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Is there a dietary requirement for DHA in pregnancy?
ARTICLE IN PRESS Prostaglandins, Leukotrienes and Essential Fatty Acids 81 (2009) 171–174
Contents lists available at ScienceDirect
Prostaglandins, Leukotrienes and Essential Fatty Acids journal homepage: www.elsevier.com/locate/plefa
Is there a dietary requirement for DHA in pregnancy? Maria Makrides a,b,c, a b c
Women’s and Children’s Health Research Institute, Level 7, Clarence Rieger Building, Women’s and Children’s Hospital, 72 King William Road, North Adelaide, SA 5006, Australia Women’s and Children’s Health Research Institute at Flinders, Flinders Medical Centre, Bedford Park, SA 5042, Australia School of Paediatrics and Reproductive Health, University of Adelaide, SA 5005 Australia
a r t i c l e in fo
Keywords: DHA Pregnancy Infant development Requirement
abstract The metabolic demand for docosahexaenoic acid (22:6 n-3, DHA) is increased during pregnancy because of the extra needs of the fetus, expanded maternal cell mass and placenta. In Western countries maternal dietary DHA intake in pregnancy is low and it is not clear whether adaptive metabolic mechanisms, such as increased DHA synthesis from precursor fatty acids, are capable of meeting the increased DHA need in pregnancy. Consequently randomized controlled trials are important to determine whether additional dietary DHA in pregnancy modifies maternal or infant health outcomes. The available randomized comparisons of DHA supplements vs placebo have assessed outcomes as diverse as maternal depression, infant visual acuity and development, and infant growth and allergy. The outcomes of these trials have not been conclusive because they have often been limited by small sample size. On the other hand, large-scale trials assessing marine oil supplementation with large doses indicate that DHA supplementation in pregnancy is safe. & 2009 Elsevier Ltd. All rights reserved.
1. Introduction The n-3 (or omega-3) long chain polyunsaturated fatty acid (LCPUFA), docosahexaenoic acid (DHA, 22:6n-3) has been of particular interest in pregnancy nutrition because of its potential effects on pregnancy outcomes, maternal health and the development of the off-spring. The metabolic demand for DHA increases during pregnancy. The last trimester of pregnancy is the time when DHA accretion into the fetal brain and nervous system is at its greatest velocity. The fetus is supplied with its DHA from the maternal circulation and post-mortem studies indicate that the fetus accumulates an average of 67 mg of n-3 fatty acids, mostly as DHA, per day during the last trimester of pregnancy [1]. In addition the mother has increased requirements to support the expanded red cell mass and placenta as well as her own base needs. This increased metabolic need for DHA in pregnancy may be furnished by maternal DHA intake, adaptive metabolic mechanisms in pregnancy such as an increased synthetic capacity to metabolise alpha-linolenic acid (ALA, 18:3n-3) to DHA [2] and a preferential use of the DHA stored in adipose tissue [3], and the DHA saved from pregnancy amenorrhea. It has not been possible to quantify the positive and negative
Corresponding author at: Women’s and Children’s Health Research Institute, Level 7, Clarence Rieger Building, Women’s and Children’s Hospital, 72 King William Road, North Adelaide, SA 5006, Australia. Tel.: +618 8161 6067; fax: +618 81618228. E-mail address: [email protected]
0952-3278/$ - see front matter & 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.plefa.2009.05.005
sides of the DHA balance equation during pregnancy to ascertain whether there is a ‘‘true’’ increased requirement. However, we do know that the DHA intake of women in industrialized countries in generally low and there is little evidence that women change their dietary habits to enhance their DHA intakes in pregnancy. Mean DHA in Western countries is 70–200 mg/day [4–8] but in some cases median intake is lower (30–50 mg/day) highlighting a skewed distribution of intakes [6] so that many women have intakes less than the estimated daily accretion of DHA into the fetus during the last trimester of pregnancy. These observations highlight a potential dietary insufficiency of DHA for both mother and baby. With this background, the scope of this paper is to review trials that have compared DHA supplementation with control or placebo in pregnancy to determine is there is a specific DHA dose associated with benefit to the mother or child and to also determine the maximal safe dose.
