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Studies on Omega-3 for Pregnancy, Fetal and Infant Development
  1. Allen KG, Harris MA. The role of n-3 fatty acids in gestation and parturition. Exp. Biol. Med. 2001; 226: 498-506.

    Abstract: Preterm birth is the most common cause of low infant birth weight and infant morbidity and mortality. Evidence from human and animal studies indicates that essential fatty acids of both the n-3 and n-6 series, and their eicosanoid metabolites, play important and modifiable roles in gestational duration and parturition, and n-3 fatty acid intake during pregnancy may be inadequate. Prostaglandins (PG) of the 2-series are involved in parturition and connective tissue remodeling associated with cervical maturation and rupture of membranes. In the absence of infections, preterm birth is characterized by lower reproductive tissue PG production and decreased inducible cyclooxygenase expression. Women who deliver prematurely have increased pools of n-6 fatty acid and decreased n-3 fatty acids, despite the lower PG production. Several human pregnancy supplementation trials with n-3 fatty acids have shown a significant reduction in the incidence of premature deliver and increased birth weight associated with increased gestational duration. Supplementation with long chain n-3 fatty acids such as docosahexaenoic acid may be useful in prolonging the duration of gestation in some high-risk pregnancies. Evidence presented in this review is discussed in terms of the roles of dietary n-3 and n-6 fatty acids in gestation and parturition, mechanisms by which they may influence gestational duration and the human trials suggesting that increased dietary long-chain n-3 fatty acids decrease the incidence of premature delivery.

  2. Araya A J, Rojas GM, Fernandez FP, Mateluna AA. Differences in percentage composition of long-chain polyunsaturated fatty acids in maternal and fetal erythrocytes in term and preterm births. Archivos Latinoamericanos de Nutricion 1998; 48(3): 210-215.

  3. Armitage JA, Pearce AD, Sinclair AJ, Vingrys AJ, Weisinger RS, Weisinger HS. Increased blood pressure later in life may be associated with perinatal n-3 fatty acid deficiency. Lipids 2003;38:459-64.

    Abstract: Hypertension is a major risk factor for cardiovascular and cerebrovascular disease. Previous work in both animals and humans with high blood pressure has demonstrated the antihypertensive effects of n-3 polyunsaturated fatty acids (PUFA), although it is not known whether these nutrients are effective in preventing hypertension. The predominant n-3 PUFA in the mammalian nervous system, docosahexaenoic acid (DHA), is deposited into synaptic membranes at a high rate during the perinatal period, and recent observations indicate that the perinatal environment is important for the normal development of blood pressure control. This study investigated the importance of perinatal n-3 PUFA supply in the control of blood pressure in adult Sprague-Dawley rats. Pregnant rat dams were fed semisynthetic diets that were either deficient in (DEF) or supplemented with (CON) n-3 PUFA. Offspring were fed the same diets as their mothers until 9 wk; then, half of the rats from each group were crossed over to the opposite diet, creating four groups, i.e., CON-CON; CON-DEF; DEF-DEF, DEF-CON. Mean arterial blood pressures (MAP) were measured directly, at 33 wk of age, by cannulation of the femoral artery. The phospholipid fatty acid profile of the hypothalamic region was determined by capillary gas-liquid chromatography. The tissue phospholipid fatty acid profile reflected the diet that the rats were consuming at the time of testing. Both groups receiving DEF after 9 wk of age (i.e., DEF-DEF and CON-DEF) had similar profiles with a reduction in DHA levels of 30%, compared with rats receiving CON (i.e., CON-CON and DEF-CON). DEF-DEF rats had significantly raised MAP compared with all other groups, with differences as great as 17 mm Hg. DEF-CON rats had raised MAP compared with CON-CON rats, and DEF-DEF rats had higher MAP than CON-DEF rats, despite the fact that their respective fatty acid profiles were not different. These findings indicate that inadequate levels of DHA in the perinatal period are associated with altered blood pressure control in later life. The way in which these long-term effects are produced remains to be elucidated.

  4. Auestad N et al. Visual acuity, erythrocyte fatty acid composition, and growth in term infants fed formulas with long chain polyunsaturated fatty acids for one year. Pediatric Research 1997; 41: 1-10.

