Marine oil supplementation in pregnancy and maternal and neonatal health outcomes
A commentary for the WHO electronic Library of Evidence for Nutrition Actions
Evidence from observational studies and randomized trials has suggested a potential association between intake of marine foods during pregnancy and certain pregnancy and birth outcomes. Researchers observed in the 1980s that women living in the Faroe Islands had longer gestational length and heavier babies than women living in Denmark. Additionally, researchers found that in Greenland Inuit women had lower rates of pre-eclampsia than Danish women. These observations instigated future research founded on the hypothesis that the intake of marine foods in pregnancy might influence maternal and neonatal health outcomes.
Marine foods are rich sources of the n-3 long-chain polyunsaturated fatty acids (LCPUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). These are bioactive LCPUFA that influence the regulation of biological processes such as eicosanoid synthesis and gene expression. Intake of marine oils could influence synthesis of bioactive molecules such as prostaglandins, which in turn influence timing of parturition. Numerous epidemiological studies and randomized trials have examined the influence marine oil intake during pregnancy on a variety of maternal, neonatal, and child health outcomes. This commentary will focus on results from randomized trials of marine oil supplementation in pregnancy, with particularly emphasis on the most recent Cochrane review on this topic.
The most recent Cochrane review examining the effect of marine oil and other prostaglandin precursor supplementation during pregnancy on maternal and neonatal health outcomes included data from six trials (2783 women) published through December 2005 1. Women with existing pre-eclampsia or suspected intrauterine growth restriction (IUGR) were excluded from the meta-analysis. This analysis, conducted by Makrides et al., measured a variety of maternal and neonatal health outcomes including maternal hypertension, pre-eclampsia, length of gestation, preterm birth, birth weight, low birth weight (LBW), and others.
Of note, women supplemented with marine oil experienced longer gestational duration than controls (2.6 days longer), and this difference was more pronounced in high risk pregnancies (8.5 days longer). Babies of supplemented mothers were 31% less likely to be born very early (less than 34 weeks), and had higher mean birth weights than controls (mean difference: 47 g). Although the clinical significance of prolonging gestation by 2.6 days and increasing birth weight by 47 g is questionable and did not translate into an effect on low birth weight, stillbirths, and neonatal deaths, the long term benefits of these improved birth outcomes have not been fully explored. The Cochrane meta-analysis showed no significant effect of marine oil supplementation on the other pre-specified pregnancy outcomes such as maternal hypertension, pre-eclampsia, and others.
Two additional meta-analyses on prenatal n-3 LCPUFA supplementation were conducted and published within a year of the Cochrane review 2, 3. A meta-analysis by Szajewska et al. in 2006 focused on low-risk pregnancies, while one by Horvath et al. in 2007 focused on high-risk pregnancies2, 3. Although the analysis by Szajewska et al. had different study inclusion and exclusion criteria than the Cochrane review, authors arrived at similar conclusions regarding gestational duration, preterm birth (less than 37 weeks) and low birth weight.
The Szajewska et al. review included six trials with a total of 1278 women and showed that n-3 LCPUFA supplementation during pregnancy prolonged gestation by 1.57 days (95% CI: 0.35, 2.78 d), but had no effect on preterm birth, low birth weight or other birth outcomes.
The Horvath et al. review focused on high-risk pregnancies and included four studies with 1264 women. The analysis of gestational duration included two studies with 295 women and showed no difference in duration of pregnancy greater than 37 weeks between groups (RR: 0.99, 95% CI: 0.9, 1.1). Likewise, the analysis of preterm delivery less than 37 weeks including three trials and 523 women showed no difference between groups (RR: 0.82, 95% CI: 0.6, 1.1). Similar to findings of the Cochrane review, this analysis showed that supplementation with n-3 LCPUFA decreased the risk of early preterm delivery (less than 34 weeks) (RR: 0.39, 95% CI: 0.18, 0.84). Other maternal and neonatal outcomes such as rates of pre-eclampsia, low birth weight, intrauterine growth restriction, and birth weight did not differ by intervention group.
