PUFA NEWSLETTER. June 2009 Contents. Volume 14 Issue 2; EDITORIAL Omega-3 Fatty Acid Research: Observations and Interpretations...

Transcription

1 PUFA NEWSLETTER Volume 14 Issue 2; June 2009 Contents EDITORIAL Omega-3 Fatty Acid Research: Observations and Interpretations... 2 GUEST ARTICLE Dietary Omega-3 Fatty Acids and DHA Status J. Thomas Brenna, Ph.D., professor, Cornell University, Ithaca, NY... 3 CARDIOVASCULAR HEALTH One Fish Serving Weekly Associated With Lower Heart Failure in Middle-Aged Men... 5 Higher Dietary Omega-3 PUFAs Linked to Fewer Premature Ventricular Beats in Acute Myocardial Infarction... 6 Acute Coronary Syndrome Patients Better Distinguished From Controls with Red Blood Cell Fatty Acids and Standard Risk Factors... 7 MATERNAL AND INFANT HEALTH Fish Intake During Pregnancy Associated With Lower Chance of Low Birthweight Infants... 8 Prenatal Availability of DHA Linked to Higher Motor Function Scores at Age IMMUNE FUNCTION Fish Consumption Before 9 Months of Age Linked to Less Eczema n-3 LC-PUFAs in Pregnancy Linked to Lower Prostaglandin E 2, But Less so in Atopy Inflammatory Markers Lower in Healthy Adults Consuming Omega-3 PUFAs and Non-fried Fish MENTAL HEALTH Perinatal Depression Less Chance of Depression in Pregnancy for Women With Higher Intakes of Fish Low Fish Consumption in Pregnancy Related to Antidepressant Prescriptions Dementia Fish Consumption Unrelated to 10-Year Incidence of Dementia in Rotterdam Study Omega-3 PUFAs Not Associated With Dementia in Older Canadians PUFA NEWSLETTER STAFF Editor Joyce A. Nettleton, DSc Communications Manager Angela Dansby Sponsor DSM Nutritional Products, Kaiseraugst, Switzerland, SCIENCE ADVISORY BOARD J. Thomas Brenna, PhD Cornell University Ithaca, NY, USA Stefan Endres, MD University of Munich Munich, Germany Marlene P. Freeman, MD Massachusetts General Hospital Boston, MA, USA William S. Harris, PhD University of Missouri Kansas City, MO, USA Maria Makrides, PhD Women s and Children Hospital Adelaide, Australia Letters and editorial comments should be submitted to joyce@fatsoflife.com and technical comments to angela@fatsoflife.com. Subscribe to the PUFA Newsletter at

2 EDITORIAL Omega-3 Fatty Acid Research: Observations and Interpretations The June issue of the PUFA Newsletter features a guest article on one of the most commonly misunderstood aspects of omega-3 fatty acids, how dietary intakes affect docosahexaenoic acid (DHA) status. Written by J. Thomas Brenna, a professor at Cornell University, New York, and newsletter reviewer, the essay shows where much of the confusion lies about alpha-linolenic acid (ALA) and DHA status. Those who follow the field of omega-3 fatty acids in detail know that the body possesses the enzyme machinery to convert the 18-carbon plant-based omega-3 alpha-linolenic acid to the 20- and 22-carbon long-chain forms. Not only do we do this highly inefficiently, but we give up at docosapentaenoic acid. Humans do not make DHA from ALA. No more succinct and up-to-date summary of this important aspect of ALA metabolism has been published. The remainder of this issue relies heavily on observational studies, which always beg the question of causation. What do associations between variables mean? Intervention studies that could establish cause are wickedly expensive, limited to relatively small numbers of highly selected participants, and open to other criticisms. Yet observational studies can break new ground, as the report on dietary omega-3s and premature ventricular beats shows. They identify connections that may warrant controlled trials to obtain further validation. The observation that high-risk infants who are fed fish before the age of 9 months have significantly less eczema, for instance, would be worth exploring in a controlled trial. Observational studies also expand the body of evidence where studies are conflicting, as the report on inflammatory markers in healthy adults does. Two articles about depressive disorder in the perinatal period suggest that fish consumption in the last trimester of pregnancy might reduce the incidence of this serious illness. And a report from India, where rates of low birthweight, preterm delivery and small-for-gestational age infants are particularly high, describes the link between small amounts of fish consumption as little as 3 to 4 g per day in the third trimester and a significant reduction in low birthweight infants. Two studies on fish or omega-3 fatty acid consumption and dementia in older adults suggest that neither dietary component affects the likelihood of cognitive loss. These observations contrast markedly with studies of DHA content and function in the brains of patients with Alzheimer disease and other neurodegenerative disorders. The observational studies might spur research into why these different approaches to brain degeneration reach opposite conclusions. In omega-3 fatty acid research, the questions are always easier to ask than answer. The PUFA Newsletter welcomes comments from readers. Joyce A. Nettleton Editor, PUFA Newsletter and Fats of Life joyce@fatsoflife.com 2

3 GUEST ARTICLE Dietary Omega-3 PUFAs and DHA Status A frequent source of conflicting nutritional information is whether dietary alpha-linolenic acid (ALA) can augment body levels of the longchain omega-3 polyunsaturated fatty acids (n-3 LC- PUFAs). The answer is yes and no, depending on which n-3 LC-PUFA is being discussed. Confusing results can also emerge from the type of study used to answer the question. The major active n-3 LC-PUFAs are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Sensitive biochemical measurements show that ALA can be converted to EPA and DHA. However, it has long been known that most ALA is burned for fuel, and much of the rest is directed to the skin. The question is, how much ALA is converted to EPA and DHA, respectively? In considering dietary interventions, seemingly conflicting results can be reconciled by attention to two concepts: supplementation versus replacement. Supplementation is the addition of a dietary nutrient with no other change in the diet. Replacement is the substitution of one food for another. In the case of ALA, supplementation is achieved by the addition of an oil rich in ALA, such as flax or perilla oil, to an otherwise unchanged diet. The major change in the diet is an increase in ALA, with insignificant changes in other fatty acids. Replacement would be achieved by substituting an ALA-rich cooking oil such as canola for ALApoor oils such as corn, safflower, sunflower and peanut. Importantly, replacement also significantly alters the dietary proportion of the omega-6 PUFA, linoleic acid, a factor that is often overlooked in the interpretation of such studies. Linoleic acid competes with ALA for conversion to long-chain PUFAs and influences the answer. We recently considered 21 studies which intervened in ALA intake. 