    Abstract: The CNS and the retina are enriched in long chain polyunsaturated (LCP) fatty acids, specifically docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (AA, 20:4n-6), which are present in human milk but not in most infant formulas. In the present study of 134 formula-fed and 63 breast-fed infants, we prospectively evaluated whether providing a source of DHA and AA or DHA alone in formula would increase red blood cell (RBC) phospholipid levels of these fatty acids, enhance visual function, or affect growth during the first year. Healthy term infants <7 d old were randomized to be fed formulas containing linoleic acid ([almost equal to]10% kcal) and[alpha]-linolenic acid ([almost equal to]1% kcal) plus (1) no added LCP fatty acids (control formula), (2) DHA (0.12 wt% fatty acids) and AA (0.43 wt%) from egg yolk phospholipid (AA + DHA formula), or (3) DHA (0.2 wt%) from fish oil (DHA formula). A breast-fed group was studied concurrently and permitted formula supplementation after 3 mo. Visual acuity was measured using both the acuity card procedure and a visual evoked potential method at 2, 4, 6, 9, and 12 mo. Infants fed the control formula had 10-40% lower RBC levels of DHA and AA than infants in the breast-fed group. Infants fed the AA+ DHA formula had levels of both LCP within [almost equal to]10% of the values for infants in the breast-fed group, and infants fed the DHA formula had 25-55% higher DHA levels and 15-40% lower AA levels. There were no differences in growth or in visual function during this 12-mo feeding study.

  5. Auestad N, Scott DT, Janowsky JS, Jacobsen C, Carroll RE, Montalto MB, Halter R, Qiu W, Jacobs JR, Connor WE, Connor SL, Taylor JA, Neuringer M, Fitzgerald KM, Hall RT. Visual, cognitive, and language assessments at 39 months: a follow-up study of children fed formulas containing long-chain polyunsaturated fatty acids to 1 year of age. Pediatrics 2003; 112(3 Pt 1): e177-183.

    Abstract: OBJECTIVE: Docosahexaenoic acid (DHA) and arachidonic acid (ARA) are long-chain polyunsaturated fatty acids found in breast milk and recently added to infant formulas. Their importance in infant nutrition was recognized by the rapid accretion of these fatty acids in the brain during the first postnatal year, reports of enhanced intellectual development in breastfed children, and recognition of the physiologic importance of DHA in visual and neural systems from studies in animal models. These considerations led to clinical trials to evaluate whether infant formulas that are supplemented with DHA or both DHA and ARA would enhance visual and cognitive development or whether conversion of linoleic acid and alpha-linolenic acid, the essential fatty acid precursors of ARA and DHA, respectively, at the levels found in infant formulas is sufficient to support adequately visual and cognitive development. Visual and cognitive development were not different with supplementation in some studies, whereas other studies reported benefits of adding DHA or both DHA and ARA to formula. One of the first trials with term infants that were fed formula supplemented with DHA or both DHA and ARA evaluated growth, visual acuity (Visual Evoked Potential; Acuity Card Procedure), mental and motor development (Bayley Scales of Infant Development), and early language development (MacArthur Communicative Developmental Inventories). Growth, visual acuity, and mental and motor development were not different among the 3 formula groups or between the breastfed and formula-fed infants in the first year of life. At 14 months of age, infants who were fed the formula with DHA but no ARA had lower vocabulary production and comprehension scores than infants who were fed the unsupplemented control formula or who were breastfed, respectively. The present follow-up study evaluated IQ, receptive and expressive vocabulary, visual-motor function, and visual acuity of children from the original trial when they reached 39 months of age. METHODS: Infants were randomized within 1 week after birth and fed a control formula (n = 65), one containing DHA (n = 65), or one containing both ARA and DHA (n = 66) to 1 year of age. A comparison group (n = 80) was exclusively breastfed for at least 3 months after which the infants continued to be exclusively breastfed or were supplemented with and/or weaned to infant formula. At 39 months, standard tests of IQ (Stanford Binet IQ), receptive vocabulary (Peabody Picture Vocabulary Test-Revised), expressive vocabulary (mean length of utterance), visual-motor function (Beery Visual-Motor Index), and visual acuity (Acuity Card Procedure) were administered. Growth, red blood cell fatty acid levels, and morbidity also were evaluated. RESULTS: Results were analyzed using analysis of variance or linear regression models. The regression model for IQ, receptive and expressive language, and the visual-motor index controlled for site, birth weight, sex, maternal education, maternal age, and the child's age at testing. The regression model for visual acuity controlled for site only. A variable selection model also identified which of 22 potentially prognostic variables among different categories (feeding groups, the child and family demographics, indicators of illness since birth, and environment) were most influential for IQ and expressive vocabulary. A total of 157 (80%) of the 197 infants studied at 12 months participated in this follow-up study. Characteristics of the families were representative of US families with children up to 5 years of age, and there were no differences in the demographic or family characteristics among the randomized formula groups. As expected, the formula and breastfed groups differed in ethnicity, marital status, parental education, and the prevalence of smoking. Sex, ethnicity, gestational age at birth, and birth weight for those who participated at 39 months did not differ from those who did not. The 12-month Bayley mental and motor scores and 14-month vocabulary scores of the children who participated also were were not different from those who did not. At 39 months, IQ, receptive and expressive language, visual-motor function, and visual acuity were not different among the 3 randomized formula groups or between the breastfed and formula groups. The adjusted means for the control, ARA+DHA, DHA, and breastfed groups were as follows: IQ scores, 104, 101, 100, 106; Peabody Picture Vocabulary Test, 99.2, 97.2, 95.1, 97.4; mean length of utterance, 3.64, 3.75, 3.93, 4.08; the visual-motor index, 2.26, 2.24, 2.05, 2.40; and visual acuity (cycles/degree), 30.4, 27.9, 27.5, 28.6, respectively. IQ was positively associated with female sex and maternal education and negatively associated with the number of siblings and exposure to cigarette smoking in utero and/or postnatally. Expressive language also was positively associated with maternal education and negatively associated with the average hours in child care per week and hospitalizations since birth but only when the breastfed group was included in the analysis. The associations between maternal education and child IQ scores are consistent with previous reports as are the associations between prenatal exposure to cigarette smoke and IQ and early language development. Approximately one third of the variance for IQ was explained by sex, maternal education, the number of siblings, and exposure to cigarette smoke. Growth achievement, red blood cell fatty acid levels, and morbidity did not differ among groups. CONCLUSIONS: We reported previously that infants who were fed an unsupplemented formula or one with DHA or with both DHA and ARA through 12 months or were breastfed showed no differences in mental and motor development, but those who were fed DHA without ARA had lower vocabulary scores on a standardized, parent-report instrument at 14 months of age when compared with infants who were fed the unsupplemented formula or who were breastfed. When the infants were reassessed at 39 months using age-appropriate tests of receptive and expressive language as well as IQ, visual-motor function and visual acuity, no differences among the formula groups or between the formula and breastfed groups were found. The 14-month observation thus may have been a transient effect of DHA (without ARA) supplementation on early vocabulary development or may have occurred by chance. The absence of differences in growth achievement adds to the evidence that DHA with or without ARA supports normal growth in full-term infants. In conclusion, adding both DHA and ARA when supplementing infant formulas with long-chain polyunsaturated fatty acids supports visual and cognitive development through 39 months.

