Three observational studies examined the connections between fish consumption in pregnancy, infancy or early adulthood and the risk of asthma or wheeze. Data on the association between fish or long-chain (LC) n-3 PUFA consumption in pregnancy are inconsistent in spite of several positive reports. Results from the Danish National Cohort indicated that eating fish five times per week or more during pregnancy was associated with significantly less asthma in children at 18 months and 7 years of age. A second study reported that children in the Netherlands who first ate fish between the ages of 6 and 12 months of age were less likely to experience wheeze at 48 months of age compared with children who did not eat fish in the first year of life. A third study examined the incidence of asthma in adults 18 to 30 years of age and reported that those who consumed the highest levels of n-3 LC-PUFAs or DHA were at a significantly lower risk of developing asthma compared with those with the lowest intakes.

Increasingly, n-3 LC-PUFAs consumed after brain or spinal cord injury are associated with less nerve damage, neuronal protection and improved functional recovery. A new report describes faster nerve recovery and better sensory and motor function in animals pretreated with a fish oil-rich diet for 8 weeks before spinal cord injury. Improvements were sustained after injury, even though the postoperative diet was not enriched with fish oil.

In other research, the children of mothers with higher levels of n-6 PUFAs and linoleic acid in late pregnancy were more likely to have greater fat mass and a lower percent of lean body mass at 4 and 6 years of age. Fat mass and lean body mass were not related to maternal n-3 LC-PUFA concentrations. In a study on the effects of n-3 LC-PUFAs and sunburn sensitivity, women whose skin sunburned easily consumed a high-dose of EPA-rich oil or a placebo for 12 weeks prior to UV radiation exposure. Women taking the EPA-rich oil had less immunosuppression at low UV-radiation level compared with women who consumed the placebo. At higher UV exposures, there was no difference in immunosuppression between the groups.

Catching another breath, we wish you enjoyable reading.

Joyce A. Nettleton, D.Sc.
Editor
joyce@fatsoflife.com

The case might have been considered closed at this point were it not for lingering concerns about the possible undesirable effects of diets relatively high in n-6 PUFAs in conjunction with a low intake of n-3 PUFAs. It was thought that such diets might increase the production of pro-inflammatory eicosanoids, thus contributing to an underlying cause of cardiovascular disease. For this reason, some experts recommended reducing the consumption of n-6 PUFAs, while increasing the consumption of n-3 PUFAs. However, we now know that dietary linoleic acid has no effect on a variety of markers of inflammation in healthy individuals. In addition, the derivatives of arachidonic acid, a long-chain product of linoleic acid metabolism, have both pro- and anti-inflammatory properties.

Others reported that diets high in linoleic acid, the predominant n-6 PUFA in the diet, reduced the concentration of EPA in plasma phospholipids, while low linoleic acid diets increased EPA in healthy men. High linoleic acid diets have also been negatively implicated in nonalcoholic fatty liver disease, endothelial dysfunction, cardiovascular disease and atherosclerosis, several chronic inflammatory conditions, Alzheimer’s disease and obesity. Recently, patients who consumed a reduced their dietary linoleic acid from 6.7% to 2.4% for 4 weeks exhibited significantly lower levels of circulating oxidized metabolites of linoleic acid that have previously been associated with atherosclerosis, Alzheimer’s disease, nonalcoholic fatty liver disease and chronic pain.

Dietary recommendations for n-6 PUFA consumption have come under renewed scrutiny. Stephen Cunnane suggested that the evidence for linoleic acid intakes was flimsy and that key information about linoleic acid metabolism is missing. Others reported that meta-analyses of randomized controlled trials yielded equivocal results depending on whether trials increased the intakes of n-6 and n-3 PUFAs or just n-6 PUFAs. Those employing higher n-6 PUFAs without increased intake of n-3 PUFAs resulted in a significant 13% higher risk of nonfatal myocardial infarction and coronary heart disease death. These findings suggested that flawed data in previous analyses were obscuring the different effects of n-6 and n-3 PUFAs on the risk of heart disease mortality. The American Heart Association robustly defended its recommendation to consume at least 5 to 10% of energy from n-6 PUFAs to reduce the risk for cardiovascular disease, further commenting that reducing current n-6 PUFA intakes from their current levels would be more likely to increase than decrease the risk of coronary heart disease.

There is now a more extensive analysis of the original data from the Sydney Diet Heart Study, a controlled intervention trial conducted from 1966 to 1973, in which 458 middle-aged men who had experienced a myocardial infarction, acute coronary insufficiency or angina were randomized to consume safflower oil and safflower margarine or received no specific dietary guidance beginning 8 weeks or more after their coronary event. The objective of the intervention was to replace dietary saturated fats and cholesterol with safflower oil, up to the level of 15% total energy. Safflower oil contains 75% linoleic acid and no other PUFAs. This protocol resulted in the increased consumption of linoleic acid without additional n-3 PUFAs. The study was single-blinded, as the dietitians involved administered the safflower oil to the intervention group and no placebo was used. Median follow-up time was 39 months.

 At the final follow-up, participants in the safflower oil group experienced a significantly higher risk of cardiovascular or coronary heart disease mortality, 70% and 74%, respectively compared with the control patients (Figure). The risk of dying from any cause (62%) was also higher in the intervention participants (P = 0.051). This was likely due to the relatively small number of participants and deaths. The investigators reported that the intervention group achieved a PUFA consumption of 15.4% of energy. The control group also increased its PUFA consumption from 6.2% at baseline to 8.4% energy at follow-up. Saturated fat intake fell in both groups. The changes in PUFA and saturated fat intakes in the control group were not significantly associated with the risk of death. Alcohol consumption and smoking modified the risk of death in the whole sample, but not in the intervention group alone.

