Time to Go Fishing: Marine Oil Supplements Good for Children?

Time to go fishing
Should intake of marine oils be encouraged (via food or supplements) for pregnant women, and perhaps even later for young children?

Maria Makrides, PhD | Child Health Research Institute | Children, Youth and Women's Health Service | Adelaide, South Australia | Child Health Research Institute at Flinders | Flinders Medical Centre | Bedford Park, South Australia | School of Pediatrics and Reproductive Health | University of Adelaide, South Australia

Robert A. Gibson, PhD | School of Agriculture, Food and Wine | University of Adelaide, South Australia | Child Health Research Institute | Children, Youth and Women's Health Service | Adelaide, South Australia | Child Health Research Institute at Flinders | Flinders Medical Centre | Bedford Park, South Australia


The last few years have witnessed the emergence of a multitude of supplements containing n-3 (or omega-3) fatty acids, predominantly as marine or fish oil. These oils have been added to prenatal vitamins and minerals as well as to food products specifically designed for pregnant women. 

 

Recruitment to our most recent clinical trial in Adelaide, Australia indicates that up to 25% of pregnant women are choosing to take a prenatal supplement with marine oil. The main motivation appears to be the suggestion that an increased supply of docosahexaenoic acid (DHA) during the last trimester of pregnancy may be important to the development of the fetal brain. (DHA is a key n-3 long chain polyunsaturated fatty acid, or LCPUFA.) In addition, population studies have shown that higher intakes of marine foods during pregnancy are associated with longer gestations, higher infant birth weights and a low incidence of pre-eclampsia. Together with the relatively confusing public-health messages regarding the intake of some fish species and unsafe levels of mercury exposure during pregnancy, this may have added to the new popularity of prenatal marine oil supplements. 

Does marine oil truly have lasting benefits for pregnant women and their developing fetuses? If so, should intake be encouraged (via food or supplements) for pregnant women, and perhaps even later for young children?

Marine-Oil Supplements Show Little Effect on Pre-eclampsia, Preterm Birth and Low Birth Weight 
The results of randomized-controlled trials of high-dose fish oil supplementation in pregnancy have demonstrated only small increases in gestation length and birth size that may be of little clinical significance. We conducted a Cochrane Systematic Review to estimate the effects.1 A total of 2,755 women from six trials were included. All six trials had a randomized design and compared a supplement or food that contained marine fatty acids with either a placebo or no treatment. The allocated dose of EPA (eicosapentaenoic acid) and DHA ranged from 133 mg/day (given as a food supplement2 to over 3 g/day (given as 12x1 g capsules per day3). The most commonly used dose was 2.7 g of EPA and DHA per day4-6, and these trials also included the majority of women 2,242. Most trials commenced supplementation after 16 weeks gestation.7-10 Three of the six trials included women with high-risk pregnancies.11-13

Women allocated to marine oil supplement had a mean gestation that was 2.6 days longer than women allocated to placebo or no treatment. Birth weight was slightly greater in infants born to women in the marine oil group compared with control, and this difference was commensurate with the small increase in gestation length. There were no overall differences in the proportion of preterm birth, low birth weight or small-for-gestational age babies. There was also no clear difference in the relative risk of pre-eclampsia. Another systematic review, also published in 2006, reported similar findings although it was limited to singleton, low-risk pregnancies.14 Collectively, these data suggest that routine use of marine oil supplements in pregnancy is safe, but likely to have little benefit in preventing pre-eclampsia, preterm birth and low birth weight.


DHA Insufficiency May be Associated with Postnatal Depression 
Emerging evidence suggests that an increased dietary supply of n-3 LCPUFA in pregnancy is associated with a reduction in symptoms of postnatal depression. The specific requirement of n-3 LCPUFA to furnish the needs of the mother, however, has been difficult to determine. Although some studies suggest adaptive metabolic mechanisms in pregnancy such as an increased synthetic capacity to metabolize ALA (alpha-linolenic acid) to DHA15 and a preferential use of the DHA stored in adipose tissue,16 it may be that an increased dietary intake is necessary to maintain optimal function in women with habitually low dietary intakes. 