  6. Birch EE et al. Visual acuity and the essentiality of docosahexaenoic acid and arachidonic acid in the diet of term infants. Pediatric Research 1998; 44: 201-209.

    Abstract: The need for a dietary supply of docosahexaenoic acid (DHA) and arachidonic aid (AA) in term infants was evaluated in a double-masked randomized clinical trial of the effects of supplementation of term infant formula with DHA (0.35% of total fatty acids) or with DHA (0.36%) and AA(0.72%) on visual acuity development. One hundred and eight healthy term infants were enrolled in the study; 79 were exclusively formula-fed from birth (randomized group) and 29 were exclusively breast-fed (gold standard group). Infants were evaluated at four time points during the first 12 mo of life for blood fatty acid composition, growth, sweep visual evoked potential(VEP) acuity, and forced choice preferential looking acuity. Supplementation of term infant formula with DHA or with DHA and AA during the first 4 mo of life yields clear differences in total red blood cell (RBC) lipid composition. Supplementation of term infant formula with DHA or with DHA and AA also yields better sweep VEP acuity at 6, 17, and 52 wk of age but not at 26 wk of age, when acuity development reaches a plateau. The RBC lipid composition and sweep VEP acuity of supplemented infants was similar to that of human milk-fed infants, whereas the RBC lipid composition and sweep VEP acuity of unsupplemented infants was significantly different from human milk-fed infants. Differences in acuity among diet groups were too subtle to be detected by the forced choice preferential looking protocol. Infants in all diet groups had similar rates of growth and tolerated all diets well. Thus, early dietary intake of preformed DHA and AA appears necessary for optimal development of the brain and eye of the human infant.

  7. Birch EE et al. Dietary essential fatty acid supply and visual acuity development. Invest Ophthalmol Vis Sci 1992; 33: 3242-3253.