1 In 19 studies of adults, 17 were straightforward supplementation studies in which ALA was provided to participants and their blood n-3 LC-PUFAs measured. In all 17 studies, blood EPA and docosapentaenoic acid increased, but DHA did not significantly increase (14 of 17 studies) or increased by only 2% to 4% (3 of 17). A recent dose-response study is consistent. 2 More surprising than the ALA result is that the situation is the same for EPA supplementation. Seven studies in adults with pure EPA supplements show no changes in blood DHA,1 or a shorter chain intermediate, stearidonic acid. 3,4 There were, however, two studies of 19 that showed increases of greater than 10% DHA. In one, 5 DHA increased by an impressive 21%, when high- ALA perilla oil was used as cooking oil in place of moderate-ala soy oil over 10 months. Perilla oil has about 15% linoleic acid, compared to more than 50% linoleic acid in soy oil, and thus linoleic J. Thomas Brenna, PhD, professor, Cornell University, Ithaca, NY acid was reduced to less than a third of pre-intervention levels. In the second study, the investigators instructed the experimental group to avoid foods high in linoleic acid, in addition to the supplementation with ALA. 6 Similar results on blood DHA were found in cooking oil substitution studies in India. 7 Thus, ALA supplementation does increase EPA, but the evidence clearly shows that precursor supplementation does not increase blood levels of DHA whether the supplement is ALA, EPA or stearidonic acid. The only known means to increase blood DHA by supplementation is through the consumption of preformed DHA. Dietary DHA and blood/breast milk DHA has a remarkably tight dose-response relationship. 8 In contrast, reducing dietary linoleic acid enhances DHA status. The situation is a bit different in infants. In two studies, very high amounts of ALA did result in increases in blood DHA. 9,10 Notably, however, the most compelling data on DHA and human health is the effect of DHA on infant visual and neural development, indicating that the measurable improvement in DHA status with greater ALA intake is insufficient to support optimal development. Should adults reduce their dietary linoleic acid intake to enhance DHA status? This question is an actively controversial issue. On the one hand, the competition between linoleic acid and ALA limits the biosynthesis and accumulation of n-3 LC-PUFAs, 11 as seen in human 3

4 GUEST ARTICLE studies. On the other hand, recent consideration of the effects of linoleic acid on cardiovascular biomarkers has led to recommendations that restricted intakes of linoleic acid are likely to pose a serious risk of increasing cardiovascular disease. 12 If human DHA status does not much improve with consuming its precursors, and since DHA is primarily found in animal foods, a common question to arise in studies of DHA nutrition concerns vegans. Indeed, vegans have low blood and breast milk DHA. Vegan intake of DHA is negligible, but there is no frank deficiency syndrome associated with DHA deficiency, as is known in severe perinatal iodine deficiency, for instance. From this simple consideration, it is apparent that, on average, humans can synthesize sufficient DHA from ALA to meet the needs to stave off frank deficiency symptoms. Notably, however, there are relatively few native populations of vegans, apart from economic vegans who cannot afford animal products, and choice among some affluent individuals. Of much more concern is DHA deficiency that is well established in the offspring of pregnant animals maintained on high n-6, n-3-deficient oils, such as corn or sunflower oils. Rhesus monkeys or rats placed on high n-6 sunflower or safflower oils through pregnancy give birth to offspring with low retina and central nervous system DHA. Importantly, the offspring have diminished retinal and cognitive function, linked to specific biochemical changes in neurotransmission. The use of high n-6 oils with low-fat vegan diets is similar to diets that induce lasting impairment of neural function in these experimental animals. Oils deficient in n-3 PUFAs, including corn oil, have been a major source of fat in industrialized countries, but in general have not been consumed in large quantities by vegan populations. Vegan diets prevalent in the developing world tend to have a very low fat content. There is an important caveat to this analysis. Blood fractions (plasma, serum, white and red cells) as well as breast milk are accessible biomarkers of n-3 PUFA status in humans. However, DHA exerts its effects on vision and cognition in the central nervous system, which cannot be sampled directly for PUFA analysis. The central nervous system is a separate compartment from the blood. Thus, central nervous system DHA status must be inferred from measurements in the blood, which are necessarily indirect measures. PUFA concentrations in the central nervous system are very different from those in the blood. This being said, measurements in animals show that blood DHA rises or plateaus when central nervous system DHA rises. That is, blood and central nervous system DHA concentrations never move in different directions, with one rising and the other falling. With this information, we can confidently say that blood DHA is a suitable biomarker for central nervous system DHA, particularly at lower DHA levels where they are best correlated. One point on which all can agree: Adults increase their DHA status when they consume DHA. References 1. Brenna JT, Salem N Jr, Sinclair AJ, et al. Prostaglandins Leukot Essent Fatty Acids 2009; 80: Barcelo-Coblijn G, Murphy EJ, Othman R. et al. Am J Clin Nutr 2008;88: Harris WS, Lemke SL, Hansen SN, et al. Lipids 2008;43: James MJ, Ursin VM, Cleland LG. Am J Clin Nutr 2003;77: Ezaki O, Takahashi M, Shigematsue T, et al. J Nutr Sci Vitaminol (Tokyo) 1999;45: Mantzioris E, James MJ, Gibson RA, et al. Am J Clin Nutr 1995;61: Ghafoorunissa, Vani A, Laxmi R, et al. Lipids 2002;37: Gibson RA, Neumann MA, Makrides M. Eur J Clin Nutr 1997;51: Clark KJ, Makrides M, Neumann MA, et al. J Pediatr 1992;120(4 Pt 2):S151-S Jensen CL, Chen H, Fraley JK, et al. Lipids 1996;31: Lands B. Prog Lipid Res 2008;47: Harris WS, Mozaffarian D, Rimm E, et al. Circulation 2009;119:

5 CARDIOVASCULAR HEALTH One Fish Serving Weekly Associated With Lower Heart Failure in Middle-Aged Men Although heart failure is becoming increasingly common, there has been only one report on whether eating fatty fish affects the chance of developing this condition. A study in Swedish men suggests that eating fatty fish once a week is helpful. Many studies have reported that fish consumption is associated with lower rates of heart disease, cardiovascular mortality and sudden death, yet the data are not entirely consistent. There is limited evidence that eating tuna or other baked or broiled fish is linked to a significantly lower occurrence of heart failure, the inability of the heart to pump sufficient blood to the body. In Europe and the U.S., heart failure affects up to 2% of the population, with the incidence rising to nearly 9% in older adults. The main contributing factors to heart failure are underlying coronary artery disease, high blood pressure and diabetes. Because the number of people over the age of 65 years is increasing in developed countries and coronary artery disease, hypertension and diabetes are common, it is expected that the prevalence of heart failure will continue to rise. Easy-to-implement strategies that might blunt the increase in heart failure would be most salutary. In the prospective observational study described here, investigators at the Harvard Medical School, Boston, USA, and the Karolinska Institute, Stockholm, Sweden, monitored a population-based cohort of 39,367 Swedish men, aged 45 to 79 years, for 7 years. Participants had no history of heart failure or cancer at baseline. Food consumption, with emphasis on the type and frequency of fish eaten, was estimated by food frequency questionnaire. Participants with a history of myocardial infarction or diabetes were excluded from the primary analysis. Hospitalization or death from heart failure was determined from the Swedish inpatient register, which captures more than 99% of in-patient care. The relationships between quintiles of fish consumption or marine omega-3 polyunsaturated fatty acid (n-3 LC-PUFA) intakes and heart failure were expressed as hazard ratios based on Cox proportional hazards models, adjusted for multiple variables. In this population, approximately 15% of the men never ate fatty fish and only 2% ate such fish 3 or more times/week. Over the 7-year observation period, 597 men without a history of myocardial infarction or diabetes developed heart failure of whom 34 died. The association between fatty fish intake and heart failure was not statistically significant with adjustment for multiple variables (Table). Those with the lowest hazard ratio for heart failure were in the middle quintile, having an average fish intake of one serving/week. The relationship between n-3 LC-PUFA intake and heart failure was similar, with the lowest hazard ratio occurring in the middle quintile of intake (P for quadratic trend = 0.02). The lowest rates of heart failure were observed in men who consumed fatty fish once a week. Higher fish intakes were not associated with lower rates of heart failure. In this large observational study, the lowest rates of heart failure were observed in men who consumed fatty fish once/week compared with men who ate no fatty fish or those who consumed 3 servings a week or more. The same was true for the relationship with n-3 LC-PUFAs, except that the risk of heart failure was 33% lower in the third compared with the first quintile. These observations contrast with the one other study that examined the relationship between heart failure and fish or n-3 LC-PUFA intake. In that study, increasing fish consumption was associated with reduced likelihood of heart failure. The reasons for the unexpected U-shaped relationship between heart failure and eating fatty fish Table. Quintiles of fish intake in men aged 45 to 79 yr and the incidence and hazard ratios (CI) of heart failure over 7 years Fatty fish intake Never < 1 serv/wk 1 serv/wk 2 serv/wk 3 serv/wk Patients with heart failure Hazard ratio* adjusted for 14 variables ( ) 0.88 ( ) 0.99 ( ) 0.97 ( ) *Adjusted for age, body mass index, physical activity, energy, alcohol, fiber, sodium, red or processed meat consumption, education, family history of myocardial infarction before age 60, cigarette smoking, marital status, self-reported history of hypertension and high cholesterol. 5

6 in this study and the lack of greater benefit with more frequent fish consumption are unclear. Consuming fatty fish was of some benefit compared with not eating any fatty fish, but the relationships with heart failure appear to be more complicated than what is revealed by correlations. Levitan EB, Wolk A, Mittleman MA. Fish consumption, marine omega-3 fatty acids, and incidence of heart failure: a population-based prospective study of middle-aged and elderly men. Eur Heart J 2009;30: In patients who have survived a myocardial infarction, the presence of premature ventricular beats or ventricular ectopy increases the risk of developing potentially fatal ventricular tachycardia. Whether omega-3 PUFAs reduce ventricular ectopy in heart attack survivors was examined in this study. Higher Dietary Omega-3 PUFAs Linked to Fewer Premature Ventricular Beats in Acute Myocardial Infarction Several lines of evidence suggest that long-chain omega-3 polyunsaturated fatty acids (n-3 LC-PUFAs) found mainly in fish and shellfish, exert many of their cardioprotective effects by improving the electrical function of the heart. For example, these fatty acids significantly reduce the risk of sudden death, are antiarrhythmic, increase heart rate variability, lower the likelihood of prolonged ventricular repolarization in a resting electrocardiogram, decrease heart rate, slow the electrical conduction between the atria and ventricles, and reduce the incidence of atrial fibrillation in patients who have had a myocardial infarction. However, their effects on arrhythmias in patients with implantable cardioverter defibrillators are inconsistent and in a limited number of studies, may be neutral or possibly adverse. These advantages have prompted clinicians to evaluate the effectiveness of n-3 LC-PUFAs in different types of heart disease patients, including those with acute coronary syndrome, heart failure, angina pectoris, myocardial infarction and different types of arrhythmias. In patients who have survived a myocardial infarction, the chance of sudden death is greatest in the 30-day period following a heart attack, with heart failure increasing the risk of cardiac mortality 4-fold. Reduced systolic function of the right ventricle is also associated with a 50% increase in the chance of fatal or non-fatal cardiac outcomes in post-heart attack survivors. Figure. Electrocardiogram showing two premature ventricular contractions. Source: Wikipedia. One type of arrhythmia believed to be common yet benign, observed in cardiac patients and those with no evidence