The Sydney Diet Heart Study is important, not only for its findings and the new rigorous analysis, but because it is one of only three randomized controlled trials that have looked at the effect on heart disease mortality of selectively increasing the consumption of linoleic acid without increasing the intake of n-3 PUFAs. The increased risks of cardiovascular and coronary heart disease mortality with a high intake of linoleic acid are consistent with the two previous trials. With the original data, these investigators were able to separate cardiovascular and coronary heart disease deaths from total mortality, making the results more specific.

The re-analysis of the Sydney Diet Heart Study has its own problems. The original study authors noted that the results could not be interpreted because the intervention turned out to be multifactorial. Many participants in both groups adopted more healthy lifestyles, such as smoking less—the percentage of nonsmokers increased from 30% at infarction to 62% at entry into the study. Participants in both groups consumed more polyunsaturated-rich margarines and less saturated fat and cholesterol at follow-up compared with entry to the study. This change reduced the differences in dietary fat intakes between the groups. Other changes included weight loss (4.7 kg in both groups since infarction) and greater physical activity. In the original multivariate analysis, the investigators found that the most important contributor to a patient’s prognosis was the extent of coronary and myocardial disease at entry to the study. Recreational physical activity had a significant protective effect.

The margarine provided to the safflower participants may have contained higher levels of trans fatty acids than originally thought and, if appreciable, would be expected to increase the risk of heart disease mortality. As data on the change in trans fatty acid consumption are lacking, it is possible that the revised findings may not be solely attributable to the effect of increased linoleic acid intake. Caution is also warranted because there were only 63 deaths from coronary or cerebrovascular disease in the whole study.

For comparison, the corn oil study enrolled 80 patients with heart disease and randomized them to high-fat diets containing 80 g/day of olive oil or corn oil compared with a control group, which was not advised about dietary fat. Study groups were advised to avoid fried and fatty foods, fatty meats, ice cream and cheese and were restricted in milk, eggs and butter. Dietary assessments during the second year of the study suggested that the control group consumed approximately 70 g/day of fat and the olive oil and corn oil groups approximately 45 and 50 g/day, respectively. At completion, 75% of the control patients were free of major cardiac events compared with 52% of the corn oil group and 57% of the olive oil group. The difference among groups approached statistical significance, but the number of participants was very small.

In the Minnesota Coronary Survey, over 9,000 institutionalized mental patients were served the usual hospital diet containing 42% energy from fat and 4.3% energy from PUFAs or a high PUFA diet containing about 20% energy from PUFAs and 45% energy from fat. The treatment diet was based on a combination of the National Diet-Heart Study diets B and C rich in vegetable oils. Over 4.5 years of study, there were no significant differences between the groups in those who survived without cardiac events. Deaths among men and women did not differ between the groups. For participants who remained in the study more than one year, deaths among the treated patients were greater than those on the control diet (31.0 vs 26.1 deaths per 1000 person-years).

However, deaths from arteriosclerotic heart disease were greater among treated men than controls (18 vs 13), but did not differ for women. The total number of deaths was small, so that statistical analysis was not reported. This study does not provide strong evidence one way or the other.

A positive note in this report is that intervention studies in which the consumption of both n-6 and n-3 PUFA increased have been associated with significantly lower cardiovascular mortality and regression of coronary artery disease. This new analysis is unlikely to alter dietary recommendations to replace saturated (and trans) fatty acids with PUFAs from both PUFA families as supported in more recent studies. As Philip Calder observed in his editorial, “there is reason to be cautious about high intakes of omega-6 PUFAs.” Their effect in reducing tissue concentrations of n-3 PUFAs and associations with a host of chronic diseases suggest that we will hear more about this question.

Ramsden CE, Zamora D, Leelarthaepin B, Majchrzak-Hong SF, Faurot KR, Suchindran CM, Ringel A, Davis JM, Hibbeln JR. Use of dietary linoleic acid for secondary prevention of coronary heart disease and death: evaluation of recovered data from the Sydney Diet Heart Study and updated meta-analysis. BMJ 2013;346:e8707. [PubMed] Open Access

Calder PC. Old study sheds new light on the fatty acids and cardiovascular health debate. [Editorial] BMJ 2013;346:f493. [PubMed] Open Access

In a variation on studies designed to examine impaired fetal growth or low birthweight and subsequent CVD risk factors, Michael Skilton from the University of Sydney and colleagues at several Finnish universities examined the change in cIMIT over 6 years and the consumption and serum concentrations of total n-3 PUFAs and DHA in young adults who had experienced impaired fetal growth. Participants were selected from the Cardiovascular Risk in Young Finns Study, a population-based study of atherosclerosis risk factors from childhood to adulthood for whom birth weight and preterm delivery data were available. Dietary data were obtained 27 years after enrolment when the participants were 31 years of age. Measurements of cIMT and serum fatty acids were performed 21 and 27 years after enrolment providing a 6-year interval to observe changes in cIMT. Data were available for 1,573 participants.

Impaired fetal growth was defined as those born at term with a birthweight below the 10th percentile for sex or born preterm with birthweight below the 25th percentile for gestational age and sex. There were 193 participants with impaired fetal growth. This group had significantly higher LDL cholesterol levels, triglycerides, high-sensitivity C-reactive protein and cIMT at the 21-year assessment.