2. High-dose n-3 LCPUFA supplementation in pregnancy Most of the early trials involving n-3 LCPUFA supplementation in pregnancy have used high doses of fish oil that was higher in eicosapentaenoic acid (EPA, 20:5n-3) than DHA. The rationale for these intervention trials was based on observational studies showing an association between high fish consumption and increased duration of pregnancy, higher birth weight and a lower incidence of pre-eclampsia [9,10]. This together with the known biochemical and physiological roles of n-3 LCPUFA in modulating
ARTICLE IN PRESS 172
M. Makrides / Prostaglandins, Leukotrienes and Essential Fatty Acids 81 (2009) 171–174
inflammatory and vascular effects as well as putative roles in altering prostaglandin balance to delay initiation of labour and cervical ripening led to a number of randomized controlled trials to assess the efficacy of fish oil supplementation in improving major pregnancy outcomes. These trials are reviewed here because they provide data regarding the safety of high n-3 LCPUFA doses. Three systematic reviews have recently aggregated the results of the relevant randomized controlled trials [11–13]. The metaanalyses showed remarkably consistent results despite the fact that these reviews had differing inclusion criteria. In brief, supplementation with marine oil in the second half of pregnancy resulted in a modest increase in the length of gestation (approximately 2.5 days) compared with no marine oil treatment. This was not reflected in a clear difference between the two groups in the risk of preterm birth (o37 weeks gestation), although women allocated to marine oil did have a lower risk of giving birth before 34 weeks gestation [11,12]. 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 between the groups in the proportion of low birth weight or small-for-gestational age babies [12]. There was also no clear difference in the relative risk of pre-eclampsia between the two groups [12]. Collectively these data suggest that routine use of marine oil supplements in pregnancy is likely to have limited benefit in preventing pre-eclampsia, preterm birth and low birth weight. Although many of the trials assessing the effects of n-3 LCPUFA supplementation on pregnancy outcomes have taken a pharmacological approach, they have been useful in providing information about safe intakes of n-3 LCPUFA. For example, supplementation with the commonly used dose of 3 g EPA+DHA per day (20 times the average intake of most pregnant women in Westernized countries) was not associated with increased risk of bleeding complications such as nasal bleeding, antepartum vaginal bleeding, maternal anaemia, vaginal blood loss after birth and blood loss at birth, a concern that has commonly been raised in relation to marine oil supplements in pregnancy because of their anticoagulant properties [12]. There were also no clear differences between the groups in the mean length of infant hospital stay or the relative risks of admission to neonatal care, congenital malformation, neonatal bleeding disorders and neonatal nonbleeding disorders [12]. As EPA is the fatty acid with greater anticoagulant properties than DHA, these data are also consistent with the safe use of high doses of DHA in pregnancy.
3. DHA intakes in pregnancy and maternal mood The data to have received most attention has been the putative link between n-3 LCPUFA and depression. A pooled analysis of cross country data showed a negative associated between the prevalence of postnatal depression and either seafood consumption or breast milk DHA concentration [14]. These observations together with the association between n-3 fatty acid deficiency and reduced brain serotonin in animal studies highlight 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. However, the available randomized trials suffer from methodological limitations. Some have had an open label design, others have been uncontrolled but all have had small sample sizes. Despite the suggestion that n-3 LCPUFA may ameliorate depressive symptoms in the perinatal period, it is not possible to exclude bias and random error [15–17,18]. Large-scale trials currently in progress
will more robustly report on the link between n-3 LCPUFA, and more specifically DHA, in pregnancy and postnatal depression.
4. DHA in pregnancy and infant outcomes 4.1. Visual acuity and global development There are few published trials assessing n-3 LCPUFA intake in pregnancy and developmental outcome in children. Two recent trials have assessed DHA intake in pregnancy and visual acuity in infancy with contrasting results [19,20]. Judge et al. [25] randomly allocated 30 pregnant women to snack bars containing either 200 mg DHA or no DHA and showed improved visual acuity measured by Teller cards in the infants at 4 but not 6 months of age. Innis and Friesen [19] assessed the effect of supplementing 135 pregnant women with either 400 mg DHA/day or placebo and showed no difference between the DHA and control group in the Teller acuity of infants at 2 months of age. Innis and Friesen [19] also conducted a number of complex multivariate analyses, which indicated that female sex and DHA study group were the positive predictors of acuity. The positive association with DHA despite no group difference is consistent with the data of Malcolm and colleagues [21], who also showed an association between infants DHA status and the maturation of pattern-reversal visual evoked potentials in response of 100 mg of daily DHA supplementation from week 15 of pregnancy. Clearly further work is required to delineate a specific DHA dose response. Another trial has assessed the effect a DHA-rich marine oil in pregnancy and the first 3 months of lactation on longer term developmental outcome of children [22,23] and reported no difference in short term surrogate measures of neurodevelopmental outcome but at 4 years of age children from DHA-rich marine oil supplemented mothers had higher scores on a test of mental processing compared with children from unsupplemented mothers [22]. 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. 4.2. Allergy and body composition The anti-inflammatory and immune modulating effects of n-3 LCPUFA have raised the possibility that improvements in n-3 LCPUFA status may be associated with a lower risk of developing childhood allergies. Some dietary intervention studies have suggested that increasing early DHA-rich tuna oil supplementation lowers the prevalence of asthma but follow-up studies have generally failed to detect an effect [24,25]. The only published 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 [26]. Atopic pregnant women were supplemented with marine oil (3.7 g n-3 LCPUFA per day; n ¼ 52) or placebo (n ¼ 46) from 20 weeks gestation until birth. Children in the marine oil group were less likely to have a positive skin prick test (IgE-mediated atopic response) to some allergens at 1 year. Although there were no differences between the groups in the frequency of atopic dermatitis, infants in the marine oil group had less severe disease [26]. 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, IFNg) to allergens [26]. 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.