of heart disease, is the premature ventricular contraction, also known as ventricular ectopy or early repolarization (Figure). An ectopic or premature ventricular complex is a depolarization that arises in either of the heart s ventricles before the next expected sinus beat, i.e., prematurely. These early ventricular contractions result in slower electrical conduction through the heart muscle and in individuals with heart disease can increase the likelihood of developing ventricular tachycardia (rapid beats) or ventricular fibrillation. There are no data on whether n- 3 LC-PUFAs affect ventricular ectopy in patients who have survived a myocardial infarction. To examine this question, Patrick Smith and colleagues at Duke University, North Carolina, USA, recruited 260 patients with acute myocardial infarction within 72 hours of their heart attack. Participants ranged from 27 to 86 years of age, with 73% having a history of smoking. Patients who were too ill, had chronic arrhythmia or left ventricular ejection fractions below 20%, had a pacemaker or were planning to undergo coronary artery bypass surgery were excluded. Food intakes were estimated from an interviewer-administered food frequency questionnaire during hospitalization. Consumption of n-3 LC-PUFAs and total n-3 PUFAs were estimated from the food intake data. Electrocardiograms were obtained during or immediately after hospitalization for the myocardial infarction. As might be expected in this US sample, the consumption of total n-3 PUFAs was low 760 mg/1,000 kcal. Consumption of eicosapentaenoic and docosahexaenoic acids was 140 mg/1,000 kcal, with the remaining n-3 PUFA intake attributable to alpha-linolenic acid. Higher intakes of total n-3 PUFAs were associated with less ventricular ectopy (Figure) after controlling for cardiovascular comorbidities (P = 0.01). Higher intakes of the marine n-3 LC-PUFAs tended to be associated with 6

7 reduced ventricular ectopy, but the relationship did not reach statistical significance (P = 0.06). Significantly less ventricular ectopy occurred with higher intakes of alpha-linolenic acid (P = 0.02). Figure. Relationship between the consumption of total n-3 PUFAs and premature ventricular beats (logtransformed data adjusted for multiple variables) in post-myocardial patients, P =0.01. Reproduced with permission from Am J Clin Nutr 2009;89: American Society for Nutrition. Higher consumption of total n-3 PUFAs was associated with fewer premature ventricular beats in the high-risk period following an acute myocardial infarction. Reduced ventricular ectopy lowers the risk of sudden death and cardiac mortality in survivors of a myocardial infarction. It is noteworthy that the reduction in ventricular ectopy occurred during the high-risk period 30 days after a myocardial infarction. Although this aspect of the antiarrhythmic effects of n-3 PUFAs has not been previously described, this report adds to the substantial literature on antiarrhythmias. In one report, n-3 LC-PUFAs did not affect the number of premature ventricular complexes in patients with frequent occurrences of them, but did reduce the number of premature ventricular beats in patients with suspected heart disease. Greater frequency of premature ventricular complexes is linked to increased likelihood of cardiac mortality and sudden death and arrhythmic events. Low serum concentrations of n-3 LC-PUFAs were associated with increased likelihood of ventricular fibrillation during an acute myocardial infarction. These findings, if confirmed in other studies of myocardial patients that include measurement of red blood cell n-3 PUFAs, would expand the reasons for ensuring that consuming n-3 PUFAs becomes a regular part of cardiovascular care and prevention. Smith PJ, Blumenthal JA, Babyak MA, Georgiades A, Sherwood A, Sketch MH Jr, Watkins LL. Association between n-3 fatty acid consumption and ventricular ectopy after myocardial infarction. Am J Clin Nutr 2009;89: Acute Coronary Syndrome Patients Better Distinguished From Controls With Red Blood Cell Fatty Acids and Standard Risk Factors Using the standard risk factors of age, sex, total or low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, blood pressure, smoking and diabetes status or recently developed prediction equations, e.g., the 3 rd Joint European Task Force or the Reynolds Risk Score, Can the predictive value of the standard risk factors typically used to gauge the risk of acute coronary syndrome be improved by including fatty acid information? This study suggests that adding data on red blood cell fatty acids enhances cardiac risk assessment. physicians have powerful tools to assess their patients risk of heart disease. Nevertheless, it is believed that additional biomarkers, already shown to be independent predictors of cardiac events, could further improve these risk assessments. Two clinical measurements independently associated with increased risk of heart disease are C-reactive protein, an indicator of subclinical inflammation, and red blood cell fatty acids, especially low concentrations of the main long-chain omega-3 polyunsaturated fatty acids (n- 3 LC-PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). In this article, Gregory Shearer and colleagues at the Sanford Cardiovascular Research Center, South Dakota, USA, explored the relationships between different patterns of red cell fatty acids and the ability to discriminate between controls and patients who had been recently admitted to the hospital with an acute coronary syndrome, which includes acute myocardial infarction or unstable angina. Patients with a confirmed acute coronary syndrome were recruited from two Missouri hospitals, whereas control participants were outpatients having blood taken for routine clinical testing. After matching and exclusions for missing data, the sample consisted of 668 cases and 680 controls. Red blood cell fatty acids were determined in all participants. The ability of the standard risk factors to discriminate between 7