A pooled analysis of cross-country data showed a negative association between the prevalence of postnatal depression and either seafood consumption or breast milk DHA concentration.17 This led to further investigation of the association between n-3 LCPUFA intake during pregnancy and symptoms of postnatal depression using the data available from the Avon Longitudinal Study of Parents and Children (ALSPAC).18

This report—with data from approximately 14,000 women—suggests that a negligible intake of seafood at 32 weeks gestation was associated with a doubling in depressive symptoms in the postnatal period, compared with a high-to-moderate seafood intake supplying at least 320 mg n-3 LCPUFA per day.19 These observations, together with the association between n-3 fatty-acid deficiency and reduced brain serotonin in animal studies, support the plausibility of the hypothesis that dietary DHA insufficiency may be associated with symptoms of postnatal depression, and clearly highlight the need for well-designed randomized controlled trials.

Although two of the three available trials indicate that n-3 LCPUFA may ameliorate depressive symptoms in the perinatal period, all three trials suffer from methodological limitations (small numbers and/or open label design) that cannot exclude bias and random error.20-22 To the best of our knowledge, at least two large-scale trials are in progress that will report on the link between n-3 LCPUFA in pregnancy and postnatal depression. 

DHA Supplements May Support Childhood Development 
Emerging evidence suggests that an increased dietary supply of n-3 LCPUFA in pregnancy is associated with improved developmental outcomes for children. The last trimester of pregnancy is the time when DHA accretion in the brain and nervous system is at its greatest velocity. The non-myelin membranes of the central nervous system contain particularly high concentrations. DHA is selectively incorporated in synaptosomal membranes so that diets deficient in n-3 fatty acids are associated with reductions in brain DHA concentrations, decreased dopamine and serotonin, reduced neuronal cell size as well as decreased visual function, impaired visual recognition memory, and compromised learning behavior.23 The fetus is supplied with its DHA from the maternal circulation. Metabolic and post-mortem studies indicate that the fetus accumulates an average of 67 mg of DHA per day during the last trimester.24 This level of DHA exceeds the intake of many pregnant women from industrialized countries with Western-style diets (e.g., the median intake of Australian women for n-3 LCPUFA is 22 mg/day—this includes all n-3 LCPUFA and would be less for DHA)25, highlighting a potential dietary insufficiency for both mother and baby. 

Unlike the data relating to postnatal supplementation of preterm and term infants, there is less information relating to the effect of prenatal n-3 LCPUFA supplementation on the developmental outcomes of the offspring. Data from cohort studies indicate that an increased supply of DHA to the fetus in late pregnancy (measured as maternal DHA status at the end of pregnancy or as the DHA levels in cord blood) is associated with more organized sleep patterns in early infancy,26 improvements in attention and less distractibility through to 2 years of age,27 relative to children with a lower supply of DHA in late pregnancy. Concordant data are also available from over 7,000 British children who were part of the ALSPAC study where maternal fish intake during pregnancy was positively associated with mean developmental scores at both 15 and 18 months of age.28 Such findings from observational studies have fueled the need for intervention studies to specifically address the question of whether an increased DHA supply to the fetus (through maternal supplementation) improves neurological development.

To date, there have only been a few DHA intervention trials in pregnant women that have assessed aspects of neural development in children, and these have been largely preliminary in nature. Malcolm and colleagues29-30 randomly allocated 100 pregnant women from 15 weeks gestation until birth to fish oil (providing 100 mg DHA/day) or high-oleic sunflower oil. Electroretinograms and pattern-reversal visual evoked potentials were used to assess the maturity of the visual system. While approximately half of the women and their babies completed the study, there was still enough evidence to draw some conclusions. Although there were no differences between the groups in any of the outcome measures, there was a positive correlation between DHA status and the maturity of both the retinal and visual evoked potential responses. 