    Abstract: The influence of dietary omega-3 fatty acid supply on visual acuity development was evaluated in very low birth weight (VLBW) infants using visual-evoked potential (VEP) and forced-choice preferential-looking (FPL) procedures at 36 and 57 wk postconception. The VLBW infants born at 27-33 wk postconception were randomized to one of three diet groups: corn oil, which provided solely linoleic acid; soy oil, which provided linoleic and alpha-linolenic acids; or soy/marine oil; which was similar to the soy oil formula but also provided preformed long chain omega-3 fatty acids. The VLBW infants in the soy/marine oil group had higher omega-3 levels in erythrocyte membranes and better VEP and FPL acuities at 36 and 57 wk than infants in the corn oil group. The soy oil group had intermediate omega-3 levels in erythrocyte membranes and significantly poorer VEP acuity at 57 wk compared with the soy/marine oil group. Only the soy/marine oil group had acuities comparable to the "gold standards" of VLBW infants fed human milk and preterm infants who were born and tested at 35-36 wk postconception. In addition, VEP and FPL acuity were poorer in a nonrandomized group of formula-fed full- term infants than in breast-fed full-term infants. The results suggest that dietary omega-3 fatty acid supply may play an important role in early human visual development.

  8. Burgess JR et al. Long-chain polyunsaturated fatty acids in children with attention-deficit hyperactivity disorder. American Journal of Clinical Nutrition 2000; 71(suppl): 327S-330S.

    Abstract: Attention-deficit hyperactivity disorder (ADHD) is the diagnosis used to describe children who are inattentive, impulsive, and hyperactive. ADHD is a widespread condition that is of public health concern. In most children with ADHD the cause is unknown, but is thought to be biological and multifactorial. Several previous studies indicated that some physical symptoms reported in ADHD are similar to symptoms observed in essential fatty acid (EFA) deficiency in animals and humans deprived of EFAs. We reported previously that a subgroup of ADHD subjects reporting many symptoms indicative of EFA deficiency (L-ADHD) had significantly lower proportions of plasma arachidonic acid and docosahexaenoic acid than did ADHD subjects with few such symptoms or control subjects. In another study using contrast analysis of the plasma polar lipid data, subjects with lower compositions of total n-3 fatty acids had significantly more behavioral problems, temper tantrums, and learning, health, and sleep problems than did those with high proportions of n-3 fatty acids. The reasons for the lower proportions of long-chain polyunsaturated fatty acids (LCPUFAs) in these children are not clear; however, factors involving fatty acid intake, conversion of EFAs to LCPUFA products, and enhanced metabolism are discussed. The relation between LCPUFA status and the behavior problems that the children exhibited is also unclear. We are currently testing this relation in a double-blind, placebo-controlled intervention in a population of children with clinically diagnosed ADHD who exhibit symptoms of EFA deficiency.

  9. Carlson SE. Long-chain polyunsaturated fatty acids and development of human infants. Acta Paediatr Suppl 1999; 430: 72-77.

  10. Carlson SE, Werkman SH. A randomized trial of visual attention of preterm infants fed docosahexaenoic acid until two months. Lipids 1996; 31: 85-90.

  11. Carlson SE et al. Visual-acuity development in healthy preterm infants: effect of marine-oil supplementation. American Journal of Clinical Nutrition 1993; 58: 35-42.

    Abstract: Docosahexaenoic acid (DHA; 22:6n-3) is important for normal visual development. We hypothesized that preterm infants fed formulas with marine oil as a source of DHA would have better visual acuity than infants fed formulas without marine oil, as measured by the Teller Acuity Card procedure. Marine oil (P < 0.001) and age (P < 0.0001) influenced visual acuity, by repeated-measures analysis of variance (ANOVA) corrected for the effect of subject. Marine-oil-supplemented infants had better visual acuity than those fed standard formulas at 2 and 4 mo of age, by Fishers' least-squares difference (LSD). Acuity of both dietary groups improved through 6.5 mo of age, then plateaued. Through 4 mo of age, acuity was inversely related to oxygen supplementation (log10 h) and positively related to DHA status, by general-linear-models (GLM) analysis. After 4 mo of age, birth weight and gestational age were the only variables consistently related to visual acuity by GLM. We conclude that marine-oil-supplemented formula improved visual acuity of preterm infants through 4 mo of age by improving DHA status.

  12. Cheruku SR, Montgomery-Downs HE, Farkas SL, Thoman EB, Lammi-Keefe CJ. Higher maternal plasma docosahexaenoic acid during pregnancy is associated with more mature neonatal sleep-state patterning. Am. J. Clin. Nutr. 2002; 76(3): 608-613.