8 acute coronary syndrome patients and controls was compared to that of several fatty acid-based metrics. The latter included a computer-selected composite of 10 fatty acids and 4 predefined fatty acid patterns. The fatty acid patterns included the omega-3 index (red blood cell EPA+DHA as a percent of total red cell fatty acids), the ratio of n-6:n-3 PUFAs, total n-3 LC-PUFAs, and the proportion of all LC-PUFAs in the n-3 class. As expected, the standard heart disease risk factors were more common in the participants with acute coronary syndrome than in the controls. In univariate analysis, the groups differed in 12 of the 18 fatty acids examined, with lower concentrations of linoleic acid, stearic acid and DHA being the most strongly predictive of acute coronary syndrome cases. The odds ratios for these fatty acids were 0.15, 0.22 and 0.33, respectively, without including the standard risk factors in the model. Including the standard risk factors had a negligible effect on the odds ratios. Compared with the ability of the standard risk factors to predict the chance of developing acute coronary syndrome, the 10-fatty acid profile provided a significant improvement (Table). The two combined improved the ability of the standard risk factors to predict acute coronary syndrome, but the predictability of the fatty acid profile was not significantly improved by including the standard risk factors (Table). None of the 4 pre-selected fatty acid patterns further improved the predictability of the standard risk factors alone. Table. Ability of standard risk factors, fatty acids or both to predict acute coronary syndrome in statistical models Risk model Variables c-statistic* P All patients Standard risk factors (7) Fatty acids (10) Standard risk factors + fatty acids *Based on area under the curve. The study observed that both n-3 and n-6 PUFAs were inversely associated with risk of acute coronary syndrome and that higher levels of trans fatty acids were linked to greater risk. The strongest association with any red blood cell fatty acid and lower risk of acute coronary syndrome was observed for linoleic acid. Perhaps surprisingly, n-3 LC-PUFAs did not improve the predictability of standard risk factors for acute coronary syndromes, as they have been reported to do for sudden death. The key observation in this study is that the red blood cell fatty acid pattern may be superior to standard risk factors for the prediction of acute coronary syndrome. However, these crosssectional findings need prospective validation. The authors noted that red blood cell fatty acid composition has several advantages as a biomarker because it reflects the fatty acid pattern prior to a cardiac event and is not affected by acute coronary events. In addition, red blood cell fatty acids are stable and are highly correlated with myocardial fatty acid composition. Taking into consideration a greater array of red blood cell fatty acids than just n-3 LC-PUFAs, for example, improved the predictability of risk models for acute coronary syndrome. This observation could stimulate other laboratories to determine the extent to which red blood cell fatty acid patterns might improve risk prediction in other settings. These findings confront more settled thinking about PUFAs and heart health and may create a place for a lipidomic approach to assessing heart health. Shearer GC, Pottala JV, Spertus JA, Harris WS. Red blood cell fatty acid patterns and acute coronary syndrome. PLoS ONE: 2009;4:e5444. MATERNAL AND INFANT HEALTH Fish Intake During Pregnancy Associated With Lower Chance of Low Birthweight Infants The effect of maternal fish consumption In countries such as India with high rates of low birthweight infants and low fish with long-chain or supplementation or long-chain omega-3 fatty omega-3 polyunsaturated fatty acids acid intakes, consuming (n-3 LC-PUFAs) during pregnancy on even small amounts of fish or omega-3s is linked to infant birthweight better birth outcomes. and the rate of low birthweight in lowand high-risk pregnancies has generally been reported as negligible or very small. Overall, studies have observed a lower chance of preterm birth and longer gestation with higher intakes of fish or n-3 LC-PUFAs, but the data are inconsistent. It is not known whether women in countries with high rates of low birthweight infants, who have higher intakes of fish or n-3 LC-PUFAs, are just 8

9 as likely to have low birthweight infants as those who consume little or no fish. In India, where n-3 LC-PUFA intakes are low, a recent report cited rates of low birthweight, preterm births and small-for-gestational-age infants substantially higher than observed in western countries. In rural West Bengal, the incidence of low birthweight was even higher than that observed in southern India (31% versus 17%). Considering the greatly increased health risks associated with low birthweight, simple, effective and economic nutritional strategies to improve birth outcomes would have substantial benefits. A low intake of n-3 LC-PUFAs reduces the amount of docosahexaenoic acid (DHA) available to the developing fetus, especially in vegetarian diets. The conversion of the plant-based precursor alpha-linolenic acid to DHA for fetal neurodevelopment is insufficient to meet the fetus needs. That leaves maternal stores as the main source of n-3 LC-PUFAs for the fetus when maternal intake is low. To explore the relationships between maternal fish intake, red blood cell n-3 LC-PUFA status and the incidence of low birthweight, investigators at the St. John s Medical College Hospital, Bangalore, India, recruited pregnant women at less than 20 weeks gestation, between the ages of 17 and 40 years, from those who attended prenatal screening at the hospital. Women with multiple pregnancies, chronic illness such as diabetes or hypertension or were HIV positive were excluded. Of the 1,300 eligible women, 897 agreed to participate and 829 completed the study at delivery. Sociodemographic data and dietary intakes for the preceding three months were ascertained at baseline and again in the second and third trimesters. The investigators used a pretested food frequency questionnaire administered by an interviewer and adapted for urban south Indian adults. Indian food composition tables or the U.S. Department of Agriculture nutrient database were used to estimate nutrient and n-3 LC-PUFA intakes. The researchers defined low birthweight as less than 2,500 g, preterm delivery as before 37 weeks gestation, and intrauterine growth retardation as birthweight less than the 10 th percentile for gestational age. There were 764 live births, of which 676 occurred in the absence of gestational diabetes. The prevalences of low birthweight and preterm delivery were 21% and 10%, respectively. Approximately half the mothers consumed fish, with median intakes among these women of 3 to 4 g/day. Consumption of eicosapentaenoic acid (EPA) was about 2 to 3 mg/day and DHA about 10 to 11 mg/day. Women who did not consume fish were 2.5 times more likely to give birth to a low birthweight infant than women Figure. Odds ratio for the chance of delivering a low birthweight infant by maternal fish or EPA intakes in the third trimester of pregnancy. Fish intakes expressed as above or below the median. EPA intakes are medians by tertiles. whose fish intake was above the median (Figure). Similarly, the lowest