In the analysis adjusted for the greatest number of confounding variables (dietary, CVD risk factors and medications), dietary consumption of total n-3 PUFAs was significantly and inversely associated with the 6-year progression in the mean and maximum cIMT in participants with impaired fetal growth (P = 0.01). Similarly, serum n-3 PUFAs and DHA were inversely associated with the 6-year change in the maximum cIMT. The study showed clearly that higher consumption of n-3 PUFAs, which leads to higher serum n-3 PUFA concentrations, was associated with a reduction in cIMT measurements in young adults. However, the association with serum n-3 PUFAs was not statistically significant when adjusted for CVD risk factors.

Participants with normal fetal growth showed no association between the 6-year change in maximum cIMT and dietary intakes or serum concentrations of n-3 PUFAs. On the other hand, serum DHA concentration was inversely associated with the 6-year increase in cIMT in those with normal fetal growth.

Impaired fetal growth and low birthweight may be viewed as markers for increased CVD risk factors in childhood and greater risk of CVD later in life. Evidence for these risks is based on the associations between impaired fetal growth and early thickening of the arterial wall at the age of 8 years, elevated blood lipids, impaired flow-mediated dilatation and increased cIMT. Some of these risk factors can be mitigated by the increased consumption of n-3 PUFAs, as demonstrated in this study and another on early arterial wall thickening. There was no effect of total n-3 PUFA consumption in participants with normal fetal growth, but DHA intake was associated with lower cIMT. It is noted that in at least 2 studies in children or young adults, increased consumption of n-3 PUFAs was associated with a regression of carotid intima-media thickness, but in adults, only one study has reported a decrease in cIMT with the consumption of EPA and several have reported no effect of n-3 PUFA consumption. One might ask whether the increased cIMT in young adults is more plastic than in older adults, and thus more amenable to dietary intervention. It will take more data to answer this question. These reports suggest that childhood is not too soon to increase the consumption of these fatty acids to reduce the risk of CVD in adulthood. These observations also increase the imperative of preventing low birthweight deliveries.

Skilton MR, Mikkilä V, Würtz P, Ala-Korpela M, Sim KA, Soininen P, Kangas AJ, Viikari JS, Juonala M, Laitinen T, Lehtimäki T, Taittonen L, Kähönen M, Celermajer DS, Raitakari OT. Fetal growth, omega-3 (n-3) fatty acids, and progression of subclinical atherosclerosis: preventing fetal origins of disease? The Cardiovascular Risk in Young Finns Study. Am J Clin Nutr 2013;97:58-65. [PubMed]

Risk of heart failure is greater among those with previous heart disease, diabetes, high blood pressure, hypercholesterolemia, overweight and obesity, smoking and arrhythmias. Preventing or controlling these factors could substantially reduce the occurrence of heart failure. However, dietary strategies involving higher intakes of long-chain omega-3 PUFAs (n-3 LC-PUFAs) may improve the prognosis of patients with chronic heart failure. Older individuals without heart disease who have higher levels of circulating n-3 LC-PUFAs or EPA (but not DHA) were less likely to develop congestive heart failure, but others reported no relationship between fish consumption or the consumption of n-3 LC-PUFAs and the risk of heart failure. In contrast, n-3 LC-PUFA consumption was associated with a significantly lower risk of heart failure in Swedish men with no history of heart failure, myocardial infarction or diabetes. In a secondary prevention trial, treatment of patients with chronic heart failure with approximately 1 g/day of n-3 LC-PUFAs for a median of 3.9 years resulted in a small, but statistically significant reduction in mortality and cardiovascular hospital admissions.

In this report, the GISSI-HF investigators enrolled 1,203 patients with chronic, stable heart failure in a multicenter study to evaluate the effects of usual and supplementary n-3 LC-PUFA consumption on biomarkers of inflammation, metabolism and cardiac stress in a 3-month trial. The supplement consisted of 850 to 882 mg of EPA + DHA, ratio 1.2:1. Control patients were given a placebo capsule. All patients received pharmacologic therapies for their medical condition. The investigators measured plasma n-3 LC-PUFA concentrations, adiponectin, C-reactive protein, pentraxin-3 (an acute phase response protein found in atherosclerotic lesions involving macrophages, neutrophils, dendritic cells or smooth muscle cells), n-terminal probrain natriuretic peptide (a biomarker for systolic/diastolic dysfunction and the risk of mortality) and high-sensitivity cardiac troponin T. Pentraxin-3 has been suggested as a biomarker for inflammatory cardiovascular disease.

As expected, plasma phospholipid levels of n-3 LC-PUFAs were associated with the frequency of eating fish. Baseline EPA and DHA levels were more than twice as high in patients in the highest tertile of fish consumption (3 or more times per week) compared with those in the lowest third. Baseline EPA and DHA concentrations ranged from 0.55 mol% to 1.31 mol% and 2.22 mol% to 4.63 mol%, respectively, across the three tertiles of n-3 LC-PUFA consumption. After 3 months’ n-3 LC-PUFA supplementation all plasma n-3 LC-PUFA concentrations increased significantly, while n-6 PUFAs decreased by 5%. Supplementation also increased the concentration of EPA, DPA and total n-3 LC-PUFAs in plasma phospholipids, regardless of the amount of fish consumed. However, DHA increased in plasma phospholipids most in those who almost never ate fish and least in those who ate fish 3 or more times per week (P = 0.03).