    Abstract: Background: The effect of docosahexaenoic acid (DHA) on the developing fetal central nervous system (CNS) and related functional outcomes in infancy remain unexplored. Sleep and wake states of newborns provide a tool for assessing the functional integrity of the CNS. Objective: We investigated whether CNS integrity in newborns, measured with sleep recordings, was associated with maternal concentrations of long-chain polyunsaturated fatty acids, especially DHA. Design: Plasma phospholipid fatty acid concentrations were measured in 17 women at parturition. On postpartum day 1 (P1) and day 2 (P2), a pressure-sensitive pad under the infants' bedding recorded body movements and respiratory patterns to measure sleep and wake states. Results: Maternal plasma phospholipid DHA ranged from 1.91% to 4.5% by wt of total fatty acids. On the basis of previously published data and the median DHA concentration, the women were divided into 2 groups: high DHA (> 3.0% by wt of total fatty acids) and low DHA ( 3.0% by wt of total fatty acids). Infants of high-DHA mothers had a significantly lower ratio of active sleep (AS) to quiet sleep (QS) and less AS than did infants of low-DHA mothers. Furthermore, the former infants had less sleep-wake transition and more wakefulness on P2. Correlations of maternal DHA status with infant sleep states were consistent with these data. Also, the ratio of maternal n-6 to n-3 fatty acids on P1 was inversely associated with QS and positively associated with arousals in QS. On P2, maternal n-6:n-3 was positively associated with AS, sleep-wake transition, and AS:QS. Conclusion: The sleep patterns of infants born to mothers with higher plasma phospholipid DHA suggest greater CNS maturity.

  13. Chiu CC, Huang SY, Su KP. Omega-3 polyunsaturated fatty acids for postpartum depression (baby blues). Am. J. Obstet. Gynecol. 2004; 190(2): 582-583.

  14. Federenko IS, Wadhwa PD. Women's mental health during pregnancy influences fetal and infant developmental and health outcomes. CNS Spectr. 2004; 9(3): 198-206.

  15. Hansen HS, Olsen SF. Sleep patterns, docosahexaenoic acid, and gestational length. Am. J. Clin. Nutr. 2004; 79(2): 334-335.

  16. Helland IB, Smith L, Saarem K, Saugstad OD, Drevon CA. Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children's IQ at 4 years of age. Pediatrics 2003; 111(1): 39-44.

  17. Hibbeln JR. Seafood consumption, the DHA content of mothers' milk and prevalence rates of postpartum depression: a cross-national, ecological analysis. Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, MD, USA. Journal of Affective Disorders 2002; 69(1-3): 15-29.

    Abstract: Background: Mothers selectively transfer docosahexaenoic acid (DHA) to their fetuses to support optimal neurological development during pregnancy. Without sufficient dietary intake, mothers become depleted of DHA and may increase their risk of suffering major depressive symptoms in the postpartum period. We postulated that the DHA content of mothers' milk and seafood consumption would both predict prevalence rates of postpartum depression across countries. Methods: Published prevalence data for postpartum depression were included that used the Edinburgh Postpartum Depression Scale (n=14 532 subjects in 41 studies). These data were compared to the DHA, eicosapentaenoic acid (EPA) and arachidonic acid (AA) content in mothers' milk and to seafood consumption rates in published reports from 23 countries. Results: Higher concentrations of DHA in mothers' milk (r=-0.84, p<0.0001, n=16 countries) and greater seafood consumption (r=-0.81, p<0.0001, n=22 countries) both predicted lower prevalence rates of postpartum depression in simple and logarithmic models, respectively. The AA and EPA content of mothers' milk were unrelated to postpartum depression prevalence. Limitations: These findings do not prove that higher omega-3 status cause lower prevalence rates of postpartum depression. Data on potentially confounding factors were not uniformly available for all countries. Conclusions: Both lower DHA content in mothers' milk and lower seafood consumption were associated with higher rates of postpartum depression. These results do not appear to be an artifact of cross-national differences in well-established risk factors for postpartum depression. Interventional studies are needed to determine if omega-3 fatty acids can reduce major postpartum depressive symptoms.

  18. Hoffman DR et al. Effects of supplementation with omega-3 long-chain polyunsaturated fatty acids on retinal and cortical development in premature infants. American Journal of Clinical Nutrition 1993; 57(suppl 5): 807S-812S.