ARTICLE IN PRESS M. Makrides / Prostaglandins, Leukotrienes and Essential Fatty Acids 81 (2009) 171–174
Another emerging area of investigation is the effect of maternal DHA supplementation in pregnancy and the effect on body composition of the off-spring. As childhood obesity is increasingly recognized as a major public health issue, any interventions that can ameliorate the development or consequences of obesity become important. The first study to explore the role of maternal n-3 LCPUFA supplementation during pregnancy, predominantly as DHA, was published last year and reported that the infants born to n-3 LCPUFA supplemented women had a reduced body weight and reduced BMI at 21 months of age, compared with control [27]. Furthermore, the BMI z-score was lower in infants of DHA-supplemented mothers throughout the first 21 months of postnatal life [27]. Although this trial was small and one cannot exclude the possibility of random error or bias, the results provide preliminary support for the hypothesis that maternal DHA supplementation can alter body composition in postnatal life and is consistent with data from animal models, which demonstrate that n-3 LCPUFA inhibit the early and late phases of development of adipose cells, thereby reducing the total pool of adipocytes present at birth and the potential for the later accumulation of excess body fat [28].
5. Summary and implications for DHA requirements in pregnancy Collectively the data available from intervention trials in pregnancy indicate that doses of up to 3 g/day of n-3 LCPUFA are safe. The potential benefits of n-3 LCPUFA supplementation, including DHA, on preventing pre-eclampsia, preterm birth and low birth weight are unlikely to be great. However, the potential effects of DHA supplementation in pregnancy on measures of early childhood development are promising and current ongoing randomized controlled trials will deliver specific information regarding dose and extent of benefit. Until such data are available, which causally link a specific DHA intake to a clinically important outcome, it will not be possible to set an estimated average requirement for DHA. Rather, there are general guidelines that have been derived from the available data [29–31]. These guidelines indicate that pregnant women should aim to achieve a dietary intake of n-3 LCPUFA that supplies a DHA intake of at least 200 mg/day. Disclosure: Salary for the author is from the Senior Fellowship Scheme of the National Health and Medical Research Council of Australia.
Acknowledgements MM is chief investigator in three large-scale clinical trials of marine oil supplementation in the perinatal period. MM has no financial interests in the production or sales of nutritional supplements or infant formula but has provided scientific advice to the nutritional supplement and formula industry. MM serves on the scientific advisory for Nestle, Nutricia and Fonterra. Associated honoraria for MM are paid to her institution to support conference travel and continuing education for post-graduate students and early career researchers. References [1] S.M. Innis, Perinatal biochemistry and physiology of long-chain polyunsaturated fatty acids, J. Pediatr. 143 (2003) S1–S8. [2] G.C. Burdge, P.C. Calder, Conversion of alpha-linolenic acid to longer-chain polyunsaturated fatty acids in human adults, Reprod. Nutr. Dev. 45 (2005) 581–597.
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[3] M. Makrides, R.A. Gibson, Long-chain polyunsaturated fatty acid requirements during pregnancy and lactation, Am. J. Clin. Nutr. 71 (2000) 307–311. [4] J. Denomme, K.D. Stark, B.J. Holub, Directly quantitated dietary (n-3) fatty acid intakes of pregnant Canadian women are lower than current dietary recommendations, J. Nutr. 135 (2005) 206–211. [5] S.M. Innis, S.L. Elias, Intakes of essential n-6 and n-3 polyunsaturated fatty acids among pregnant Canadian women, Am. J. Clin. Nutr. 77 (2003) 473–478. [6] B.J. Meyer, N.J. Mann, J.L. Lewis, G.C. Milligan, A.J. Sinclair, P.R. Howe, Dietary intakes and food sources of omega-6 and omega-3 polyunsaturated fatty acids, Lipids 38 (2003) 391–398. [7] S.J. Otto, A.C. Houwelingen, M. Antal, A. Manninen, K. Godfrey, P. LopezJaramillo, et al., Maternal and neonatal essential fatty acid status in phospholipids: an international comparative study, Eur. J. Clin. Nutr. 51 (1997) 232–242. [8] K.D. Stark, S. Beblo, M. Murthy, M. Buda-Abela, J. Janisse, H. Rockett, et al., Comparison of bloodstream fatty acid composition from African-American women at gestation, delivery, and postpartum, J. Lipid Res. 46 (2005) 516–525. [9] S.F. Olsen, H.D. Joensen, High liveborn birth weights in the Faroes: a comparison