tertile of maternal eicosapentaenoic acid (EPA) intake (median, 0.3 mg/day) was associated with a nearly 3-fold greater chance of having a low birthweight infant compared with women in the highest tertile of consumption (9.5 mg/day). Fish intake during the first two trimesters was unrelated to the likelihood of delivering a low birthweight infant. The investigators did not present the odds ratios for dietary or red blood cell DHA and the chance of low birthweight. Neither fish nor EPA consumption were related to the length of gestation. The investigators also noted that during pregnancy the red cell membrane status of arachidonic acid and EPA declined. Others have reported that maternal plasma phospholipid DHA concentrations remain relatively constant throughout pregnancy, but that the essential fatty acid index declines because of the increase in total plasma fatty acids with pregnancy. Among women who eat little fish or long-chain omega-3 fatty acids, consuming small amounts of fish significantly reduced the chance of delivering a low birthweight infant. In a population with high rates of low birthweight infants and low intakes of fish and n-3 LC-PUFAs, women who consumed the most fish during pregnancy, median about 4 g/day, were significantly less likely to have a low 9

10 birthweight infant compared with women who did not eat fish. The researchers reported a similar relationship between maternal red blood cell EPA and the chance of low birthweight, suggesting that it is likely the n- 3 LC-PUFA content of fish that links fish consumption and birthweight. There was no significant association between fish or EPA intakes and length of gestation. What stands out in this report is that even very small intakes of fish and n-3 LC-PUFAs may make a measurable difference in achieving healthy birth outcomes. Muthayya S, P Dwarkanath P, T Thomas T, S Ramprakash S, R Mehra R, Mhaskar A, Mhaskar R, Thomas A, Bhat S, Vaz M, A V Kurpad AV. The effect of fish and _-3 LCPUFA intake on low birth weight in Indian pregnant women. Eur J Clin Nutr 2009;63: Prenatal Availability of DHA Linked to Higher Motor Function Scores at Age 7 The Prenatal availability of long-chain PUFAs may be more important for children s neurodevelopment than postnatal supply. DHA status at birth was associated with higher motor function scores at age 7. rapid growth of the brain and central nervous system during the last trimester of fetal life and for at least two years after birth requires sufficient amounts of long-chain polyunsaturated fatty acids (LC-PUFAs) for brain cell structure and function. During pregnancy, the fetus obtains these fatty acids from the mother s diet, body stores, and to a lesser extent, synthesis from 18-carbon precursor fatty acids. The two main LC-PUFAs needed are arachidonic acid (ARA), an omega-6 LC-PUFA, which appears to be under tight regulatory control, and docosahexaenoic acid (DHA), an omega-3 LC-PUFA. The availability of DHA is highly dependent on the mother s dietary intake, because synthesis from precursors is extremely limited. Many studies have reported that infants receiving DHA during the last trimester of pregnancy through increased maternal consumption of preformed DHA, or postnatally from the consumption of breast milk or DHA-supplemented infant formula have superior neurodevelopmental outcomes compared with infants whose mothers have low DHA intakes or those fed unsupplemented infant formula. These findings, although sometimes inconsistent, have led to the concept that DHA is a conditionally essential nutrient for the developing infant. In healthy term infants, the benefits of enhanced DHA nutrition have been more difficult to demonstrate compared with preterm infants. For example, maternal supplementation with DHA during pregnancy did not enhance visual maturation in healthy term infants, but the investigators observed more mature visual function. Global assessments of cognitive development have been less likely to report improved outcomes with greater DHA availability compared with more specific measures of cognition, such as attention and memory. Thus, the specific developmental measurement itself can influence the findings. When developmental outcomes are evaluated also makes a difference. Motor development in infants of mothers who consumed 200 mg of DHA during the first 4 months of lactation did not differ from those of unsupplemented mothers during the first year of life. However, at 30 months of age, infants of DHAsupplemented mothers had significantly higher motor development scores and at 5 years of age higher sustained attention compared with the infants of unsupplemented mothers. Others have reported higher children s IQ at 4 years of age with maternal cod liver oil supplementation, which contains both eicosapentaenoic acid and DHA, and better mental and psychomotor development at 11 months of age with higher cord blood DHA concentrations. Toddlers of mothers who consumed fish oil during pregnancy had higher eyehand coordination scores at age 2.5 years. However, at age 7, infants whose mothers consumed cod liver oil during pregnancy did not differ from infants of unsupplemented mothers in their scores on the Kaufman Assessment Battery for Children, although their sequential processing scores were associated with maternal DHA plasma phospholipid concentrations during pregnancy. The Kaufman Assessment evaluates intelligence and achievement in children 2.5 to 12 years of age, while sequential processing, a subscale of the Kaufman assessment, is designed to assess problem solving and information processing. In this report, investigators from the Netherlands Open University and Maastricht University examined the relationships between the ARA and DHA concentrations in umbilical venous plasma phospholipids and motor function in 306 children 7 years of age. Participants were part of a long-term study on the relationships between essential fatty acid status at birth and mental development in childhood. Mothers were not supplemented with fatty acids during pregnancy. The children s motor function was assessed using the Maastricht Motor Test, a multi-component evaluation tool that assesses the qualitative and quantitative aspects of movement. The relationships between fatty acid status at birth or at age 7 and motor function were analyzed by backward stepwise multiple regression analyses, which 10