    Abstract: Deficiency of omega 3 long-chain polyunsaturated fatty acids (LCPUFAs) in vertebrates produces subtle adverse effects on visual and neural function. Preterm infants 1) are deprived of vital intrauterine fat accretion during late pregnancy, 2) must rely solely on formula for fatty acid supplies if not breastfed, and 3) may have limited postnatal desaturase activity. In a study to evaluate the necessity of dietary omega 3 LCPUFAs, preterm infants were fed human milk, corn-oil-based formula (omega 3 fatty acid deficient), soy-oil-based formula (rich in precursor fatty acids), or marine-oil-supplemented formula (containing docosahexaenoic acid). At 36 and 57 wk postconception, the LCPUFA profiles in red blood cell lipids were nearly equivalent in the human- milk and marine-oil groups whereas the corn-oil group had markedly lower values for omega 3 fatty acids. Rod photoreceptor function was significantly less mature in the corn-oil group compared with the human- milk and marine-oil-enriched groups in early postnatal development (36 wk). The corn-oil group also had impaired visual acuity at both 36 and 57 wk. The potential benefit of omega 3 LCPUFA-enriched full-term formula is discussed. The study supports a role for omega 3 LCPUFAs as required nutrients for the optimal maturation of visual and cortical function in preterm infants.

  19. Hoffman DR, Uauy R. Essentiality of dietary omega-3 fatty acids for premature infants: plasma and red blood cell fatty acid composition. Lipids 1992; 27: 886-895.

  20. Makrides M, et al. Fatty acid composition of brain, retina, and erythrocytes in breast- and formula-fed infants. American Journal of Clinical Nutrition 1994; 60: 189-194.

    Abstract: Breast-fed infants score better on visual and developmental tests than do formula-fed infants and this has been related to higher concentrations of erythrocyte docosahexaenoic acid (DHA, 22:6 omega 3). This prompted an investigation into the relationship between brain, retina, and erythrocyte fatty acids and diet in infancy. Total lipids of erythrocytes, retina, and brain cortex from 35 term infants were analyzed by capillary gas chromatography. Breast-fed infants had a greater proportion of DHA in their erythrocytes and brain cortex relative to those fed formula (P < 0.005) but differences were not observed in retina. Cortex DHA increased in breast-fed (but not formula- fed) infants with age (r2 = 0.72, P < 0.01, n = 15), largely an effect of length of feeding (r2 = 0.62, P < 0.01, n = 35). There was an association between age at death and erythrocyte DHA with cortex DHA (r2 = 0.50, P < 0.01). In contrast, accretion of cortex arachidonic acid was dependent on age but not diet. The higher concentration of DHA in brains of breast-fed infants may explain the improved neurodevelopment reported in breast-fed compared with formula-fed infants.

  21. McCann JC, Ames BN. Is docosahexaenoic acid, an n-3 long-chain polyunsaturated fatty acid, required for development of normal brain function? An overview of evidence from cognitive and behavioral tests in humans and animals. Am J Clin Nutr 2005;82:281-95.

    Abstract: This review is part of a series intended for nonspecialists that will summarize evidence relevant to the question of whether causal relations exist between micronutrient deficiencies and brain function. Here, we focus on experiments that used cognitive or behavioral tests as outcome measures in experimental designs that were known to or were likely to result in altered brain concentrations of the n-3 fatty acid docosahexaenoic acid (DHA) during the perinatal period of "brain growth spurt." Experimental designs reviewed include observational breastfeeding studies and randomized controlled trials in humans and studies in rodents and nonhuman primates. This review is based on a large number of expert reviews and commentaries and on some 50 recent studies in humans and animals that have not yet been included in published reviews. Expert opinion regarding the strengths and weaknesses of the major experimental systems and uncertainties associated with interpreting results is summarized. On the basis of our reading of this literature, we conclude that evidence from several types of studies, particularly studies in animals, suggests that, within the context of specific experimental designs, changes in brain concentrations of DHA are positively associated with changes in cognitive or behavioral performance. Additional experimental information required to conclude that a causal association exists is discussed, as are uncertainties associated with applying results from specific experimental designs to the question of whether infant formula should be supplemented with DHA.

  22. McGregor JA, Allen KG, Harris MA, Reece M, Wheeler M, French JI, et al. The omega-3 story: nutritional prevention of preterm birth and other adverse pregnancy outcomes. Obstet Gynecol Surv 2001;56 (5 Suppl 1):S1-13.

  23. Nettleton JA. Are Omega-3 fatty acids essential nutrients for fetal and infant development? J. Am. Diet. Assoc. 1993; 93(1): 58-64.