Another study conducted in Norway assessed a much higher concentration of DHA.31-32This time, 590 women in mid pregnancy were randomly allocated to 10 ml of either cod liver oil (providing approximately 1200 DHA mg/day) or corn oil. The supplementation period started in mid-pregnancy and continued through to 3 months post-partum. All babies were fully or partly breastfed. The children in the trial were subject to a number of different developmental tests—EEG maturity at 3 months, novelty preference (the Fagan test) at 6 and 9 months and the Kaufmann Assessment Battery for Children at 4 years. The authors reported no differences in short-term early age surrogate measures of neurodevelopmental outcome (EEG maturity and novelty preference), but at 4 years of age children from cod-liver-oil-supplemented mothers had higher scores of mental processing compared with children from unsupplemented mothers.33 However, only 84 children of 590 women (14%) originally randomized were assessed at 4 years, and it is not possible to exclude bias in these results because of high attrition. 

High quality trials with better follow-up are needed to establish whether children of n-3 LCPUFA supplemented women have a developmental advantage compared with those of unsupplemented women. To the best of our knowledge, at least three such trials are currently in progress (in Australia, Mexico and the U.S.), with initial reports expected in early 2009. 


Anti-Allergy Effects of DHA
The anti-inflammatory and immune modulating effects of n-3 LCPUFA have raised the possibility that improvements in n-3 LCPUFA status in early life may be associated with a lower risk of developing childhood allergies. Large cross sectional studies of children have indicated that allergic conditions such as eczema are inversely related to n-3 LCPUFA intake, resulting in a variety of dietary intervention studies. The most notable has been the Childhood Asthma Prevention Study (CAPS)34 in which 616 high-risk infants were randomly allocated to a fish oil supplement as well as margarines and cooking oils with a high n-3/n-6 ratio—or a vegetable oil placebo as well as margarines and cooking oils with a low n 3/n-6 ratio.35-36 The intervention commenced from 6 months of age and included modification of solid foods. The n-3 fatty acid intervention group received a supplement of tuna oil and canola oil-based oils and spreads for use in cooking, while the control group received a vegetable oil supplement and n-6 rich polyunsaturated oils and spreads for use in home-prepared foods. Atopy and symptoms of asthma were assessed at 18 months, 3 and 5 years of age. Although the intervention resulted in a reduction in the proportion of children with wheeze at 18 months37 and cough at 3 years of age,38 there were no differences in the prevalence of atopy, asthma or wheeze at 5 years.39 The implications of these transient effects are not clear and further research is needed to determine if earlier or modified n-3 fatty acid interventions have the potential to influence allergy and asthma outcomes.

Concerning pregnant women, a randomized, controlled trial of marine oil supplementation in pregnancy was designed to determine the feasibility, safety and effectiveness of maternal marine oil supplementation in modifying neonatal immune function.40 Atopic pregnant women were supplemented with marine oil (3.7 g n-3 LCPUFA per day; n=52) or placebo (n=46) from 20 weeks gestation until birth. A number of trends were observed, with the children in the marine oil group less likely to develop positive skin prick tests (IgE-medicated atopic response) or have allergic symptoms. These data were also consistent with the down-regulation of a range of cord blood mononuclear cell cytokine responses (IL-5, IL-13, IL-10, IFNY) to allergens.41 While not all observations reached statistical significance because of insufficient sample size, the consistency of the clinical and biochemical data indicate that further investigation is warranted.

To Supplement or Not to Supplement
A challenge for nutritionists is to make dietary recommendations that will improve n-3 LCPUFA status. Although an obvious strategy is to eat more fish or seafood or consume marine oil capsules, there is confusion in the minds of the public concerning doses and the safety of some sources of fish in pregnancy. To complicate things further, Western diets are rich in n-6 fats, particularly linoleic acid (LA, 18:2n-6), that is a major inhibitor of n-3 LCPUFA incorporation. Thus, small amounts of fish eaten in the context of diets rich in n-6 rich oils and spreads will result in little improvement in n-3 LCPUFA status. 