between birth weights in the Faroes and in Denmark, J. Epidemiol. Community Health 39 (1985) 27–32. [10] S.F. Olsen, H.S. Hansen, T.I.A. Sorensen, B. Jensen, N.J. Secher, S. Sommer, et al., Intake of marine fat, rich in (n-3)-polyunsaturated fatty acids, may increase birthweight by prolonging gestation, Lancet 2 (1986) 367–369. [11] A. Horvath, B. Koletzko, H. Szajewska, 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, Br. J. Nutr. 98 (2007) 253–259. [12] M. Makrides, L. Duley, S.F. Olsen, Marine oil, and other prostaglandin precursor, supplementation for pregnancy uncomplicated by pre-eclampsia or intrauterine growth restriction, Cochrane Database Syst Rev 3 (2006) CD003402. [13] H. Szajewska, A. Horvath, B. Koletzko, 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, Am. J. Clin. Nutr. 83 (2006) 1337–1344. [14] J.R. Hibbeln, Seafood consumption, the DHA content of mothers’ milk and prevalence rates of postpartum depression: a cross-national, ecological analysis, J. Affect Disord. 69 (2002) 15–29. [15] M.P. Freeman, J.R. Hibbeln, K.L. Wisner, M. Watchman, A.J. Gelenberg, An open trial of omega-3 fatty acids for depression in pregnancy, Acta Neuropsychiatr. 18 (2006) 21–24. [16] M.P. Freeman, M. Davis, P. Sinha, K.L. Wisner, J.R. Hibbeln, A.J. Gelenberg, Omega-3 fatty acids and supportive psychotherapy for perinatal depression: A randomized placebo-controlled study, J. Affect Disord. (2008). [17] M.P. Freeman, J.R. Hibbeln, K.L. Wisner, B.H. Brumbach, M. Watchman, A.J. Gelenberg, Randomized dose-ranging pilot trial of omega-3 fatty acids for postpartum depression, Acta Psychiatr. Scand. 113 (2006) 31–35. [18] K.P. Su, S.Y. Huang, T.H. Chiu, K.C. Huang, C.L. Huang, H.C. Chang, et al., Omega-3 fatty acids for major depressive disorder during pregnancy: results from a randomized, double-blind, placebo-controlled trial, J. Clin. Psychiatry 69 (2008) 644–651. [19] S.M. Innis, R.W. Friesen, Essential n-3 fatty acids in pregnant women and early visual acuity maturation in term infants, Am. J. Clin. Nutr. 87 (2008) 548–557. [20] M.P. Judge, O. Harel, C.J. Lammi-Keefe, A docosahexaenoic acid-functional food during pregnancy benefits infant visual acuity at four but not six months of age, Lipids 42 (2007) 117–122. [21] C.A. Malcolm, D.L. McCulloch, C. Montgomery, A. Shepherd, L.T. Weaver, Maternal docosahexaenoic acid supplementation during pregnancy and visual evoked potential development in term infants: a double blind, prospective, randomised trial, Arch. Dis. Child Fetal Neonatal Ed. 88 (2003) F383–F390. [22] I.B. Helland, L. Smith, K. Saarem, O.D. Saugstad, C.A. Drevon, Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children’s IQ at 4 years of age, Pediatrics 111 (2003) e39–e44. [23] I.B. Helland, O.D. Saugstad, L. Smith, K. Saarem, K. Solvoll, T. Ganes, et al., Similar effects on infants of n-3 and n-6 fatty acids supplementation to pregnant and lactating women, Pediatrics 108 (2001) E82. [24] G.B. Marks, S. Mihrshahi, A.S. Kemp, E.R. Tovey, K. Webb, C. Almqvist, et al., Prevention of asthma during the first 5 years of life: a randomized controlled trial, J. Allergy Clin. Immunol. 118 (2006) 53–61. [25] J.K. Peat, S. Mihrshahi, A.S. Kemp, G.B. Marks, E.R. Tovey, K. Webb, et al., Three-year outcomes of dietary fatty acid modification and house dust mite reduction in the Childhood Asthma Prevention Study, J. Allergy Clin. Immunol. 114 (2004) 807–813. [26] J.A. Dunstan, T.A. Mori, A. Barden, L.J. Beilin, A.L. Taylor, P.G. Holt, et al., Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: a randomized, controlled trial, J. Allergy Clin. Immunol. 112 (2003) 1178–1184. [27] P.L. Bergmann, K.E. Bergmann, E. Haschke-Becher, R. Richter, J.W. Dudenhausen, D. Barclay, F. Haschke, Does maternal docosahexaenoic acid supplementation during pregnancy and lactation lower BMI in late infancy?, J. Perinatol. Med. 35 (2007) 295–300. [28] G. Ailhaud, F. Massiera, P. Weill, P. Legrand, J.M. Alessandri, P. Guesnet, Temporal changes in dietary fats: role of n-6 polyunsaturated fatty acids in
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excessive adipose tissue development and relationship to obesity, Prog. Lipid Res. 45 (2006) 203–236. [29] L. Kaiser, L.H. Allen, Position of the American Dietetic Association: nutrition and lifestyle for a healthy pregnancy outcome, J. Am. Diet. Assoc. 108 (2008) 553–561.
[30] B. Koletzko, I. Cetin, J.T. Brenna, Dietary fat intakes for pregnant and lactating women, Br. J. Nutr. 98 (2007) 873–877. [31] P.M. Kris-Etherton, S. Innis, D.A. American, Dietitians of Canada. Position of the American dietetic association and dietitians of Canada: dietary fatty acids, J. Am. Diet. Assoc. 107 (2007) 1599–1611.