Baseline levels of circulating EPA, but not DHA, were inversely associated with all the biomarkers assessed. Supplementation with EPA and DHA for 3 months led to a further significant decrease in the concentration of pentraxin-3, which was associated with higher levels of EPA, but not with DHA. Supplementation was not associated with changes in any other biomarker.

Circulating levels of EPA, but not DHA or total n-3 LC-PUFAs, were associated with a significantly lower risk of all-cause and cardiovascular mortality (Figure). These associations remained significant after adjustment for anthropometric, clinical, laboratory values and medications, but not after additional adjustment for circulating biomarkers.

The key finding in this study is the association between higher circulating levels of EPA with a significantly lower risk of all-cause and cardiovascular mortality in patients with chronic heart failure. Mortality was not associated with circulating DHA concentrations. Regardless of fish consumption, even at levels of 3 times per week, circulating and phospholipid concentrations of n-3 LC-PUFAs were increased by supplementation with about 1 g per day of EPA + DHA in heart failure patients. In addition, higher levels of plasma EPA were associated with significantly lower concentrations of pentraxin-3, an inflammatory biomarker involved in the pathogenesis of atherosclerosis and ischemic heart disease. Although this marker is associated with the development of vascular inflammation and atherosclerosis, it has been suggested that its increase in atherosclerosis may be a protective response. Thus, decreases in pentraxin-3 levels with higher levels of EPA may be complicated to interpret. This study increases the evidence that EPA and DHA may affect cardiovascular disease through different mechanisms.

Masson S, Marchioli R, Mozaffarian D, Bernasconi R, Milani V, Dragani L, Tacconi M, Marfisi RM, Borgese L, Cirrincione V, Febo O, Nicolis E, Maggioni AP, Tognoni G, Tavazzi L, Latini R. Plasma n-3 polyunsaturated fatty acids in chronic heart failure in the GISSI-Heart Failure Trial: Relation with fish intake, circulating biomarkers, and mortality. Am Heart J 2013;165:208-215. [PubMed] Open Access

Participants in the study were mostly male (78%), 65 years of age on average, likely to have hypertension (67%) and smoke (63%). Approximately 10% of participants had a previous myocardial infarction. Blood samples were taken within 10 days of the onset of myocardial infarction to avoid the effects of acute phase responses and 3, 6 and 12 months thereafter. The investigators monitored the participants for 5 years. The primary outcome was duration of survival without heart failure, with hospitalization for heart failure and all-cause mortality as secondary outcomes. Patients were grouped according to baseline tertiles of serum EPA and DHA concentrations. The DHA tertiles were: low, ≤ 61.4 μg/mL; intermediate, 61.5 to 83.5 μg/mL; high, > 83.5 μg/mL. Corresponding tertiles for EPA were: low, ≤ 24.6; intermediate, 24.7 to 38.8 μg/mL; high, > 38.8 μg/mL.

As shown in the Figure, survival rates free from heart failure were significantly greater for patients in the highest 2 tertiles of either EPA or DHA compared with those in the lowest tertile. Risk of hospitalization for heart failure was also greatest in patients in the lowest EPA tertile, but all-cause mortality was highest for those in the lowest DHA tertile. These findings for heart failure support those of one other study that reported a significantly lower risk of incident heart failure in adults without heart disease who had the highest levels of plasma phospholipid EPA. In that study, low DHA levels were not associated with the risk of heart failure.

Taken together, these studies demonstrate a benefit of n-3 LC-PUFAs on the outcomes of heart failure following myocardial infarction. In addition, another study reported improvements in ejection fraction in hart failure patients with higher levels of n-3 LC-PUFAs. As shown in the current study, EPA in particular may benefit those at risk of heart failure for any reason or because of a myocardial infarction. A reduced risk of heart failure was observed in myocardial infarction survivors with plasma EPA levels of at least 24.7 μg/mL. Low DHA levels were associated with a higher risk of all-cause death. Thus, higher rather than lower levels of EPA and DHA may be beneficial in reducing the risk of heart failure, hospitalization for heart failure and death from any cause in patients who have incurred an acute myocardial infarction.

Hara M, Sakata Y, Nakatani D, Suna S, Usami M, Matsumoto S, Hamasaki T, Doi Y, Nishino M, Sato H, Kitamura T, Nanto S, Hori M, Komuro I; Osaka Acute Coronary Insufficiency Study (OACIS) Investigators. Low levels of serum n-3 polyunsaturated fatty acids are associated with worse heart failure-free survival in patients after acute myocardial infarction. Circ J 2013;77:153-162. [PubMed] Open Access

Worth Noting

Gustafson KM, Carlson SE,  Colombo J, Yeh H-W, Shaddy DJ, Li S, Kerling EH. Effects of docosahexaenoic acid supplementation during pregnancy on fetal heart rate and variability: A randomized clinical trial. Prostaglandins Leukot Essent Fatty Acids 2013; doi:10.1016/j.plefa.2013.01.009 [PubMed]

Kelsall CJ, Hoile SP, Irvine NA, Masoodi M, Torrens C, Lillycrop KA, Calder PC, Clough GF, Hanson MA, Burdge GC. Vascular dysfunction induced in offspring by maternal dietary fat involves altered arterial polyunsaturated fatty acid biosynthesis. PLoS One 7:e34492. doi:10.1371/journal.pone.0034492. [PubMed]  Open Access

Skilton MR, Raitakari OT, Celermajer DS. High intake of dietary long-chain ω-3 fatty acids is associated with lower blood pressure in children born with low birth weight: NHANES 2003-2008. Hypertension 2013;61:972-976. [PubMed]

Investigators at the University of Southampton, U.K., conducted a study of healthy nonpregnant women aged 20 to 34 years to characterize preconceptual maternal factors with the potential to affect fetal growth and development and monitored the development of the offspring of all pregnancies. This report focused on the relationship between maternal PUFAs in late pregnancy and the body composition of the children. From a total of 1,987 singleton live births, 293 mother-child pairs completed the assessment of maternal plasma phosphatidylcholine (PC) fatty acids at 34 weeks’ gestation and anthropometric measurements in the children at ages 4 and 6. The researchers measured the children’s body composition using dual-energy x-ray absorptiometry from which lean and fat mass were calculated.