  24. Olsen SF, Hansen HS, Sommer S, Jensen B, Sřrensen TI, Secher NJ, et al. Gestational age in relation to marine n-3 fatty acids in maternal erythrocytes: a study of women in the Faroe Islands and Denmark. Am J Obstet Gynecol 1991; 164: 1203-1209.

  25. Olsen SF, Secher NJ, Bjornsson S, Weber T, Atke A. The potential benefits of using fish oil in relation to preterm labor: the case for a randomized controlled trial. Acta. Obstet. Gynecol. Scand. 2003; 82(11): 978-982.

    Abstract: Discusses the potential benefits of long-chain n-3 fatty acids from fish oil in relation to premature labor. Delaying effect of long-chain n-3 fatty acids on timing of delivery; Tocolytic effect; Randomized controlled trial.

  26. Prescott SL, Calder PC. Omega-3 polyunsaturated fatty acids and allergic disease. Curr. Opin. Clin. Nutr. Metab. Care 2004; 7(2): 123-129.

    Abstract: Purpose of review: With escalating rates of allergic disease, it is vital to explore novel causal pathways. This review examines the evidence for a potential role of changing dietary intake of [omega]-3 polyunsaturated fatty acids in the development, treatment and prevention of allergic diseases. Recent findings: Although it is difficult to determine the contribution of altered (decreased) dietary intake of [omega]-3 polyunsaturated fatty acids to the recent rise in the incidence of allergic disease, there is growing evidence that these nutrients have antiinflammatory properties and may modulate immune responses. These fatty acids have few side effects, and may be of some benefit in established allergic diseases (such as asthma and atopic dermatitis), although these effects are not strong. Because of this limited efficacy in established disease, the focus has shifted to the potential benefits of these immune modulators in earlier life for disease prevention. Two recent preliminary reports in infants suggest that dietary [omega]-3 polyunsaturated fatty acid supplements in pregnancy or in the early postnatal period could have immunomodulatory properties and associated clinical effects, although more studies are now needed. Novel synthetic polyunsaturated fatty acids with more potent and selective antiinflammatory effects may also provide safe therapeutic and preventive strategies in the future. Summary: Dietary factors are important but still under-explored candidates in the search for environmental strategies to reduce the enormous impact of allergic diseases in modernized societies. There is an ongoing need for further research into the role of [omega]-3 polyunsaturated fatty acids in allergic disease, particularly in early life before atopy is established.

  27. Stene LC, Ulriksen J, Magnus P, Joner G. Use of cod liver oil during pregnancy associated with lower risk of type I diabetes in the offspring. Diabetologia 2000; 43: 1093-1098.

    Abstract: Aims/hypothesis. To test whether cod liver oil or vitamin D supplements either taken by the mother during pregnancy or by the child in the first year of life is associated with lower risk of Type I (insulin-dependent) diabetes mellitus in children. Methods. We carried out a population-based case control study in Vest-Agder county of Norway, evaluating the use of supplements by a mailed questionnaire. We received responses from 85 diabetic subjects and 1071 control subjects. Odds ratios (OR) with 95 % confidence intervals (CI) were estimated using logistic regression analyses. Results. When mothers took cod liver oil during pregnancy their offspring had a lower risk of diabetes. The unadjusted OR was 0.30, 95 % CI: (0.12 to 0.75), p = 0.01. This association changed very little and was still significant after adjusting for age, sex, breastfeeding and maternal education. Mothers taking multivitamin supplements during pregnancy [adjusted OR = 1.11, 95 % CI: (0.69 to 1.77)], infants taking cod liver oil in the first year of life [adjusted OR = 0.82, 95 % CI: (0.47 to 1.42) and the use of other vitamin D supplements in the first year of life [adjusted OR = 1.27, 95 % CI: (0.70 to 2.31)] was significantly associated with the risk of diabetes. Conclusion/interpretation. We found that cod liver oil taken during pregnancy was associated with reduced risk of Type I diabetes in the offspring. This suggests that vitamin D or the n-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid in the cod liver oil, or both, have a protective effect aginst Type I diabetes.

  28. Valenzuela A, Nieto MS. Docosahexaenoic acid (DHA) in fetal development and in infant nutrition. Rev. Med. Chil. 2001; 129(10): 1203-1211.