Contents lists available at ScienceDirect
Prostaglandins, Leukotrienes and Essential Fatty Acids journal homepage: www.elsevier.com/locate/plefa
Is there a dietary requirement for DHA in pregnancy? Maria Makrides a,b,c, a b c
Women’s and Children’s Health Research Institute, Level 7, Clarence Rieger Building, Women’s and Children’s Hospital, 72 King William Road, North Adelaide, SA 5006, Australia Women’s and Children’s Health Research Institute at Flinders, Flinders Medical Centre, Bedford Park, SA 5042, Australia School of Paediatrics and Reproductive Health, University of Adelaide, SA 5005 Australia
a r t i c l e in fo
Keywords: DHA Pregnancy Infant development Requirement
abstract The metabolic demand for docosahexaenoic acid (22:6 n-3, DHA) is increased during pregnancy because of the extra needs of the fetus, expanded maternal cell mass and placenta. In Western countries maternal dietary DHA intake in pregnancy is low and it is not clear whether adaptive metabolic mechanisms, such as increased DHA synthesis from precursor fatty acids, are capable of meeting the increased DHA need in pregnancy. Consequently randomized controlled trials are important to determine whether additional dietary DHA in pregnancy modifies maternal or infant health outcomes. The available randomized comparisons of DHA supplements vs placebo have assessed outcomes as diverse as maternal depression, infant visual acuity and development, and infant growth and allergy. The outcomes of these trials have not been conclusive because they have often been limited by small sample size. On the other hand, large-scale trials assessing marine oil supplementation with large doses indicate that DHA supplementation in pregnancy is safe. & 2009 Elsevier Ltd. All rights reserved.
1. Introduction The n-3 (or omega-3) long chain polyunsaturated fatty acid (LCPUFA), docosahexaenoic acid (DHA, 22:6n-3) has been of particular interest in pregnancy nutrition because of its potential effects on pregnancy outcomes, maternal health and the development of the off-spring. The metabolic demand for DHA increases during pregnancy. The last trimester of pregnancy is the time when DHA accretion into the fetal brain and nervous system is at its greatest velocity. The fetus is supplied with its DHA from the maternal circulation and post-mortem studies indicate that the fetus accumulates an average of 67 mg of n-3 fatty acids, mostly as DHA, per day during the last trimester of pregnancy [1]. In addition the mother has increased requirements to support the expanded red cell mass and placenta as well as her own base needs. This increased metabolic need for DHA in pregnancy may be furnished by maternal DHA intake, adaptive metabolic mechanisms in pregnancy such as an increased synthetic capacity to metabolise alpha-linolenic acid (ALA, 18:3n-3) to DHA [2] and a preferential use of the DHA stored in adipose tissue [3], and the DHA saved from pregnancy amenorrhea. It has not been possible to quantify the positive and negative
Corresponding author at: Women’s and Children’s Health Research Institute, Level 7, Clarence Rieger Building, Women’s and Children’s Hospital, 72 King William Road, North Adelaide, SA 5006, Australia. Tel.: +618 8161 6067; fax: +618 81618228. E-mail address: [email protected]
0952-3278/$ - see front matter & 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.plefa.2009.05.005
sides of the DHA balance equation during pregnancy to ascertain whether there is a ‘‘true’’ increased requirement. However, we do know that the DHA intake of women in industrialized countries in generally low and there is little evidence that women change their dietary habits to enhance their DHA intakes in pregnancy. Mean DHA in Western countries is 70–200 mg/day [4–8] but in some cases median intake is lower (30–50 mg/day) highlighting a skewed distribution of intakes [6] so that many women have intakes less than the estimated daily accretion of DHA into the fetus during the last trimester of pregnancy. These observations highlight a potential dietary insufficiency of DHA for both mother and baby. With this background, the scope of this paper is to review trials that have compared DHA supplementation with control or placebo in pregnancy to determine is there is a specific DHA dose associated with benefit to the mother or child and to also determine the maximal safe dose.