Boys and girls were similar in height and weight at 4 and 6 years of age, but girls had significantly greater fat mass and less lean mass than boys at both ages. Some maternal PUFAs were significantly related to the children’s height and weight at 4 and 6 years of age, but these associations were not statistically significant when the analysis was adjusted for maternal age, parity, social class and 8 other variables. Maternal total and individual n-3 PUFAs were not associated with the children’s height, weight, fat or lean mass at either age in multivariate analysis. The investigators observed a trend toward a positive association between maternal n-3 PUFAs and EPA and the child’s height at age 4, but these associations were not observed in multivariate analysis. The observation with total n-3 PUFAs and height was significant at age 6, however (Table).

In contrast, maternal plasma PC total n-6 PUFAs and linoleic acid were significantly associated with greater fat mass and percent fat mass in the multivariate analysis of children at both 4 and 6 years of age (Table). Only total n-6 PUFAs did not reach statistical significance in the adjusted analysis of the percent fat mass in 6-year-old children. Arachidonic acid was not associated with any body composition measurement in the adjusted analysis of children at both ages. Lean body mass was not associated with any maternal PUFA in multivariate analysis, but percent lean mass was significantly lower with higher maternal linoleic acid in the adjusted analysis at both ages.

The observation that maternal plasma PC n-6 PUFAs and linoleic acid were associated with greater adiposity in the offspring at age 4, which persisted to age 6, suggests that prenatal exposure to n-6 PUFAs in the presence of low concentrations of n-3 LC-PUFAs might increase the risk of childhood obesity. Such a relationship has been demonstrated in animals, but was not observed in a U.S. pregnancy cohort. However, high intakes of linoleic acid have been postulated as an early determinant of childhood obesity. It will be worth watching to see whether the risk of obesity is greater in the offspring of mothers with higher concentrations of n-6 PUFAs when they are older. It would be noteworthy, too, if these observations were confirmed in other studies, especially those using dual x-ray absorptiometry to assess body fat. Whether these associations would be observed in the presence of higher maternal concentrations of n-3 LC-PUFAs is also unknown.

Moon RJ, Harvey NC, Robinson SM, Ntani G, Davies JH, Inskip HM, Godfrey KM, Dennison EM, Calder PC, Cooper C; the SWS Study Group. Maternal plasma polyunsaturated fatty acid status in late pregnancy is associated with offspring body composition in childhood. J Clin Endocrinol Metab 2013;98:299-307. [PubMed]

Factors associated with childhood obesity may relate to conditions in utero. For instance, maternal obesity in pregnancy and excess gestational weight gain have been associated with greater fat mass and percent body fat in the neonate. As suggested in the preceding article, a child’s greater fat mass may also be related to the mother’s plasma n-6 PUFA and linoleic acid concentrations in late pregnancy. Low birthweight has also been associated with a higher risk of central obesity in adulthood. On the other hand, breastfeeding has been associated with a lower risk of childhood overweight and obesity. The lower protein content of breast milk compared with infant formula may be one reason why breastfeeding is less conducive to childhood overweight.

More recently, a greater exposure to n-6 PUFAs in the presence of relatively low amounts of n-3 PUFAs has been associated with increased adiposity and fat mass in animals and humans (see preceding article). Maternal dietary fatty acid patterns are reflected in the fatty acid composition of breast milk, which generally reflect the abundant consumption of n-6 PUFAs and low intakes of long-chain (LC) n-3 PUFAs. The abundance of n-6 PUFAs might not be a worry were it not for their links to obesity and their ability to reduce the incorporation of n-3 LC-PUFAs into tissues.

In this report, investigators at the Karolinska Institute, Sweden, compared the fatty acid composition of the breast milk from normal-weight and obese nondiabetic mothers along with the plasma phospholipids of their infants. A subgroup of obese mothers participated in a weight control program during pregnancy. Mother-infant pairs were excluded for preterm delivery, multiple births and major infant malformations. Forty-one obese and 41 normal-weight mothers enrolled in the study, with another 29 obese women taking part in the weight control program. Participants were intended to reflect the general population of a medium-high socioeconomic area of Stockholm.

The weight control intervention for women with a BMI >30kg/m² included dietary advice and increased physical activity beginning at the first prenatal visit at 8 to 10 weeks’ gestation. The program continued until 6 to 8 weeks postpartum. In Sweden, all pregnant women are advised to eat fish 2 to 3 times a week.

Infant blood samples were collected on the third day after birth. Breast milk samples were obtained after nursing at days 3 and 10, then 1 and 2 months after birth. Obese mothers were more likely to smoke, deliver by Cesarean section and eat less fish than control mothers.

