Assessing Omega-3 Fatty Acid Supplementation During Pregnancy and Lactation to Optimize Maternal Mental Health and Childhood Cognitive Development

Chelsea M Klemens; Kataneh Salari; Ellen L Mozurkewich


Clin Lipidology. 2012;7(1):93-109. 

In This Article

Findings of Nonrandomized & Randomized Studies of Omega-3 Fatty Acid Supplementation of Maternal Diet or Supplemented Infant Formula & Child Development

Observational Studies of Prenatal Dietary Omega-3 Fatty Acid Intake & Child Development

In a longitudinal cohort study of over 11,000 pregnant women in the UK, Hibbeln et al. assessed maternal seafood intake by use of a food frequency questionnaire administered at 32 weeks' gestation.[14] Cognitive development of children born to mothers enrolled in the study was assessed by means of parental questionnaires administered by post 6, 18, 30 and 42 months of age and by IQ testing at 8 years of age.[14] The authors found that children born to mothers who ate no seafood or whose seafood consumption was less than 340 g per week during pregnancy were at increased risk to have a verbal IQ score in the lowest quartile (no seafood consumption odds ratio: 1.48, 95% CI: 1.16–1.90; some: 1.09, 95% CI: 0.92–1.29; overall trend, p = 0.004).[14] That is greater maternal intake of seafood during pregnancy was associated with lower risk of suboptimum verbal IQ.[14] In this study, seafood consumption above the 340 g dietary limit currently advocated by the FDA was actually associated with improved neurocognitive outcomes compared with consumption of lesser amounts or no seafood.[14]

More recently, a prospective longitudinal observational study of 154 Inuit children reported that higher umbilical cord blood DHA levels at birth were associated with improved measures of memory function at school age (mean 11.3 years).[73]

Interventional Studies of Maternal Supplementation During Pregnancy & Lactation

Several randomized trials have been undertaken to assess the potential benefits of either maternal or infant omega-3 fatty acid supplementation in child development. A randomized placebo-controlled trial of 98 pregnant women who received either fish oil or olive oil from 20 weeks' gestation until delivery revealed significantly higher scores for hand–eye coordination in children whose mothers received fish oil versus those who received placebo.[74] Similarly, a randomized intervention trial of cod liver oil supplementation of 82 women during pregnancy and lactation showed improvements in verbal IQ at 4 years of age compared with children born to 62 women who received corn oil.[75] However, in a later follow-up evaluation of children born in the trial, Kaufman Assessment Battery for Children scores at 7 years of age did not differ between the groups.[76]

The available trials of omega-3 fatty acid supplementation during pregnancy have been recently summarized in two systematic reviews.[6,77] In a systematic review of 13 trials of omega-3 fatty acid supplementation during pregnancy and/or lactation that aimed to demonstrate improvement in fetal/infant cognitive development, Dziechciarz et al. found that evidence from the available randomized controlled trials has not demonstrated a clear and consistent benefit for omega-3 fatty acid supplementation in pregnancy on infant cognitive development.[6] They noted that although individual trials reported improvements in limited domains on intellectual tests, these improvements were not consistent across trials, nor did they tend to persist over time.[6] Similarly, a Cochrane systematic review of omega-3 fatty acid supplementation during lactation (six trials, 1280 women) found that supplementation during lactation had no significant effect on childrens' neurodevelopment.[77] The trials included in the Dziechciarz systematic review, as well as the subsequent trials described below, are summarized in Table 2.[44,74–76,78–86]

Subsequent to the search dates of these systematic reviews, several additional trials evaluating the effects of maternal omega-3 fatty acid supplementation on offspring's cognitive development have been published. A large multicenter trial of DHA supplementation (800 mg/day) did not show any benefit for the intervention on the infants' cognitive function at 18 months of life.[44] A total of 2399 women with singleton pregnancies who were enrolled before 21 weeks gestation were randomly assigned to receive either DHA or vegetable oil, which was continued until birth. A subset of 726 infants born to women participating in the trial was assessed for developmental outcome using the Bayley Scales of Infant and Toddler Development at 18 months of age. There were no differences found in mean cognitive composite score or mean language composite score between the groups. Children born to mothers who received DHA supplementation were significantly less likely to have a cognitive standard score <85. This group difference was most significant among boys. However, an unexpected and unexplained finding of this trial was that girls born to mothers receiving DHA had a lower language standardized score than girls born to mothers who received placebo; although there was no difference in language standardized score for the total group. These findings require further study in long-term follow-up of children born in this trial.[44]

