Associations of maternal long-chain polyunsaturated fatty acids, methyl mercury, and infant development in the Seychelles Child Development Nutrition Study
Introduction
Fish consumption during gestation can provide the fetus with long-chain polyunsaturated fatty acids (LCPUFA) and other nutrients essential for growth and development of the brain. However, fish consumption also exposes the fetus to the neurotoxicant, methyl mercury (MeHg). The impact of combined LCPUFA and MeHg from fish consumption during pregnancy may lead to contradictory influences on child development outcomes, as suggested in a companion paper by (Davidson et al., 2008).
All fish contain small amounts of MeHg. The developmental effects of prenatal exposure to MeHg from maternal consumption of a diet high in fish are unclear. Epidemiological studies from New Zealand (Kjellstrom et al., 1989) and the Faeroe Islands (Grandjean et al., 1997, Debes et al., 2006), reported subtle adverse effects on child development outcomes. In contrast, results from the Seychelles Child Development Study have found no consistent neurodevelopmental or neuropathological impairments (Davidson et al., 1998, Myers et al., 2003, Lapham et al., 1995). In fact, enhanced child development was correlated with increasing maternal hair MeHg levels for some endpoints. This apparently anomalous finding might be related to the beneficial effects of nutrients, such as LCPUFA intake, from fish.
The LCPUFA, docosahexaenoic acid (DHA, 22:6 Ω-3) and arachidonic acid (AA, 20:4 Ω-6) accumulate preferentially in the developing brain where they are major structural components of brain lipids and play important functional roles in visual and neural processes (Innis, 2005a, Innis, 2005b). The Ω-3 LCPUFA, DHA, can affect neurotransmitter metabolism, ion channel activity, signalling pathways and gene expression, while the Ω-6 LCPUFA, AA, plays a role in cell signalling and synaptic transmission via specific eicosanoids and leukotrienes (Innis, 2003). Diffusion to the fetus of LCPUFA from circulating maternal triglycerides and free fatty acids is thought to occur via lipoprotein receptors, lipoprotein lipase activity, placental intracellular lipase activities and plasma membrane fatty acid binding protein (Herrera, 2002). Placental transfer of LCPUFA occurs predominantly during the last trimester when brain growth is most rapid.
The endogenous syntheses of DHA and, especially AA, are not trivial in the preterm infant (Carnielli et al., 2007). However, it appears that the fetus cannot synthesize adequate amounts of DHA or AA from their respective essential fatty acid precursors, alpha-linolenic acid (ALA, 18:3 Ω-3) and linoleic acid (LA 18:2 Ω-6), respectively (Carlson, 2001). Data from randomized controlled trials indicate that maternal supplementation with high dose DHA (>1 g/day) can significantly increase DHA status in offspring in contrast to maternal supplementation with lower doses of DHA or high doses (>10 g/day) of ALA (Decsi and Koletzko, 2005). One randomized controlled trial evaluated children born to women who took cod liver oil rich in the Ω-3 DHA during pregnancy and compared them with children whose mothers had taken maize oil rich in the Ω6 LA (Helland et al., 2003). Children whose mothers received cod liver oil scored higher on the Mental Processing Composite of the Kaufman Assessment Battery for Children (K-ABC) at age 4 years. Dunstan et al. (2006) showed that children aged 2.5 years born to mothers who were supplemented with Ω-3 LCPUFA from week 20 of gestation until delivery had significantly improved eye and hand coordination compared to those whose mothers received placebo (olive oil). Judge et al. (2007) studied infants born to mothers who consumed DHA-containing foods during pregnancy and compared them to infants whose mothers consumed placebo (maize oil) containing foods. Those receiving DHA-containing foods scored better for problem solving, but not for visual recognition memory, at age 9 months
These experimental studies of supplemental DHA, the Ω-3 LCPUFA found in fish, are supported by observational epidemiological studies. The ALSPAC study in the UK reported that children of women who consumed more fish during pregnancy had higher developmental scores at age15 months (Daniels et al., 2004). More recently they reported that high (>340 g per week) maternal seafood consumption was associated with improved child development at age 7 years (Hibbeln et al., 2007). They concluded that guidelines from some advisories to limit seafood consumption during pregnancy could possibly be detrimental. In the US, Oken et al. (2005) reported that infants whose mothers had higher fish intake in the second trimester had higher percent novelty preference scores on visual recognition memory testing at 6 months of age.
Neonatal AA status is reported to be less dependent on maternal status than DHA (Otto et al., 1997). This finding fits with the recent experimental confirmation that endogenous AA synthesis from LA in the preterm newborn is significantly higher than DHA synthesis from ALA (Carnielli et al., 2007). Both LA and ALA compete for the same desaturation enzymes in the biosynthetic pathways to AA and DHA respectively. Consequently, the ratio between the relative amounts of Ω-6 and Ω-3 LCPUFA (Ω-6/Ω-3 ratio) might be important in neurodevelopment. The precursor LCPUFA, LA and ALA, are found in varying amounts in different vegetable fats and oils, but preformed AA and DHA are found primarily in animal lipids. Fish is a particularly rich source of DHA and its immediate precursor, eicosapentaenoic acid (EPA, 20:5 Ω-3). Although many studies have indicated a role in neurodevelopment for DHA, we have been unable to find any data linking EPA to neurodevelopment.