Infant birth characteristics and neonatal outcomes did not differ among the 3 groups. At 12 months of age, there were no differences in body weight, length and BMI among the infants. At 3 days postpartum, the phospholipid fatty acids in the infants’ plasma were higher in linoleic acid in the intervention group compared with the infants of the control or obese mothers. Total n-3 PUFAs and EPA were significantly lower in the infants of obese mothers compared with those of control or intervention mothers.

For breast milk PUFAs, the total n-6 PUFA content was highest in the control group at 3 days postpartum and increased significantly over the 2-month period only in the intervention mothers. Likewise, linoleic concentrations were significantly higher in the control than the obese mothers and increased significantly by 2 months only in the intervention mothers (Table). Arachidonic acid concentrations decreased over the study period in all groups. Total n-3 PUFA concentrations were highest in the control mothers’ breast milk and significantly lower in the obese mothers, remaining so over the 2-month period. DHA and EPA concentrations were highest in the control group, lowest in the obese mothers, and decreased in all groups over the study period.

Breast milk fatty acid composition reflects the mother’s diet, especially her fish consumption, but can be affected by genetic factors, smoking, diabetes and preterm delivery. In this study, obesity was accompanied by a reduction in total n-6 and n-3 PUFAs, and lower linoleic acid and DHA concentrations in breast milk samples obtained at 3 days and 2 months postpartum. The study also reported that weight control intervention among obese women during pregnancy partially restored the PUFA patterns of breast milk toward those observed in normal-weight mothers.

The only other study that compared the fatty acid composition of breast milk between normal, overweight and obese mothers reported a significant increase in total n-6 PUFAs and linoleic acid with increasing BMI. Patterns of n-3 PUFAs, including DHA, did not differ significantly among the three groups. However, the number of participants in each group was small, with only 9 observations for obese mothers.

The study flags the association of obesity in pregnancy with a significantly lower concentration of n-3 PUFAs, especially EPA and DHA in the mothers’ breast milk. When intakes of n-3 LC-PUFAs are already low among women with Western dietary habits, the further apparent reduction in breast milk n-3 LC-PUFAs suggests that pregnant obese women might benefit from counseling to increase their fish and n-3 LC-PUFA consumption and for weight control.

Storck Lindholm ES, Strandvik B, Altman D, Möller A, Kilander CP. Different fatty acid pattern in breast milk of obese compared to normal-weight mothers. Prostaglandins Leukot Essent Fatty Acids 2013;88:211-217. [PubMed]

Worth Noting

Muhlhausler BS, Ailhaud GP. Omega-6 polyunsaturated fatty acids and the early origins of obesity. Curr Opin Endocrinol Diabetes Obes 2013;20:65-61. [PubMed]

This report analyzes data from the Danish National Birth Cohort, a very large observational study on early life factors and the risk of disease in later life. Of the 101,045 participants originally enrolled, the investigators limited their analysis to the first enrolled pregnancy of women with a singleton birth who did not take fish oil during pregnancy and for whom fish intake data were available. The total number of participants was 28,936. Fish consumption was determined from 2 interviews during pregnancy and the frequency divided into 5 categories: never, monthly or less, weekly, weekly with low frequency and weekly with high frequency, i.e., hot meals or sandwiches more than 5 times per week.

The occurrence of asthma at 18 months of age, as reported by the parent, was defined as a doctor diagnosis, with wheeze considered as wheezing or whistling in the chest. Asthma at age 7 was based on standardized questions, with current asthma being a positive response to ever having a doctor-diagnosis of asthma and wheezing symptoms in the past 12 months. The investigators also collected all hospital admissions for asthma, emergency room treatments and outpatient contacts from the Danish National Patient Registry. They used the Register of Medical Product Statistics to determine the number of asthma prescription drugs that had been filled.

The investigators noted significant differences in fish consumption with age, with younger mothers less likely to eat fish. Thus, analyses were adjusted for maternal age. Only 5% of women reported eating no fish. The odds ratios for asthma were adjusted only for socioeconomic variables. Interestingly, breastfeeding accounted for the largest reduction in risk of asthma. Because of missing outcome data, 7,643 participants were excluded from the analysis at 18 months of age.

Asthma occurred in 17 percent of children at 18 months of age and wheeze in 27%. Multivariate analysis of asthma and wheeze at 18 months of age showed that never eating fish during pregnancy was associated with a 30 percent greater risk of childhood asthma compared with eating fish several times per week (OR = 1.30, 95% CI, 1.05 – 1.63, P = 0.02). Wheeze was not associated with maternal fish consumption.

At the age of 7, asthma was present in 6 percent of children as defined above and 31 percent according to hospital admission and prescription data. About 4 percent of children were considered to have current asthma. As at the earlier age, children whose mothers never ate fish during pregnancy were more likely to have an asthma diagnosis by hospital admission (OR – 1.46, 95% CI, 0.99 – 2.13, P = 0.05). The relationship for current asthma was in the same direction but did not reach statistical significance.

This study documented a significant relationship between higher consumption of fish during pregnancy and a lower risk of doctor-diagnosed asthma at 18 months and 7 years of age, about the time that asthma peaks. Maternal fish consumption was not associated with childhood wheeze or allergic rhinitis. The associations between asthma and maternal fish consumption were significant when doctor-diagnosis, hospital admission or prescription asthma medicine were assessed, but not for self-reported asthma. Another interesting finding was the protective effect of longer breastfeeding, i.e., for 7 to 9 months or longer. Women who breastfed longer were more likely to consume fish frequently, but the two factors were only modestly correlated. The investigators found no association between childhood asthma and dietary n-3 PUFA intakes based on food frequency questionnaire data, nor with early childhood fish consumption. This study supports other reports in which higher fish consumption in pregnancy was associated with a lower risk of childhood asthma.