The n-3 LCPUFA dose in the few current pregnancy intervention studies available on trial registers ranges from 500-1,000 mg/day. Such doses are of the right order of magnitude to be biologically significant. As a comparator, the American Heart Association,42 the Australian National Heart Foundation43 and the ISSFAL working group44 all suggest that a daily intake of 300-500 mg/day of n-3 LCPUFA may be cardio-protective. 

However, such doses are difficult to obtain from the typical Western diet where it is uncommon to frequently consume foods—such as fish and other seafood and offal meats—which are among the richest dietary sources of n-3 LCPUFA. This issue is magnified for pregnant women who have been counseled to limit their consumption of long-lived predatory fish such as shark, swordfish and marlin—which contain high levels of organic mercury—because of the possible negative impact of mercury on fetal and early childhood development.45-47 Indeed, according to the data of Oken et al.48 (in a sample of 2,235 pregnant women), after the mercury advisory was issued, the consumption of all types of fish declined. 

Two other issues may further conspire to limit pregnant women's intake of n-3 LCPUFA. Firstly, advice to minimize the risk of listeriosis in pregnancy includes the avoidance of raw seafood such as oysters, smoked salmon, sashimi and pate.49-50 Secondly, a single serving of omega-3-rich liver exceeds the maximum recommended level of retinol (vitamin A) in pregnancy by about 10 times.* 

Conclusion
Based on the best available evidence to date, there is little justification for pregnant women to consume supplements containing n-3 LCPUFA during pregnancy to reduce the risk of pre-eclampsia, preterm birth or low birth weight. However, ongoing trials should provide answers to whether prenatal n-3 LCPUFA supplementation improves maternal mood and early childhood development. Given the popularity of supplements, pregnant women should be counseled to choose supplements that contain oils derived from the body of the fish rather than organ oils (such as cod liver oil) and those that have been tested and labeled as containing low levels of heavy metals (such as mercury) and lipid soluble contaminants (such as dioxins and PCBs).

The safety issues surrounding fish and fish oils typically opens up another question: how to create adequate consumption of DHA and related fatty acids in infants and young children? Some mothers may worry about exposing their babies to mercury through breast milk or infant formula. However, the mercury content of mother's milk is generally not high enough to be of concern, and the manufacturers of infant formulas with added DHA use highly purified supplements with negligible contamination. As for children who are old enough to consume seafood, some countries advise that from ages 1-6 years, they limit their consumption, following the same guidelines issued for pregnant women (which typically recommend two servings per week), while others have no specific advisories. The key for the well informed health professional will be to keep up to date with local government advisories regarding fish and seafood consumption. 

* Excess vitamin A increases the risk of birth defects. Although drugs related to vitamin A that are used for treating acne (with retinoic acid as the active ingredient) have been responsible for most cases, many health authorities have set maximum tolerable levels of intake and require multivitamin supplements that contain vitamin A to carry a warning label about the risks during pregnancy.

Disclosure: This report is based on a manuscript written by the authors for NeoReviews. The Senior Fellowship Scheme of the National Health and Medical Research Council of Australia provides salaries for Doctors Makrides and Gibson, both of whom are investigators in a large-scale clinical trial of marine oil supplementation in pregnancy. The authors have no financial interests in the production or sales of pregnancy supplements but have provided scientific advice to the nutritional supplement industry. 

Maria Makrides, PhD, is the Director of the Child Nutrition Research Centre (CNRC) in Adelaide, Australia. The CNRC is a joint venture between the Child Health Research Institute, the Women's and Children's Hospital and the Flinders Medical Centre. Dr. Makrides is a dietitian with a strong commitment to improving the health of mothers and their babies through dietary interventions. She has over 70 peer-reviewed publications and currently serves on the Nutrition Committee of the Australian Academy of Science.

Robert Gibson, PhD, is the Professor of Functional Food Science and Nutrition at the University of Adelaide. He is a lipid biochemist with an extensive track record in both metabolic and clinical studies regarding the health effects of fatty acids. Dr. Gibson has published more than 150 peer-reviewed papers and is on the Board of Directors of the International Society of the Study of Fatty Acids and Lipids.

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