed oil, cod-liver oil, or fish-oil supplements in the last month Follow-up of 2 years Secondary prevention |
n-3 supplement |
Amount |
Results |
Conclusion** |
Treatment: 1.8 g/day fish oil (42% EPA and 30% DHA) Placebo: Olive oil (73% oleic acid, 12% palmitic acid, 0% EPA+DHA) |
There was a significant difference in the number of patients hospitalized for neurological conditions among those assigned to the placebo compared to those assigned to the treatment (p=0.04). However, there were no other significant differences found in mortality, hospitalizations, coronary revascularization, myocardial infarction, cancer, and diarrhea between the two groups. There were no significant differences in the time to first episode of implantable cardioverter/defibrillator therapy for ventricular tachycardia or ventricular fibrillation after randomization between the two groups (p=0.19). However, among those with qualified arrhythmia at the time of study entry, those assigned to fish oil had significantly greater incidence of ventricular tachycardia or ventricular fibrillation treated by the implantable cardioverter defibrillator compared to those assigned to placebo (p=0.007). |
A |
Author |
Study Type |
Subjects |
Exposure |
Baer et al., 2004 |
Randomized Crossover Trial |
Men (n=50) Aged 25-60 years All races Beltsville, MD In good health, with no hypertension, hyperlipidemia, diabetes, peripheral vascular disease, gout, liver or kidney disease, or endocrine disorders Fasting plasma HDL-c >0.65 mmol/L, triacylglycerol <3.39 mmol/L, and 85-120% of their sex-specific ideal BMI No lipid-lowering drugs, blood pressure medication, or dietary supplements, or eating habits inconsistent with the study protocol 30-week intervention (six diets for 5 weeks each) Primary prevention |
Diet |
Amount |
Results |
Conclusion** |
Diets 1-5: 38.9% energy from fat, 15% energy from protein, 46.1% energy from digestible carbohydrates Diet 6: 30.4% energy from fat, 54.6% energy from carbohydrate Diet 1 (carbohydrate diet): 8.5% of energy from fat replaced by digestible carbohydrate Diet 2 (oleic acid diet): 8% of energy enriched with oleic acid Diet 3 (LMP diet): 8% of energy enriched with lauric (L), myristic (M), and palmitic (P) acids Diet 4 (stearic acid diet): 8% of energy enriched with stearic acid Diet 5 (trans fatty acid diet): 8% of energy enriched with trans fatty acids Diet 6 (trans fatty acid + stearic acid diet): 4% energy enriched with trans fatty acids and 4% of energy enriched with stearic acid |
After 5 weeks on the stearic acid diet, the least squares mean plasma fibrinogen levels were significantly higher than after 5 weeks on all other diets (p<0.05). After 5 weeks on the trans fatty acid diet, the least squares mean plasma C-reactive protein levels were significantly higher than after 5 weeks on all other diets (p<0.05). After 5 weeks on the oleic acid diet, the least squares mean plasma interleukin 6 levels were significantly lower than after 5 weeks on all other diets, except for the trans fatty acid + stearic acid diet (p<0.05). After 5 weeks on the trans fatty acids diet, the least squares mean plasma C-reactive protein levels were significantly higher than after 5 weeks on the carbohydrate diet, the oleic diet, and the trans fatty acid + stearic acid diet (p<0.05). After 5 weeks on the oleic acid diet, the least squares mean plasma interleukin 6 levels were significantly lower than after 5 weeks on the trans fatty acid diet, stearic acid diet, or the LMP diet (p<0.05). After 5 weeks on the oleic acid diet, the least squares mean plasma E-selectin levels were significantly lower than after 5 weeks on all other diets, except for the carbohydrate diet (p<0.05). After 5 weeks on the trans fatty acids diet, the least squares mean plasma E-selectin levels were significantly higher than after 5 weeks on all other diets (p<0.05). There were no other significant differences reported between the diets with regards to fibrinogen, C-reactive protein, interleukin 6, or E-selectin levels. |
N |
Author |
Study Type |
Subjects |
Exposure |
Burr et al., 2003 |
Randomized Controlled Trial |
Men (n=3114) Aged <70 years South Wales, UK Being treated with angina Mortality ascertained at 3-9 years after enrollment No exertional chest pain or discomfort; men awaiting coronary artery by-pass surgery, men who already ate oily fish twice a week, men who could not tolerate oily fish or fish oil, men who appeared to be unsuitable on other grounds (e.g., other serious illness, likelihood of moving out of area) The Diet and Angina Randomized Trial (DART 2) Follow-up of 3 years (after last subject was recruited) Secondary prevention |
Dietary advice |
Amount |
Results |
Conclusion** |
Fish advice = eat at least 2 portions of oily fish each week or take up to 3 g of fish oil as a partial or total substitute Fruit/vegetable advice = eat 4-5 portions of fruit and vegetables and drink at least 1 glass of natural orange juice daily, and also increase the intake of oats Both = a combination of both of these forms of advice Sensible eating = non-specific advice that did not include either form of advice |
Those given fish advice had significantly higher percentage of cardiac deaths (p=0.02) and sudden deaths (p=0.02) compared to those who did not receive fish advice. There was not a significant difference in the number of total deaths between these two groups. No significant differences were found between the fruit/vegetable advice group and the no fruit/vegetable advice group for total number of deaths, number of cardiac deaths, or number of sudden deaths. After adjusting for age, smoking, previous MI, history of high blood pressure, diabetes, BMI, serum cholesterol, medication, and fruit advice or fish advice: Those who received fish advice had a slightly significant higher hazard ratio for cardiac deaths (HR=1.26, p=0.047) and a significant higher hazard ratio for sudden death (HR=1.54, p=0.025), compared to those who did not receive fish advice. There were no significant associations found between those who received fruit/vegetable advice vs. those who did not and all deaths, cardiac deaths, or sudden deaths. |
A |
Author |
Study Type |
Subjects |
Exposure |
Marchioli et al., 2002 |
Randomized Controlled Trial |
Men and women (n=11,323) No age limits Gruppo Italiano per lo Studio della Sopravivivenza nell’Infarto miocardico-Prevenzione (GISSI trial) Recent MI Follow-up of 3.5 years (about 38,418 person-years) Secondary prevention |
n-3 supplement |
Amount |
Results |
Conclusion** |
n-3 fatty acids group = 1 g/day Vitamin E group = 300 mg/day Combination group Control group |
After adjusting for age, sex, complications after myocardial infarction, smoking habits, history of diabetes mellitus and arterial hypertension, total blood cholesterol, HDL cholesterol, fibrinogen, leukocyte count, and claudication intermittens: Those who received n-3 fatty acids had a significantly lower relative risk of death, nonfatal MI, and nonfatal stroke at 9 months, 12 months, and 42 months of follow-up than the controls (RR=0.76, 95% CI 0.60-0.97 at 9 months, RR=0.79, 95% CI 0.63-0.98 at 12 months, and RR=0.85, 95% CI 0.74-0.98 at 42 months). The relative risks at 3 and 6 months of follow-up were also lower in the n-3 fatty acid group compared to the controls, but they were not significant. Those who received n-3 fatty acids had a significantly lower relative risk of CVD death, nonfatal MI, and nonfatal stroke at 9 months (RR=0.75, 95% CI 0.58-0.97), 12 months (RR=0.78, 95% CI 0.62-0.99), and 42 months (RR=0.80, 95% CI 0.68-0.94) of follow-up than the controls. The relative risks at 3 and 6 months of follow-up were also lower in the n-3 fatty acid group compared to the controls, but they were not significant. |
B |
Amount |
Results |
Conclusion** |
Fish advice = eat at least 2 portions of fatty fish each week and as much other fish as they could manage (using fish oil capsule as a partial or total replacement if necessary) Fat advice = aimed at reducing total fat and increasing the polyunsaturated to saturated fat ratio Fiber advice = eat at least 6 slices of wholemeal bread per day or an equivalent amount of cereal fiber |
After adjusting for myocardial infarction, angina, hypertension at baseline; x-ray evidence of cardiomegaly, pulmonary congestion or pulmonary edema at baseline; and treatment with β-blockers, other anti-hypertensives, digoxin/antiarrhythmics, or anticoagulants: Those who received fish advice had a significantly lower hazard ratio for all-cause mortality at 0-2 years of follow-up (HR=0.73, 95% CI 0.56-0.95) and a significantly higher hazard ratio at 2-5 years of follow-up (HR=1.31, 95% CI 1.01-1.71) compared to those who did not receive fish advice. However, there were no significant differences between the two groups and all-cause mortality after 5 years of follow-up; Those who received fish advice had a significantly lower hazard ratio for coronary heart disease at 0-2 years of follow-up (HR=0.68, 95% CI 0.51-0.91) compared to those who did not receive fish advice. After 2 years of follow-up, there were no significant differences between the two groups and their risk of coronary heart disease; and There were no significant differences between those who received fish advice vs. those who did not and risk of stroke throughout 10 years of follow-up. |
N |
Author |
Study Type |
Subjects |
Exposure |
Nilsen et al., 2001 |
Randomized Controlled Trial |
Men and women (n=300) Aged >18 years Central Hospital in Rogaland, Stavanger, Norway Suffered from acute MI Discontinued regular supplementation of other fish oil products No assumed noncompliance; expected survival <2 years because of severe heart failure; ongoing gastrointestinal bleeding or verified stomach ulcer; thrombocytopenia or blood platelets <100×109/L; liver insufficiency; participation in any other study; residence outside the recruitment area Mean follow-up time of 1.5 years Secondary prevention |
n-3 supplement |
GISSI Investigators, 1999* |
Randomized Controlled Trial |
Men and women (n=11,324) No age limits Recent MI (≤3 months) No contraindications to the dietary supplements; were able to provide informed written consent, had no unfavorable short-term outlook (e.g., overt congestive heart failure, cancer, etc.) 42 months of follow-up Gruppo Italiano per lo Studio della Sopravivivenza nell’Infarto miocardico-Prevenzione (GISSI trial) Secondary prevention |
n-3 supplement |
Amount |
Results |
Conclusion** |
Fish oil = 850-880 mg EPA+DHA/capsule Control = same amount in corn oil 2 capsules twice a day |
When compared to the corn oil group, there were no significant associations found between fish oil and fatal cardiac events and resuscitations, nonfatal cardiac events, revascularization, total mortality, time to first event, or cardiac event or revascularization. |
N |
n-3 PUFA alone vs. vitamin E alone vs. combination of the two vs. no supplement (control) Absolute amounts not specified |
In the four-way analysis, those who received n-3 PUFA had a significantly lower relative risk of death, nonfatal MI, and nonfatal stroke (RR=0.85, 95% CI 0.74-0.98) and cardiovascular death, nonfatal MI, and nonfatal stroke (RR=0.80, 95% CI 0.68-0.95) compared to the controls. In the four-way analysis, those who received n-3 PUFA had a significantly lower relative risk of all fatal events (RR=0.80, 95% CI 0.67-0.94), all cardiovascular deaths (RR=0.70, 95% CI 0.56-0.87), cardiac death (RR=0.65, 95% CI 0.51-0.82), coronary death (RR=0.65, 95% CI 0.51-0.84), and sudden death (RR=0.55, 95% CI 0.40-0.76). Similar results were also found in the two-way analysis. |
B |
Author |
Study Type |
Subjects |
Exposure |
Singh et al., 1997 |
Randomized Controlled Trial |
Men and women (n=360) Mean age of 48.5 years Admitted to the Medical Hospital and Research Center, Moradabad Clinical diagnosis of acute MI in the preceding 24 hours Indian Experiment of Infarct Survival (IEIS-4) Secondary prevention |
n-3 supplement |
Burr et al., 1989 |
Randomized Controlled Trial |
Men (n=2033) Aged <70 years South Wales, UK From those admitted to 21 hospitals for acute MI No diabetes, those awaiting cardiac surgery, or those who already intended to eat one of the intervention diets 2 years of follow-up The Diet and Reinfarction Trial (DART) Follow-up of 2 years Secondary prevention |
Dietary advice |
Amount |
Results |
Conclusion** |
Fish oil = 1.08 g/day EPA + 0.72 g/day DHA Mustard oil = 2.9 g/day ALA Placebo = 100 mg/day aluminum hydroxide |
Compared to the placebo group, those in the fish oil group had significantly lower relative risks of angina pectoris (RR=0.42, 95% CI 0.22-0.77), total arrhythmias (RR=0.46, 95% CI 0.21-0.98), total cases with poor left ventricular function (RR=0.48, 95% CI 0.28-0.82), NYHA class III and IV heart failure (RR=0.44, 95% CI 0.18-0.88), and total cardiac events (RR=0.70, 95% CI 0.29-0.90). Compared to the placebo group, the fish oil group also had lower relative risks of ventricular ectopic beats (>8/minute and >3 consecutively), left ventricular enlargement, hypotension, sudden cardiac death, total cardiac death, and nonfatal reinfarction, but these were not significant. Serious concerns have been raised about the performance and conclusions of this trial and other related publications by this investigator. |
B |
Fat advice = reduce fat to 30% of total energy and increase polyunsaturated to saturated ratio to 1.0 Fish advice = consume at least 2 weekly portions of 200-400 g fatty fish (or 0.15 g of MaxEPA capsules daily if one could not tolerate fish) Fiber advice = increase intake of cereal fiber to 18 g daily |
Total mortality and IHD mortality was significantly lower in the fish advice group than in the non-fish advice group (p<0.05 and p<0.01, respectively). There were no significant differences in nonfatal MI or IHD events in the fish advice group and the non-fish advice group. There were no significant differences in total mortality, IHD deaths, nonfatal MI, or IHD events between the fat advice group and the non-fat advice group or between the fiber advice group and the non-fiber advice group. After controlling for history of MI, angina, or hypertension; X-ray evidence of cardiomegaly, pulmonary congestion, or pulmonary edema; and treatment (at entry) with β-blockers, other antihypertensives, digoxin/antiarrhythmics, or anticoagulants; those in the fish advice group had a significantly lower relative risk of all deaths than those not in the fish advice group (p<0.05); similar results were also found in the unadjusted comparison. |
B |
Amount |
Results |
Conclusion** |
Categories of fish intake: 1 = Never-<1 time/month 2 = 1-3 times/month 3 = 1 time/week 4 = 2-4 times/week 5 = ≥5 times/week |
Based on pooled relative risks of CHD mortality, those who ate fish 1 time/week, 2-4 times/week, and ≥5 times/week had significantly lower risk of CHD mortality than those who never ate fish (RR=0.85, 95% CI 0.76-0.96; RR=0.77, 95% CI 0.66-0.89; RR=0.62, 95% CI 0.46-0.82, respectively). Those who ate fish 1-3 times/month also had a lower relative risk compared to those who never ate fish, but it was not significant (RR=0.89, 95% CI 0.79-1.01). “Each 20-g/day increase in fish intake was related to a 7% lower risk of CHD mortality (p for trend = 0.03).” |
B |
Amount |
Results |
Conclusion** |
Consumed fish on a regular basis vs. consumed little or no fish Level of fish consumption: <2, 2-<4, ≥4 portions per week |
In 6 cohort studies, those consuming any amount of fish had a significantly lower risk of coronary heart disease mortality compared to those who ate no fish; in seven cohort studies no significant associations were found between fish consumption and coronary heart disease mortality. Based on pooled estimates from a random-effects model, those who ate any fish (pooled RR=0.83, 95% CI 0.76-0.90), those who ate <2 portions of fish/week (pooled RR=0.83, 95% CI 0.75-0.92), and those who ate 2-<4 portions of fish/week (pooled RR=0.75, 95% CI 0.62-0.92) had a significantly lower risk of coronary heart disease mortality compared to those who ate no fish; a significant difference was not found between those who ate ≥4 portions of fish/week and those who never ate fish. In one cohort study and five case-control studies those consuming any amount of fish had a significantly lower risk of total coronary heart disease compared to those who ate no fish; in one cohort study, those who ate fish had a significantly higher risk of total coronary heart disease compared to those who ate no fish (RR≈1.8, 95% CI 1.2-3.2); in five cohort studies no significant associations were found between fish consumption and total coronary heart disease. Based on pooled estimates from a random-effects model, those who ate any fish (pooled RR=0.86, 95% CI 0.81-0.92), those who ate <2 portions of fish/week (pooled RR=0.85, 95% CI 0.80-0.91), and those who ate 2-<4 portions of fish/week (pooled RR=0.83, 95% CI 0.69-0.99) had a significantly lower risk of total coronary heart disease compared to those who ate no fish; a significant difference was not found between those who ate ≥4 portions of fish/week and those who never ate fish. |
B |
Author |
Study Type |
Subjects |
Exposure |
Calder, 2004 |
Review |
Primary and secondary prevention studies in humans (n=25) |
Seafood or n-3 supplement |
Marckmann and Gronbaek, 1999 |
Review |
Prospective cohort studies (n=9) Letter (n=1) Short report (n=1) Sample size and length of follow-up varied between studies Primary prevention |
Seafood |
Amount |
Results |
Conclusion** |
|
“Substantial evidence from epidemiological and case-control studies indicates that consumption of fish, fatty fish, and long-chain n-3 PUFAs reduces the risk of cardiovascular mortality.” “Secondary prevention studies using long-chain n-3 PUFAs in patients post-myocardial infarction have shown a reduction in total and cardiovascular mortality.” “Long-chain n-3 PUFAs have been shown to decrease blood triacylglycerol (triglyceride) concentrations, to decrease production of chemoattractants, growth factors, adhesion molecules, inflammatory eicosanoids and inflammatory cytokines, to lower blood pressure, to increase nitric oxide production, endothelial relaxation and vascular compliance, to decrease thrombosis and cardiac arrhythmias and to increase heart rate variability.” |
B |
|
Both Krohout (1985) and Daviglus (1997) showed a significant inverse relationship between fish intake (g/day) and risk of coronary heart disease (p for trend <0.05 and p for trend = 0.04, respectively). “Our overall conclusion is that individuals at low risk of CHD and with healthy lifestyles do not gain any additional protection against CHD from eating fish. On the other hand, high-risk individuals appear to benefit in a dose-dependent manner from increasing their fish consumption up to an optimum of 40-60 g.” |
N |
Author |
Study Type |
Subjects |
Exposure |
Iso et al., 2006 |
Cohort |
Men (n=19,985) Women (n=21,593) Aged 40-59 years Japan (Iwate Prefecture, Akita, Nagano, Okinawa) The Japan Public Health Center-based Study Cohort I No myocardial infarction, angina pectoris, stroke, or cancer at baseline 477,325 person-years of follow-up Primary prevention |
Seafood |
Amount |
Results |
Conclusion** |
One serving = 100 g for fresh fish, 20 g for dried or salted fish, 20 g for salted fish roe, 20 g for salted fish preserves n-3 amounts per serving = 1.22 g for fresh fish and shellfish, 0.40 g for dried fish, 0.52 g for salted eggs, and 0.11 g for salted fish gut Quintiles of fish and n-3 intakes: 1 (low) = mean of 23 g/day 2 = mean of 51 g/day 3 = mean of 78 g/day 4 = mean of 114 g/day 5 (high) = mean of 180 g/day |
After adjusting for age; sex; cigarette smoking; alcohol intake; BMI; histories of hypertension and diabetes; medication use for hypercholesterolemia; education level; sports at leisure time; quintiles of dietary intake of fruits, vegetables, saturated fat, monounsaturated fat, n-6 polyunsaturated fat, cholesterol; total energy; and public health center: Those in the 5th quintile of fish intake had a significantly lower HR of definite MI (HR=0.44, 95% CI 0.24-0.81) and nonfatal coronary events (HR=0.43, 95% CI 0.23-0.81) than those in the 1st quintile. Those in the 2nd, 3rd, and 4th quintiles also had lower hazard ratios of definite MI and nonfatal coronary events, but they were not significant; No significant associations were found between quintiles of fish intake and coronary heart disease, total MI, sudden cardiac death, or fatal coronary events; Those in the 5th quintile of n-3 intake had significantly lower HRs of coronary heart disease (HR=0.58, 95% CI 0.35-0.97), total MI (HR=0.43, 95% CI 0.24-0.78), definite MI (HR=0.35, 95% CI 0.18-0.66), and nonfatal coronary heart disease (HR=0.33, 95% CI 0.17-0.63) than those in the 1st quintile; Those in the 4th quintile of n-3 intake had a significantly lower HR of nonfatal coronary events (HR=0.57, 95% CI 0.34-0.98) than those in the 1st quintile. However, there were no significant associations found between n-3 intake and coronary heart disease, total MI, or definite MI, sudden cardiac death, or fatal coronary events when comparing the 4th quintile to the 1st quintile; and Those in the 3rd quintile of n-3 intake had significantly lower HRs of definite MI (HR=0.59, 95% CI 0.37-0.94) and nonfatal coronary events (HR=0.61, 95% CI 0.38-0.97) than those in the 1st quintile. However, there were no significant associations found between n-3 intake and coronary heart disease, total MI, sudden cardiac death, or fatal coronary events when comparing the 3rd quintile to the 1st quintile. |