Maslova E, Strøm M, Oken E, Campos H, Lange C, Gold D, Olsen SF. Fish intake during pregnancy and the risk of child asthma and allergic rhinitis – longitudinal evidence from the Danish National Birth Cohort. Br J Nutr 2013; Mar 8:1-13. [PubMed]

In the first, the investigators looked at maternal fish consumption in pregnancy and the risks of wheezing or eczema in childhood in the first 4 years of life. They focused on the types of fish and frequency of seafood consumption. Participants included 2,796 mothers whose fish consumption was assessed during the first trimester of pregnancy. Fish categories included total, fatty, lean and shellfish. On average, mothers ate 83 g (3 oz) of fish per week, with nearly 19% of women not eating any fish. Thirty-eight percent of mothers had a history of asthma or atopy.

There was no association between the consumption of all fish or fatty fish during pregnancy with childhood wheezing from ages 1 to 4 years in multivariate-adjusted analysis. However, at age 3, a higher intake of lean fish was associated with a lower risk of wheezing, with a significant trend for less wheezing as fish consumption increased. In contrast, eating 1 to 13 g (< ½ oz) per week of shellfish, but not larger amounts, was linked to a significantly higher risk of wheezing in the first 4 years of life. The investigators also observed a higher risk of eczema in infants whose mothers ate 35 to 69 g of fatty fish per week (~1 to 2.5 oz per week), but risk was not greater with higher intakes. Eating small amounts of shellfish (1 to 13 g/week) was also associated with a higher risk of eczema, but the association was not observed with intakes above 14 g per week (1/2 oz). Stratification by maternal history of asthma or atopy abolished the statistical significance of the associations with eczema, but not for asthma.

This study provides little evidence that maternal fish consumption of any type in pregnancy is associated with a lower risk of childhood wheezing or eczema. Instead, it raises the question of whether consuming fatty fish or a small amount of shellfish in the first trimester increases the risk of eczema. These observations have not been previously reported and need confirmation in other studies before they can be considered reliable.

In the second report, the investigators looked at the relationship between the timing of the introduction of fish into a child’s diet and asthma-like symptoms at 36 or 48 months of age. There is some evidence that introducing fish into the child’s diet before the age of 1 year is associated with a lower risk of recurrent wheeze. Others reported a lower occurrence of allergic disease in children who consume fish before their first birthday. However, parents may hesitate to introduce fish into the child’s diet too early because of the risk of fish allergy.

These findings are based on nutritional and medical data for 7,210 children obtained using a food frequency questionnaire when the child was 14 months of age. Parents were twice asked how old the child was when first given fish. Fish was defined as fatty fish, other fish, including fish fingers, and white fish and consumption categories were none, less than half a serving per week or at least half a serving per week. The categories of introducing fish into the diet in the first year of life were never, 0 to 6 and 6 to 12 months. The presence of wheeze and shortness of breath was determined by questionnaire when the children were 36 and 48 months of age. Agreement with physician diagnosis was 75%.

In this population, only 0.1% of the children did not eat any fish at 14 months of age. Those who ate fish in the first year of life ate more fish at 14 months of age than those who were introduced to fish after 1 year of age. Children who fist ate fish between 6 and 12 months of age were significantly less likely to experience wheezing at 48 months of age compared with children who did not eat fish in their first year (Table). Wheezing at 36 months of age was also lower in this group, but the difference was not statistically significant.

In contrast to these observations, the prevalence of wheeze at 48 months of age was greater in children whose fish introduction was between 0 and 6 months of age and in those who did not eat fish when compared with children given fish between 6 and 12 months of age. The amount and type of fish consumed was unrelated to the risk of wheeze. Although these findings do not provide conclusive answers to questions about the early consumption of fish and the risk of asthma-like symptoms, they confirm previous reports of a lower risk of wheeze in children who eat fish in the first year of life. In addition, they suggest that fish is best introduced between 6 and 12 months of age and that consumption before 6 months of age confers no advantage and might increase the risk of wheeze.

Taken together, these studies suggest that a lower risk of childhood wheeze is associated with fish consumption between 6 and 12 months of age and that maternal fish consumption during pregnancy is not associated with the risk of wheeze in childhood.

Leermakers ET, Sonnenschein-van der Voort AM, Heppe DH, de Jongste JC, Moll HA, Franco OH, Hofman A, Jaddoe VW, Duijts L. Maternal fish consumption during pregnancy and risks of wheezing and eczema in childhood: The Generation R Study. Eur J Clin Nutr 2013;67:353-359. [PubMed]

Kiefte-de Jong JC, deVries JH, Franco OH, Jaddoe VW, Hofman A, Raat H, de Jongste JC, Moll HA. Fish consumption in infancy and asthma-like symptoms at preschool age. Pediatrics 2012;130:1060-1068. [PubMed] Open Access

Prenatal influences and epigenetics—heritable changes in gene expression caused by chemical modifications in a chromosome—have emerged as important contributors to the development of asthma and allergic diseases, especially in high-risk infants. The mother’s allergic and asthma status also has a strong influence on the development of allergic disease in the infant. Exposures during fetal and early infant life have become the center of studies on the development of asthma and other allergic diseases. The involvement of n-3 LC-PUFAs in the development of asthma receives considerable attention because of the anti-inflammatory effects of these PUFAs, their relatively low intakes during pregnancy and their ability to modify immune development during fetal life. Observational data suggest that children whose mothers ate more fruits, vegetables and oily fish weekly during pregnancy were significantly less likely to develop asthma at the age of 3 years.