Overall, the three meta-analyses show that supplementation with marine oil or n-3 LCPUFA is safe in pregnancy and is generally well tolerated. Rates of serious adverse events were similar between treatment groups and occurrence of side effects (e.g. vomiting, nausea, and diarrhoea) was generally similar except for belching and bad taste, which occurred more frequently in the marine oil-supplemented groups. The Makrides and Szajewska analyses showed a prolongation of gestational duration with n-3 LCPUFA or marine oil supplementation, and the Makrides and Horvath reviews showed a decreased risk of early preterm delivery (less than 34 weeks) in the n-3 LCPUFA or marine oil supplemented groups. Results should be interpreted with care because the number of included studies was small for certain outcomes (e.g. early preterm delivery) and several of the included studies were potentially biased due to issues such as inadequate or unknown allocation concealment. However, studies deemed low quality were not included in the Cochrane analysis.
Several studies of marine oil supplementation in pregnancy have been published since publication of the above reviews and results have been mixed 4–15. Of note, results from a large trial conducted by Makrides et al. in 2010 showed a reduced risk of early preterm delivery (less than 34 weeks) (adjusted RR: 0.49, 95% CI: 0.25, 0.94) and low birth weight (RR: 0.65, 95% CI: 0.44, 0.95) in the fish oil supplemented group 12. The finding of a reduction in very early preterm delivery concurs with findings from the meta-analyses, while the finding of reduction in low birth weight is inconsistent with conclusions from the previous reviews.
Pregnant women in many low-, middle- and high-income countries do not achieve the recommended intake of at least 200 mg of DHA per day, with the exception of coastal countries where fish and other marine foods are easily accessible, affordable and commonly consumed 16. Studies of LCPUFA content in breast milk reveal large variations in DHA concentrations worldwide, indicating differences in dietary intake of DHA 17. In non-coastal under resourced settings, intake of marine oil supplements in pregnancy or increased consumption of marine foods in pregnancy is likely not to be economically feasible. Furthermore, the effect of prenatal marine oil supplementation in under-resourced settings on low birth weight, preterm birth and pre-eclampsia is largely unknown. However, because studies have shown that marine oil supplementation is safe in pregnancy, dietary counselling that promotes consumption of marine foods, where feasible, could potentially benefit pregnant women by also increasing their intake of other important nutrients found in marine foods (e.g. protein, vitamin A and iron). Generally, consuming one to two fish meals per week would not pose a threat of adverse pregnancy outcomes due to environmental contaminants.
Most randomized trials of prenatal marine oil supplementation have been conducted in high-income countries and therefore the findings are not generalizable to populations in low- and middle-income countries. A recent trial in Mexico (1094 women) showed that prenatal DHA supplementation had no overall effect on maternal and neonatal health outcomes; however, this study was conducted in a middle-class, fairly well educated urban population where the rate of low birth weight was low (less than 6%) 9.
Further research is needed to determine any benefit of prenatal marine oil supplementation on populations in low income settings, especially where:
- intake of marine foods is low
- the rate of adverse maternal and neonatal health outcomes, including intrauterine growth restriction, is high.
Several prenatal marine oil supplementation trials have suggested a benefit on subsequent infant and child outcomes such as cognitive development; however, results have been mixed and inconclusive. Trials have also shown a potential benefit of prenatal fish oil supplementation on maternal mood but results are also inconclusive.
1 Makrides M, Duley L, Olsen SF. Marine oil, and other prostaglandin precursor, supplementation for pregnancy uncomplicated by pre-eclampsia or intrauterine growth restriction. Cochrane Database of Systematic Reviews, 2006, 3:CD003402.