B |
Amount |
Results |
Conclusion** |
Categories of fish intake (tuna/other or fried fish/fish sandwich): 1 = <1 time/month 2 = 1-3 times/month 3 = 1-4 times/week 4 = ≥5 times/week |
After adjusting for age, gender, race, education, diabetes, BMI, prevalent coronary heart disease, prevalent valvular heart disease, smoking status, pack-years of smoking, leisure-time activity, total caloric intake, alcohol, saturated fat, beef/pork, fruits, vegetables, cereal fiber, systolic blood pressure, diastolic blood pressure, left ventricular systolic function at baseline, treated hypertension, C-reactive protein: Those who ate tuna/other fish 1-4 times/week or ≥5 times/week had significantly lower HR of atrial fibrillation than those who ate tuna/ other fish <1 time/month (HR=0.72, 95% CI 0.57-0.90 and HR=0.70, 95% CI 0.53-0.93, respectively). Those who ate tuna/other fish 1-3 times/month also had a lower HR of atrial fibrillation than those who ate tuna/other fish <1 time/month, but it was not significant. There was no significant association found between fried fish/fish sandwich intake and the risk of atrial fibrillation. |
B |
Amount |
Results |
Conclusion** |
Categories of fish intake (tuna/other or fried fish/fish sandwich): 1 = <1 time/month 2 = 1-3 times/month 3 = 1 time/week 4 = 2 times/week 5 = ≥3 times/week |
After adjusting for age, gender, education, diabetes, current smoking, pack-years of smoking, BMI, systolic blood pressure, LDL-C, HDL-C, triglycerides, C-reactive protein, and intake of saturated fat, alcohol, beef/pork, fruits, and vegetables: Those who ate tuna/other fish 2 times/week and ≥3 times/week had a significantly lower RR of total IHD death than those who ate tuna/other fish <1 time/month (RR=0.53, 95% CI 0.30-0.96 and RR=0.47, 95% CI 0.27-0.82, respectively). Those who ate tuna/other fish 1-3 times/month and 1 time/week also had lower RR of total IHD death compared to those who ate tuna/other fish <1 time/month, but they were not significant; Those who ate tuna/other fish ≥3 times/week had a significantly lower RR of arrhythmic IHD death than those who ate tuna/other fish <1 time/month (RR=0.32, 95% CI 0.15-0.70). The other categories of intake also showed lower RR of arrhythmic IHD death compared to the 1st category of intake but they were not significant; and There were no significant associations found between tuna/other fish intake and nonfatal MI and between fried fish/fish sandwiches and total IHD death, arrhythmic IHD death, or nonfatal MI. After adjusting for age, gender, education, diabetes, current smoking, and pack-years of smoking: Those who ate tuna/other fish ≥3 times/week had a significantly lower RR of total IHD death and arrhythmic IHD death than those who ate tuna/other fish <1 time/month (RR=0.51, 95% CI 0.31-0.83 and RR=0.42, 95% CI 0.21-0.84, respectively). There were no other significant associations found between the other categories of tuna/other fish intake and the risk of death from total IHD, arrhythmic IHD, or nonfatal MI; and Those who ate fried fish/fish sandwiches ≥3 times/week had a significantly higher RR of nonfatal MI death than those who ate fried fish/fish sandwiches <1 time/month (RR=2.30, 95% CI 1.18-4.46). There were no other significant associations found between the other categories of fried fish/fish sandwich intake and the risk of death from total IHD, arrhythmic IHD, or nonfatal MI. |
B |
Author |
Study Type |
Subjects |
Exposure |
Osler et al., 2003 |
Cohort |
Men (n=4513) Women (n=3984) Aged 30-70 years Copenhagen County, Denmark general population MONICA 1 = born in 1922, 1932, 1942, or 1952; examined in 1982 MONICA 2 = born in 1927, 1937, 1947, or 1957; examined in 1987 MONICA 3 = born in 1922, 1932, 1942, 1952, or 1962; examined in 1992 No CHD in the preceding 5 years before enrollment (fatal or nonfatal CHD as an end point) 52,607 person-years of follow-up for men 48,596 person-years of follow-up for women Primary prevention |
Seafood |
Amount |
Results |
Conclusion** |
Categories of fish intake: 1 = Never 2 = ≤1 time/month 3 = 2 times/month 4 = 1 time/week 5 = ≥2 times/week |
After adjusting for smoking status, physical activity, alcohol, educational status, healthy diet score, total cholesterol, total cholesterol, BMI: Those who consumed fish 2 times/month had a significant lower HR of all-cause mortality compared to those who ate fish 1 time/week (HR=0.84, 95% CI 0.73-0.96). No other significant differences were found between categories of fish consumption and all-cause mortality, CHD mortality and morbidity, and CHD mortality. |
B |
Author |
Study Type |
Subjects |
Exposure |
Hu et al., 2002 |
Cohort |
Women (n=84,688) Aged 30-55 years Nurses living in the United States Nurses’ Health Study Exclude those who left 10 or more items blank on the dietary questionnaire, those with reported total food intakes judged to be implausible, and those who had a history of cancer, angina, myocardial infarction, coronary revascularization, stroke, or other cardiovascular disease at baseline Follow-up of 16 years Primary prevention |
Seafood |
Amount |
Results |
Conclusion** |
Serving sizes: Dark-meat fish = 3-5 oz (1.51 g EPA/DHA) Canned tuna = 3-4 oz (0.42 g EPA/DHA) Other fish = 3-5 oz (0.48 g EPA/DHA) Shrimp/lobster/scallops = 3.5 oz (0.32 g EPA/DHA) Categories of fish intake: 1 = <1 time/month 2 = 1-3 times/month 3 = 1 time/week 4 = 2-4 times/week 5 = ≥5 times/week |
After adjusting for age, time periods, smoking status, BMI, alcohol intake, menopausal status and postmenopausal hormone use, vigorous to moderate activity, number of times aspirin was used per week, multivitamin use, vitamin E supplement use, history of hypertension, hypercholesterolemia, diabetes, and intake of transfat, the ratio of polyunsaturated fat to saturated fat, and dietary fiber: Those in categories 2-5 of fish intake all had significantly lower RR of coronary heart disease compared to those in category 1 (RR=0.79, 95%CI 0.64-0.97; RR=0.72, 95% CI 0.59-0.88; RR=0.72, 95% CI 0.57-0.91; RR=0.69, 95% CI 0.52-0.93, respectively) (p for trend = 0.007); Those in categories 3 and 5 of fish intake had significantly lower RR of fatal CHD compared to those in category 1 (RR=0.65, 95% CI 0.46-0.91 and RR=0.55, 95% CI 0.33-0.91, respectively). Those in categories 2 and 4 also had lower RRs but they were not significant (p for trend = 0.01); and Those in categories 3 and 4 had significantly lower RR of nonfatal MI compared to those in category 1 (RR=0.75, 95% CI 0.59-0.96 and RR=0.71, 95% CI 0.53-0.96, respectively). Those in categories 2 and 5 also had lower RRs but they were not significant (p for trend = 0.10); and Similar results were found when the model did not also adjust for intake of transfat, the ratio of polyunsaturated fat to saturated fat, and dietary fiber. |
B |
Amount |
Results |
Conclusion** |
Quintiles of fish intake (median g/day): Quintile 1 = 46.2 for men, 36.6 for women Quintile 2 = 68.1 for men, 53.9 for women Quintile 3 = 86.8 for men, 68.8 for women Quintile 4 = 111.9 for men, 88.1 for women Quintile 5 = 157.8 for men, 122.4 for women Quintiles of fish oil intake (medium mg/day): Quintile 1 = 410 for men, 332 for women Quintile 2 = 602 for men, 486 for women Quintile 3 = 788 for men, 635 for women Quintile 4 = 1051 for men, 832 for women Quintile 5 = 1582 for men, 1253 for women |
After adjusting for age, total energy intake, marital status, BMI, smoking status, alcohol intake, coffee intake, exercise, and history of hypertension and diabetes mellitus: There were no significant associations between quintiles of fish intake and risk of all-cause mortality among men or women; Men in the 2nd quintile of fish oil intake had a significantly lower HR of all-cause mortality than men in the 1st quintile of fish oil intake (HR=0.82, 95% CI 0.67-0.99). Men in the higher quintiles of fish oil intake also had lower HR of all-cause mortality compared to men in the 1st quintile of fish oil intake, but they were not significant; and Women in the 5th quintile of fish oil intake had a significantly lower HR of all-cause mortality than women in the 1st quintile of fish oil intake (HR=0.77, 95% CI 0.62-0.94). Women in the other quintiles of fish oil intake also had lower HR of all-cause mortality compared to women in the 1st quintile of fish oil intake, but they were not significant. There were no significant associations found between quintiles of fish oil intake and cardiovascular disease mortality among men or women. |
N |
Amount |
Results |
Conclusion** |
Fresh fish = 0.57 g n-3 fatty acids/100 g Salted fish = 0.44 g n-3 fatty acids/100 g Shellfish = 0.36 g n-3 fatty acids/100 g Fish and shellfish categories (g/week): 1 = <50 (<1 serving/week) 2 = 50-<100 (1 serving/week) 3 = 100-<150 (2 servings/week) 4 = 150-<200 (3 servings/week) 5 = ≥200 (≥4 servings/week) Quintiles of n-3 fatty acid intake (g/week): 1 = <0.27 2 = 0.27-0.43 3 = 0.44-0.72 4 = 0.73-1.09 5 = ≥1.10 |
After controlling for age, total energy intake, level of education, BMI, current smoker at recruitment, average number of cigarettes smoked/day, number of alcoholic drinks consumed/week, history of diabetes, and history of hypertension: Those in the 2nd and 5th categories of fish/shellfish intake had significantly lower RR of acute myocardial infarction mortality than those in the 1st category (RR=0.55, 95% CI 0.33-0.91 and RR=0.41, 95% CI 0.22-0.78, respectively) (p for trend = 0.03). Similar results were found for the categories of fish only, but there were no associations found between shellfish only and risk of acute myocardial infarction mortality; and Those in the 2nd, 4th, and 5th quintiles of n-3 fatty acid intake had significantly lower RR of acute myocardial infarction mortality than those in the 1st quintile (RR=0.39, 95% CI 0.20-0.75; RR=0.53, 95% CI 0.29-0.97; RR=0.43, 95% CI 0.23-0.81, respectively). Those in the 3rd quintile also had a lower RR compared to the 1st quintile, but it was not significant (RR=0.67, 95% CI 0.42-1.08). There were no significant associations between fish intake and other ischemic heart disease mortality or stroke mortality or between n-3 fatty acid intake and other ischemic heart disease mortality. |
B |
Author |
Study Type |
Subjects |
Exposure |
Gillum et al., 2000 |
Cohort |
Men and women (n=8825) White (n=7421) Black (n=1404) Aged 25-74 years US general population (civilian, non-institutionalized) excluding Alaska, Hawaii, and reservation lands of American Indians National Health and Nutrition Examination Survey (NHANES) I Epidemiologic Follow-up Study No history of heart disease at baseline No unknown baseline fish consumption, systolic blood pressure, serum cholesterol concentration, history of diabetes, cigarette smoking status, alcohol intake, body mass index, history of heart disease, nonrecreational physical activity, or educational attainment Average follow-up of 18.8 years Primary prevention |
Seafood |
Oomen et al., 2000 |
Cohort |
Men Aged 50-69 years Finland (n=1088), Italy (n=1097), Netherlands (n=553) cohorts of the Seven Countries Study Free of CHD at baseline Follow-up of 20 years Primary prevention |
Seafood |
Amount |
Results |
Conclusion** |
Categories of fish consumption: 1 = Never 2 = <1 occasion/week 3 = 1 occasion/week 4 = >1 occasion/week |
After adjusting for baseline age, smoking, history of diabetes, education <high school graduate, systolic blood pressure, serum cholesterol concentration, BMI, alcohol intake, and physical activity: Among White men, those who ate fish 1 occasion/week had a significantly lower RR of all-cause mortality (RR=0.76, 95% CI 0.63-0.91) and noncardiovascular disease mortality (RR=0.68, 95% CI 0.53-0.88) compared to those who never ate fish. No other comparisons between categories of fish consumption, and all-cause, cardiovascular disease, or noncardiovascular disease, mortality were significant; There were no significant associations found between fish intake and all-cause, cardiovascular disease, and noncardiovascular disease mortality among Black men, White women, or Black women; and There were no significant associations found between fish intake and incidence of coronary heart disease among White or Black men or women. |
B |
Finland fish consumption: 1 = 0-19 g/day 2 = 20-39 g/day 3 = ≥40 g/day Italy fish consumption: 1 = 0 g/day 2 = 1-19 g/day 3 = 20-39 g/day 4 = ≥40 g/day Netherlands fish consumption: 1 = 0 g/day 2 = 1-19 g/day 3 = ≥20 g/day |
After adjusting for age, BMI, cigarette smoking, and intake of energy, vegetables, fruit, alcohol, meat, butter, and margarine, there were no significant associations found between total fish consumption and the risk of 20-year CHD mortality in any of the three countries. Similar results were found when the model did not adjust for intake of vegetables, fruit, alcohol, meat, butter, and margarine. After stratifying by country cohort and pooling the data, the overall RR for CHD mortality for intake of 1-19 g/day of fatty fish was 0.57 (95% CI 0.40-0.80) and for intake of ≥20 g/day of fatty fish was 0.87 (95% CI 0.59-1.27) compared to no fatty fish consumption. |
N |
Author |
Study Type |
Subjects |
Exposure |
Albert et al., 1998 |
Cohort |
Men (n=20,551) Aged 40-84 years US physicians Physicians’ Health Study Free of MI, stroke, transient ischemic attack, or cancer at baseline 2-by-2 factorial design to receive aspirin, beta carotene, both active drugs, or both placebo 11 years of follow-up (253,777 person-years) Primary prevention |
Seafood |
Amount |
Results |
Conclusion** |
Categories of fish intake: <1 meal per month 1-3 meals per month 1-<2 meals per week 2-5 meals per week ≥5 meals per week |
After adjusting for age, those who ate fish 1-<2 meals per week, 2-<5 meals per week, and ≥5 meals per week had a significantly lower RR of sudden death than those who ate fish only <1 per month (RR=0.42, 95% CI 0.21-0.88; RR=0.46, 95% CI 0.23-0.93; RR=0.34, 95% CI 0.14-0.83, respectively) (p for trend = 0.03). After combining the higher quartiles of fish consumption, those who ate fish ≥1 per week had a significantly lower relative risk of sudden death than those who ate fish only <1 per month (RR=0.44, 95% CI 0.22-0.86) (p for trend = 0.006). After adjusting for age, aspirin, and beta carotene treatment assignment, evidence of cardiovascular disease prior to 12-month questionnaire, BMI, smoking status, history of diabetes, history of hypertension, history of hypercholesterolemia, alcohol consumption, vigorous exercise, and vitamin E, vitamin C, and multivitamin use: Those who ate fish 1-<2 meals per week and ≥5 meals per week had a significantly lower RR of sudden death than those who ate fish only <1 per month (RR=0.47, 95% CI 0.23-0.98 and RR=0.39, 95% CI 0.15-0.96, respectively) (p for trend = 0.11); and After combining the higher quartiles of fish consumption, those who ate ≥1 fish meal per week had a significantly lower RR of sudden death than those who ate only <1 fish meal per month (RR=0.48, 95% CI 0.24-0.96) (p for trend = 0.03). |
B |
Author |
Study Type |
Subjects |
Exposure |
Daviglus et al., 1997 |
Cohort |
Men (n=1822) Aged 40-55 years Chicago, IL Employed for at least 2 years at the Western Electric Company Hawthorne Works in Chicago; occupations related to manufacturing telephones Chicago Western Electric Study Free of CVD at baseline Follow-up of 30 years Primary prevention |
Seafood |
Mann et al., 1997 |
Cohort |
Men (n=4102) Women (n=6700) Vegetarians and their nonvegetarian friends and family Aged 16-79 years UK No cancer at entry Excluded those who failed to provide full information concerning smoking habits, height, weight, and employment category Follow-up of 13.3 years (over 143,000 person-years) Primary prevention |
Seafood |
Rodriquez et al., 1996 |
Cohort |
Men (n=3310) Aged 45-68 years Oahu, Hawaii Japanese ancestry Current smokers Honolulu Heart Program Free of CHD, stroke, cancer at baseline Follow-up of 23 years Primary prevention |
Seafood |
Amount |
Results |
Conclusion** |
Categories of fish intake: 1 = 0 g/day 2 = 1-17 g/day 3 = 18-34 g/day 4 = ≥35 g/day |
After controlling for baseline age and education, religion, systolic blood pressure, serum cholesterol, number of cigarettes smoked per day, BMI, presence or absence of diabetes, presence or absence of electrocardiographic abnormalities, and daily intake of energy, cholesterol, saturated, monounsaturated, and polyunsaturated fatty acids, total protein, carbohydrate, alcohol, iron, thiamine, riboflavin, niacin, vitamin C, beta carotene, and retinol: Those who consumed fish had a lower relative risk of death from MI, CVD, CHD, and all causes. However, the only significant differences were between the 4th category of fish consumption compared to the 1st category for death from overall MI (RR=0.56, 95% CI 0.33-0.93), all CHD (RR=0.62, 95% CI 0.40-0.94), and nonsudden death from MI (RR=0.33, 95% CI 0.12-0.91). |
B |
Categories of fish intake: 1 = None 2 = <1 time/week 3 = ≥1 time/week |
After adjusting for age, sex, smoking, and social class, there were no significant associations found between fish intake and the risk of death from ischemic heart disease or all causes (for those with no evidence of preexisting disease at the time of recruitment). |
N |
Categories of fish intake: 1 = Almost never 2 = <2 times/week 3 = 2-4 times/week 4 = Almost daily 5 = >1 time/day Low = <2 times/week High = ≥2 times/week |
After adjusting for age, years lived in Japan, total calories/day, alcohol intake, physical activity, years smoked, hypertension, and serum cholesterol, glucose, and uric acid levels: In the high-smoking group, those with high fish intake had a significantly lower risk of CHD mortality compared to those with low fish intake (RR=0.5, 95% CI 0.28-0.91). There was no significant association found between fish intake and CHD mortality among past smokers (p=0.6). |
N |
Author |
Study Type |
Subjects |
Exposure |
Ascherio et al., 1995 |
Cohort |
Men (n=44,895) Aged 40-75 years US health professionals Health Professional Follow-up Study Free of known CVD at baseline; no previous diagnosis of MI, angina, stroke, transient ischemic attack, peripheral arterial disease, or had undergone coronary artery surgery 6 years of follow-up (242,029 person-years) Primary prevention |
Seafood |
Amount |
Results |
Conclusion** |
Quintiles of n-3 fatty acids (g/day): 0.01-0.11, 0.12-0.19, 0.20-0.28, 0.29-0.41, 0.42-6.52 Category of fish intake: 1 = <1 time/month 2 = 1-3 times/month 3 = 1 time/week 4 = 2-3 times/week 5 = 4-5 times/week 6 = ≥6 times/week |
There were no significant associations found between dietary intake of n-3 fatty acids and the risk of coronary artery bypass grafting, nonfatal MI, fatal CHD, any MI, or any CHD. After controlling for age, those in the 4th category of fish intake had a significantly lower RR of nonfatal MI compared to those in the 1st category (RR=0.65, 95% CI 0.45-0.94). Those in the 2nd, 4th, and 5th categories of fish intake had significantly lower RR of any MI compared to those in the 1st category (RR=0.67, 95% CI 0.46-0.99; RR=0.69, 95% CI 0.51-0.94; RR=0.65, 95% CI 0.47-0.92, respectively). After controlling for age, BMI, smoking habits, alcohol consumption, history of hypertension, history of diabetes, history of hypercholesterolemia, family history of MI before 60 years of age, and profession: Those in the 5th and 6th categories of fish intake had a significantly higher RR of coronary artery bypass grafting than those in the 1st category (RR=1.71, 95% CI 1.09-2.68 and RR=1.65, 95% CI 1.03-2.64, respectively); Those in the 2nd and 4th categories of fish intake had a significantly lower RR of nonfatal MI than those in the 1st category (RR=0.62, 95% CI 0.39-1.00 and RR=0.67, 95% CI 0.46-0.97, respectively); Those in the 5th category of fish intake had a significantly lower relative risk of fatal CHD than those in the 1st category (RR=0.54, 95% CI 0.29-1.00); Those in the 2nd, 4th, and 5th categories of fish intake had a significantly lower RR of any MI than those in the 1st category (RR=0.66, 95% CI 0.44-0.97; RR=0.69, 95% CI 0.51-0.94; RR=0.65, 95% CI 0.46-0.92, respectively); and No other significant associations were found between fish intake and CHD. |
B |
Author |
Study Type |
Subjects |
Exposure |
Kromhout et al., 1995 |
Cohort |
Men (n=137) Women (n=135) Aged 64-87 years for men Aged 64-85 years for women Rotterdam, Netherlands All patients of the same general practice Follow-up of 17 years Primary prevention |
Seafood |
Salonen et al., 1995 |
Cohort |
Men (n=1833) Aged 42, 48, 54, or 60 years Eastern Finland Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) No CHD, history of cerebrovascular stroke, claudication, or cancer at baseline Mean follow-up time for AMI for individuals of 5 years Mean follow-up time for death of 6 years Primary prevention |
Seafood |
Amount |
Results |
Conclusion** |
Fish intake = yes or no |
After adjusting for age, gender, prevalence of MI and angina pectoris, systolic blood pressure, total cholesterol, smoking, alcohol and energy intake/body weight, those who ate fish had a significant lower RR of CHD mortality than those who did not eat fish (RR=0.51, 95% CI 0.29-0.89). The difference in CHD mortality between the fish eaters and the non-fish eaters became apparent after 5 years of follow-up. |