Studies in which pregnant women have consumed n-3 LC-PUFA supplements or DHA have produced inconsistent results. Some have reported a significant reduction in the occurrence of asthma, while others observed no effects. A recent systematic review reported that n-3 LC-PUFA supplementation in pregnancy was associated with a significant reduction in childhood asthma in 2 trials. A primary health care intervention in Norway to reduce childhood allergies reported that increased oily fish and n-3 LC-PUFA consumption along with a reduction in smoking during pregnancy and early childhood was associated with a significant reduction in asthma in the offspring at the age of 2. The reduction in asthma was particularly dramatic in girls.

In adults, studies on fatty acids and asthma have been inconsistent. A prospective study among adult women reported no association with intakes of linoleic or n-3 PUFAs. Similarly, plasma n-3 PUFAs were not associated with the risk of asthma in young adults. An observational study of dietary patterns in 3 European countries reported that neither the intake of fish, fruits and vegetables, nor meats and potatoes, was associated with the risk of asthma in adults. In Japan, the consumption of fish 1 to 2 times per week was associated with a higher risk of asthma in children 6 to 15 years of age. In contrast, middle-aged adults with higher intakes of n-3 PUFAs and alpha-linolenic acid had improved asthma control, while a high ratio of n-6:n-3 PUFA was linked to a greater risk of uncontrolled asthma. In Norway, weekly fish intake among adults was associated with fewer asthmatic symptoms and those who never ate fish in childhood experienced a greater risk for asthma. Fish oil supplementation in exercise-induced bronchoconstriction in asthmatic athletes was associated with improved pulmonary function and less use of bronchodilator therapy.

Investigators at the University of North Carolina, U.S., and other American institutions, examined data from the Coronary Artery Risk Development in Young Adults study to assess the relationship between the consumption of fish and n-3 LC-PUFAs and the 20-year incidence of asthma. Participants were African American and white men and women aged 18 to 30 recruited from 4 U.S. cities in 1985 to 1986. They were monitored until 2005 and provided dietary, medical and demographic information and blood samples. Participants were excluded if data were missing on n-3 LC-PUFA consumption, asthma, key factors such as smoking and alcohol consumption and if energy intakes were implausible or participants were pregnant. A total of 4,162 individuals were assessed.

Asthma was identified by physician diagnosis or the use of asthma-control medicine at any follow-up exam. Long-term n-3 LC-PUFA consumption was determined using cumulative average intakes from 3 follow-up assessments over the course of the study. For analysis, participants were divided into quintiles by n-3 LC-PUFA intake, with consumption ranging from ≤ 0.050 g/day in the lowest group to ≥ 0.24 g/day in the highest quintile. Three hazard regression models were developed, each adjusting for additional confounding variables. Controlling for the most confounding variables, the investigators reported that the 20-year risk of incident asthma was significantly lower with increasing consumption of total n-3 LC-PUFAs, EPA and DHA, with the strongest effect (HR = 0.30, 95% CI, 0.22 to 0.41) observed for the highest quintile of DHA intake (Figure). Non-fried fish consumption was not associated with risk of asthma.

In a sub-analysis, the investigators explored the effect of n-6 PUFA intakes on the risk of asthma. Consumption of n-6 PUFAs weakened the lower risk associated observed with n-3 LC-PUFA intakes, but the trend for reduced asthma risk remained significant for n-6 PUFA intakes below the median. With n-6 PUFA intakes above the median, the trend for reduced risk observed with n-3 PUFAs did not reach statistical significance (P = 0.06). This finding suggests that higher intakes of n-6 PUFAs interfere with or counteract the protective effects of higher n-3 LC-PUFA consumption on the risk of asthma.

Asthma appears responsive to higher intakes of n-3 LC-PUFAs, which have anti-inflammatory properties. The observation that higher levels of DHA were associated with lower risks compared with EPA is consistent with other studies reporting the greater potency of DHA in weakening inflammatory responses. As this study observed, intakes as little as 240 mg per day, the amount some recommend for reducing the risk of cardiovascular disease, might also reduce the risk of asthma in adults.

Li J, Xun P, Zamora D, Sood A, Liu K, Daviglus M, Iribarren C, Jacobs D Jr, Shikany JM, He K. Intakes of long-chain omega-3 (n-3) PUFAs and fish in relation to incidence of asthma among American young adults: the CARDIA study. Am J Clin Nutr 2013;97:173-178. [PubMed] Open Access

Worth Noting

Calder PC, Ahluwalia N, Albers R, Bosco N, Bourdet-Sicard R, Haller D, Holgate ST, Jönsson LS, Latulippe ME, Marcos A, Moreines J, M’rini C, Müller M, Pawelec G, van Neerven RJ, Watzl B, Zhao J. A consideration of biomarkers to be used for evaluation of inflammation in human nutritional studies. Br J Nutr 2013;109 Suppl 1:S1-S34. [PubMed]

Dotterud CK, Storrø O, Simpson MR, Johnsen R, Oien T. The impact of pre- and postnatal exposures on allergy related diseases in childhood: a controlled multicentre intervention study in primary health care. BMC Public Health 2013;13:123-131. [PubMed] Open Access