11 allowed the identification of confounding variables and predictors of outcome. Because of a ceiling effect in the quantitative motor scores, results were analyzed in terms of being above or below the median. Total motor scores and qualitative scores were normally distributed. Covariables included sex, cognitive performance, gestational age, and age at measurement. Analytical results were available for 290 of the 306 children. Table. Standardized regression coefficients for the relationships between umbilical DHA and ARA and total motor test scores in 7-year-old children, corrected for covariables Variables Standardized regression P-value coefficient (SD) Umbilical plasma DHA Cognitive function 0.37 < Age at measurement Female sex 0.28 < Umbilical plasma ARA Cognitive function 0.35 < Age at measurement Female sex 0.28 < Gestational age The researchers reported significant differences between girls and boys, favoring girls, in the overall total motor scores, the total quantitative and qualitative scores, static and dynamic balance scores in both quantitative and qualitative assessments and the qualitative manual dexterity scores. Total motor and quality motor test scores, but not motor quantity scores, were significantly associated with umbilical plasma DHA levels, but not with ARA concentrations (Table). Cognitive performance and age at measurement were also significantly correlated with total and qualitative motor function scores. Fatty acid measurements in the 7-year-old children were unrelated to motor test scores, although cognitive function and age at measurement were significantly associated with the total motor test scores in the children. In summary, this study observed a significant association between umbilical DHA concentrations, which reflect prenatal DHA Umbilical DHA concentrations availability, and were significantly related to total motor test scores and motor total motor test scores and quality scores in motor quality scores in the children at age offspring at age 7. There was 7. ARA concentrations did not no association with motor quantity scores. exhibit significant associations with these assessments. LC-PUFAs were not related to the motor quantity scores. Significant covariables were cognitive function, being female and age at measurement. These findings are consistent with the less favorable neurologic status observed in 18-month old children in the lowest category of umbilical DHA. Also in agreement with previous reports, the ARA and DHA status of the 7-year old children was unrelated to any of their motor scores. Bakker E, Hornstra G, Blanco CE, Vles JSH. Relationship between long-chain polyunsaturated fatty acids at birth and motor function at 7 years of age. Eur J Clin Nutr 2009;63: IMMUNE FUNCTION Fish Consumption Before 9 Months of Age Linked to Less Eczema Childhood atopic Contrary to what many diseases, commonly assume, introducing foods eczema, asthma, with potential allergens wheezing, conjunctivitis and allergic before age one may reduce rhinitis, are increasing in prevalence the chance of developing some allergic childhood worldwide. Reasons diseases, such as eczema. for their increase are poorly understood and there is some evidence that early contact with allergens may be protective. Atopic conditions are hypersensitivity reactions to various allergens, often food, pollen, dander or insect venoms and are characterized by elevated levels of immunoglobulin E (IgE). Heredity is a major factor in their occurrence, but protective factors, such as dietary lactobacilli and other probiotics and dietary long-chain omega-3 polyunsaturated fatty acids (n-3 LC-PUFAs), may reduce their development or severity. In the case of n-3 LC-PUFAs and certain microorganisms, data are inconsistent and contradictory. One factor that may affect the development of these allergic conditions is the age at which the child first contacts the potential allergens. A cross-sectional epidemiological study of Swedish children reported that those who consumed fish in the first year of life were 25% less likely to develop allergic disease by the time they were 4 years old compared with children who did not eat fish until after one year of age. A study in the Netherlands also reported that delaying the introduction of potentially allergenic foods was associated with a greater risk of eczema and atopy. In a new study in Swedish children, investigators monitored infants from the age of 6 to 12 months for the occurrence of eczema 11

12 or food allergy and infant food intakes. The researchers took note of other relevant variables, such as having furry pets or a bird in the home, cow s milk allergy and parental history of allergies. The results from this study by Bernt Alm and colleagues at the University of Gothenburg, Sweden, are described here. Participants in the study were randomly selected from an ongoing study in western Sweden on infant health outcomes. Of the 5,605 families who initially agreed to participate at baseline when the infant was 6 months old, 4,941 also completed the questionnaire information when the child was 12 months of age. Medical birth register data were available for 4,921 participants. Parents reported a previous or current eczema condition in 14% of the 6-month-old infants and 21% of 12-month-olds. The median age of onset was 4 months and family history of eczema was strongly associated with the condition in the offspring. These observations are similar to those reported in the Dutch study mentioned previously and approximately comparable to the prevalence of 25% observed in Stockholm, Sweden. Table. Odds ratios for significant risk factors for eczema at 12 months of age in Swedish infants in multivariate analysis Variable Odds ratio (95% CI) P Maternal eczema 1.5 ( ) < Sibling with eczema 1.9 ( ) < Bird in the home 0.4 ( ) Eating fish before 9 months of age 0.8 ( ) Cow s milk allergy 3.6 ( ) < The key dietary finding was the 25% lower chance (odds ratio, 0.76, 95% CI ) of developing eczema by 12 months of age in infants who consumed fish before the age of 9 months (Table). In contrast, never eating fish was associated with a nearly 3-fold increase in the likelihood of eczema. Nearly 80% of participants usually ate lean fish, 17% usually ate salmon, but there was no association by the type of fish consumed. Another food-related variable was the frequency of eating lactic acid-containing foods, such as yogurt. Never consuming those products was associated with a nearly 3-fold increase in the occurrence of eczema. Pondering the implications of the early introduction fish into a child s diet, the acceptability or even the possibility of doing so could present considerable challenges in countries and communities where fish consumption is already low. Nevertheless, Swedish infants who began the ability of a nutritional eating fish before the age change to of 9 months were 25% less likely to develop eczema lower the likelihood or severity of childhood eczema, would by age one compared with be a strong