B |
Continuous variable = g/day Binary variable = <30 or ≥30 g/day |
After adjusting for age, examination year, ischemic exercise ECG, and maximal oxygen uptake, family history of CHD, cigarette-years, mean systolic blood pressure, diabetes, socioeconomic status, place of residence, dietary iron intake, and serum apolipoprotein B, HDL-cholesterol, and ferritin concentrations: Each one unit (g/day) increase in fish intake significantly increased the risk of fatal or non-fatal AMI (RR=1.004, 95% CI 1.001-1.007). There were no significant associations between fish intake (as a continuous variable) and death from CHD, CVD, or all causes; and Those who consumed ≥30 g/day of fish had a significantly higher risk of fatal or nonfatal AMI compared to those who consumed >30 g/ day (RR=1.87, 95% CI 1.13-3.09). There was no significant association found between fish intake ≥30 g/day and CHD, CVD, or all-cause mortality. Similar results were found when the model only adjusted for age, examination year, ischemic exercise ECG, and maximal oxygen uptake. |
A |
Author |
Study Type |
Subjects |
Exposure |
Dolecek, 1992 |
Cohort (nested in an RCT) |
Men (n=6250) Aged 35-57 years 22 US clinical centers Multiple Risk Factor Intervention Trial (MRFIT) Only included those in the usual care group for this analysis At high risk of developing CHD because of smoking status, diastolic blood pressure, and serum cholesterol levels Follow-up of 10.5 years Primary prevention |
Seafood |
Fraser et al., 1992 |
Cohort |
Men and women (n=26,473) Mean age 51 years (men) Mean age 53 years (women) California Non-Hispanic White Adventists The Adventist Health Study No history of heart disease or diabetes at baseline; almost no current smokers (although some past smokers) Follow-up of 6 years Primary prevention |
Seafood |
Amount |
Results |
Conclusion** |
Quintiles of fish n-3s: Quintile 1 = mean of 0.000 g Quintile 2 = mean of 0.009 g Quintile 3 = mean of 0.046 g Quintile 4 = mean of 0.153 g Quintile 5 = mean of 0.664 g |
After adjusting for age, race, smoking, baseline diastolic blood pressure, high density lipoprotein, low density lipoprotein, and alcohol: A one-unit increase in fish n-3 consumption, expressed in grams, significantly decreased one’s risk of CVD mortality (β=−0.9598, p<0.01) and CHD mortality (β=−0.93388, p<0.05); however there were no significant associations found between fish n-3 consumption and risk of mortality from cancer or all causes; and A one-unit increase in fish n-3 consumption, expressed as % kcal, significantly decreased one’s risk of CVD mortality (β=−0.4499, p<0.01), CHD mortality (β=−0.4715, p<0.05), and all-cause mortality (β=−0.2590, p<0.05); however there was no significant association found between fish n-3 consumption and risk of mortality from cancer. |
B |
Categories of fish intake: 1 = None 2 = 0<x<1 time/week 3 = ≥1 time/week |
After stratifying for age, sex, smoking, exercise, relative weight, and high blood pressure, no significant RRs were found for definite nonfatal MI, definite fatal CHD, or fatal CHD as determined by death certificate, based on fish intake. However, there seemed to be a trend of lower RRs for higher intakes of fish. |
N |
Amount |
Results |
Conclusion** |
Categories of fish intake: 1 = 0 g/day 2 = 1-14 g/day 3 = 15-29 g/day 4 = 30-44 g/day 5 = ≥45 g/day |
After adjusting for age, systolic blood pressure, serum total cholesterol, cigarette smoking, subscapular skinfold thickness, physical activity, energy intake, dietary cholesterol, prescribed diet, and occupation: Those in category 4 of fish intake had a significantly lower RR of death from coronary heart disease than those in the 1st category (RR=0.36, 95% CI 0.14-0.93); and Those in the 2nd, 3rd, and 5th fish consumption categories also had lower RRs of death from coronary heart disease than those in the 1st category, but they were not significant (p for trend = <0.05). |
B |
Author |
Study Type |
Subjects |
Exposure |
Albert et al., 2002 |
Case-control (nested) |
Cases (n=94) = sudden death occurred (first manifestation of CVD) Controls (n=184) = free of confirmed CVD Men Aged 40-84 years US physicians Physicians’ Health Study Free of MI, stroke, transient ischemic attacks, or cancer at baseline 2-by-2 factorial design to receive aspirin, beta carotene, both active drugs, or both placebo 17 years of follow-up (time from study enrollment to sudden death = 0.7-16.9 years) Primary prevention |
Baseline blood fatty acid levels |
Amount |
Results |
Conclusion** |
Quartiles of n-3 fatty acids (% total fatty acids): 2.12-4.32, 4.33-5.19, 5.20-6.07, 6.08-10.2 |
After adjusting for age and smoking status: The RR of sudden death was significantly lower for those in the 3rd and 4th quartiles of n-3 fatty acid intake (RR=0.37, 95% CI 0.17-0.83 and RR=0.31, 95% CI 0.13-0.75, respectively) compared to those in the 1st quartile (p for trend = 0.004). After adjusting for assignment to aspirin and beta carotene treatment or placebo, BMI, history of diabetes, history of hypertension, history of hypercholesterolemia, alcohol consumption, frequency of vigorous exercise and parental history of MI before the age of 60: The RR of sudden death was significantly lower for those in the 3rd and 4th quartiles of n-3 fatty acid intake (RR=0.28, 95% CI 0.09-0.87 and RR=0.19, 95% CI 0.05-0.71, respectively) compared to those in the 1st quartile (p for trend = 0.007). After adjusting for assignment to aspirin and beta carotene treatment or placebo, BMI, history of diabetes, history of hypertension, history of hypercholesterolemia, alcohol consumption, frequency of vigorous exercise, parental history of myocardial infarction before the age of 60, trans unsaturated fatty acid and monounsaturated fatty acid levels: The RR of sudden death was significantly lower for those in the 3rd and 4th quartiles of n-3 fatty acids (RR=0.19, 95% CI 0.05-0.69 and RR=0.10, 95% CI 0.02-0.48, respectively) compared to those in the 1st quartile (p for trend = 0.001). |
B |
Author |
Study Type |
Subjects |
Exposure |
Martinez-Gonzalez et al., 2002 |
Case-control |
Cases = suffered first definite AMI; admitted to hospital (n=171) Controls = admitted to same hospital during same month for unrelated conditions (n=171) Men and women Aged <80 years Three tertiary hospitals of Pamplona, Spain No history of angina pectoris, a previous diagnosis of CHD, or other prior diagnosis of major cardiovascular disease Secondary prevention |
Seafood |
Sasazuki et al., 2001 |
Case-control |
Cases = first episode of AMI (n=632) Controls = residents from same municipalities as the cases (n=1214) Men and women Aged 40-79 years 22 collaborating hospitals in Fukuoka City, Japan, and in 21 adjacent municipalities Fukuoka Heart Study Secondary prevention |
Seafood |
Amount |
Results |
Conclusion** |
Categories of fish intake: 1 = <60 g/day 2 = 60-77 g/day 3 = 77-106 g/day 4 = 106-142 g/day 5 = >142 g/day |
After adjusting for age, hospital, gender, smoking, BMI, high blood pressure, high blood cholesterol, diabetes, leisure-time physical activity, socioeconomic status, and total energy: Those in the 3rd and 5th categories of fish intake had significantly lower ORs of first MI compared to those in the 1st category (OR=0.28, 95% CI 0.10-0.77 and OR=0.31, 95% CI 0.11-0.85, respectively). Those in the 2nd and 4th categories of fish intake also had lower ORs compared to those in the 1st category, but they were not significant. Those in the three upper quintiles of fish intake had a significantly lower OR of a first MI compared to those in the lower quintile (OR=0.36, 95% CI 0.15-0.87). After further adjusting for olive oil, fiber, fruits, vegetables, alcohol, meat/meat products, and white bread/ rice/pasta intake, this association was not significant (OR=0.37, 95% CI 0.13-1.03). |
B |
Categories of fish consumption (men and women): Low = <2/week Intermediate = 2-3/week High = 4+/week |
After adjusting for smoking, alcohol use, sedentary job, leisure-time physical activity, hyperlipidemia, hypertension, diabetes mellitus, angina pectoris, and obesity: Men who consumed intermediate and high levels of fish had a significantly lower RR of acute MI compared to those who consumed low levels of fish (RR=0.5, 95% CI 0.3-0.8 and RR=0.6, 95% CI 0.4-0.9, respectively); and The relative risks for acute MI based on fish consumption were not significant among women. Similar results were found when also adjusting for fruit and tofu intake. |
B |
Author |
Study Type |
Subjects |
Exposure |
Tavani et al., 2001 |
Case-control |
Cases = first episode of nonfatal AMI; admitted to hospital (n=507) Controls = admitted to same hospital for unrelated conditions (n=478) Men and women Aged 25-79 years Greater Milan, Italy area Secondary prevention |
Seafood |
Siscovick et al., 1995 |
Case-control |
Case = primary cardiac arrest patients (n=334) Controls = from community (n=493) Men and women Aged 25-74 years Married Seattle and suburban King County, WA Free of prior clinical heart disease, major comorbidities, and use of fish-oil supplements On average, 4 months between the date of cardiac arrest and in-person interview Primary prevention |
Seafood |
Amount |
Results |
Conclusion** |
Mixed Mediterranean fish = 0.94 g of n-3 per portion Other fish = 0.49 g of n-3/portion Canned tuna, mackerel, and sardines = 0.34 g of n-3/portion Categories of n-3 PUFA: Lowest = <0.81 g/week Intermediate = 0.81-1.28 g/week Highest = >1.28 g/week Categories of total fish and fresh fish: 1 = <1 portion/week 2 = 1-<2 portions/week 3 = ≥2 portions/week Categories of canned fish: 1 = 0 portions/week 2 = >0-<1 portion/week 3 = ≥1 portion/week |
After adjusting for age; sex; education; BMI; cholesterol; smoking; coffee, alcohol, meat, vegetables, fruit, and calorie intake; physical activity; hyperlipidemia; diabetes; hypertension; and family history of AMI in first-degree relative: Those who consume an intermediate or high level of n-3 PUFAs had a significantly lower OR of AMI compared to those who consumed a low level of n-3 PUFAs (OR=0.67, 95% CI 0.47-0.96 and OR=0.67, 95% CI 0.47-0.95, respectively). Those who consume two or more portions of total fish/week had a significantly lower OR of AMI compared to those who consume less than one portion/week (OR=0.68, 95% CI 0.47-0.98). Those who consume 1-<2 portions/week of total fish also had a lower OR of AMI than those who consume <1 portion/week, but it was not significant. There were no significant associations found between fresh fish intake and canned fish intake and the risk of AMI. Similar results were found when the model only adjusted for age and sex. |
B |
Average serving size = 3 oz of fish Quartiles of n-3 fatty acids (g/month): Quartile 1 = 0.12-1.95 Quartile 2 = 1.96-4.05 Quartile 3 = 4.06-7.40 Quartile 4 = 7.41-42.72 |
After adjusting for age, current smoking, former smoking, family history of MI or sudden death, fat intake scale, hypertension, diabetes mellitus, physical activity, weight, height, and education: Those in quartiles 2, 3, and 4 of dietary n-3 fatty acid intakes all had significantly lower ORs of primary cardiac arrest compared to those who never consumed fish (OR=0.7, 95% CI 0.6-0.9; OR=0.5, 95% CI 0.4-0.8; OR=0.4, 95% CI 0.2-0.7, respectively). Those in the 1st quartile also had a lower OR of primary cardiac arrest compared to those who never consumed fish, but it was not significant. |
B |
Author |
Study Type |
Subjects |
Exposure |
Gramenzi et al., 1990 |
Case-control |
Cases = an acute MI (n=287) Controls = acute disorders unrelated to ischemic heart disease (n=649) Women Aged 22-69 years for cases Aged 21-69 years for controls 30 hospitals in northern Italy No chronic or digestive conditions; cardiovascular, malignant, hormonal, or gynecological disease; or any disorder that was potentially related to consumption of alcohol or smoking Primary prevention |
Seafood |
Amount |
Results |
Conclusion** |
Tertiles of fish intake (# portions/week): Tertile 1 = <1 Tertile 2 = 1 Tertile 3 = >1 |
After adjusting for age, area of residence, education, smoking, hyperlipidemia, diabetes, hypertension, and BMI, the OR for MI was 0.8 for the 2nd tertile of fish intake and 0.7 for the 3rd tertile of fish intake, compared to the 1st tertile (p<0.05). After adjusting for age, area of residence, education, smoking, hyperlipidemia, diabetes, hypertension, BMI, carrots, green vegetables, fresh fruit, meat, ham and salami, butter, total fat score, coffee, and alcohol, the OR for MI was 1.0 for the 2nd tertile of fish intake and 0.8 for the 3rd tertile of fish intake, compared to the 1st tertile, and they were not significant. |
B |
Amount |
Results |
Conclusion** |
Total lipids (g/L±SD): Eskimo men = 6.17±0.89 Eskimo women = 6.13±0.88 Danish men = 7.12±1.24 Danish women = 7.29±1.16 Cholesterol (g/L±SD): Eskimo men = 2.33±0.35 Eskimo women = 2.22±0.43 Danish men = 2.73±0.49 Danish women = 2.86±0.49 Triglycerides (g/L±SD): Eskimo men = 0.57±0.28 Eskimo women = 0.44±0.13 Danish men = 1.29±0.62 Danish women = 1.08±0.51 Pre-β-lipoproteins (g/L±SD): Eskimo men = 0.48±0.31 Eskimo women = 0.43±0.33 Danish men = 1.70±0.86 Danish women = 1.08±0.51 β-lipoproteins (g/L±SD): Eskimo men = 4.38±0.93 Eskimo women = 4.45±0.89 Danish men = 5.11±1.16 Danish women = 5.31±1.32 α-lipoproteins (g/L±SD): Eskimo men = 4.02±1.39 Eskimo women = 3.91±1.41 Danish men = 2.78±0.82 Danish women = 3.64±0.94 |
Among males, the Eskimos had significantly lower plasma total lipids (p<0.001), cholesterol (p<0.001), triglycerides (p<0.001), pre-β-lipoproteins (p<0.001), β-lipoproteins (p<0.001), and α-lipoproteins (p<0.001) compared to the Danes. However, the differences in total lipids and cholesterol among men 31-40 years and β-lipoproteins among men 31-50 years between the Eskimos and the Danes were not significant. Among women, the Eskimos had significantly lower plasma total lipids (p<0.001), cholesterol (p<0.001), triglycerides (p<0.001), pre-β-lipoproteins (p<0.001), and β-lipoproteins (p<0.001). However, the difference in β-lipoproteins among women 31-50 years between the Eskimos and the Danes was not significant. There were no significant differences in α-lipoproteins among the female Eskimos and Danes. |
B |
**N = Evidence of no association or no clear association; B = Evidence of a benefit; A = Evidence of an adverse effect. |
TABLE B-2b Studies on Stroke
Author |
Study Type |
Subjects |
Exposure |
Hooper et al., 2005 |
Cochrane Review |
48 RCTs At least 6 months of omega-3 fatty acids vs. placebo or control 26 cohorts (47 analyses) Follow-up of 4-25 years |
n-3 supplement |
Bouzan et al., 2005 |
Meta-analysis |
5 cohort studies 1 case-control study |
Seafood |
He et al., 2004a |
Meta-analysis |
9 cohorts (from 8 studies) English language |
Seafood |
Amount |
Results |
Conclusion** |
|
Based on RCTs, no significant association was found between omega-3 intake and risk of total stroke based on a meta-analysis (RR=1.17, 95% CI 0.91-1.51) or sensitivity analysis (RR=0.87, 95% CI 0.72-1.04). |
N |
Servings/week, a continuous variable |
In the linear regression model, for each one-unit increase in servings/week of fish, the change in the risk ratio of total stroke is −0.20 (95% CI −0.06 to 0.027), but this is not significant. In the quadratic regression model, for each one-unit increase in servings/week of fish, the change in the risk ratio of total stroke is 0.0037 (95% CI −0.0096 to 0.017), but this is not significant. |
N |
Categories of fish consumption: 1 = <1 time/month 2 = 1-3 times/month 3 = 1 time/week 4 = 2-4 times/week 5 = ≥5 times/week |
Based on pooled RRs, those who consumed fish 1 time/week, 2-4 times/week, and ≥5 times/week had significantly lower RR of stroke compared to those who consumed fish <1 time/month (RR=0.87, 95% CI 0.77-0.98; RR=0.82, 95% CI 0.72-0.94; and RR=0.69, 95% CI 0.54-0.88, respectively); the RR was not significant for those who consumed fish 1-3 times/month compared to those who consumed fish <1 time/month. Based on pooled RRs, those who consumed fish 1-3 times/month, 1 time/week, 2-4 times/week, and ≥5 times/week had significantly lower RR of ischemic stroke compared to those who consumed fish <1 time/month (RR=0.69, 95% CI 0.48-0.99; RR=0.68, 95% CI 0.52-0.88; RR=0.66, 95% CI 0.51-0.87; and RR=0.65, 95% CI 0.46-0.93, respectively). There were no significant associations found between fish consumption and hemorrhagic stroke. |
B |
Amount |
Results |
Conclusion** |
Categories of tuna/other fish intake: 1 = <1 time/month 2 = 1-3 times/month 3 = 1-4 times/week 4 = ≥5 times/week Categories for fried fish/fish sandwich intakes: 1 = <1 time/month 2 = 1-3 times/month 3 = ≥1 time/week |
After adjusting for age, sex, education, diabetes, coronary heart disease, smoking status, pack-years of smoking, aspirin use, BMI, leisure-time physical activity, alcohol use, total caloric intake, systolic blood pressure, LDL-c, HDL-c, triglyceride, and C-reactive protein levels: Those who consumed tuna/other fish 1-4 times/week had a significantly lower risk of total stroke and ischemic stroke compared to those who consumed tuna/other fish <1 time/month (HR=0.74, 95% CI 0.56-0.98 and HR=0.73, 95% CI 0.54-0.98, respectively). Those who consumed tuna/ other fish 1-3 times/month and ≥5 times/week also had lower risks of total stroke and ischemic stroke compared to those who consumed tuna/other fish <1 time/month, but they were not significant; Those who consumed fried fish/fish sandwiches ≥1 time/week had significantly higher risk of total stroke and ischemic stroke compared to those who consumed fried fish/fish sandwiches <1 time/month (HR=1.33, 95% CI 1.05-1.68 and HR=1.39, 95% CI 1.08-1.79, respectively); and There were no significant associations found between tuna/other fish intake or fried fish/fish sandwich intake and the risk of hemorrhagic stroke. |
B |
Author |
Study Type |
Subjects |
Exposure |
Sauvaget et al., 2003 |
Cohort |
Men (n=14,209) Women (n=22,921) Aged 34-103 years Nagasaki and Hiroshima, Japan The Life Span Study Atomic bomb survivors and their non-exposed controls No prevalent cases of cancer, self-reported cases of stroke, ischemic heart disease, and both stroke and ischemic heart disease Follow-up of 16 years |
Seafood |
Amount |
Results |
Conclusion** |
Categories of fish intake: 1 = Never 2 = ≤1 time/week 3 = 2-4 times/week 4 = Almost daily Tertiles of fish intake: Low = 11-18 g/day Moderate = 30 g/day High = 46-65 g/day |
After adjusting for sex, birth cohort, city, radiation dose, self-reported BMI, smoking status, alcohol habits, education level, history of diabetes, and hypertension: There was no significant association found between fish (except broiled) intake and the risk of total stroke mortality, when fish intake was defined as never, ≤1 time/week, 2-4 times/week, and almost daily; however, there was a significant trend (p=0.046); Those who ate broiled fish almost daily had a significantly lower RR of total stroke mortality compared to those who never ate broiled fish (HR=0.60, 95% CI 0.37-0.98); Those who ate moderate and high levels of fish products had significantly lower RRs of total stroke (RR=0.85, 95% CI 0.75-0.97 and RR=0.85, 95% CI 0.75-0.98, respectively) and intracerebral hemorrhage (RR=0.70, 95% CI 0.54-0.91 and RR=0.70, 95% CI 0.54-0.92, respectively) compared to those who ate low levels of fish products; and There were no significant associations between intake (defined as low, moderate, and high) of fish products and cerebral infarction. |
B |
Author |
Study Type |
Subjects |
Exposure |
He et al., 2002* |
Cohort |
Men (n=43,671) Aged 40-75 years US health professionals Health Professional Follow-up Study No previously diagnosed stroke, MI, coronary artery surgery, angina pectoris, peripheral arterial disease, diabetes mellitus, transient ischemic attack, or other cardiovascular disease Follow-up of 12 years |
Seafood and dietary n-3 fatty acid intake |
Amount |
Results |
Conclusion** |
Serving sizes: Dark-meat fish = 3-5 oz (1.60 g n-3) Canned tuna = 3-4 oz (0.41 g n-3) Other fish = 3-5 oz (0.56 g n-3) Shrimp/lobster/scallops = 3.5 oz (0.26 g n-3) Categories of fish intake: 1 = <1 time/month 2 = 1-3 times/month 3 = 1 time/week 4 = 2-4 times/week 5 = ≥5 times/week Quintiles of n-3 fatty acids: 1 = <0.05 g/day 2 = 0.05-<0.2 g/day 3 = 0.2-<0.4 g/day 4 = 0.4-<0.6 g/day 5 = ≥0.6 g/day |
After adjusting for BMI, physical activity, history of hypertension, smoking status, use of aspirin, fish oil, multivitamins, intake of total calories, total fat, saturated fat, trans-unsaturated fat, alcohol, potassium, magnesium, total servings of fruits and vegetables, and hypercholesterolemia at baseline: Those in the higher quintiles of cumulative fish consumption all had significantly lower RR of ischemic stroke compared to those who consumed fish <1 time/month (RR=0.57, 95% CI 0.35-0.95; RR=0.56, 95% CI 0.37-0.84; RR=0.55, 95% CI 0.36-0.85; and RR=0.54, 95% CI 0.31-0.94, respectively); Those in the 4th quintile of cumulative fish intake had a significantly lower RR of total stroke than those in the 1st quintile (RR=0.67, 95% CI 0.46-0.96). The other quintiles also had lower relative risks compared to the 1st quintile, but they were not significant; There were no significant associations found between cumulative fish intake and the risk of hemorrhagic stroke; similar results were found for most recent fish intake; Those in the 2nd, 3rd, and 4th quintiles of n-3 PUFA intake had significantly lower RRs of ischemic stroke compared to those in the first quintile (RR=0.56, 95% CI 0.35-0.88; RR=0.63, 95% CI 0.40-0.98; RR=0.54, 95% CI 0.32-0.91, respectively). Those in the 5th quintile also had a lower RR of ischemic stroke compared to those in the 1st quintile, but it was not significant; and There were no significant associations found between n-3 PUFA intake and total stroke or hemorrhagic stroke. |