2. High-dose n-3 LCPUFA supplementation in pregnancy Most of the early trials involving n-3 LCPUFA supplementation in pregnancy have used high doses of fish oil that was higher in eicosapentaenoic acid (EPA, 20:5n-3) than DHA. The rationale for these intervention trials was based on observational studies showing an association between high fish consumption and increased duration of pregnancy, higher birth weight and a lower incidence of pre-eclampsia [9,10]. This together with the known biochemical and physiological roles of n-3 LCPUFA in modulating
ARTICLE IN PRESS 172
M. Makrides / Prostaglandins, Leukotrienes and Essential Fatty Acids 81 (2009) 171–174
inflammatory and vascular effects as well as putative roles in altering prostaglandin balance to delay initiation of labour and cervical ripening led to a number of randomized controlled trials to assess the efficacy of fish oil supplementation in improving major pregnancy outcomes. These trials are reviewed here because they provide data regarding the safety of high n-3 LCPUFA doses. Three systematic reviews have recently aggregated the results of the relevant randomized controlled trials [11–13]. The metaanalyses showed remarkably consistent results despite the fact that these reviews had differing inclusion criteria. In brief, supplementation with marine oil in the second half of pregnancy resulted in a modest increase in the length of gestation (approximately 2.5 days) compared with no marine oil treatment. This was not reflected in a clear difference between the two groups in the risk of preterm birth (o37 weeks gestation), although women allocated to marine oil did have a lower risk of giving birth before 34 weeks gestation [11,12]. 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 between the groups in the proportion of low birth weight or small-for-gestational age babies [12]. There was also no clear difference in the relative risk of pre-eclampsia between the two groups [12]. Collectively these data suggest that routine use of marine oil supplements in pregnancy is likely to have limited benefit in preventing pre-eclampsia, preterm birth and low birth weight. Although many of the trials assessing the effects of n-3 LCPUFA supplementation on pregnancy outcomes have taken a pharmacological approach, they have been useful in providing information about safe intakes of n-3 LCPUFA. For example, supplementation with the commonly used dose of 3 g EPA+DHA per day (20 times the average intake of most pregnant women in Westernized countries) was not associated with increased risk of bleeding complications such as nasal bleeding, antepartum vaginal bleeding, maternal anaemia, vaginal blood loss after birth and blood loss at birth, a concern that has commonly been raised in relation to marine oil supplements in pregnancy because of their anticoagulant properties [12]. There were also no clear differences between the groups in the mean length of infant hospital stay or the relative risks of admission to neonatal care, congenital malformation, neonatal bleeding disorders and neonatal nonbleeding disorders [12]. As EPA is the fatty acid with greater anticoagulant properties than DHA, these data are also consistent with the safe use of high doses of DHA in pregnancy.
3. DHA intakes in pregnancy and maternal mood The data to have received most attention has been the putative link between n-3 LCPUFA and depression. A pooled analysis of cross country data showed a negative associated between the prevalence of postnatal depression and either seafood consumption or breast milk DHA concentration [14]. These observations together with the association between n-3 fatty acid deficiency and reduced brain serotonin in animal studies highlight 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. However, the available randomized trials suffer from methodological limitations. Some have had an open label design, others have been uncontrolled but all have had small sample sizes. Despite the suggestion that n-3 LCPUFA may ameliorate depressive symptoms in the perinatal period, it is not possible to exclude bias and random error [15–17,18]. Large-scale trials currently in progress
will more robustly report on the link between n-3 LCPUFA, and more specifically DHA, in pregnancy and postnatal depression.
4. DHA in pregnancy and infant outcomes 4.1. Visual acuity and global development There are few published trials assessing n-3 LCPUFA intake in pregnancy and developmental outcome in children. Two recent trials have assessed DHA intake in pregnancy and visual acuity in infancy with contrasting results [19,20]. Judge et al. [25] randomly allocated 30 pregnant women to snack bars containing either 200 mg DHA or no DHA and showed improved visual acuity measured by Teller cards in the infants at 4 but not 6 months of age. Innis and Friesen [19] assessed the effect of supplementing 135 pregnant women with either 400 mg DHA/day or placebo and showed no difference between the DHA and control group in the Teller acuity of infants at 2 months of age. Innis and Friesen [19] also conducted a number of complex multivariate analyses, which indicated that female sex and DHA study group were the positive predictors of acuity. The positive association with DHA despite no group difference is consistent with the data of Malcolm and colleagues [21], who also showed an association between infants DHA status and the maturation of pattern-reversal visual evoked potentials in response of 100 mg of daily DHA supplementation from week 15 of pregnancy. Clearly further work is required to delineate a specific DHA dose response. Another trial has assessed the effect a DHA-rich marine oil in pregnancy and the first 3 months of lactation on longer term developmental outcome of children [22,23] and reported no difference in short term surrogate measures of neurodevelopmental outcome but at 4 years of age children from DHA-rich marine oil supplemented mothers had higher scores on a test of mental processing compared with children from unsupplemented mothers [22]. 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. 4.2. Allergy and body composition The anti-inflammatory and immune modulating effects of n-3 LCPUFA have raised the possibility that improvements in n-3 LCPUFA status may be associated with a lower risk of developing childhood allergies. Some dietary intervention studies have suggested that increasing early DHA-rich tuna oil supplementation lowers the prevalence of asthma but follow-up studies have generally failed to detect an effect [24,25]. The only published 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 [26]. Atopic pregnant women were supplemented with marine oil (3.7 g n-3 LCPUFA per day; n ¼ 52) or placebo (n ¼ 46) from 20 weeks gestation until birth. Children in the marine oil group were less likely to have a positive skin prick test (IgE-mediated atopic response) to some allergens at 1 year. Although there were no differences between the groups in the frequency of atopic dermatitis, infants in the marine oil group had less severe disease [26]. 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, IFNg) to allergens [26]. 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.