2 Szajewska H, Horvath A, Koletzko B. Effect of n-3 long-chain polyunsaturated fatty acid supplementation of women with low-risk pregnancies on pregnancy outcomes and growth measures at birth: a meta-analysis of randomized controlled trials. American Journal of Clinical Nutrition,2006, 83(6):1337–44.
3 Horvath A, Koletzko B, Szajewska H. Effect of supplementation of women in high-risk pregnancies with long-chain polyunsaturated fatty acids on pregnancy outcomes and growth measures at birth: a meta-analysis of randomized controlled trials. British Journal of Nutrition, 2007, 98(2):253–9.
4 Knudsen VK et al. Fish oil in various doses or flax oil in pregnancy and timing of spontaneous delivery: a randomised controlled trial. British Journal of Obstetrics and Gynaecology, 2006, 113(5):536–43.
5 Judge MP, Harel O, Lammi-Keefe CJ. A docosahexaenoic acid-functional food during pregnancy benefits infant visual acuity at four but not six months of age. Lipids, 2007, 42(2):117–22.
6 Krauss-Etschmann S et al. Effects of fish-oil and folate supplementation of pregnant women on maternal and fetal plasma concentrations of docosahexaenoic acid and eicosapentaenoic acid: a European randomized multicenter trial. American Journal of Clinical Nutrition, 2007, 85(5):1392–400.
7 Krauss-Etschmann S et al. Decreased cord blood IL-4, IL-13, and CCR4 and increased TGF-beta levels after fish oil supplementation of pregnant women. Journal of Allergy and Clinical Immunology, 2008, 121(2):464–70.
8 Olsen SF et al. Duration of pregnancy in relation to fish oil supplementation and habitual fish intake: a randomised clinical trial with fish oil. European Journal of Clinical Nutrition, 2007, 61(8):976–85.
9 Ramakrishnan U et al. Effects of docosahexaenoic acid supplementation during pregnancy on gestational age and size at birth: randomized, double-blind, placebo-controlled trial in Mexico. Food and Nutrition Bulletin, 2010, 31(Suppl. 2):S108–16.
10 Harper M et al. Omega-3 fatty acid supplementation to prevent recurrent preterm birth: a randomized controlled trial. Obstetrics and Gynecology, 2010, 115:234–42.
11 Barden AE et al. n-3 fatty acid supplementation during pregnancy in women with allergic disease: effects on blood pressure, and maternal and fetal lipids. Clinical Science, 2006, 111(4):289–94.
12 Makrides M et al. Effect of DHA supplementation during pregnancy on maternal depression and neurodevelopment of young children: a randomized controlled trial. Journal of the American Medical Association, 2010, 304(15):1675–83.
13 Dunstan JA et al. Cognitive assessment of children at age 2(1/2) years after maternal fish oil supplementation in pregnancy: a randomised controlled trial. Archives of the Diseases of Childhood, Fetal and Neonatal, 2008, 93(1):F45–50.
14 Helland IB et al. Effect of supplementing pregnant and lactating mothers with n-3 very-long-chain fatty acids on children's IQ and body mass index at 7 years of age. Pediatrics, 2008, 122(2):e472–9.
15 Bergmann RL et al. Supplementation with 200 mg/day docosahexaenoic acid from mid-pregnancy through lactation improves the docosahexaenoic acid status of mothers with a habitually low fish intake and of their infants. Annals of Nutrition and Metabolism, 2008, 52(2):157–66.
16 Koletzko B et al. The roles of long-chain polyunsaturated fatty acids in pregnancy, lactation and infancy: review of current knowledge and consensus recommendations. Journal of Perinatal Medicine, 2008, 36(1):5–14.
17 Brenna JT et al. Docosahexaenoic and arachidonic acid concentrations in human breast milk worldwide. American Journal of Clinical Nutrition, 2007, 85(6):1457–64.
The named authors alone are responsible for the views expressed in this document.
Declarations of interests
Conflict of interest statements were collected from all named authors and no conflicts were identified.