B |
Author |
Study Type |
Subjects |
Exposure |
Iso et al., 2001* |
Cohort |
Women (n=79,839) Aged 34-59 years US nurses Nurses’ Health Study No history of cancer, angina, myocardial infarction, coronary revascularization, stroke, other cardiovascular diseases before baseline; or a history of physician-diagnosed diabetes or high serum cholesterol levels Follow-up of 14 years (1,086,261 person-years) |
Seafood and dietary n-3 fatty acid intake |
Amount |
Results |
Conclusion** |
Serving sizes: Dark-meat fish = 3-5 oz (1.51 g EPA/DHA) Canned tuna = 3-4 oz (0.42 g EPA/DHA) Other fish = 3-5 oz (0.48 g EPA/DHA) Shrimp/lobster/scallops = 3.5 oz (0.32 g EPA/DHA) Categories of fish intake: 1 = <1 time/month 2 = 1-3 times/month 3 = 1 time/week 4 = 2-4 times/week 5 = ≥5 times/week Quintiles of n-3 PUFAs (median in grams): 1 = 0.077 g/day 2 = 0.118 g/day 3 = 0.171 g/day 4 = 0.221 g/day 5 = 0.481 g/day |
After adjusting for Joules, BMI, alcohol intake, menopausal status and postmenopausal hormone use, vigorous exercise, usual aspirin use, multivitamin use, history of hypertension, and frequency of total fruit and vegetable intake and for intake of saturated fat, trans-unsaturated fat, linoleic acid, animal protein, and calcium: Those who consume 2-4 servings of fish/week had a signficantly lower RR of thrombotic infarction than those who ate fish <1 time/month (RR=0.52, 95% CI 0.27-0.99). Although all other categories of higher fish consumption had lower RRs of thrombotic infarction than the 1st category, they were not significant; Those who ate fish 2 or more times per week had sigificantly lower RR of lacunar infarction than those who ate fish <1 time/month (RR=0.28, 95% CI 0.12-0.67). Although all other categories of higher fish consumption had lower RRs of lacunar infarction than the 1st category, they were not significant; There were no significant associations found between fish consumption and total stroke, ischemic stroke, large-artery occlusive infarction, hemorrhagic stroke, subarachnoid hemorrhage, or intraparenchymal hemorrhage; Those in quintile 3 of omega-3 PUFA intake had a significantly lower RR of total stroke (RR=0.69, 95% CI 0.53-0.89), ischemic stroke (RR=0.67, 95% CI 0.47-0.98), and thrombotic infarction (RR=0.64, 95% CI 0.43-0.95) compared to those in quintile 1; Those in quintile 5 of omega-3 PUFA intake had a significantly lower RR of total stroke (RR=0.72, 95% CI 0.53-0.99) and lacunar infarction (RR=0.37, 95% CI 0.19-0.73) compared to those in quintile 1; and There were no significant associations found between omega-3 PUFA intake and large-artery occlusive infarction, hemorrhagic stroke, subarachnoid hemorrhage, or intraparenchymal hemorrhage. |
B |
Amount |
Results |
Conclusion** |
Fresh fish = 0.57 g n-3 fatty acids/100 g Salted fish = 0.44 g n-3 fatty acids/100 g Shellfish = 0.36 g n-3 fatty acids/100 g Fish and shellfish categories (g/week): 1 = <50 (<1 serving/week) 2 = 50-<100 (1 serving/week) 3 = 100-<150 (2 servings/week) 4 = 150-<200 (3 servings/week) 5 = ≥200 (≥4 servings/week) Quintiles of n-3 fatty acids: (g/week) 1 = <0.27 2 = 0.27-0.43 3 = 0.44-0.72 4 = 0.73-1.09 5 = ≥1.10 |
After controlling for age, total energy intake, level of education, BMI, current smoker at recruitment, average number of cigarettes smoked per day, number of alcoholic drinks consumed per week, history of diabetes, and history of hypertension: There were no significant associations found between fish consumption and risk of stroke mortality; and Those in the 3rd quintile of n-3 fatty acid intake had significantly lower RR of stroke mortality compared to those in the 1st quintile (RR=0.76, 95% CI 0.58-0.98). Those in the 2nd, 4th, and 5th quintiles also had lower RRs of stroke mortality compared to those in the 1st quintile, but they were not significant. |
B |
Author |
Study Type |
Subjects |
Exposure |
Gillum et al., 1996* |
Cohort |
Men and women (n=5192) Aged 45-74 years White (n=4410) Black (n=782) National Health and Nutrition Examination Survey (NHANES) I No history of stroke at baseline Excluded those with unknown baseline fish consumption, systolic blood pressure, serum cholesterol level, diabetes history, number of cigarettes smoked, BMI, history of heart disease, or educational attainment Average follow-up of 12 years |
Seafood |
Orencia et al., 1996* |
Cohort |
Men (n=1847) Aged 40-55 years Employed at least 2 years at the Hawthorne Works of the Western Electric Co. in Chicago, IL 65% first- or second-generation Americans, predominantly of German, Polish, or Bohemian ancestry Chicago Western Electric Study Free of CHD and stroke at baseline Follow-up of 30 years (46,426 person-years) |
Seafood |
Amount |
Results |
Conclusion** |
Categories of fish consumption: 1 = Never 2 = <1 time/week 3 = 1 time/week 4 = >1 time/week |
After adjusting for baseline age, smoking, history of diabetes, history of heart disease, education less than high school graduate, systolic blood pressure, serum albumin concentration, serum cholesterol concentration, BMI, alcohol intake, and physical activity: White women aged 45-74 years who ate fish >1 time/week had a significantly lower RR of acute stroke incidence compared to those who never ate fish (RR=0.55, 95% CI 0.32-0.93); Significant RRs were not found when the women were separated and analyzed based on different age groups (45-64 years and 65-74 years) or for White men; and Black men and women who ate any fish had a significantly lower RR of acute stroke incidence (RR=0.51, 95% CI 0.30-0.88) and stroke death (RR=0.26, 95% CI 0.11-0.64) compared to those who never ate fish. |
B |
Categories of fish consumption: 1 = None 2 = 1-17 g/day 3 = 18-34 g/day 4 = ≥35 g/day |
After adjusting for age, systolic blood pressure, cigarette smoking, serum cholesterol, diabetes, ECG abnormalities, table salt use, alcohol intake, iron, thiamine, riboflavin, niacin, vitamin C, beta-carotene, retinol, total energy, polyunsaturated fatty acids, carbohydrates, and total protein, there were no significant associations found between fish consumption and risk of fatal and nonfatal stroke. |
N |
Author |
Study Type |
Subjects |
Exposure |
Morris et al., 1995* |
Cohort |
Men (n=21,185) Aged 40-84 years US physicians Physicians’ Health Study No history of MI, stroke, transient ischemic attacks, cancer, liver or renal disease, peptic ulcer, gout, current use of aspirin, other platelet-active drugs, or nonsteroidal anti-inflammatory agents Follow-up of 4 years |
Seafood and dietary n-3 fatty acid intake |
Amount |
Results |
Conclusion** |
Categories of fish: 1 = Canned tuna 2 = Dark-meat fish (4-6 oz) 3 = Other fish (4-6 oz) 4 = Shrimp, lobster, or scallops Categories of fish intake: 1 = <1 meal/week 2 = 1 meal/week 3 = 2-4 meals/week 4 = ≥5 meals/week Quintiles of n-3 fatty acids intake (g/week): 1 = <0.5 2 = 0.5-<1.0 3 = 1.0-<1.7 4 = 1.7-<2.3 5 = ≥2.3 |
After adjusting for each level of fish consumption, age, aspirin and beta-carotene assignment, smoking, alcohol consumption, obesity, diabetes mellitus, vigorous exercise, parental history of MI before age 60 years, history of hypertension, history of hypercholesterolemia, vitamin supplement use, and saturated fat intake: Those who consumed 1 fish meal/week had a significantly higher RR of total MI (RR=1.5, 95% CI 1.1-2.1) and cardiovascular deaths (RR=2.6, 95% CI 1.4-4.8) compared to those who consume fish <1 meal/week; No other significant RRs of total myocardial infarction, nonfatal myocardial infarction, stroke, cardiovascular deaths, or total cardiovascular events were found based on weekly fish consumption; Those in the 2nd quintile of omega-3 fatty acid intake had a higher RR of total MI than those in the 1st quintile (RR=1.6, 95% CI 1.1-2.4); and No other significant RR of total MI, nonfatal MI, stroke, cardiovascular deaths, or total cardiovascular events were found based on weekly omega-3 fatty acid intake. |
B |
Author |
Study Type |
Subjects |
Exposure |
Keli et al., 1994* |
Cohort |
Men (n=552) Aged 50-69 years Zutphen, Netherlands The Zutphen Study (Dutch contribution to the Seven Countries Study) Free of stroke at baseline Follow-up of 15 years |
Seafood |
Kromann and Green, 1980 |
Cohort |
Men and women (n=1800) All ages Born in Greenland and/or with Greenlandic mothers in the Upernavik district, northwest Greenland 5-10% persons of other origin Follow-up of 25 years (40,472 person-years) |
Diet |
Amount |
Results |
Conclusion** |
Categories of fish consumption: Low = ≤20 g/day High = >20 g/day |
Fish consumption (g/day) was significantly different in those who did not suffer from a stroke (18.3±19.8) than those who did (12.8±12.3) after 15 years of follow-up (p<0.05). After adjusting for age, average systolic blood pressure 1960-1970, average serum cholesterol 1960-1970, cigarette smoking until 1970, and intake of energy and vegetable protein, alcohol consumption, and prescribed diet in 1970: Those who consumed >20 g/day of fish had a lower, but not statistically significant, HR of stroke incidence than those who ate ≤20 g/day of fish (HR=0.49, 95% CI 0.24-1.01); Those who always consumed fish did not have a significantly lower HR of stroke incidence than those who ate fish “not always” (HR=0.71, 95% CI 0.38-1.33). |
B |
This population is mainly occupied with whaling and sealing, fowling, and to a lesser degree fishing The traditional diet is supplemented with Danish food |
Summarizes the disease patterns of cancer, “apoplexy,” epilepsy, peptic ulcer, acute myocardial infarction, rheumatic fever, chronic polyarthritis, chronic pyelonephritis, chronic glomerulonephritis, diabetes mellitus, psoriasis, psychosis, multiple sclerosis, and thyrotoxicosis. The pattern of disease in this study “differs from that of Western Europe, as we have found frequent occurrence of apoplexy and grand mal epilepsy, but rare or nonoccurrence of acute myocardial infarction, diabetes mellitus, thyrotoxicosis, bronchial asthma, multiple sclerosis and psoriasis.” |
N |
Author |
Study Type |
Subjects |
Exposure |
Caicoya, 2002* |
Case-control |
Cases (n=440) = incident cases of stroke Controls (n=473) = no acute stroke, living in study area at time of study Aged 40-85 years Asturias, Spain (a northern region) |
Seafood and dietary n-3 fatty acid intake |
Jamrozik et al., 1994 |
Case-control |
Cases (n=501) = stroke, drawn from the register of acute cerebrovascular events compiled as part of the Perth Community Stroke Study (PCSS) Controls (n=931) = drawn from electoral rolls for the study area of the PCSS Men and women Perth, Western Australia |
Seafood |
Amount |
Results |
Conclusion** |
Categories of fish consumption (based on the 20th, 50th, and 80th percentiles): 1 = Noneaters, eaters of ≤11.2 g/day 2 = 11.3 g/day < x < 28.7 g/day 3 = 28.8 g/day ≤ x < 46.5 g/day 4 = ≥46.5 g/day Categories of n-3 fatty acid intake: 20th percentile = 115 mg/day 50th percentile = 328 mg/day 80th percentile = 660 mg/day |
After adjusting for hypertension, alcohol intake, atrial fibrillation, and peripheral artery disease: Those who ate 1-22.5 g of fish/day had a significantly lower OR of stroke compared to those who never ate fish (OR=0.30, 95% CI 0.12-0.78). No significant ORs for stroke were found for those who consumed 23-45, 46-90, or 91-250 g of fish/day; and Those who ate >46.5 g of fish/day had a significantly higher OR of cerebral infarction compared to those who never ate fish (OR=1.98, 95% CI 1.08-3.45). No significant ORs for cerebral infarction were found for those who consumed 11.3-28.7 or 28.8-46.5 g of fish/day; and There was no significant association found between intake of n-3 fatty acids (mg/day) and risk of stroke. |
B |
Consumption of fish >2 times/month |
After adjusting for alcohol and tobacco use, history of hypertension, claudication (for first ever stroke), diabetes mellitus (for primary intracerebral hemorrhage), previous stroke or transient ischemic attack, use of reduced-fat or skim milk: Eating fish >2 times/month significantly lowered the odds of a first-ever stroke (OR=0.60, 95% CI 0.36-0.99) and primary intracerebral hemorrhage (OR=0.42, 95% CI 0.19-0.90), compared to not eating fish >2 times/month. No significant ORs were found for all strokes and ischemic stroke based on consuming fish >2 times/month. |
B |
Amount |
Results |
Conclusion** |
|
“Ecologic/cross-sectional and case-control studies have generally shown an inverse association between consumption of fish and fish oils and stroke risk. Results from five prospective studies have been less consistent, with one showing no association, one showing a possible inverse association, and three demonstrating a significantly inverse association.” “Consumption of fish several times per week reduces the risk of thrombotic stroke but does not increase the risk of hemorrhagic stroke.” |
B |
|
“Fish consumption was independently, significantly, and inversely associated with mortality from all causes, ischemic heart disease, and stroke in both sexes.” The statistics for these associations are p<0.001, 0.01<p<0.001, and 0.05<p<0.001, respectively. |
B |
TABLE B-2c Studies on Lipid Profile
Author |
Study Type |
Subjects |
Exposure |
Dunstan et al., 2003 |
Randomized Controlled Trial |
Women (n=83) Booked for delivery at St. John of God Hospital, Subiaco, Western Australia Atopic pregnancy Allergic women No smoking, other medical problems, complicated pregnancies, preterm delivery, seafood allergy; normal diet intake did not exceed two meals of fish per week From 20 weeks of pregnancy to delivery |
n-3 supplement |
Christensen et al., 1999 |
Randomized Controlled Trial |
Men (n=35) Women (n=25) Medical staff, bank employees, and students at institutions in Aalborg, Denmark No medications, no known diseases Follow-up of 12 weeks |
n-3 supplement |
Amount |
Results |
Conclusion** |
Fish oil group: 1.0 g fish oil/capsule, 4 capsules/day 3.7 g n-3 PUFA/capsule (56% DHA, 27.7% EPA) Placebo group: 1 g olive oil/capsule, 4 capsules/day (66.6% n-9 oleic acid, <1% n-3 PUFA) |
“Levels of n-6 PUFA AA were significantly lower in the fish oil group (15.02±1.44%, p<0.001), compared with the placebo group (17.45±1.17%). There was no difference in the levels of oleic acid between the groups.” “Interleukin-13 levels were significantly lower (geometric mean 9.61, 95% CI 5.46-16.93, p=0.025) in neonates whose mothers received fish-oil supplements in pregnancy compared to the placebo group (geometric mean 26.32, 95% CI 13.44-51.55).” “There were no significant differences in the frequency of lymphocyte subsets between the two groups with respect to total T cells, T helper cells, T suppressor cells, NK cells, and B cells.” |
B |
High n-3 group: 10 capsules 6.6 g/day n-3 PUFA (3 g EPA/2.9 g DHA) Low n-3 group: 3 capsules n-3, 7 capsules of olive oil 2 g/day n-3 PUFA 0.9 g EPA/0.8 g DHA Placebo group: 10 capsules Olive oil |
n-3 PUFA in granulocytes (both for EPA and DHA) and in platelets (both for EPA and DHA) were significantly higher after supplementation, compared to before supplementation, for those in the high n-3 group and the low n-3 group (p<0.01). Plasma triacylglycerols were significantly lower after supplementation, compared to before supplementation, for those in the high n-3 group (p<0.01) and the low n-3 group (p<0.05). The changes in DHA in granulocytes and plasma triacylglyercols after supplementation were significantly higher in the high n-3 group compared to the placebo group (p<0.05). The changes in EPA in granulocytes and EPA and DHA in platelets were significantly higher in the high n-3 group than in the low n-3 group and the placebo group (p<0.05). |
B |
Author |
Study Type |
Subjects |
Exposure |
Vericel et al., 1999 |
Randomized Controlled Trial |
Men and women (n=20) Aged 70-83 years France Diastolic blood pressure <95 mmHg and systolic blood pressure <180 mmHg No metabolic, malignant, or degenerative diseases Follow-up of 42 days |
n-3 supplement |
Leng et al., 1998* |
Randomized Controlled Trial |
Men and women (n=120) Mean age about 66 years Edinburgh, UK Intermittent claudication on the Edinburgh Claudication Questionnaire An ankle brachial pressure index ≤0.9 in at least one limb No clinical evidence of critical ischemia; unstable angina or a MI within the previous 3 months; severe intercurrent illnesses including severe liver disorders, malignancy, or epilepsy; concurrent treatment with anticoagulants, other oils, lithium, or phemothiazines; pregnant or actively trying to conceive; already participating in a clinical trial Follow-up of 2 years |
n-3 supplement |
Amount |
Results |
Conclusion** |
RO-PUFA treatment capsule: 600 mg oil = 150 mg DHA, 30 mg EPA, 1900 ppm alphatocopherol Control capsule: 600 mg sunflower oil and 600 ppm alpha-tocopherol |
“The composition of platelet total phospholipids was not affected by the low supplementation of RO-PUFA or sunflower oil.” “Neither the GSH-Px activities nor the enzyme levels were affected by any supplement of oil.” Compared to baseline, RO-PUFA significantly increased platelet phosphatidylethanolamine DHA (2.7±0.2 mol% to 3.4±0.1 mol%, p<0.001). |
N |
Polyunsaturated fatty acids group: 280 mg GLA, 45 mg EPA/capsule 2 capsules twice/day for first 2 weeks, 3 capsules twice daily thereafter Placebo group: 500 mg sunflower oil 2 capsules twice/day for first 2 weeks, 3 capsules twice daily thereafter |
Among completers, VLDL was significantly higher in the polyunsaturated fatty acids group at 6 months (p<0.05) and HDL was significantly higher at 24 months (p<0.01) compared to the placebo group. At baseline, hematocrit (%) and fibrin D-dimer (ng/ml) were significantly lower in the polyunsaturated fatty acids group compared to the placebo group (p<0.05). At 6 months, hematocrit (%) was significantly higher in the polyunsaturated fatty acids group compared to the placebo group (p<0.01). There were no significant differences in hemostatis factors at 24 months between the two groups. |
B |
Author |
Study Type |
Subjects |
Exposure |
Luo et al., 1998* |
Randomized Controlled Trial (crossover) |
Men (n=10) Mean age of 54 years Patients of the Department of Diabetes outpatient clinic (diabetics) Type II diabetes, a fasting plasma glucose of 7.84-14.0 mmol/L, HbA1c <10.5%, plasma triacylglycerol of 1.72-4.6 mmol/L No abnormal renal, hepatic, and thyroid functions; gastrointestinal disorders Follow-up of 2 months while on each supplement |
n-3 supplement |
Amount |
Results |
Conclusion** |
Fish oil group: 6 g fish oil 30% n-3 fatty acids; 18% EPA, 12% DHA 2 capsules 3 times/day Sunflower oil group: 6 g sunflower oil 65% n-6 fatty acids; 0.2% n-3 fatty acids 2 capsules 3 times/day Recommended to consume 55% of calories as carbohydrates, 15% as protein, 30% as fat |
There were no significant differences in fasting plasma glucose, insulin, or HbA1c between the two groups. After 2 months of sunflower oil and fish oil treatments, the fish oil treatment significantly lowered triacylglycerols and lipoprotein(a) compared to the the sunflower oil treatment (p<0.05 and p<0.02, respectively). There were no other significant differences between the two treatments in the other fasting circulating lipid and lipoprotein concentrations measured. |
B |
Author |
Study Type |
Subjects |
Exposure |
Dunstan et al., 1997* |
Randomized Controlled Trial |
Men (n=40) Women (n=15) Aged 30-65 years Perth, Australia With treated noninsulin-dependent diabetes mellitus Nonsmokers, not taking fish-oil supplements or eating >1 fish meal/week, sedentary for the previous 6 months Excluded if taking insulin or medication for lipid disorders; drinking >30 ml alcohol/day; had a previous history or evidence of heart, liver, or renal disease; neuropathy; retinopathy; or had asthma or any orthopedic disorder that precluded exercise participation Follow-up of 8 weeks |
Diet (includes seafood) and exercise |
Amount |
Results |
Conclusion** |
Group 1: Low-fat diet (30% energy from fat) + moderate exercise (55-65% of Vo2max) Group 2: Low-fat diet (≤30% energy from fat) + light exercise (heart rate <100 bpm) Group 3: Low-fat diet with the inclusion of 1 fish meal daily (3.6 g n-3/day) + moderate exercise (55-65% of Vo2max) Group 4: Low-fat diet with the inclusion of 1 fish meal daily (3.6 g n-3/day) + light exercise (heart rate <100 bpm) |
After adjusting for baseline age, sex, and change in body weight: Relative to no fish and light exercise, fish and moderate exercise (Group 3) significantly lowered serum triglycerides (−1.21±0.28; p=0.0001) and significantly raised HDL2 (0.08±0.03, p=0.02); Relative to no fish and light exercise, fish and light exercise (Group 4) significantly lowered serum triglycerides (−1.22±0.28; p=0.0001) and significantly raised HDL2 (0.08±0.03, p=0.02); and Relative to no fish and light exercise, no fish and moderate exercise (Group 1) significantly lowered serum triglycerides (−0.68±0.29; p=0.03). |
B |