    Abstract: Docosahexanoic acid (C22:6, DHA) is a highly unsaturated omega-3 fatty acid that forms part of the central nervous and visual system structures. DHA is synthesized from its precursor, alfa-linolenic acid, that is also a omega-3 fatty acid and can be obtained from vegetable oils. Marine organisms, specially fish, are good nutritional sources of DHA and eicosapentanoic acid (EPA), another omega-3 fatty acid that has a role in vascular homeostasis. DHA increases membrane fluidity, improving neurogenesis, synaptogenesis and the activity of retinal photoreceptors. The fetus, specially during the last trimester of pregnancy, has high DHA requirements. It is provided by the mother, since fetal DHA synthesis is negligible in this stage of development. Breast feeding provides DHA to the child, but most replacement artificial formulas do not provide this fatty acid. At the present moment, many products for infant nutrition contain DHA (Rev Méd Chile 2001; 129: 1203-11).

  29. Werkman SH, Carlson SE. A randomized trial of visual attention of preterm infants fed docosahexaenoic acid until nine months. Lipids 1996; 31: 91-97.

  30. Whalley LJ, Fox HC, Wahle KW, Starr JM, Deary IJ. Cognitive aging, childhood intelligence, and the use of food supplements: possible involvement of n-3 fatty acids. Am. J. Clin. Nutr. 2004; 80(6): 1650-1657.

    Abstract: Background: Food supplement use is widely promoted, but little is known about the cognitive effects of food supplements. Objective: We examined the effects of food supplement use on cognitive aging. Design: This was an observational study of subjects born in 1936 whose mental ability was tested in 1947 and who were followed up in 2000-2001, at which time cognition, diet, food supplement use, and risk factors for vascular disease were assessed. In a nested case-control study, fish-oil users were matched with nonusers, and cognitive function was related to erythrocyte n-3 fatty acid composition. Results: Childhood intelligence quotient (IQ) did not differ significantly by category of food supplement use (ie, none, fish oil, vitamins, and other). At the age of 64 y, cognitive function was higher in food supplement users than in nonusers before adjustment for childhood IQ. After adjustment for childhood IQ, digit symbol (mental speed) test scores were higher in food supplement users. Fish-oil supplement users consumed more vitamin C and vegetable and cereal fiber than did non-supplement-users. In a nested case-control study, erythrocyte membrane n-3 content was higher in fish-oil supplement users than in nonusers, but cognitive function did not differ significantly between groups. Total erythrocyte n-3 fatty acids and the ratio of docosahexaenoic acid to arachidonic acid was associated with better cognitive function in late life before and after adjustment for childhood IQ. Conclusions: Food supplement use and erythrocyte n-3 content are associated with better cognitive aging. If associations with n-3 content are causal, optimization of n-3 and n-6 fatty acid intakes could improve retention of cognitive function in old age.

  31. Willatts P. Long chain polyunsaturated fatty acids improve cognitive development. J. Fam. Health Care 2002; 12(6 Suppl.): 5.

  32. Williams MA, Zingheim RW, King IB, Zebelman AM. Omega-3 fatty acids in maternal erythrocytes and risk of preeclampsia. Epidemiology 1995; 6: 232-237.

    Abstract: Preeclampsia is a systemic disease characterized by diffuse endothelial dysfunction, increased peripheral vascular resistance, coagulation abnormalities, antioxidant deficiency, persistent elevations of maternal leukocyte-derived cytokines, and hyperlipidemia. Fish oil, rich in omega-3 polyunsaturated fatty acids, is known to reduce fasting and postprandial triglycerides and to decrease platelet and leukocyte reactivity; it may also decrease blood pressure. Additionally, omega-3 fatty acids may beneficially influence vessel wall characteristics and blood rheology. In light of the potential beneficial effects of dietary omega-3 fatty acids, we conducted a cross-sectional case-control study to examine the hypothesized exposure-effect relation between maternal dietary intake of marine omega-3 fatty acids and risk of preeclampsia. We measured polyunsaturated fatty acids in erythrocytes obtained from 22 preeclamptic women and 40 normotensive women; we measured polyunsaturated fatty acids as the percentage of total fatty acids from gas chromatography. We employed logistic regression procedures to estimate odds ratios (ORs) and 95% confidence intervals (CIs). After adjusting for confounders, women with the lowest levels of omega-3 fatty acids were 7.6 times more likely to have had their pregnancies complicated by preeclampsia as compared with those women with the highest levels of omega-3 fatty acids (95% CI = 1.4-40.6). A 15% increase in the ratio of omega-3 to omega-6 fatty acids was associated with a 46% reduction in risk of preeclampsia (OR = 0.54; 95% CI = 0.41-0.72). Low erythrocyte levels of omega-3 fatty acids and high levels of some omega-6 fatty acids, particularly arachidonic acid, appear to be associated with an increased risk of preeclampsia.
 
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