motivating force to modify infants who did not eat any fish. usual food habits. As evidence accumulates, the introduction of particular foods, such as fish or yogurt, before a child s first birthday might reduce the risk of childhood allergies, especially in children at increased risk for developing them. Updating childhood feeding practices may become a useful way to prevent or delay these allergic conditions. Alm B, Åberg N, Erdes L, Möllborg P, Pettersson R, Norvenius G, Goksör, Wennergren G. Early introduction of fish decreases the risk of eczema in infants. Arch Dis Child 2009;94: n-3 LC-PUFAs in Pregnancy Linked to Lower Prostaglandin E 2, But Less so in Atopy The immunological effects of omega-6 (n-6) and omega- 3 (n-3) polyunsaturated fatty acids (PUFAs) have been studied in healthy individuals and those with various diseases. Exaggerated inflammatory responses with high levels of inflammatory markers are characteristic of many chronic conditions, including atherosclerosis, diabetes, obesity and immune-based diseases such as rheumatoid arthritis. Increased consumption of the long-chain n-3 PUFAs (n-3 LC-PUFAs) in patients with these conditions, but generally not in healthy individuals, is associated with reduced inflammatory markers and a moderating effect on disease symptoms. In a recent report, high fish consumption and high docosahexaenoic acid (DHA) intakes were associated with significant reductions, 75% to 80%, in allergic sensitization the production of immunoglobulin E (IgE) in response to an allergen in women, but not men. The effects of maternal supplementation with n-3 LC-PUFAs or high fish intakes on allergic disease in their offspring have yielded inconsistent findings. For example, maternal supplementation with 3 g/day n- 3 LC-PUFAs was associated with a 63% to 87% lower incidence of asthma or allergic asthma in the offspring at age 16. In a different study of fish oil supplementation in atopic women during pregnancy, investigators reported less severe atopic dermatitis in the offspring at one year of age, but no difference in the frequency of the disease compared with control infants. In fish oil-supplemented pregnant women without atopy, maternal inflammatory cytokines were significantly 12

13 decreased and fetal Th2 helper cells reduced. These responses may reflect more mature development of the fetus immune system. Several studies have reported lower concentrations of inflammatory cytokines in the neonates of fish oil-supplemented mothers, but the occurrence of allergic diseases is usually unaffected or at best delayed. Less attention has been given to the immune modification of pregnant women, rather than their offspring, by means of fish oil or n-3 LC-PUFA consumption. Comparisons in the responses to n-3 LC-PUFA supplementation between women with and without allergic diseases, including eczema, allergic rhinitis or conjunctivitis, asthma, urticaria and food allergy are scarce. Existing evidence suggests that nonatopic women are more immune responsive to n-3 LC-PUFAs than those with atopy. In the study described here, Kristina Warstedt and colleagues at Linköping University, Sweden, examined immune modulators in pregnant women with and without atopic conditions who were supplemented with PUFAs. Treatments included 2.7 g/day of n-3 LC-PUFAs or soybean oil containing 2.5 g of linoleic acid and 0.3 g alpha-linolenic acid. Pregnant women without fish or soy allergies, but with self-reported allergic symptoms, such as eczema, allergic rhinitis or conjunctivitis, were recruited from the community. Supplementation was begun at the 25 th week of gestation and continued during pregnancy and lactation to one week postpartum for an average of 30 weeks. Of the 145 women recruited into the study, 120 remained in the study until delivery. postpartum. Nutrient intakes were obtained from the participants 3-day food records. The investigators measured many monocyte-derived cytokines (immunomodulating proteins), chemokines (small cytokines that attract and guide the migration of cells) and eicosanoids in whole blood cell culture supernatants with and without lipopolysaccharide stimulation, which enhances immune responses. Serum or plasma phospholipid fatty acids were also determined in both groups at enrolment and one week postpartum. As has been reported previously, maternal supplementation with n-3 LC-PUFAs was accompanied by a significant reduction in plasma phospholipid n-6 PUFAs between the 25 th week of gestation and one week postpartum. At the same time, concentrations of n-3 LC-PUFAs increased significantly, as expected. There were no differences in phospholipid responses between atopic and nonatopic mothers. The LPS-stimulated secretion of prostaglandin E 2 from whole blood cell culture supernatants was significantly decreased in the n-3 LC-PUFA-supplemented mothers during supplementation, but increased in the placebo group. This arachidonic acid-derived eicosanoid is a potent mediator of inflammatory responses. Prostaglandin E 2 inhibits the production of Th-1 cytokines, favoring the maintenance of the Th-2 phenotype, but it also has anti-inflammatory effects, such as the reduced production of leukotriene B 4. The production and release of prostaglandin E 2 from cell membranes are inhibited by n-3 LC-PUFAs. The responses to the n-3 LC-PUFAs were more pronounced in the nonatopic mothers in both groups, but differences were not significant. It may be that atopic mothers may be less responsive to the anti-inflammatory effects of n-3 LC-PUFAs. Consumption of n-3 LC-PUFAs and atopic status had no effect on the secretion cytokines or chemokines with or without lipopolysaccharide stimulation. The investigators confirmed the partici- Atopic and nonatopic women who consumed pants allergic status n-3 LC-PUFAs in the third with measurements of trimester of pregnancy IgE antibodies and the had lower levels of presence of allergic prostaglandin E symptoms by interview 2 in their blood, but responses with an allergy nurse. were more pronounced Those with allergic symptoms and a positive IgE test were con- in nonatopic women. sidered atopic. Blood samples were collected at baseline and one week Reduced production of maternal prostaglandin E 2 with n-3 LC-PUFA supplementation in pregnancy might favor the production of Th-1 cytokines in the fetus, encouraging the maturation of the fetal immune system. Immunoregulation in pregnancy is a vital aspect of the development and function of the fetal immune system and in preventing its rejection by the mother. A shift in the type of T-helper cells in the fetus from Th-2 cells to Th-1 cells is thought to reflect the continuing maturation of the fetus immune system. 13