Author |
Study Type |
Subjects |
Exposure |
Schaefer et al., 1996* |
Randomized Controlled Trial |
Men and women (n=22) Mean age of 63 (all >40 years, all women postmenopausal) Plasma LDL-cholesterol within the 10th and 90th percentile for their age and sex No medication known to affect plasma lipoprotein cencentrations; no endocrine, liver, or kidney disease Nonsmokers, did not consume alcohol regularly Follow-up of 24 weeks National Cholesterol Education Program (NCEP) Step 2 diet |
Seafood |
Amount |
Results |
Conclusion** |
Baseline diet: 14.1±2.2 % energy from saturated fat 14.5±1.0 % energy from monounsaturated fat 4.1±0.2 % energy from LA 0.7±0.2 % energy from ALA <0.01 % energy from AA, EPA, DHA each High-fish diet: 4.5±0.7 % energy from saturated fat 11.6±1.4 % energy from monounsaturated fat 7.0±0.4 % energy from LA 1.9±0.6 % energy from ALA 0.1±0.1 % energy from AA 0.2±0.1 % energy from EPA 0.5±0.2 % energy from DHA Low-fish diet: 4.0±0.4 % energy from saturated fat 10.8±0.9 % energy from monounsaturated fat 7.1±0.8 % energy from LA 2.0±0.2 % energy from ALA <0.02 % energy from AA <0.02 % energy from EPA 0.1±0.1 % energy from DHA |
Those on the high-fish diet significantly lowered their total cholesterol, LDL-C, HDL-C, apolipoprotein B, apolipoprotein A-I (p<0.0001), and postprandial tricylglycerols (p<0.05). There were no significant changes found for VLDL-C, TC:HDL-C, (triacylglycerols, lipoprotein(a), or LDL particle score. Those on the low-fish diet significantly lowered their total cholesterol, LDL-C, HDL-C, apolipoprotein B, apolipoprotein A-I (p<0.0001), and significantly increased their LDL particle score (p<0.05). There were no significant changes found for VLDL-C, TC:HDL-C, triacylglycerols, postprandial triacylglycerols, and lipoprotein(a). |
B |
Author |
Study Type |
Subjects |
Exposure |
Eritsland et al., 1995* |
Randomized Controlled Trial |
Men (n=523) Women (n=78) Aged 36-81 years Oslo, Norway With stenosing coronary artery disease Referred for coronary artery bypass grafting Follow-up of 6 months Reference group (for serum Lp(a)): Men (n=79) Women (n=20) Aged 25-81 years Apparently healthy Current or retired employees attending a regular health check-up |
n-3 supplement |
Sacks et al., 1995 |
Randomized Controlled Trial |
Men and women (n=59) Aged 30-75 years Boston, MA Had narrowing of ≥30% lumen diameter of a major coronary artery, a total cholesterol concentration <250 mg/dL, and triglyceride level <350 mg/dL No congestive heart failure, liver, renal, or serious gastrointestinal disease, insulin-dependent diabetes mellitus, current cigarette smoking, or alcohol intake >14 drinks/week Follow-up of 2.4 years |
n-3 supplement |
Amount |
Results |
Conclusion** |
n-3 PUFA group: 4 capsules/day Each capsule = 1 g n-3 PUFA (51% EPA, 32% DHA) + 3.7 IU alpha-tocopherol |
Serum EPA, DHA, and total n-3 concentrations significantly increased in the n-3 PUFA group between baseline and the 6-month assessment (p<0.001). The changes in serum EPA, DHA, and total n-3 concentrations from baseline to the 6-month assessment were also significantly higher in the n-3 PUFA group compared to the control group (p<0.001). Among those who had a baseline Lp(a) of ≥20 mg/dL, the change in serum Lp(a) levels from baseline to the 6-month assessment was significantly different in the n-3 PUFA group (29.7 mg/dL to 28.7 mg/dL) than in the control group (30.3 mg/dL to 30.8 mg/dL) (p=0.023). There were no significant differences in the change of serum Lp(a) found between the two groups among those who had a baseline Lp(a) of <20 mg/dL. |
B |
Fish oil group: 12 capsules/day 500 mg n-3 fatty acids/capsule (240 mg EPA, 160 mg DHA, 100 mg mostly DPA) 6 g of n-3 fatty acids/day Control group: 12 capsules of olive oil/day |
From baseline to follow-up, there was a significant increase in body weight, LDL-C, apolipoprotein B, and Lp(a), and a significant decrease in triglycerides among those in the fish oil group (p<0.01; p<0.05 for lipoprotein Lp(a)). From baseline to follow-up there was a significant increase in body weight (p<0.01), cholesterol (p<0.05), and apolipoprotein B (p<0.01) among those in the control group. The change in triglycerides from baseline to follow-up was significantly different among the fish oil group (−28±53 mg/dL) and the control group (6±35 mg/dL) (p<0.01). After 2.4 years of supplementation, the fish oil group had significantly higher EPA, DPA, DHA, and EPA+DPA+DHA (p<0.0001) and significantly lower palmitic acid (p=0.048), oleic acid (p=0.0009), and arachidonic acid (p=0.001) in the adipose tissue compared to the control group. |
B |
Author |
Study Type |
Subjects |
Exposure |
Mori et al., 1994* |
Randomized Controlled Trial |
Men (n=120) Aged 30-60 years Perth, Australia Eating not more than one fish meal/week or drinking more than an average of 30 mL alcohol/day (3 standard drinks) With high-normal blood pressure and elevated serum cholesterol No history of unstable heart, renal, or liver disease, hypercholesterolemia, asthma, or any major allergies Follow-up of 12 weeks |
Seafood and n-3 supplements |
Amount |
Results |
Conclusion** |
Seven dietary groups: 40% total energy from fat and: 1 = placebo 2 = fish (1 fish meal/day) 3 = fish-oil capsules (0.8 g/day DHA, 2.6 g n-3/day) 4 = fish (1 fish meal/day) and fish-oil capsules (0.8 g/day DHA, 2.6 g n-3/day) 5 = twice the dosage of fish-oil capsules (1.6 g/day DHA, 5.2 g n-3/day) 30% total energy from fat and: 6 = control group 7 = fish (1 fish meal/day) Fish meals included: Greenland turbot fillets (160 g/day) = 1.5 g/day DHA, 3.5 g/day total n-3 fatty acids Canned sardines (95 g/day) = 1.7 g/day DHA, 4.1 g/day total n-3 fatty acids Tuna (90 g/day) = 1.3 g/day DHA, 3.2 g/day total n-3 fatty acids Salmon (90 g/day) = 2.4 g/day DHA, 3.8 g/day total n-3 fatty acids |
Among those in Groups 1-5, there were significant differences between the groups in the change in percentage of daily fat intake from polyunsaturated fatty acids (change (%) = −4.5, 0.9, −7.1, 0.9, and −1.9, respectively; p<0.001). Among those in Groups 6-7, there were significant differences between the groups in the change in percentage of daily fat intake from polyunsaturated fatty acids (change (%) = 13.0 and 18.9, respectively; p<0.01). Among those in Groups 1-5, there were significant differences between the groups in regards to the change in cholesterol (change (mg/d) = 124.3, −33.8, 188.3, 103.4, and 58.7, respectively; p<0.01). There were no significant changes in % of energy from total fat, % of daily fat from monounsaturated fatty acids or saturated fatty acids, total carbohydrate, total protein, or fiber intake. |
B |
Author |
Study Type |
Subjects |
Exposure |
Vandongen et al., 1993 |
Randomized Controlled Trial |
Men (n=120) Aged 30-60 years Perth, Australia BMI <33 kg/m2, SBP 130-159 mmHg, DBP 80-99 mmHG, serum cholesterol 5.2-6.9 mmol/L, nonsmoking, not taking any medication, no significant illness or allergic disorder Eating ≤1 fish meal and drinking <210 mL alcohol/week Follow-up of 12 weeks |
Seafood and n-3 supplements |
Amount |
Results |
Conclusion** |
Seven dietary groups: 40% total energy from fat and: 1 = placebo 2 = fish (1 fish meal/day) 3 = fish-oil capsules (1.3 g n-3/day) 4 = fish (1 fish meal/day) and fish-oil capsules (1.3 g n-3/day) 5 = twice the dosage of fish-oil capsules (2.6 g n-3/day) 30% total energy from fat and: 6 = control group 7 = fish (1 fish meal/ day) Fish meals included: Greenland turbot fillets (≈160 g/day) 3.5 g/day total n-3 fatty acids Canned sardines (95 g/day) 4.1 g/ day total n-3 fatty acids Tuna (90 g/day) ≈3.2 g/day total n-3 fatty acids Salmon (90 g/day) 3.8 g/day total n-3 fatty acids |
A significant group effect was found for the change in heart rate (p<0.01 for supine; p = 0.06 for erect) from baseline to end of intervention. No significant differences were found between groups in SBP, DBP, weight, 24-hour urine potassium levels, sodium, blood glucose, or blood insulin from baseline to end of intervention. |
B |
Author |
Study Type |
Subjects |
Exposure |
Cobiac et al., 1991* |
Randomized Controlled Trial |
Men (n=31) Aged 30-60 years Adelaide, South Australia Mildly hyperlipidemic and normotensive No history of heart disease, hypertension, bleeding disorders, liver or renal disorders, gout, diabetes, recent cerebrovascular accident, or obesity No steroids, nonsteroidal anti-inflammatory drugs, aspirin, beta-blockers, allopurinol, or cardiac glycosides No excessive alcohol intake (>40 g/day) or smoked >20 cigarettes/day Follow-up of 8 weeks |
Seafood and n-3 supplementation |
Hanninen et al., 1989* |
Randomized Controlled Trial |
Men (n=100) Mean age of 23.5 years Kuopio, Finland Healthy students Follow-up of 12 weeks |
Seafood |
Amount |
Results |
Conclusion** |
Fish treatment: 1 kg (raw) Atlantic salmon + 150 g sardines in sild oil per week 4.5 g EPA+DHA/day Fish-oil treatment: 105 g MaxEPA/week 4.6 g EPA+DHA/day Continued with meats as during baseline Control diet: Continuation of baseline diet |
After the fish treatment (compared to baseline values), cholesterol, triglycerides, VLDL-C, LDL-C, VLDL triglycerides, Apo A-I, and Apo A-II were significantly lower and HDL, Apo A-I:Apo A-II, and HDL-C:Apo A-I were significantly higher (p<0.05). After the fish-oil treatment (compared to baseline values), triglycerides, VLDL-C, VLDL triglycerides, Apo A-I, Apo-AII, and Apo A-I:Apo B were significantly lower, and HDL-C, Apo A-I:Apo A-II, and HDL-C:Apo A-I were significantly higher (p<0.05). After the control treatment (compared to baseline values), lipids, LDL-C, and Apo A-I were significantly lower and HDL-C:Apo A-I was significantly higher (p<0.05). The changes in triglycerides, VLDL-C, VLDL triglycerides, and HDL-C:Apo A-I in the fish and fish-oil groups were significantly greater than the changes in the control group (p<0.05, p=0.002 for HDL-C:Apo A-I); the change in HDL-C was significantly greater in the fish-oil group than in the control group (p<0.05). The changes in fibrinogen, thromboxane, and bleeding time after treatment were significantly different in the fish group compared to the control group (p<0.05). |
B |
Fish meal groups: 0.9, 1.5, 2.3, or 3.8 fish meals/week Controls: 1 fish meal/2 weeks Meals = Finnish freshwater fish (rainbow trout, vendace, and perch) and brackish water fish (Baltic herring) Portion size = 150 g |
Those who ate 3.8 fish meals/week lowered their serum triglycerides and apolipoprotein B significantly (p<0.02 and p<0.05, respectively) after eating the fish diet for 12 weeks; there were no significant changes after 12 weeks for those who ate 0.9, 1.5, and 2.3 fish meals/week. There were no significant changes in serum cholesterol, serum apolipoprotein A-I, hemoglobin, thrombocytes, vitamin E, or vitamin A after eating the fish diets for 12 weeks. |
B |
Amount |
Results |
Conclusion** |
Plasma phospholipids = relative percentages of total fatty acids by weight Fish and marine mammal intake from 24-hour recalls Consumption of traditional and market food stuffs from a food frequency questionnaire |
After adjusting for age, sex, waist girth, smoking status, and alcohol intake: EPA, DHA, EPA+DHA, EPA:AA, and n-3:n-6 are positively associated with total cholesterol (p=0.0001); EPA (p=0.005), DHA (p=0.0003), EPA+DHA (p=0.0007), EPA:AA (p=0.002), and n-3:n-6 (p=0.003) are positively associated with LDL; EPA (p=p=0.0001), DHA (p=0.004), EPA+DHA (p=0.0001), EPA:AA (p=0.0001), and n-3:n-6 (p=0.0001) are positively associated with HDL; EPA (p=0.04) and EPA:AA (p=0.05) are negatively associated with total cholesterol:HDL; EPA (p=0.0001), EPA+DHA (p=0.0003), EPA:AA (p=0.0002), and n-3:n-6 (p=0.001) are negatively associated with triacylglycerols; and EPA (p=0.02), DHA (p=0.01), EPA+DHA (p=0.008), EPA:AA (p=0.02), and n-3:n-6 (p=0.008) are positively associated with glucose. |
N |
TABLE B-2d Studies on Blood Pressure
Author |
Study Type |
Subjects |
Exposure |
Hooper et al., 2005 |
Cochrane Review |
7 studies (2743 participants) After 6 months of supplementation |
n-3 supplement |
Geleijnse et al., 2002* |
Meta-analysis |
36 RCTs (22 with double-blinded design) Adult study populations (mean age ≥18 years) Published after 1966 No sick/hospitalized populations, including renal and diabetic patients Mean trial duration of 11.7 weeks (range = 3-52 weeks) |
n-3 supplement |
Amount |
Results |
Conclusion* |
|
“Neither [systolic or diastolic blood pressure] were significantly affected by omega-3 supplementation” (SBP mean difference = 1.03 mmHg, 95% CI −3.30 to 1.25, p=0.18; DBP mean difference = −0.23 mmHg, 95% CI 1.10-0.64, p=0.92). |
N |
Doses of fish oil: <1.0 g/day in 1 trial 1.0-1.9 g/day in 5 trials 2.0-2.9 g/day in 4 trials 3.0-15.0 g/day in 26 trials mean dose = 3.7 g/day |
In the univariate analysis: Based on all trials, fish oil decreased SBP and DBP significantly more among those >45 years of age compared to those ≤45 years of age (p=0.023 for SBP and p=0.020 for DBP) and in those with hypertension compared to those without hypertension (p=0.008 for SBP and p=0.041 for DBP). Fish oil also decreased SBP and DBP more in populations with males and females compared to those with only males and among those with a BMI >26.8kg/m2 compared to those with BMI ≤26.8 kg/m2, but the differences were not significant; and Based on double-blinded trials, fish oil decreased SBP and DBP significantly more among those with hypertension compared to those without hypertension (p=0.005 for SBP and p=0.010 for DBP). Fish oil also decreased SBP and DBP more among those >45 years of age compared to those ≤45 years of age; in populations with males and females compared to those with only males, and among those with a BMI >26.8kg/m2 compared to those with BMI ≤26.8 kg/m2, but the differences were not significant. After adjusting for age, percent males, baseline BP, study design, and fish oil dose: Fish oil decreased SBP and DBP more among those >45 years of age compared to those ≤45 years of age, in populations with males and females compared to those with only males, in those with hypertension compared to those without hypertension, and among those with a BMI >26.8kg/m2 compared to those with BMI ≤26.8 kg/m2, but the differences were not significant. |
N |
Author |
Study Type |
Subjects |
Exposure |
Ness et al., 1999 |
Randomized Controlled Trial |
Men (n=2033) Aged <70 years From 21 hospitals in South Wales and the south west of England Diet and Reinfarction Trial (DART) Suffered from recent MI Excluded if they already intended to eat one of the study diets, if they had serious illnesses (e.g., diabetes, cancer, or renal function), if they were being considered for cardiac surgery, if they were participating in a local cohort study, if they planned to live outside the study area, if they were averse to one of the proposed diets Follow-up of 2 years |
Dietary advice |
Vericel et al., 1999 |
Randomized Controlled Trial |
Men and women (n=20) Aged 70-83 years France Diastolic blood pressure <95 mmHg and systolic blood pressure <180 mmHg No metabolic, malignant, or degenerative diseases Follow-up of 42 days |
n-3 supplement |
Leng et al., 1998* |
Randomized Controlled Trial |
Men and women (n=120) Mean age about 66 years Edinburgh Intermittent claudication on the Edinburgh Claudication Questionnaire An ankle brachial pressure index ≤0.9 in at least one limb No clinical evidence of critical ischemia; unstable angina or a myocardial infarction within the previous 3 months; severe intercurrent illnesses including severe liver disorders, malignancy, or epilepsy; concurrent treatment with anticoagulants, other oils, lithium, or phemothiazines; pregnant or actively trying to conceive; already participating in a clinical trial Follow-up of 2 years |
n-3 supplement |
Amount |
Results |
Conclusion* |
Eight dietary regimes: 1 = Fat advice 2 = Fish advice 3 = Fiber advice 4 = Fat and fish advice 5 = Fat and fiber advice 6 = Fish and fiber advice 7 = Fat, fish, and fiber advice 8 = No advice |
After adjusting for 5-year age group and BP at baseline: At 6 months, those who received fish advice had lower SBP and DBP than those who did not receive fish advice (difference in SBP = −0.61, 95% CI −2.15 to 0.92 and difference in DBP = −0.50, 95% CI −1.47 to 0.46), but the differences were not significant; and At 2 years, those who received fish advice had higher SBP and DBP than those who did not receive fish advice (difference in SBP = 0.40, 95% CI −1.33 to 2.13 and difference in DBP = 0.19, 95% CI −0.88 to 1.26), but the differences were not significant. |
B |
RO-PUFA treatment capsule: 600 mg oil = 150 mg DHA, 30 mg EPA, 1900 ppm alphatocopherol Control capsule: 600 mg sunflower oil and 600 ppm alpha-tocopherol |
Compared to baseline, RO-PUFA significantly lowered systolic blood pressure (145.5±5.1 mmHg to 131.5±4.5 mmHg, p<0.001). There was no significant change in diastolic blood pressure. |
B |
Polyunsaturated fatty acids group: 280 mg GLA, 45 mg EPA/capsule 2 capsules twice/day for first 2 weeks, 3 capsules twice/day thereafter Placebo group: 500 mg sunflower oil 2 capsules twice/day for first 2 weeks, 3 capsules twice/day thereafter |
There were no significant differences in systolic blood pressure or diastolic blood pressure between the two groups at baseline or at 6 months. At 24 months systolic blood pressure was significantly lower in the polyunsaturated fatty acids group compared to the placebo group (150.1±3.5 mmHg vs. 161.8±3.1 mmHg, p≤0.05). |
B |
Author |
Study Type |
Subjects |
Exposure |
Vandongen et al., 1993 |
Randomized Controlled Trial |
Men (n=120) Aged 30-60 years Perth, Australia BMI <33 kg/m2, SBP 130-159 mmHg, DBP 80-99 mmHG, serum cholesterol 5.2-6.9 mmol/L, nonsmoking, not taking any medication, no significant illness or allergic disorder Eating ≤1 fish meal and drinking <210 mL alcohol/week Follow-up of 12 weeks |
Seafood and n-3 supplements |
Amount |
Results |
Conclusion* |
Seven dietary groups: 40% total energy from fat and: 1 = placebo 2 = fish (1 fish meal/day) 3 = fish-oil capsules (1.3 g n-3/day) 4 = fish (1 fish meal/day) and fish-oil capsules (1.3 g n-3/day) 5 = twice the dosage of fish-oil capsules (2.6 g n-3/day) 30% total energy from fat and: 6 = control group 7 = fish (1 fish meal/ day) Fish meals included: Greenland turbot fillets (≈160 g/day) ≈3.5 g/day total n-3 fatty acids Canned sardines (≈95 g/day) ≈4.1 g/day total n-3 fatty acids Tuna (≈90 g/day) ≈3.2 g/day total n-3 fatty acids Salmon (≈90 g/day) 3.8 g/day total n-3 fatty acids |
There was a significant difference in change in heart rate (bpm) from baseline until the end of the intervention between the groups (p<0.01). Heart rate went down in Groups 2, 3, 4, 5, and 7 and heart rate went up in Groups 1 and 6. |
B |
Author |
Study Type |
Subjects |
Exposure |
Cobiac et al., 1991* |
Randomized Controlled Trial |
Men (n=31) Aged 30-60 years Adelaide, South Australia Mildly hyperlipidemic and normotensive No history of heart disease, hypertension, bleeding disorders, liver or renal disorders, gout, diabetes, recent cerebrovascular accident, or obesity No steroids, nonsteroidal anti-inflammatory drugs, aspirin, beta-blockers, allopurinol, or cardiac glycosides No excessive alcohol intake (>40 g/day) or smoked >20 cigarettes/day Follow-up of 8 weeks |
Seafood and n-3 supplementation |
Dewailly et al., 2001 |
Cohort |
Men and women (n=426) Aged 18-74 years Permanent residents of Nunavik, Canada Inuit Excluded households of only non-Inuit persons, persons not related to an Inuit, and institutionalized persons |
Plasma phospholipid composition; seafood; diet |
Amount |
Results |
Conclusion* |
Fish treatment: 1 kg (raw) Atlantic salmon + 150 g sardines in sild oil per week 4.5 g EPA+DHA/day Fish-oil treatment: 105 g MaxEPA/week 4.6 g EPA+DHA/day Continued with meats as during baseline Control diet: Continuation of baseline diet |
After fish treatment, compared to baseline values, systolic and diastolic blood pressure were significantly lower (p<0.05). After the fish-oil treatment, compared to baseline values, systolic blood pressure was significantly lower (p<0.05). After the control treatment, compared to baseline values, diastolic blood pressure was significantly lower (p<0.05). There were no significant differences between the changes in the three treatment groups. |
B |
Plasma phospholipids = relative percentages of total fatty acids by weight Fish and marine mammal intake from 24-hour recalls Consumption of traditional and market food stuffs from a food frequency questionnaire |
After adjusting for age, sex, waist girth, smoking status, and alcohol intake, no significant associations were found between EPA, DHA, EPA+DHA, EPA: AA or n-3:n-6 and systolic blood pressure or diastolic blood pressure. |
N |
Amount |
Results |
Conclusion* |
Four diet groups: Meat eaters Fish eaters = ate fish but no meat Vegetarians = ate neither meat nor fish but did eat dairy products and/or eggs Vegans = did not eat any meat, fish, eggs, or dairy products |