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Another emerging area of investigation is the effect of maternal DHA supplementation in pregnancy and the effect on body composition of the off-spring. As childhood obesity is increasingly recognized as a major public health issue, any interventions that can ameliorate the development or consequences of obesity become important. The first study to explore the role of maternal n-3 LCPUFA supplementation during pregnancy, predominantly as DHA, was published last year and reported that the infants born to n-3 LCPUFA supplemented women had a reduced body weight and reduced BMI at 21 months of age, compared with control [27]. Furthermore, the BMI z-score was lower in infants of DHA-supplemented mothers throughout the first 21 months of postnatal life [27]. Although this trial was small and one cannot exclude the possibility of random error or bias, the results provide preliminary support for the hypothesis that maternal DHA supplementation can alter body composition in postnatal life and is consistent with data from animal models, which demonstrate that n-3 LCPUFA inhibit the early and late phases of development of adipose cells, thereby reducing the total pool of adipocytes present at birth and the potential for the later accumulation of excess body fat [28].
5. Summary and implications for DHA requirements in pregnancy Collectively the data available from intervention trials in pregnancy indicate that doses of up to 3 g/day of n-3 LCPUFA are safe. The potential benefits of n-3 LCPUFA supplementation, including DHA, on preventing pre-eclampsia, preterm birth and low birth weight are unlikely to be great. However, the potential effects of DHA supplementation in pregnancy on measures of early childhood development are promising and current ongoing randomized controlled trials will deliver specific information regarding dose and extent of benefit. Until such data are available, which causally link a specific DHA intake to a clinically important outcome, it will not be possible to set an estimated average requirement for DHA. Rather, there are general guidelines that have been derived from the available data [29–31]. These guidelines indicate that pregnant women should aim to achieve a dietary intake of n-3 LCPUFA that supplies a DHA intake of at least 200 mg/day. Disclosure: Salary for the author is from the Senior Fellowship Scheme of the National Health and Medical Research Council of Australia.
Acknowledgements MM is chief investigator in three large-scale clinical trials of marine oil supplementation in the perinatal period. MM has no financial interests in the production or sales of nutritional supplements or infant formula but has provided scientific advice to the nutritional supplement and formula industry. MM serves on the scientific advisory for Nestle, Nutricia and Fonterra. Associated honoraria for MM are paid to her institution to support conference travel and continuing education for post-graduate students and early career researchers. References [1] S.M. Innis, Perinatal biochemistry and physiology of long-chain polyunsaturated fatty acids, J. Pediatr. 143 (2003) S1–S8. [2] G.C. Burdge, P.C. Calder, Conversion of alpha-linolenic acid to longer-chain polyunsaturated fatty acids in human adults, Reprod. Nutr. Dev. 45 (2005) 581–597.
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[3] M. Makrides, R.A. Gibson, Long-chain polyunsaturated fatty acid requirements during pregnancy and lactation, Am. J. Clin. Nutr. 71 (2000) 307–311. [4] J. Denomme, K.D. Stark, B.J. Holub, Directly quantitated dietary (n-3) fatty acid intakes of pregnant Canadian women are lower than current dietary recommendations, J. Nutr. 135 (2005) 206–211. [5] S.M. Innis, S.L. Elias, Intakes of essential n-6 and n-3 polyunsaturated fatty acids among pregnant Canadian women, Am. J. Clin. Nutr. 77 (2003) 473–478. [6] B.J. Meyer, N.J. Mann, J.L. Lewis, G.C. Milligan, A.J. Sinclair, P.R. Howe, Dietary intakes and food sources of omega-6 and omega-3 polyunsaturated fatty acids, Lipids 38 (2003) 391–398. [7] S.J. Otto, A.C. Houwelingen, M. Antal, A. Manninen, K. Godfrey, P. LopezJaramillo, et al., Maternal and neonatal essential fatty acid status in phospholipids: an international comparative study, Eur. J. Clin. Nutr. 51 (1997) 232–242. [8] K.D. Stark, S. Beblo, M. Murthy, M. Buda-Abela, J. Janisse, H. Rockett, et al., Comparison of bloodstream fatty acid composition from African-American women at gestation, delivery, and postpartum, J. Lipid Res. 46 (2005) 516–525. [9] S.F. Olsen, H.D. Joensen, High liveborn birth weights in the Faroes: a comparison between birth weights in the Faroes and in Denmark, J. Epidemiol. Community Health 39 (1985) 