Maternal fish consumption brings nutritional benefits, particularly from LCPUFA. However, it also brings possible risk to the developing fetal brain in the form of MeHg, a toxicant known to accumulate in aquatic food chains worldwide (Myers et al., 2003, Clarkson and Strain, 2004). The Food and Agricultural Organization (FAO) of the United Nations estimates that one billion people, most of them living in developing countries, depend on fish as their main protein source (FAO, 2000). This makes fish consumption during pregnancy a subject of scientific interest and public health concern (Cohen et al., 2005a, Cohen et al., 2005b, Mozaffarian and Rimm, 2006).
In order to address the risks and benefits of fish consumption, we studied the relationship of maternal LCPUFA and prenatal MeHg exposure to children's neurodevelopment in a longitudinal observational study in a population consuming large quantities of fish. In a companion paper (Davidson et al., 2008) we report on the covariate adjusted effects of two LCPUFA, AA and DHA, and other nutritional and dietary measures on outcome measures. Here we expand our enquiry by focusing on the associations of the Ω-3 and Ω-6 LCPUFA (DHA, AA, EPA, LA, and ALA) with the BSID-II outcomes.
Section snippets
Subjects
We recruited 300 women during their first visit to the ante-natal clinic on Mahé, the main island in Seychelles, during 2001. Inclusion criteria included age over 16 years, native born Seychellois, and residing on Mahé. Six infants were excluded, 4 with major congenital anomalies and 1 set of twins. The study setting and methods are described in detail in the companion paper (Davidson et al., 2008). We include only those methods pertinent to the secondary analysis reported here. The study was
Results
In this cohort of 229 mother-infant pairs, the mean maternal hair Hg concentration was 5.7 ppm (S.D. = 3.7; range 0.2–18.5). Mothers reported consuming an average of 9 meals containing fish per week or an estimated 537 g of fish per week. Table 1 shows the characteristics of the mothers and children studied. Table 2 shows summary statistics for the LCPUFA status of mothers and the BSID outcomes for the children. There were no mothers in this cohort with evidence of clinical nutritional
Discussion
We found that maternal serum Ω-3 LCPUFA as measured during the last trimester was positively associated with the psychomotor development measured at 9 months of age as maternal values for Ω-3 increased, the PDI scores improved. Psychomotor development was also inversely related to the Ω-6/Ω-3 ratio. As the Ω-6/Ω-3 ratio increased the PDI scores declined. There were no significant associations with the MDI at 9 or 30 months or with the PDI at the 30-month evaluation. The associations we found
Conflict of interest
None.
Acknowledgements
This study was supported exclusively by grants 5-R01-ES010219 and 2-T32-ES007271 from the US National Institute of Environmental Health Sciences, National Institutes of Health, and by the Government of Seychelles.
References (39)
Docosahexaenoic acid and arachidonic acid in infant development
Semin Neonatal
(2001)- et al.
Synthesis of long-chain polyunsaturated fatty acids in preterm infants fed formula with long chain polyunsaturated fatty acids
Am J Clin Nutr
(2007) - et al.
N-3 fatty acids and cognitive and visual acuity development: methodologic and conceptual considerations
Am J Clin Nutr
(2006) - et al.
Effect of α-linolenic acid supplementation during pregnancy on maternal and neonatal polyunsaturated fatty acid status and pregnancy outcome
Am J Clin Nutr
(2004) - et al.
Impact of prenatal methylmercury exposure on neurobehavioral function at the age of 14 years
Neurotoxicol Teratol
(2006) Nutrition and the developing brain: nutrient priorities and measurement
Am J Clin Nutr
(2007)- et al.
Cognitive deficit in 7-year-old children with prenatal exposure to methylmercury
Neurotoxicol Teratol
(1997) Implications of dietary fatty acids during pregnancy on placental, fetal and postnatal development—a review
Placenta
(2002)- et al.
Healthy intakes of n-3 and n-6 fatty acids: estimations considering worldwide diversity
Am J Clin Nutr
(2006) - et al.
Maternal seafood consumption in pregnancy and neurodevelopmental outcomes in childhood (ALSPAC study): an observational cohort study
Lancet
(2007)
Essential fatty acid transfer and fetal development
Placenta
Maternal consumption of a docosahexaenoic acid-containing functional food during pregnancy: benefit for infant performance on problem-solving but not on recognition memory tasks at age 9 months
Am J Clin Nutr
Efficacy and safety of long-chain polyunsaturated fatty acid supplementation of infant-formula milk: a randomized trial
Lancet
Prenatal methyl-mercury exposure from ocean fish consumption in the Seychelles Child Development Study
Lancet
Evolutionary aspects of diet, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic disease
Biomed Pharmacother
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
Long-chain polyunsaturated fatty acids and neurological developmental outcome at 18 months in healthy term infants
Acta Paediatr
Methyl mercury: loaves versus fishes
Seychelles Med Dent J
Cited by (191)
Adolescence as a sensitive period for neurotoxicity: Lifespan developmental effects of methylmercury
2022, Pharmacology Biochemistry and Behavior