After adjusting for age, there were significant differences between the diet groups in regards to SBP among men (p<0.005), SBP among women (p<0.005), DBP among men (p<0.005) and DBP among women (p<0.0001). After adjusting for age and BMI, the only significant difference in blood pressure was for DBP among women (p<0.01). After adjusting for age, BMI, alcohol intake and vigorous exercise (for men), and hormone exposure (for women), the only significant difference in blood pressure was for DBP among women (p<0.01). After adjusting for age, BMI, alcohol intake and vigorous exercise (for men), hormone exposure (for women), protein, carbohydrate, total fat, saturated fat and polyunsaturated fat, energy, P/S ratio, and NSP intake, the only significant difference in blood pressure was for DBP among women (p=0.02). After adjusting for age, BMI, alcohol intake and vigorous exercise (for men), hormone exposure (for women), protein, carbohydrate, total fat, saturated fat and polyunsaturated fat, energy, P/S ratio, and NSP intake, sodium (from food only), potassium, calcium, and magnesium intakes, the only significant difference in blood pressure was for DBP among women (p=0.02). After adjusting for age, the prevalence of self-reported hypertension for meat eaters, fish eaters, vegetarians, and vegans was 15.0%, 9.8%, 9.8%, and 5.8% for men, respectively, and 12.1%, 9.6%, 8.9%, and 7.7% for women, respectively. After adjusting for age and BMI, the prevalence of self-reported hypertension for meat eaters, fish eaters, vegetarians, and vegans was 12.9%, 9.3%, 9.5%, and 6.1% for men, respectively, and 10.6%, 9.7%, 8.7%, and 8.3% for women, respectively. |
B |
**N = Evidence of no association or no clear association; B = Evidence of a benefit. |
TABLE B-2e Studies on Arrhythmia
Author |
Study Type |
Subjects |
Exposure |
Leaf et al., 2003 |
Review |
Clinical trials (n=6 analyses) Animal and laboratory studies (for potential mechanisms) |
n-3 supplement |
Christensen et al., 1999 |
Randomized Controlled Trial |
Men (n=35) Women (n=25) Medical staff, bank employees, and students at institutions in Aalborg, Denmark No medications, no known diseases 12 weeks of follow-up |
n-3 supplement |
Christensen et al., 1996 |
Randomized Controlled Trial |
Men and women (n=49) Aged ≤75 years Aalborg Hospital, Denmark Discharged after MI and ventricular ejection fraction <0.40 No pacemakers or permanent tachyarrhythmias, or serious non-cardiac disease Follow-up of 12 weeks |
n-3 supplement |
Amount |
Results |
Conclusion* |
|
From the randomized controlled trials, “the evidence has been strengthened that fish oil fatty acids can prevent sudden cardiac death in humans, and this may prove to be their major cardiac benefit.” From the randomized controlled trials, there were no significant associations found between fish oil fatty acids and the reduction of nonfatal MIs. “If there is a family history of sudden cardiac death, then the supplement should be increased to 1 to 2 g of EPA plus DHA.” “These n-3 fatty acids are antiarrhythmis and can prevent sudden cardiac death in humans.” |
B |
High n-3 group: 10 capsules 6.6 g/day n-3 PUFA 3 g EPA/2.9 g DHA Low n-3 group: 3 capsules n-3, 7 capsules of olive oil 2 g/day n-3 PUFA 0.9 g EPA/0.8 g DHA Placebo group: 10 capsules Olive oil |
There were no significant differences between the three diet groups in regards to the changes in six heart rate variability indexes from before to after supplementation. |
B |
n-3 fatty acid group: 5.2 g n-3 PUFA 4.3 g EPA and DHA Placebo group: Olive oil |
After n-3 polyunsaturated fatty acid treatment, the mean heart rate variability, defined as standard deviation of all normal RR intervals in 24-hour Holter recording, was significantly higher compared to baseline (124 ms vs. 115 ms, p=0.04). The mean difference in heart rate variability, defined as standard deviation of all normal RR intervals in 24-hour Holter recording, was significantly different after n-3 polyunsaturated fatty acid treatment (mean difference = −8.3, 95% CI −16 to −−1) compared to after the control treatment (mean difference = 9.4, 95% CI −2 to 20, p=0.01). |
A |
Amount |
Results |
Conclusion* |
Frequency of fish consumption: Never, <1 time/month, 1 time/month, 2-3 times/month, 1 time/week, 2-4 times/week, 5-6 times/week, 1 time/day, 2-3 times/day, 4-5 times/day, 6-7 times/day, ≥8 times/day Quintiles of n-3 PUFA from fish (g/day): Quintile 1 = 0.16±0.08 Quintile 2 = 0.36±0.06 Quintile 3 = 0.52±0.07 Quintile 4 = 0.74±0.10 Quintile 5 = 1.29±0.47 |
After adjusting for age, sex, height, BMI, smoking, consumption of alcohol, total energy intake, systolic blood pressure, treatment for hypertension, total serum cholesterol, and level of education: Those in Quintile 5 of n-3 PUFA from fish had a significantly higher hazard rate ratio of atrial fibrillation or flutter, when compared to those in Quintile 1 (HRR=1.34, 95% CI 1.02-1.76); and The association between n-3 PUFA from fish and risk of atrial fibrillation or flutter was not significant for any other quintiles when compared to Quintile 1, however there was a positive trend (p=0.006). |
N |
3 groups of DHA content in platelets: 1 = <2.26% 2 = 2.26-3.14% 3 = >3.14% Fish intake: 1 = 0 times/week 2 = 1 time/week 3 = ≥2 times/week |
The standard deviation of all normal RR intervals in the entire 24-hour recording was higher in those who ate fish at least 1 time/week (122 ms for those who ate fish 1 time/week and 119 ms for those who ate fish ≥2 times/week), compared to those who ate fish 0 times per week (103 ms), but these differences were not significant. The standard deviations of all normal RR intervals in the entire 24-hour recording for those in the first, second, and third tertile of DHA contents in platelets were approximately 98 ms, 116 ms, and 140 ms, respectively. |
A |
TABLE B-2f Studies on Other Cardiac Indicators
Author |
Study Type |
Subjects |
Exposure |
Agren et al., 1997* |
Randomized Controlled Trial |
Men (n=55) Healthy students Kuopio, Finland Follow-up of 15 weeks |
Seafood and n-3 supplementation |
Cobiac et al., 1991* |
Randomized Controlled Trial |
Men (n=31) Aged 30-60 years Adelaide, South Australia Mildly hyperlipidemic and normotensive No history of heart disease, hypertension, bleeding disorders, liver or renal disorders, gout, diabetes, recent cerebrovascular accident, or obesity No steroids, nonsteroidal anti-inflammatory drugs, aspirin, beta-blockers, allopurinol, or cardiac glycosides No excessive alcohol intake (>40 g/day) or who smoked >20 cigarettes/day Follow-up of 8 weeks |
Seafood and n-3 supplementation |
*Included in Balk E, Chung M, Lichtenstein A, Chew P, Kupelnick B, Lawrence A, DeVine D, Lau J. 2004. Effects of Omega-3 Fatty Acids on Cardiovascular Risk Factors and Intermediate Markers of Cardiovascular Disease. Summary, Evidence Report/Technology Assessment No. 93. (Prepared by the Tufts-New England Medical Center Evidence-based Practice Center, Boston, MA). AHRQ Publication No. 04-E010-1. Rockville, MD: Agency for Healthcare Research and Quality. ** N = Evidence of no association or no clear association; B = Evidence of a benefit. |
Amount |
Results |
Conclusion** |
Fish-diet group: 4.30±0.50 fish containing meals/week 0.38±0.04 g EPA and 0.67±0.098 g DHA/day Fish-oil group: 4 g/day 1.33 g EPA and 0.95 g DHA/day DHA-oil group: 4 g/day 1.68 g DHA/day |
The change in Factor X (% of normal) from baseline to 15 weeks was significantly greater in the fish-diet group compared to the control group (p<0.05). The change in collagen (50 µg/ml) from baseline to 15 weeks was significantly greater in the fish-diet group and the fish-oil group when compared to the controls (p<0.05). No other significant associations were found between the diet groups with regards to the change in PT (ratio), APTT (ratio), Factor VII (% of normal), Factor X (% of normal), fibrinogen (g/l), prothrombin fragment 1+2 (nmol/L), tissue factor pathway inhibitor (ng/mL), platelet aggregation (%T), ADP (2.0 µmol/L), ADP (5.0 µmol/L), and collagen (50 µg/L). |
N |
Fish treatment: 1 kg (raw) Atlantic salmon + 150 g sardines in sild oil per week 4.5 g EPA+DHA/day Fish-oil treatment: 105 g MaxEPA/week 4.6 g EPA+DHA/day Continued with meats as during baseline Control diet: Continuation of baseline diet |
The changes in fibrinogen and thromboxane were significantly lower and the change in bleeding time was significantly longer in the fish-diet group compared to the control diet group (p<0.05). |
B |
TABLE B-2g Studies on Diabetes
Author |
Study Type |
Subjects |
Exposure |
Dunstan et al., 1999* |
Randomized Controlled Trial |
Men and women (n=55) Mean age about 53 years Western Australia Nonsmoking, treated type II diabetes Fasting serum triglyceride >1.8 mmol/L and/or HDL-C <1.0 mmol/L and BMI <36.0 kg/m2 Follow-up of 8 weeks |
Diet (includes seafood) and exercise |
Amount |
Results |
Conclusion** |
Group 1: Low-fat diet (≤30% energy from fat) + moderate exercise (55-65% of Vo2max) Group 2: Low-fat diet (≤30% energy from fat) + light exercise (heart rate <100 bpm) Group 3: Low-fat diet with the inclusion of 1 fish meal daily (3.6 g n-3/day) + moderate exercise (55-65% of Vo2max) Group 4: Low-fat diet with the inclusion of 1 fish meal daily (3.6 g n-3/day) + light exercise (heart rate <100 bpm) |
The change in erythrocyte omega-3 fatty acids from baseline to end of intervention were significantly different for both the fish and moderate exercise (Group 3) and the fish and light exercise (Group 4) compared to the controls (p<0.05). The change in plasma tPa antigen from baseline to end of intervention were significantly different for the fish and moderate exercise (Group 3), fish and light exercise (Group 4), and no fish and moderate exercise (Group 1) groups compared to the controls (p<0.05). The change in erythrocyte omega-6 fatty acids from baseline to end of intervention were significantly different for both the fish and moderate exercise (Group 3) and the fish and light exercise (Group 4) compared to the controls (p<0.05). The change in plasma factor VII from baseline to end of intervention was significantly different for the fish and light exercise group compared to the control group (p<0.05). There were no significant differences in change in plasma PAI-1 antigen or change in plasma fibrinogen from baseline to end of intervention for the three other treatment groups compared to the controls. |
B |
Author |
Study Type |
Subjects |
Exposure |
Mori et al., 1999* |
Randomized Controlled Trial |
Men and women (n=63) Aged 40-70 years Royal Perth Hospital, Australia Nonsmoking men and postmenopausal women Overweight, BMI >25, systolic blood pressure 125-180 mmHg, diastolic blood pressure <110 mmHg Receiving antihypertensive treatment for ≥3 months No lipid-lowering or antiinflammatory drugs, no more than 1 fish meal/week, drank <175 g alcohol/week Follow-up of 16 weeks |
Seafood; diet |
Sirtori et al., 1998* |
Randomized Controlled Trial |
Men and women (n=935) Aged 45-75 for men Aged 55-80 for women Italy (63 clinical groups) Presenting with hyperlipoproteinemias type IIb or IV, associated with at least one further risk factor No severe intercurrent ailments, kidney or renal disease, intestinal malabsorptions, duodenal ulcer nonresponsive to therapy, BMI ≥30, history of vascular or nonvascular brain disease, severe hyperlipidemia needing drug treatment, severe hypertension, myocardial infarction in the preceding 3 months, or unstable angina Follow-up of 1 year |
n-3 supplement |
Amount |
Results |
Conclusion** |
Control group = weight-maintaining diet Fish group = weight-maintaining diet + fish daily (about 3.65 n-3/day) Weight loss group = energy restricted diet (to achieve 5-8 kg weight loss) Fish + weight loss group = energy restricted diet + fish daily |
From baseline to end of intervention, the fish + weight loss diet significantly increased plasma phospholipid n-3 fatty acids (p<0.0001) and significantly decreased plasma phospholipid n-6 fatty acids (p<0.0001), fasting insulin (p<0.05), and insulin AUC (p<0.05) compared to the control diet. From baseline to end of intervention, the fish diet (with weight maintenance) significantly increased plasma phospholipid n-3 fatty acids (p<0.0001) and plasma phospholipid n-6 fatty acids (p<0.0001) compared to the control group. From baseline to end of intervention, the change in fasting insulin levels and insulin AUC levels was significantly different in the fish group compared to the weight loss group and the fish + weight loss group (p<0.05). There was no association found between diet group and change in fasting glucose or glucose AUC. |
N |
For first 2 months: Group 1 = 1530 mg EPA/1050 mg DHA Group 2 = olive oil placebo After 2 months until 6 months: Group 1 = 1020 mg EPA/700 mg DHA Group 2 = olive oil placebo Open phase from 6-12 months: 2 g/day of n-3 ethyl esters |
No statistical differences could be detected between the two groups in terms of fasting glucose levels, Hb AIc and insulinemia after 1 year of treatment. |
N |
Author |
Study Type |
Subjects |
Exposure |
Grundt et al., 1995* |
Randomized Controlled Trial |
Men (n=51) Women (n=6) Aged 18-70 years Stavanger, Norway Outpatient center Has combined hyperlipidemia No dietary supplementation or medication containing omega-3 fatty acids during the run-in period, no antihyperlipemic medication No MI or other serious disease occurring within 3 months of enrollment, known diabetes mellitus, serious psychological disease, known drug or alcohol abuse, pregnancy or lactation Follow-up of 12 weeks |
n-3 supplement |
Kesavulu et al., 2002 |
Trial |
Men and women (n=34) Nonobese, type II diabetic On oral antidiabetic drugs, but not on lipid lowering drugs or antioxidant therapy Normotensive; no other clinical complications other than diabetes, no diabetic complications Follow-up of 3 months |
n-3 supplement |
Amount |
Results |
Conclusion** |
Treatment: 2 g concentrated ethylester compound 85% EPA/DHA Control: 2 g concentrated ethylester compound 85% corn oil |
There were no statistical differences between the two groups or within the groups (between 2 weeks before treatment and after 12 weeks of treatment) with regards to serum glucose, plasma insulin, plasma proinsulin, insulin:glucose ratio, and proinsulin:glucose ratio. |
N |
Group 1 diabetics: 1 month of antidiabetic drugs alone 2 months of omega-3 supplement (1080 mg EPA and 720 mg DHA/day) along with the antidiabetic drugs Group 2 diabetics: 3 months of antidiabetic drugs alone Group 3: Non-diabetic controls |
After combined therapy, fasting blood glucose and glycated hemoglobin were significantly higher in the Group 1 diabetics than in the controls (p<0.001). After 3 months of antidiabetic treatment, there were no significant differences in fasting blood glucose and glycated hemoglobin between Group 2 diabetics and the controls. |
B |
Author |
Study Type |
Subjects |
Exposure |
Madsen et al., 2001* |
Cross-sectional |
Men (n=171) Women (n=98) Aged 39-77 years Aalborg, Denmark Referred for coronary angiography because of clinical suspicion of CAD; clinically stable No acute myocardial infarction in past 6 months, nonischemic cardiomyopathy, pacemaker, or permanent tachyarrhythmias |
PUFA in granulocyte membranes; seafood |
*Included in Balk E, Chung M, Lichtenstein A, Chew P, Kupelnick B, Lawrence A, DeVine D, Lau J. 2004. Effects of Omega-3 Fatty Acids on Cardiovascular Risk Factors and Intermediate Markers of Cardiovascular Disease. Summary, Evidence Report/Technology Assessment No. 93. (Prepared by the Tufts-New England Medical Center Evidence-based Practice Center, Boston, MA). AHRQ Publication No. 04-E010-1. Rockville, MD: Agency for Healthcare Research and Quality. **B = Evidence of a benefit; N = Evidence of no association or no clear association. |
Amount |
Results |
Conclusion** |
Fish Score: (sum for lunch and dinner, can range from 2-12) 1 = never eating fish 2 = eating fish 1 time/month 3 = eating fish 2-3 times/month 4 = eating fish 1 time/week 5 = eating fish 2-3 times/week 6 = eating fish at least 1 time/day |
“Subjects with CRP levels in the lower quartiles had significantly higher contents of DHA in granulocytes than subjects with CRP levels in the upper quartile” (p=0.02). There were no significant associations found between CRP and LA, ALA, AA, EPA, or DPA content in granulocyte membranes or between CRP and fish score. |
N |
TABLE B-2h Studies on Adult Asthma and Allergies
Amount |
Results |
Conclusion* |
Quintiles of total fat intake (median): 1 = 51.9 g 2 = 62.7 g 3 = 69.9 g 4 = 77.0 g 5 = 87.4 g Quintiles of omega-3 (median): 1 = 0.05 g 2 = 0.09 g 3 = 0.13 g 4 = 0.21 g 5 = 0.36 g |
After adjusting for age, smoking, BMI, area of residence, number of physician’s visits, and quintiles of energy intake: There were no significant associations found between total fat intake, saturated fat intake, or omega-3 fat intake and the risk of asthma; Those in Quintile 3 of monounsaturated fat intake (median = 28.6 g) had a significantly lower RR of asthma than those in Quintile 1 (median = 20.1 g) (RR=0.74, 95% CI 0.59-0.93); and Those in Quintiles 2 and 4 of LA intake (median = 6 g and 11.1 g, respectively) had significantly lower RR of asthma than those in Quintile 1 (median = 4.49 g) (RR=0.71, 95% CI 0.57-0.89; RR=0.74, 95% CI 0.59-0.93; respectively). |
N |
Quartiles of fish intake, absolute amounts unspecified |
There were no significant differences found between the quartiles of all fish, shellfish, other seafood intake and prevalence of physician-diagnosed asthma (p=0.82, p=0.12, p=0.99, respectively). There was a significant difference among the quartiles of oily fish and the prevalence of physician-diagnosed asthma (quartile 1 = 1.5%, quartile 2 = 2.5%, quartile 3 = 4.6%, and quartile 4 = 4.9%; p=0.01). There were no significant differences found between the quartiles of all fish, oily fish, shellfish, other seafood intake and prevalence of physician-diagnosed allergic rhinitis (p=0.39, p=0.65, p=0.45, p=0.15, respectively). |
B |
TABLE B-2i Studies on Cancer
Author |
Study Type |
Subjects |
Exposure |
Stolzenberg-Solomon et al., 2002 |
Randomized Controlled Trial |
Men (n=27,111) Aged 50-69 years Southwestern Finland Smoked ≥5 cigarettes/day Alpha-tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study No history of malignancy other than nonmelanoma cancer of the skin or carcinoma in situ, severe angina upon exertion, chronic renal insufficiency, liver cirrhosis, chronic alcoholism, receipt of anticoagulant therapy, other medical problems which might limit long-term participation, and current use of supplements containing vitamin E (>20 mg/day), vitamin A (>20,000 IU/day), or beta-carotene (>6 mg/day) Follow-up of up to 13 years (260,006 person-years) |
Seafood; dietary fatty acids |
MacLean et al., 2006 |
Review |
Part of a larger systematic literature review Cohorts (n=20 cohorts; 38 articles) 11 different types of cancer |
Seafood; dietary fatty acids |
Amount |
Results |
Conclusion* |
Randomized to 50 mg/day of alpha-tocopherol, 20 mg/day of beta-carotene, both, or placebo Quantiles of fish intake and n-3 fish oil intake, absolute amount unspecified |
After adjusting for energy intake, age, and years of smoking, there were no significant associations found between quantities of fish intake or quantiles of n-3 fish oil intake and the risk of pancreatic cancer. |
N |
|
“For each breast, lung, and prostate cancer, there were significant associations for both increased and decreased risk and far more estimates that did not demonstrate any association.” “No trend was found across many different cohorts and many different categories of omega-3 fatty acid consumption to suggest that omega-3 fatty acids reduce overall cancer risk.” |
N |
Author |
Study Type |
Subjects |
Exposure |
Terry et al., 2003 |
Review |
7 cohort studies on breast cancer 8 cohort studies on prostate cancer 1 cohort study on endometrial cancer 19 case-control studies on breast cancer 9 case-control studies on prostate cancer 7 case-control studies on endometrial cancer 5 case-control studies on ovarian cancer |
Seafood, n-3 supplement, serum phospholipids, adipose tissue, and erythrocyte membrane fatty acids |
Amount |
Results |
Conclusion* |
|
“The development and progression of breast and prostate cancers appear to be affected by processes in which EPA and DHA play important roles.” However, “whether the consumption of fish containing marine fatty acids can alter the risk of these cancers or of other hormone-dependent cancers is unclear.” “Although there is ample evidence from in vitro and animal studies that these essential fats can inhibit the progression of tumors in various organs, particularly the breast and prostate, the evidence from epidemiologic studies is less clear.” “Although most of the studies did not show an association between fish consumption or marine fatty acid intake and the risk of hormone-related cancers, the results of the few studies from populations with a generally high intake of marine fatty acids are encouraging.” |
N |
Author |
Study Type |
Subjects |
Exposure |
Norat et al., 2005 |
Cohort |
Men and women (n=478,040) Aged 35-70 years 23 centers in 10 European countries European Prospective Investigation into Cancer and Nutrition (EPIC) Recruited from general population Free of cancer at baseline, other than nonmelanoma skin cancer Average follow-up of 4.8 years (2,279,075 person-years) |
Seafood |
Amount |
Results |
Conclusion* |
Categories of fish intake: 1 = <10 g/day 2 = 10-20 g/day 3 = 20-40 g/day 4 = 40-80 g/day 5 = ≥80 g/day |