Another recent large, randomized controlled trial involved 315 healthy pregnant women, of whom 161 completed follow-up. Participants were supplemented with fish oil (500 mg DHA plus 150 mg EPA), 400 µg/day of 5-methyltetrahydrofolate, both or placebo from 20 weeks until delivery. This study did not show any beneficial or harmful effects of the omega-3 fatty acid supplementation on children's developmental outcomes at 4, 5.5 or 6.5 years of age.[84,85] Likewise, a smaller randomized, blinded study (n = 114) comparing low dose prenatal supplementation with DHA (220 mg), DHA plus ARA (220 mg DHA + 220 mg ARA), or placebo from 15.6 to 17.4 weeks' gestation through pregnancy and the first 3 months of lactation failed to show any difference in neurodevelopmental outcome at 18 months of age.[86]

Secondary Analyses of Data From Randomized Controlled Trials

Despite negative results from the primary analyses from these trials, several authors have noted associations between omega-3 fatty acid levels and cognitive development in secondary analyses that were not carried out on an intent-to-treat basis; for example, in a secondary analysis of data from the study by Helland et al., maternal plasma phospholipid ALA, DHA and omega-3:omega-6 ratios at 35 weeks' gestation were positively correlated with sequential processing scores at 7 years of age.[75,76] EPA from umbilical cord blood was also positively correlated with the sequential processing score.[76] Similarly, in a secondary analysis of data from the trial conducted by Escolano-Margarit et al., higher levels of DHA in the cord blood of infants born to study participants were shown by regression analysis to be associated with greater likelihood of optimal cognitive development at 5.5 years of age.[84] The discrepancies between the results of the primary and secondary analyses suggest that differences in compliance and in fatty acid metabolism among subjects may have influenced the outcomes reported.

Interventional Studies of Postnatal Supplementation of Children Born Preterm

In a study involving 657 infants born preterm, Makrides et al., found that supplementing infant formula with DHA or supplementing lactating mother's breast milk via dietary tuna oil did not alter the infants' mental development index (MDI) at 18 months of age overall.[87] However, girls born to mothers randomized to the high DHA group were at reduced risk for significantly delayed cognitive development; similarly, the mean MDI among girls assigned to the high DHA group was higher than the MDI of girls assigned to the standard DHA group..[87]

By contrast, a Cochrane review that included 17 trials of supplementation of infant formula with long-chain PUFAs did not show any beneficial effects for supplementation on visual acuity or neurocognitive development.[88] The long-chain PUFA supplements under study in the included trials were, in most cases, a mixture of omega-3 and omega-6 fatty acids.[88]

Interventional Studies of Postnatal Supplementation of Children Born at Term

In a postnatal dietary supplementation study, Agostoni and coworkers randomized 1160 healthy neonates born at term to receive either 20 mg liquid DHA or placebo daily, starting at 24 h after hospital discharge and continuing daily through 1 year of life.[89] All infants also received 400 units of vitamin D3 per day. The primary outcome for this study was achievement on four gross motor milestones: sitting without support, hands and knees crawling, standing without support and walking.[89] Although infants assigned to receive DHA were able to sit without support approximately 1 week earlier on average than infants receiving placebo, there were no differences in any other outcome of interest.[89]

A recent Cochrane review on long-chain PUFA supplementation of formula for term infants analyzed the results of 15 randomized controlled trials.[90] Supplemented infant formula contained DHA alone or DHA plus ARA. The authors concluded that results of the most well-conducted randomized controlled trials have not shown beneficial effects of long-chain PUFA supplementation of formula milk on the neurodevelopment of infants born at term.[90] Therefore, it is unclear whether or not omega-3 fatty acid supplementation should be recommended for pregnant women or their infants, and further research in this area is needed.

More recently, a dose-ranging, randomized controlled trial comparing varying doses of DHA (along with a fixed dose of ARA) to standard infant formula during the first year of life revealed improved cognitive function in 18-month-old infants who received DHA supplemented formula.[91] Higher concentrations of DHA in the formula were not more effective than the lower doses, and a DHA concentration of 0.32% was found to be sufficient to optimize development.[91]


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