27–32. [10] S.F. Olsen, H.S. Hansen, T.I.A. Sorensen, B. Jensen, N.J. Secher, S. Sommer, et al., Intake of marine fat, rich in (n-3)-polyunsaturated fatty acids, may increase birthweight by prolonging gestation, Lancet 2 (1986) 367–369. [11] A. Horvath, B. Koletzko, H. Szajewska, 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, Br. J. Nutr. 98 (2007) 253–259. [12] M. Makrides, L. Duley, S.F. Olsen, Marine oil, and other prostaglandin precursor, supplementation for pregnancy uncomplicated by pre-eclampsia or intrauterine growth restriction, Cochrane Database Syst Rev 3 (2006) CD003402. [13] H. Szajewska, A. Horvath, B. Koletzko, 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, Am. J. Clin. Nutr. 83 (2006) 1337–1344. [14] J.R. Hibbeln, Seafood consumption, the DHA content of mothers’ milk and prevalence rates of postpartum depression: a cross-national, ecological analysis, J. Affect Disord. 69 (2002) 15–29. [15] M.P. Freeman, J.R. Hibbeln, K.L. Wisner, M. Watchman, A.J. Gelenberg, An open trial of omega-3 fatty acids for depression in pregnancy, Acta Neuropsychiatr. 18 (2006) 21–24. [16] M.P. Freeman, M. Davis, P. Sinha, K.L. Wisner, J.R. Hibbeln, A.J. Gelenberg, Omega-3 fatty acids and supportive psychotherapy for perinatal depression: A randomized placebo-controlled study, J. Affect Disord. (2008). [17] M.P. Freeman, J.R. Hibbeln, K.L. Wisner, B.H. Brumbach, M. Watchman, A.J. Gelenberg, Randomized dose-ranging pilot trial of omega-3 fatty acids for postpartum depression, Acta Psychiatr. Scand. 113 (2006) 31–35. [18] K.P. Su, S.Y. Huang, T.H. Chiu, K.C. Huang, C.L. Huang, H.C. Chang, et al., Omega-3 fatty acids for major depressive disorder during pregnancy: results from a randomized, double-blind, placebo-controlled trial, J. Clin. Psychiatry 69 (2008) 644–651. [19] S.M. Innis, R.W. Friesen, Essential n-3 fatty acids in pregnant women and early visual acuity maturation in term infants, Am. J. Clin. Nutr. 87 (2008) 548–557. [20] M.P. Judge, O. Harel, C.J. Lammi-Keefe, A docosahexaenoic acid-functional food during pregnancy benefits infant visual acuity at four but not six months of age, Lipids 42 (2007) 117–122. [21] C.A. Malcolm, D.L. McCulloch, C. Montgomery, A. Shepherd, L.T. Weaver, Maternal docosahexaenoic acid supplementation during pregnancy and visual evoked potential development in term infants: a double blind, prospective, randomised trial, Arch. Dis. Child Fetal Neonatal Ed. 88 (2003) F383–F390. [22] I.B. Helland, L. Smith, K. Saarem, O.D. Saugstad, C.A. Drevon, Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children’s IQ at 4 years of age, Pediatrics 111 (2003) e39–e44. [23] I.B. Helland, O.D. Saugstad, L. Smith, K. Saarem, K. Solvoll, T. Ganes, et al., Similar effects on infants of n-3 and n-6 fatty acids supplementation to pregnant and lactating women, Pediatrics 108 (2001) E82. [24] G.B. Marks, S. Mihrshahi, A.S. Kemp, E.R. Tovey, K. Webb, C. Almqvist, et al., Prevention of asthma during the first 5 years of life: a randomized controlled trial, J. Allergy Clin. Immunol. 118 (2006) 53–61. [25] J.K. Peat, S. Mihrshahi, A.S. Kemp, G.B. Marks, E.R. Tovey, K. Webb, et al., Three-year outcomes of dietary fatty acid modification and house dust mite reduction in the Childhood Asthma Prevention Study, J. Allergy Clin. Immunol. 114 (2004) 807–813. [26] J.A. Dunstan, T.A. Mori, A. Barden, L.J. Beilin, A.L. Taylor, P.G. Holt, et al., Fish oil supplementation in pregnancy modifies neonatal allergen-specific immune responses and clinical outcomes in infants at high risk of atopy: a randomized, controlled trial, J. Allergy Clin. Immunol. 112 (2003) 1178–1184. [27] P.L. Bergmann, K.E. Bergmann, E. Haschke-Becher, R. Richter, J.W. Dudenhausen, D. Barclay, F. Haschke, Does maternal docosahexaenoic acid supplementation during pregnancy and lactation lower BMI in late infancy?, J. Perinatol. Med. 35 (2007) 295–300. [28] G. Ailhaud, F. Massiera, P. Weill, P. Legrand, J.M. Alessandri, P. Guesnet, Temporal changes in dietary fats: role of n-6 polyunsaturated fatty acids in
ARTICLE IN PRESS 174
M. Makrides / Prostaglandins, Leukotrienes and Essential Fatty Acids 81 (2009) 171–174
excessive adipose tissue development and relationship to obesity, Prog. Lipid Res. 45 (2006) 203–236. [29] L. Kaiser, L.H. Allen, Position of the American Dietetic Association: nutrition and lifestyle for a healthy pregnancy outcome, J. Am. Diet. Assoc. 108 (2008) 553–561.
[30] B. Koletzko, I. Cetin, J.T. Brenna, Dietary fat intakes for pregnant and lactating women, Br. J. Nutr. 98 (2007) 873–877. [31] P.M. Kris-Etherton, S. Innis, D.A. American, Dietitians of Canada. Position of the American dietetic association and dietitians of Canada: dietary fatty acids, J. Am. Diet. Assoc. 107 (2007) 1599–1611.