After adjusting for age, sex, energy from nonfat sources, energy from fat sources, height, weight, occupational physical activity, smoking status, dietary fiber, alcohol intake, and stratified for center: Those in the 4th and 5th categories of fish intake had a significantly lower HR of colorectal cancer than those in the 1st category (HR=0.67, 95% CI 0.56-0.82; and HR=0.69, 95% CI 0.54-0.88, respectively). The HR for the 2nd and 3rd categories of fish intake were also lower compared to the 1st category, but they were not significant; Those in the 4th and 5th categories of fish intake had a significantly lower HR of rectal cancer than those in the 1st category (HR=0.64, 95% CI 0.47-0.88; and HR=0.49, 95% CI 0.32-0.76, respectively). The HR for the 2nd and 3rd categories of fish intake were also lower compared to the 1st category, but they were not significant; Those in the 4th category of fish intake had a significantly lower HR of colon cancer than those in the 1st category (HR=0.69, 95% CI 0.54-0.88). The HR for the 2nd, 3rd, and 5th categories of fish intake were also lower compared to the 1st category, but they were not significant; and Every 100 g increase in daily fish intake significantly lowered the HR for colorectal cancer (HR=0.70, 95% CI 0.57-0.87), colon cancer (HR=0.76, 95% CI 0.59-0.99), and rectal cancer (HR=0.61, 95% CI 0.43-0.87). |
B |
Author |
Study Type |
Subjects |
Exposure |
Allen et al., 2004 |
Cohort |
Men (n=18,115) Mean age at entry was 51 years Mean age at diagnosis was 75 years Hiroshima and Nagasaki, Japan Life Span Study/The Adult Health Study In Hiroshima or Nagasaki during the time of the bombs and who were residents of one of the cities in the 1950 census, or not present in either city at the time of the bombs No prostate cancer at baseline Average follow-up of 16.9 years (252,602 person-years) |
Seafood |
English et al., 2004 |
Cohort |
Men and women (n=37,112) Aged 27-75 years Melbourne, Australia The Melbourne Collaborative Cohort Study Deliberately recruited Italian and Greek migrants Free of colorectal cancer, diabetes, a heart attack, or angina at baseline Average follow-up of 9 years |
Seafood |
Amount |
Results |
Conclusion* |
Scores of intake for each food: 1 = Missing or <2 times/week 2 = 2-4 times/week 3 = Almost daily Total fish/broiled fish intake: Low = Score of 2 Intermediate = Score of 3-4 High = Score of ≥5 |
After adjusting for age, calendar period, city of residence, radiation dose, and education level: Those who ate fish almost daily had a significantly higher RR of prostate cancer compared to those who ate fish <2 times/week (RR=1.54, 95% CI 1.03-2.31). Those who ate fish 2-4 times/week also had a higher RR of prostate cancer compared to those who ate fish <2 times/week, but this association was not significant (RR=1.18, 95% CI 0.83-1.67); There were no significant associations found between broiled fish intake and risk of prostate cancer; and Those in the highest category of total fish intake had a significantly higher RR of prostate cancer compared to those in the lowest category (RR=1.77, 95% CI 1.01-3.11). Those in the intermediate category also had a higher RR of prostate cancer compared to those in the lowest category, but this association was not significant (RR=1.19, 95% CI 0.82-1.73). |
A |
Categories of fish intake: 1 = < 1.0 time/week 2 = 1.0-1.4 times/week 3 = 1.5-2.4 times/week 4 = 2.5+ times/week |
After adjusting for sex, country of birth, and intake of energy, fat, and cereal products: There were no significant associations found between fish intake (defined by four categories) and the risk of colorectal cancer, colon cancer, or rectal cancers; and There were no significant associations found between fish intake (defined as a continuous variable) and the risk of colorectal cancer (HR=0.99, 95% CI 0.91-1.08), colon cancer (HR=1.01, 95% CI 0.90-1.12), and rectal cancer (HR=0.97, 95% CI 0.84-1.12). |
N |
Author |
Study Type |
Subjects |
Exposure |
Folsom and Demissie, 2004 |
Cohort |
Women (n=41,836) Aged 55-69 years Iowa Iowa Women’s Health Study Group 1 = no heart disease or cancer at baseline Group 2 = no cancer at baseline, but a history of myocardial infarction, angina, or other heart disease Follow-up of 442,965 person-years |
Seafood; dietary fatty acids |
Augustsson et al., 2003 |
Cohort |
Men (n=47,882) Aged 40-75 years US health professionals Health Professionals Follow-up Study No diagnosis of cancer at baseline Follow-up of 12 years |
Seafood |
Amount |
Results |
Conclusion* |
Categories of fish intake: 1 = <0.5 times/week 2 = 0.5-1.0 times/week 3 = 1.0-1.5 times/week 4 = >1.5-<2.5 times/week 5 = ≥2.5 times/week Quintiles of omega-3 fatty acid intake: 1 = ≤0.05 g/day 2 = 0.06-0.10 g/day 3 = 0.11-0.16 g/day 4 = 0.17-0.26 g/day 5 = ≥0.27 g/day |
After adjusting for age, energy intake, education level, physical activity, alcohol consumption, smoking status, pack-years of cigarette smoking, age at first live birth, estrogen use, vitamin use, BMI, waist/hip ratio, diabetes, hypertension, intake of whole grains, fruit and vegetables, red meat, cholesterol, and saturated fat: Among women with no cancer or heart disease at baseline, no significant associations were found between frequency of fish intake and risk of cancer mortality or breast cancer; and Among women with no cancer or heart disease at baseline, no significant associations were found between quintiles of omega-3 fatty acid intake and risk of total mortality or breast cancer incidence. |
N |
Categories of fish consumption: 1 = <2 times/month 2 = 2 times/month to 1 time/week 3 = 2-3 times/week 4 = >3 times/week |
After adjusting for age, calories, fatty acids, lycopene, retinol, vitamin D, and physical activity: Those who ate fish >3 times/week had a significantly lower RR of metastatic prostate cancer than those who ate fish <2 times/month (RR=0.56, 95% CI 0.37-0.86). No other comparisons for metastatic prostate cancer were significant; There were no significant associations found between total fish consumption and all prostate cancer or advanced prostate cancer; and Each additional 0.5 g/day of marine fatty acids was associated with a RR of 0.76 (95% CI 0.58-0.98) for metastatic prostate cancer. “When fish intake was analyzed as a continuous variable, an increase in three servings of fish per week was associated with a RR of 0.75 (95% CI 0.60-0.94) for metastatic prostate cancer.” |
B |
Amount |
Results |
Conclusion* |
Categories of fish intake: 1 = ≤0.13 servings/day 2 = 0.14-0.20 servings/day 3 = 0.21-0.27servings/day 4 = 0.28-0.39 servings/day 5 = ≥0.40 servings/day |
After adjusting for age, 2-year time period, total energy intake, alcohol intake, parity and age at first birth, BMI at age 18, weight change since age 18, height in inches, family history of breast cancer, history of benign breast disease, age at menarche, menopausal status, age at menopause and hormone replacement therapy use, and duration of menopause: There was no significant association found between fish intake and the risk of breast cancer for the whole cohort or when premenopausal women and postmenopausal women were analyzed separately; and Similarly nonsignificant results were found when fish intake was defined as no intake, <1 serving/day and ≥1 serving/day. |
N |
Amount |
Results |
Conclusion* |
Lean fish = ≤8 g/100 g Fatty fish = >8 g/100 g Percentiles of lean fish intake: 5th percentile = 7 g/day 25th percentile = 16 g/day 75th percentile = 32 g/day 95th percentile = 56 g/day Percentiles of fatty fish intake: 5th percentile = 2 g/day 25th percentile = 6 g/day 75th percentile = 19 g/day 95th percentile = 39 g/day Percentiles of fried fish intake: 5th percentile = 5 g/day 25th percentile = 13 g/day 75th percentile = 30 g/day 95th percentile = 55 g/day Percentiles of boiled fish intake: 5th percentile = 0 g/day 25th percentile = 4 g/day 75th percentile = 11 g/day 95th percentile = 23 g/day Percentiles of processed fish intake: 5th percentile = 2 g/day 25th percentile = 6 g/day 75th percentile = 19 g/day 95th percentile = 40 g/day |
After adjusting for parity, benign breast tumor, years of school, use of hormone replacement therapy, duration of HRT use, BMI, and alcohol: Every 25 g/day increase in total fish consumption significantly increased the risk of breast cancer (IRR=1.13, 95% CI 1.03-1.23); and The risk of breast cancer is also increased for every 25 g/day increase in fatty fish (IRR=1.11, 95% CI 0.91-1.34), lean fish (IRR=1.13, 95% CI 0.99-1.29), fried fish (IRR=1.09, 95% CI 0.95-1.25), boiled fish (IRR=1.09, 95% CI 0.85-1.42), and processed fish (IRR=1.12, 95% CI 0.93-1.34), but the IRR were not. |
A |
Amount |
Results |
Conclusion* |
Categories of fish and shellfish intake: Low = <1 time/week Middle = 1-2 times/week High = ≥3 times/week |
After adjusting for age, sex, smoking, and occupation, those in the high-fish and -shellfish intake category had a significantly lower RR for incident lung cancer than those in the low category (RR=0.32, 95% CI 0.13-0.76) (p for trend = 0.003). The middle intake group also had a smaller RR but it was not significant (RR=0.99, 95% CI 0.48-2.03). After adjusting for age, sex, smoking, and occupation: Those in the middle and high categories of total fish intake (regardless of preparation method) had a significantly lower RR for incident lung cancer than those in the low category (RR=0.43, 95% CI 0.20-0.95; and RR=0.23, 95% CI 0.10-0.54; respectively); Those in the high categories of broiled and boiled fish intake had significantly lower RR for incident lung cancer than those in the low categories (RR=0.40, 95% CI 0.17-0.93; and RR=0.27, 95% CI 0.09-0.81; respectively). Those in the middle categories of broiled and boiled fish intake also had lower RR for incident lung cancer than those in the low category but they were not significant; and There were no significant associations found between raw or deep-fried fish intake and the risk of incident lung cancer. Similar results were found when the model further adjusted for drinking, exercise habit, consumption of meat, green-yellow vegetables, and salty/dried fish. |
B |
Author |
Study Type |
Subjects |
Exposure |
Ngoan et al., 2002 |
Cohort |
Men (n=5917) Women (n=7333) Aged >15 years Fukuoka Prefecture, Japan Follow-up of 139,390 person-years |
Seafood |
Ozasa et al., 2001 |
Cohort |
Men (n=42,940) Women (n=55,308) Aged 40-79 years 19 prefectures throughout Japan Japanese Collaborative Cohort (JACC) Study No history of lung cancer Average follow-up of 92 months |
Seafood |
Terry et al., 2001 |
Cohort |
Men (n=6272) Mean age of 55.6 years (baseline) Twin pairs from the Sweden Twin registry Sweden Follow-up of 30 years |
Seafood |
Amount |
Results |
Conclusion* |
Categories of cuttle fish intake: Low = seldom or never Medium = 2-4 times/month High = 2-4 times or more/week Categories of fish intake: Low = 2-4 times or less/month Medium = 2-4 times/week High = 1 time or more/day |
After adjusting for age, there was no significant association found between intake of fresh fish, processed fish, or cuttle fish and the risk of stomach cancer among men and women. After adjusting for age, sex, smoking, processed meat, liver, cooking or salad oil, suimono, and pickled food, there was no significant association found between intake of fresh fish, processed fish, or cuttle fish either including the first 3 years of follow-up or excluding the first 3 years of follow-up. |
N |
Categories of fish intake: 1 = ≤1-2 times/week 2 = 3-4 times/week 3 = Almost every day |
After adjusting for age, parents’ history of lung cancer, smoking status, smoking index and time since quitting smoking, there was no significant association found between fish intake and risk of lung cancer death in men or women. |
N |
Categories of fish intake: 1 = Never/seldom part of diet 2 = Small part of diet 3 = Moderate part of diet 4 = Large part of diet |
After adjusting for age, BMI, physical activity, smoking, and consumption of alcohol, red meat, processed meat, fruit and vegetables, and milk: Those who never or seldomly ate fish had a significantly higher RR of all prostate cancers than those who made fish a moderate part of their diet (RR=2.3, 95% CI 1.2-4.5, p<0.05); Those who never or seldomly ate fish had a significantly higher RR of prostate cancer deaths than those who made fish a moderate part of their diet (RR=3.3, 95% CI 1.8-6.0, p<0.01); and No other comparisons between fish consumption and all prostate cancers or prostate cancer deaths were significant. |
B |
Author |
Study Type |
Subjects |
Exposure |
Key et al., 1999 |
Cohort |
Women (n=34,759) Hiroshima and Nagasaki, Japan Life Span Study In Hiroshima or Nagasaki during the time of the bombs and city residents during the 1950 census, or not in either city at the time of the bombs Follow-up of 488,989 person-years |
Seafood |
Kato et al., 1997 |
Cohort |
Women (n=14,727) Aged 34-65 years New York and Florida New York University Women’s Health Study No use of hormonal medication or pregnancy in preceding 6 months Follow-up of 105,044 person-years |
Seafood |
Amount |
Results |
Conclusion* |
Categories of fish intake: 1 = ≤ 1 time/week 2 = 2-4 times/week 3 = ≥5 times/week 4 = Unknown |
After adjusting for attained age, calendar period, city, age at time of bombing, and radiation dose: There were no significant associations found between categories of fish (not dried) intake and risk of breast cancer; and Those in the “unknown” category of dried fish intake had a significantly lower RR of breast cancer than those in the 1st category (RR=0.77, 95% CI 0.60-0.98). No other comparisons for dried fish intake were significant. |
N |
Quartile of fish intake, absolute amounts not specified |
After adjusting for calories intake, age, place at enrollment, and highest level of education: Those in the 4th quartile of fish intake had a significantly lower RR of colorectal cancer compared to those in the 1st quartile (RR=0.49, 95% CI 0.27-0.89). The RR for those in the 2nd and 3rd quartiles were not significant (p for trend = 0.007); Those in the 4th quartile of fish protein intake had a significantly lower RR of colorectal cancer compared to those in the 1st quartile (RR=0.42, 95% CI 0.23-0.77). The RR for those in the 2nd and 3rd quartiles were also lower but not significant (p for trend = 0.016); Those in the 4th quartile of fish calcium intake had a significantly lower RR of colorectal cancer compared to those in the 1st quartile (RR=0.41, 95% CI 0.22-0.74). The RR for those in the 2nd and 3rd quartiles were also lower but not significant (p for trend = 0.001); and No significant association was found between fish fat intake and risk of colorectal cancer (p for trend = 0.056). |
B |
Author |
Study Type |
Subjects |
Exposure |
Veierod et al., 1997 |
Cohort |
Men (n=25,956) Women (n=25,496) Aged 16-56 years Norway Attended Norwegian health screening between 1977 and 1983 Average follow-up of 11.2 years (578,047 person-years) |
Seafood; n-3 supplements |
Chiu et al., 1996 |
Cohort |
Women (n=35,156) Aged 55-69 years Iowa Iowa Women’s Health Study No self-reported history of cancer at baseline or prior use of chemotherapy Follow-up of 7 years (233,261 person-years) |
Seafood |
Amount |
Results |
Conclusion* |
Cod-liver oil intake: yes or no Sardines, pickled herring (sandwich spread): yes or no Categories of fish liver intake: 1 = <1 time/week in season 2 = 1-2 times/week in season 3 = ≥3 times/week in season Categories of main meals with fish: 1 = <1 time/week 2 = 1-2 times/week 3 = 3-4 times/week 4 = ≥5 times/week |
After adjusting for smoking status, gender, age at inclusion, and attained age: Those taking cod liver oil had a lower incidence rate ratio of lung cancer compared to those not taking cod liver oil (IRR=0.5, 95% CI 0.3-1.0), but it was not significant; Those who consumed sardines and pickled herring had a significantly higher incidence rate ratio compared to those not consuming sardines and pickled herring (IRR=1.5, 95% CI 1.1-2.2); Those who consumed fish liver ≥3 times/week in season had a significantly higher incidence rate ratio of lung cancer compared to those who consumed fish liver <1 time/week in season (IRR=2.6, 95% CI 1.2-6.0). Those who consumed fish liver 1-2 times/week in season also had a higher incidence rate ratio compared to those who consumed fish liver1 time/week in season (IRR=1.1, 95% CI 0.7-1.7), but it was not significant; and Those who consumed main meals with fish ≥5 times/week had a significantly higher incidence rate ratio of lung cancer compared to those who ate main meals with fish <1 time/week (IRR=3.0, 95% CI 1.2-7.3). Those who consumed main meals with fish 1-2 times/week and 3-4 times/ week also had higher incidence rate ratios of lung cancer compared to those who consumed main meals with fish <1 time/week (IRR=1.1, 95% CI 0.6-2.2; and IRR=1.0, 95% CI 0.5-2.1), but they were not significant. |
B |
Categories of fish intake: 1 = <4 servings/month 2 = 4-6 servings/month 3 = >6 servings/month |
After adjusting for age and total energy intake, there were no significant associations found between intake of all fish or polyunsaturated fat and risk of non-Hodgkins lymphoma. |
N |
Author |
Study Type |
Subjects |
Exposure |
Chyou et al., 1995 |
Cohort |
Men (n=7995) Born in 1900-1919 Examined from 1965-1968 Oahu, Hawaii American men of Japanese ancestry Participated in the Honolulu Heart Program Follow-up of 24 years |
Seafood |
Giovannucci et al., 1994 |
Cohort |
Men (n=47,949) Aged 40-75 years US health professionals Health Professionals Follow-up Study No diagnosed cancer at baseline |
Seafood |
Le Marchand et al., 1994 |
Cohort |
Men (n=20,316) Aged <45 years Permanent resident of Hawaii Nonmilitary Japanese, Caucasian, Filipino, Hawaiian/part Hawaiian, and Chinese No invasive cancer within 5 years before entry, no diagnosis of prostate cancer earlier than 5 years before interview Median follow-up of 6 years (between entry and diagnosis for cases) |
Seafood |
Chyou et al., 1993 |
Cohort |
Men (n=7995) Born in 1900-1919 Examined from 1965-1968 Oahu, Hawaii American men of Japanese ancestry Participated in the Honolulu Heart Program Follow-up of 22 years |
Seafood |
Amount |
Results |
Conclusion* |
Categories of fish intake: 1 = ≤1 serving/week 2 = 2-4 servings/week 3 = ≥5 servings/week |
After adjusting for age, alcohol, number of cigarettes/day and number of years smoked: There was no significant association found between fish intake and the risk of upper aerodigestive tract cancer (RR=1.02, 95% CI 0.65-1.61 for 2-4 times/week compared to ≤1 time/week; and RR=1.37, 95% CI 0.70-2.69 for ≥5 times/week compared to ≤1 time/week). |
N |
Categories of fish intake (median): 1 = 8.4 g/day 2 = 20.9 g/day 3 = 31.0 g/day 4 = 47.8 g/day 5 = 83.4 g/day |
After adjusting for age, there was no significant association found between fish intake and the risk of colon cancer. |
N |
Quantile of fish intake, absolute amounts not specified |
After adjusting for age, ethnicity, and income, no significant association was found between risk of prostate cancer and quantile of fish intake at baseline. |
N |
Categories of fish intake: 1 = ≤1 serving/week 2 = 2-4 servings/week 3 = ≥5 servings/week |
After adjusting for age and smoking, there was no significant association found between fish intake and bladder cancer (RR=0.90, 95% CI 0.59-1.39 for 2-4 times/week compared to ≤1 time/week; and RR=0.67, 95% CI 0.26-1.67 for ≥5 times/week compared to ≤1 time/week). |
N |
Author |
Study Type |
Subjects |
Exposure |
Vatten et al., 1990 |
Cohort |
Women (n=14,500) Aged 35-51 years Norway Participated in the National Health Screening Service Follow-up of 11-14 years (mean = 12 years) |
Seafood |
Willett et al., 1990 |
Cohort |
Women (n=88,751) Aged 30-55 years US nurses Nurses’ Health Study (NHS) No history of cancer, inflammatory bowel disease, or familial polyposis at baseline Follow-up of 6 years (512,488 person-years) |
Seafood |
Amount |
Results |
Conclusion* |
Categories of overall fish intake: 1 = ≤2 times/week 2 = >2 times/week Categories of poached fish intake: 1 = <2 times/month 2 = 2-4 times/month 3 = ≥5 times/month |
After adjusting for age: Those who ate fish >2 times/week had a higher IRR of breast cancer when compared to those who ate fish ≤2 times/week, but it was not significant (IRR=1.2, 95% CI 0.8-1.7); and Those who ate poached fish 2-4 times/month and ≥5 times/month had lower IRR of breast cancer when compared to those who ate poached fish <2 times/week, but they were not significant (IRR=0.8, 95% CI 0.5-1.1; and IRR=0.7, 95% CI 0.4-1.0; respectively). |
N |
Categories of fish intake: 1 = <1 time/month 2 = 1-3 times/month 3 = 1 time/week 4 = 2-4 times/week 5 = ≥5 times/week Quintiles of chicken and fish intake: 1 = <22 g/day 2 = 22-28 g/day 3 = 29-40 g/day 4 = 41-64 g/day 5 = ≥65 g/day |
After adjusting for age, there was no significant association found between fish intake and incidence of colon cancer. After adjusting for age and total energy intake: Those in the 4th and 5th quintiles of chicken and fish intake had significantly lower RR of colon cancer compared to those in the 1st quintile (RR=0.47, 95% CI 0.27-0.81; and RR=0.56, 95% CI 0.34-0.92; respectively); and Those in the 2nd and 3rd quintiles of chicken and fish intake also had lower RR of colon cancer compared to those in the 1st quintile (RR=0.75, 95% CI 0.46-1.22; and RR=0.99, 95% CI 0.63-1.54; respectively), but they were not significant. |
N |
Author |
Study Type |
Subjects |
Exposure |
Mills et al., 1989 |
Cohort |
Men (n=about 15,000) Aged ≥25 years California Seventh-day Adventists Follow-up of 6 years (78,000 person-years) |
Seafood |
Kvale et al., 1983 |
Cohort |
Men (n=13,785) Women (n=2928) Men in a probability sample of the general population of Norway A roster of male siblings, living in Norway, of migrants to the US Male and female family members of patients interviewed in a Norwegian case-control study of gastrointestinal cancer Follow-up of 11.5 years |
Seafood |
Pan et al., 2004 |
Case-control |
Cases = with incident ovarian cancer (n=442) Controls = without cancer from eight provinces, except Manitoba (n=2135) Women Mean age of 55 years Canada National Enhanced Cancer Surveillance Study (NECSS) |
Seafood; dietary fatty acids |
Amount |
Results |
Conclusion* |
Categories of fish intake: 1 = Never 2 = <1 time/week 3 = ≥1 time/week |
After adjusting for age: Those who ate fish <1 time/week had a significantly higher RR of prostate cancer compared to those who never ate fish (RR=1.68, 95% CI 1.16-2.43); and Those who ate fish ≥1 time/week also had a higher relative risk of prostate cancer compared to those who never ate fish, but it was not significant (RR=1.47, 95% CI 0.84-2.60). After adjusting for age; education; current use of meat, poultry or fish, beans, legumes or peas, citrus fruit, dry fruit; and index of fruit, nuts, and tomatoes: No significant association was found between current use of fish and prostate cancer risk (RR=1.37, 95% CI 0.95-1.96 for <1 time/week compared to never and RR=1.57, 95% CI 0.88-2.78 for ≥1 time/week compared to never). |
A |
Index of frequency of fish intake (scores): 1 = <10 2 = 10-14 3 = 15-19 4 = ≥20 |
After adjusting for age, cigarette smoking, region, and urban/rural place of residence, no significant association was found between the fish intake (the highest score of fish intake compared to the lowest score of fish intake) and the risk of lung cancer, with either histologically verified primary tumor (β=−0.07±0.13, p=0.63) or squamous and small-cell carcinomas (β=−0.01±0.17, p=0.99). |
N |
Serving size=4 oz/week Quartiles of fish and fatty acid intakes, absolute amount unspecified |
After adjusting for 10-year age group, province of residence, education, alcohol consumption, cigarette pack-years, BMI, total caloric intake, recreational physical activity, number of live births, menstruation years, and menopause status: There were no significant associations found between fish intake or fatty acid intake (saturated, monounsaturated, or polyunsaturated) and risk of ovarian cancer. |
N |
Amount |
Results |
Conclusion* |
Categories of fish intake: 1 = 0 g/day 2 = 0-10 g/day 3 = 10-20 g/day 4 = >20 g/day Quintiles of fatty acids |
After adjusting for age and energy: Men in the 3rd category of fish intake had a significantly lower RR of colon cancer compared to men in the 1st category of fish intake (RR=0.41, 95% CI 0.21-0.83). No other significant relative risks of colon cancer were found based on fish intake for men, women, or both sexes; and No significant associations were found between risk of colon cancer and intake of energy, fat, saturated fat, monounsaturated fat, polyunsaturated fat, or protein for among men, women, or both sexes. |
B |
|
“Increasing evidence from animal and in vitro studies indicates that n-3 fatty acids, especially the long-chain polyunsaturated fatty acids EPA and DHA, present in fatty fish and fish oils, inhibit carcinogenesis.” “The epidemiologic data on the association between fish consumption, as a surrogate marker for n-3 fatty acid intake, and cancer risk are, however, somewhat less consistent.” n-3 fatty acids may modify the carcinogenic process by suppressing AA-derived eicosanoid biosynthesis; influencing transcription factor activity, gene expression, and signal transduction pathways; modulating estrogen metabolism; increasing or decreasing the production of free radicals and reactive oxygen species; and influencing insulin sensitivity and membrane fluidity. |
N |
TABLE B-2j Studies on Aging and Other Neurological Outcomes
Author |
Study Type |
Subjects |
Exposure |
Chen et al., 2003 |
Cohort |
Men with incident Parkinson’s disease (n=191) Women with incident Parkinson’s disease (n=168) Data from Health Professionals Follow-up Study and Nurses’ Health Study No Parkinson’s disease, stroke, or cancer at baseline Follow-up of 2 years |
Dietary fatty acids |
Amount |
Results |
Conclusion* |
Quintiles of polyunsaturated fatty acids, fish n-3 fatty acids, EPA, and DHA; absolute amounts not specified |
After adjusting for baseline age, length of follow-up, smoking, energy intake, alcohol consumption, and caffeine intake: There were no significant associations found between quintiles of polyunsaturated fatty acids, fish n-3 fatty acids, EPA, or DHA and risk of Parkinson’s disease. |
N |
Author |
Study Type |
Subjects |
Exposure |
Morris et al., 2003 |
Cohort (nested in a randomized controlled trial) |
Men and women (n=815) Aged ≥65 years Chicago, IL (south-side) 62% Black, 38% White, 61% female, mean education level 11.8 years Chicago Health and Aging Project Free of Alzheimer’s disease at baseline follow-up of 3 years |
Seafood and dietary n-3 fatty acids |
Amount |
Results |
Conclusion* |
Quintiles of n-3 fatty acids (g/day): 0.37-1.05, 1.06-1.22, 1.23-1.39, 1.40-1.60, 1.61-4.10 Categories of fish intake: Never, 1-3 times/month, 1 time/week, ≥2 times/week |
After adjusting for age, period of observation, and fish consumption (1-3 times/months, 1 time/week, and ≥2 times/week): There were no significant associations found between fish consumption and risk of incident Alzheimer’s disease; Those in the 5th quintile of total n-3 fatty acid intake had a significantly lower RR of incident Alzheimer’s disease than those in the 1st quintile (RR=0.3, 95% CI 0.1-0.7); and Those in the 4th quintile of DHA intake had a significantly lower RR of incident Alzheimer’s disease than those in the 1st quintile (RR=0.3, 95% CI 0.1-0.9). After adjusting for age, period of observation, fish consumption (1-3 times/month, 1 time/week, and ≥2 times/week), sex, race, education, total energy intake, APOE-ε4, and race × APOE-ε4 interaction: The higher categories of fish intake had lower RR of incident Alzheimer’s disease compared to those who never ate fish (RR=0.6, 95% CI 0.3-1.3 for 1-3 times/month; RR=0.4, 95% CI 0.2-0.9 for 1 time/week; and RR=0.4, 95% CI 0.2-0.9 for ≥2 times/week); Those in the 5th quintile of total n-3 fatty acid intake had a significantly lower RR of incident Alzheimer’s disease than those in the 1st quintile (RR=0.4, 95% CI 0.1-0.9); and Those in the 4th and 5th quintiles of DHA intake had a significantly lower RR of incident Alzheimer’s disease than those in the 1st quintile (RR=0.2, 95% CI 0.1-0.8; and RR=0.3, 95% CI 0.1-0.9; respectively). There were no other significant associations found between intake of n-3 fatty acids, DHA, EPA, and LA and the risk of incident Alzheimer’s disease. |
B |
Amount |
Results |
Conclusion* |
Categories of fish or seafood consumption: 1 = Once a day 2 = At least once a week (but not everyday) 3 = From time to time (but not weekly) 4 = Never |
After adjusting for age and sex, those who ate fish or seafood at least once a week had a significantly lower risk of being diagnosed with dementia in the 7 years of follow-up (HR=0.66, 95% CI 0.47-0.93). After adjusting for age and sex, those who ate fish or seafood at least once a week had a lower risk of developing Alzheimer’s disease in the 7 years of follow-up (HR=0.69, 95% CI 0.47-1.01), with borderline significance. After adjusting for age, sex, and education, those who ate fish or seafood at least once a week had a lower risk of being diagnosed with dementia in the 7 years of follow-up (HR=0.73, 95% CI 0.52-10.3), but it was not significant. There was a “significant trend between increasing consumption of fish or seafood and decreasing incidence of dementia (p for trend = 0.0091).” |
B |
Author |
Study Type |
Subjects |
Exposure |
Kalmijn et al., 1997a |
Cohort |
Men and women (n=5386) Aged >55 years Rotterdam, Netherlands Rotterdam Study About 43% former smokers, about 23% current smokers About 2% history of stroke, about 7% history of myocardial infarction Average follow-up of 2.1 years |
Dietary fatty acids |
Zhang et al., 2000 |
Cohort |
Women (n=92,422 in NHS, n=95,389 in NHS II) Aged 30-55 years in NHS Aged 25-42 years in NHS II US nurses living in 11 states Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHS II)—pooled Follow-up of 14 years in NHS and 4 years in NHS II |
Seafood and dietary fatty acids |
Amount |
Results |
Conclusion* |
Tertiles of total fat intake: ≤75.5 g/day, 75.5-85.5 g/ day, >85.5 g/day Tertiles of saturated fat intake: ≤29.0 g/day, 29.0-34.0 g/ day, >34.0 g/day Tertiles of cholesterol intake: ≤208.5 mg/day, 208.5-254.5 mg/day, >254.5 mg/day Tertiles of LA intake: ≤9.5 g/day, 9.5-15.0 g/day, >15.0 g/day Tertiles of fish intake: ≤3.0 g/day, 3.0-18.5 g/day, >18.5 g/day |
After adjusting for age, sex, education, and total energy: Those in the 3rd tertile of total fat intake had a significantly higher RR of total dementia than those in the 1st tertile (RR=2.4, 95% CI 1.1-5.2). Those in the 2nd tertile also had a higher RR of total dementia compared to those in the 1st tertile, but it was not significant; Those in the 3rd tertile of fish intake had a significantly lower RR of total dementia (RR=0.4, 95% CI 0.2-0.9) and Alzheimer’s disease without cerebrovascular disease (RR=0.3, 95% CI 0.1-0.9) than those in the 1st tertile. Those in the 2nd tertile also had a lower RR of total dementia and Alzheimer’s disease without cerebrovascular disease compared to those in the 1st tertile, but they were not significant; and No other significant RR were found for total dementia, Alzheimer’s disease without cerebrovascular disease, or dementia with a vascular component based on daily intake of total fat, saturated fat, cholesterol, LA and fish. |
B |
Categories of fish intake: 1 = <1 time/week 2 = 1-2.9 times/week 3 = 3-4.9 times/week Quintiles of total energy, total fat, animal fat, vegetable fat, saturated fat, monounsaturated fat, n-6 polyunsaturated fat, trans-unsaturated fat, cholesterol; absolute amounts not specified |
After adjusting for age, total energy, tier at birth, and pack-years of smoking: There were no significant RR of multiple sclerosis based on one unit daily increments of oleic acid (RR=0.7, 95% CI 0.4-1.4), LA (RR=0.3, 95% CI 0.1-1.1), AA (RR=0.9, 95% CI 0.7-1.2), fish omega-3 fatty acids (RR=1.1, 95% CI 0.9-1.3), EPA (RR=1.3, 95% CI 0.9-1.9), or DHA (RR=1.1, 95% CI 0.9-1.5) ; There were no significant RR of multiple sclerosis based on categories of fish and other seafood (RR=1.0, 95% CI 0.8-1.4 for category 2 compared to category 1; RR=0.9, 95% CI 0.6-1.3 for category 3 compared to category 1). |
N |
Author |
Study Type |
Subjects |
Exposure |
Kalmijn et al., 1997b |
Cohort |
Men (n=939) Aged 69-89 years Zutphen, Netherlands The Zutphen Elderly Study (continuation of the Zutphen Study) Follow-up of 3 years |
Dietary fatty acids |
Ghadirian et al., 1998 |
Case-control |
Cases = incident MS patients (n=197) Controls = from general population (n=202) Men and women Mean age of 42 years for male cases Mean age of 37.5 years for female cases Montreal, Canada |
Seafood |
Amount |
Results |
Conclusion* |
Total energy, n-6 PUFA, n-3 PUFA, fish as continuous variables Tertiles of n-3 fatty acids intake: Low = 0.0-37.5 mg/day Medium = 37.5-155.5 mg/day High = 155.5-2110.5 mg/day |
No significant differences in the change in daily intake of total energy, n-6 PUFA, n-3 PUFA, or fish from 1985-1990 were found between those with normal and impaired cognitive function. Those with normal cognitive function had significantly higher mean daily intakes of energy (p=0.03), DHA (p=0.05), and fish (p=0.02); and significantly lower mean daily intakes of total fat (p=0.02), total PUFA (p=0.002), and LA (p=0.006) than those with impaired cognitive function. The adjusted OR for prevalent cognitive impairment are OR=1.09 (95% CI 0.65-1.80) for medium n-3 fatty acid intake and OR=0.96 (95% CI 0.57-1.62) for high n-3 fatty acid intake compared to the low n-3 fatty acid intake (p for trend = 0.9). They are not significant. The adjusted OR for cognitive decline are OR=0.85 (95% CI 0.40-1.82) for medium n-3 fatty acid intake and OR=0.78 (95% CI 0.35-1.73) for high n-3 fatty acid intake compared to the low n-3 fatty acid intake (p for trend = 0.5). They are not significant. |
N |
100 g increments of intake/day |
After adjusting for total energy and BMI, every 100 g increase in daily fish intake decreases the risk of multiple sclerosis (OR=0.91, 95% CI 0.78-1.05). For males this statistic is 1.08 (95% CI 0.84-1.40), and for females this statistic is 0.83 (95% CI 0.69-1.00). |
B (females only) |
Amount |
Results |
Conclusion* |
Categories of fish/fish product intake: 1 = <1 time/week 2 = 1 time/week 3 = >1 time/week |
After adjusting for age of child, sex, maternal age at delivery, maternal age at menarche, maternal chronic disease, previous spontaneous abortions, persistent vomiting during index pregnancy, multiple pregnancy, number of obstetric visits, timing of membrane rupture in relation to index delivery, use of general anaesthesia in the index delivery, mode of delivery, abnormal placenta, head circumference, evident congenital malformation, place of index delivery, use of supplementary Fe during index pregnancy, intentional physical exercise during index pregnancy, painless delivery classes, energy intake, cereals and starchy roots, sugars and syrups, pulses and nuts/seeds, vegetables, fruits, meat and meat products, milk and milk products, and oils and fats: Each one weekly serving increase in fish and fish products during pregnancy lowered the odds of having a child with cerebral palsy (OR=0.63, 95% CI 0.37-1.08, p=0.09), but this statistic was not significant. |
N |
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Recommendations for Seafood and EPA/DHAConsumption
TABLE B-3 Recommendations for Seafood and EPA/DHA Consumption
Organization |
Audience |
Purpose of Recommendtion |
American Heart Association |
Healthy adults (without documented coronary heart disease) |
Reduce cardiovascular disease by dietary and lifestyle facts among the general population |
American Heart Association |
People with documented heart disease |
Secondary prevention |
American Heart Association |
People with elevated triglycerides |
Lower triglycerides |
Dietary Guidelines Advisory Committee |
Unspecified |
Provide sound and current dietary guidelines to consumers |
MyPyramid |
Americans |
Help Americans make healthy food choices, given their sex, age, and activity level |
National Cholesterol Education Program, National Heart, Lung, and Blood Institute |
People with high LDL-cholesterol/those adopting therapeutic lifestyle changes (TLC) |
Healthy lifestyle recommendation for a healthy heart |
American Diabetes Association |
Unspecified |
Lower risk of diabetes, and protect your heart and blood vessels |
World Health Organization |
Unspecified |
To protect against coronary heart disease and ischaemic stroke |
European Society of Cardiology |
General population |
To offer advice on food choices to compose a diet associated with the lowest risk of cardiovascular disease |
United Kingdom Scientific Advisory Committee on Nutrition |
General population and pregnant women |
To reduce risk of cardiovascular disease |
European Food Safety Authority |
Unspecified |
Reach daily intake for LC n-3 PUFA recommended for potential benefits to health |
National Heart Foundation of Australia |
People with coronary heart disease |
Preventing cardiovascular events |
Recommendations |
||
Type of Fish/Seafood |
Serving size |
# of Servings |
All fish, particularly fatty fish (salmon, albacore tuna, mackerel, lake trout, herring, and sardines) |
3 ounces cooked (or 4 ounces raw) |
Two per week |
EPA+DHA per day, preferably from fatty fish; supplements can be considered with physician consultation |
1 gram EPA+DHA |
One per day |
EPA+DHA per day as a capsule with physician consultation |
2-4 grams EPA+DHA |
One per day |
Fish, especially salmon, trout, white (albacore or bluefin) tuna, mackerel, or other fish that are high in EPA and DHA |
4 ounces |
Two per week |
Fish rich in omega-3 fatty acids, such as salmon, trout, and herring |
Not specified |
More often |
Fish, type unspecified |
≤5 ounces |
One per day |
Fish |
Not specified |
2–3 per week |
Fish, type unspecified |
Equivalent to 200–500 mg of EPA+DHA |
1–2 per week |
Fish, particularly oily fish |
Not specified |
Consumption encouraged |
Fish |
Not specified |
Two per week, one of which should be oil fish (≈450 mg/ day of LCPUFA) |
Fish, especially fatty fish |
130 grams |
1–2 per week |
Fish, preferably oily fish |
Unspecified |
At least 2 per week |
FDA and EPA Safety Levels in Regulations and Guidance
TABLE B-4 FDA and US EPA Safety Levels in Regulations and Guidance
Product |
Level |
Reference |
Ready-to-eat fishery products (minimal cooking by consumer) |
Enterotoxigenic Escherichia coli (ETEC)—1 × 103 ETEC/gram, LT or ST positive. |
Compliance Program 7303.842 |
Ready-to-eat fishery products (minimal cooking by consumer) |
Listeria monocytogenes—presence of organism. |
Compliance Program 7303.842 |
All fish |
Salmonella species—presence of organism. |
Sec 555.300 Compliance Policy Guide |
All fish |
|
Compliance Program 7303.842 |
Ready-to-eat fishery products (minimal cooking by consumer) |
Vibrio cholerae—presence of toxigenic 01 or non-01. |
Compliance Program 7303.842 |
Ready-to-eat fishery products (minimal cooking by consumer) |
Vibrio parahaemolyticus—levels equal to or greater than 1 × 104/gram (Kanagawa positive or negative). |
Compliance Program 7303.842 |
Ready-to-eat fishery products (minimal cooking by consumer) |
Vibrio vulnificus—presence of pathogenic organism. |
Compliance Program 7303.842 |
All fish |
Clostridium botulinum—
|
Compliance Program 7303.842 |
Clams and oysters, fresh or frozen—imports |
Microbiological—
|
Sec 560.600 Compliance Policy Guide |
Product |
Level |
Reference |
Clams, oysters, and mussels, fresh or frozen—domestic |
Microbiological—
|
Compliance Program 7303.842 |
Salt-cured, air-dried uneviscerated fish |
Not permitted in commerce (Note: small fish exemption). |
Sec 540.650 Compliance Policy Guide |
Tuna, mahi mahi, and related fish |
Histamine—500 ppm based on toxicity. 50 ppm defect action level, because histamine is generally not uniformly distributed in a decomposed fish. Therefore, 50 ppm is found in one section, there is the possibility that other units may exceed 500 ppm. |
Sec 540.525 Compliance Policy Guide |
All fish |
Polychlorinated Biphenyls (PCBs)—2 ppm (edible portion).a |
21 CFR 109.30 |
Fin fish and shellfish |
Aldrin and dieldrin—0.3 ppm (edible portion). |
Sec 575.100 Compliance Policy Guide |
Frog legs |
Benzene hexachloride—0.3 ppm (edible portion). |
Sec 575.100 Compliance Policy Guide |
All fish |
Chlordane—0.3 ppm (edible portion). |
Sec 575.100 Compliance Policy Guide |
All fish |
Chlordecone—0.4 ppm crabmeat and 0.3 ppm in other fish (edible portion). |
Sec 575.100 Compliance Policy Guide |
All fish |
DDT, TDE, and DDE—5 ppm (edible portion). |
Sec 575.100 Compliance Policy Guide |
All fish |
Heptachlor and heptachlor epoxide—0.3 ppm (edible portion). |
Sec 575.100 Compliance Policy Guide |
All fish |
Mirex—0.1 ppm (edible portion). |
Sec 575.100 Compliance Policy Guide |
All fish |
Diquat—0.1 ppm.a |
40 CFR 180.226 |
Product |
Level |
Reference |
Fin fish and crayfish |
Fluridone—0.5 ppm.a |
40 CFR 180.420 |
Fin fish |
Glyphosate—0.25 ppm.a |
40 CFR 180.364 |
Shellfish |
Glyphosate—3 ppm.a |
40 CFR 180.364 |
Fin fish |
Simazine—12 ppm.a |
40 CFR 180.213a |
All fish |
2,4-D—1 ppm.a |
40 CFR 180.142 |
Salmonids, catfish, and lobster |
Oxytetracycline—2 ppm. |
21 CFR 556.500 |
All fish |
Sulfamerazine—no residue permitted. |
21 CFR 556.660 |
Salmonids and catfish |
Sulfadimethoxine/ormetoprim combination—0.1 ppm. |
21 CFR 556.640 |
All fish |
Unsanctioned drugsb—no residue permitted. |
Sec 615.200 Compliance Policy Guide |
Crustacea |
Toxic elements: 76 ppm arsenic; 3 ppm cadmium; 12 ppm chromium; 1.5 ppm lead; 70 ppm nickel. |
FDA Guidance Documents |
Clams, oysters, and mussels |
Toxic elements: 86 ppm arsenic; 4 ppm cadmium; 13 ppm chromium; 1.7 ppm lead; 80 ppm nickel. |
FDA Guidance Documents |
All fish |
Methyl mercury—1 ppm.c |
Sec 540.600 Compliance Policy Guide |
All fish |
Paralytic shellfish poison—0.8 ppm (80 µg/100 g) saxitoxin equivalent. |
Sec 540.250 Compliance Policy Guide, and Compliance Program 7303.842 |
Clams, mussels and oysters, fresh, frozen or canned |
Neurotoxic shellfish poison—0.8 ppm (20 mouse units/100 grams) brevetoxin-2 equivalent. |
National Shellfish Sanitation Program Manual of Operations |
All fish |
Amnesic shellfish poison—20 ppm domoic acid, except in the viscera of dungeness crab, where 30 ppm is permitted. |
Compliance Program 7303.842 |
All fish |
Hard or sharp foreign object—generally 0.3 (7 mm) to 1.0 (25 mm) in length. |
Sec 555.425 Compliance Policy Guide |
aThese values are tolerances; bSanctioned drugs are approved drugs and drugs used under an INAD; cThe term “fish” refers to fresh or saltwater fin fish, crustaceans, other forms of aquatic animal life other than birds or mammals, and all mollusks, as defined in 21 CFR 123.3(d) (FDA, 2005c). SOURCE: CFSAN, 2001. |