Association between omega-3 fatty acid status of pregnant women and cognitive functioning in their five-year-old offspring


INTRODUCTION

Worldwide, there is an increase in evidence for associations between prenatal factors and development during infancy. These factors are called 'environmental determinants' and may be smoking, nutrition, alcohol and maternal stress. Recently lot of research has been done for associations between nutrients intake during pregnancy and physical development of infants (1).
Although maternal nutrition has since long been accepted as critical to fetal growth and has been accepted as relevant for the general development of the offspring, it is still obscure how maternal nutrition influences the development on their offspring. Beside physical development, development of the brains plays an important role during pregnancy and is linked to cognitive development of the children. Despite all the research that has already been done, it is still not entirely clear what maternal nutrition does with the cognitive development of the children.
 One of the most important nutrients for brain development is DHA, which is an omega-3 fatty acid. (2) Docosahexaenoic acid (DHA:22:6n-3) and eicosapentaenoic acid (EPA:20:5n-3) are the principal n-3 long chain polyunsaturated fatty acids (LCPUFA) (3) in mammalian brain tissue and make up 10-20% of total fatty acid composition (4).
n-3 fatty acids are mostly located in the synapses of the neurons (5) and accomplish an important role in signal transduction (6), are critical building blocks for fetal brain and retina, and play a role in determining the length of gestation and in preventing perinatal depression (7).
The formation of n-3 LCPUFA is a complex metabolic pathway, in which a-linolenic acid (18:3n-3) is the precursor fatty acid (8). Because the human body can not synthesize LCPUFA, these precursor fatty acids need to be obtained from the diet (9), to produce i.a. DHA and EPA.
The major source of n-3 LCPUFA is oily fish and results derived from recent studies have found that maternal fish intake is associated with improved cognitive developmental outcomes in infants. (10, 11) 
 In several studies, neonates fed with LCPUFA-enriched formulas were found to have better results on cognitive developmental scales, than neonates fed with standard formula (12, 13). There are also diverse promising indications that supplementation with n-3 fatty acids during pregnancy may benefit for visual and cognitive development during infancy (14).
However, the long term effects of LCPUFA during pregnancy on childhood, rather than infancy, are still obscure and more research is warranted. Therefore, we want to examine the relation between the n-3 fatty acid status of pregnant women and cognitive functioning in five-years-old. 
We investigated children's cognitive functioning with a task related to reaction time (RT). With this task, we measured i.a. the children's processing speed (mean RT), that requires minimal cognitive effort.
Based on previous studies, we hypothesized that there is an association between n-3 fatty acid status during pregnancy and children's cognitive functioning at age 5. We expect high status of n-3 fatty acids during pregnancy to be related to alterations in the children's cognitive functioning, such as shorter RT and smaller intra-individual variability in RT.

This study may be important to contribute to dietary guidelines for pregnant women and to gain more insight inton                                                                                                                              the relation between maternal nutrition and cognitive functioning of the child. If the n-3 fatty acid status among pregnant women proves to be relevant, this may open new opportunities to optimize children's cognitive development.

SUBJECTS AND METHODS

Study population and design
This study is part of the Amsterdam Born Children and their Development (ABCD) study (www.abcd-study.nl), a prospective, unselected, and community-based cohort study. The ABCD study is initiated in 2003 by the Public Health Service Amsterdam, to gain more insight into the influence of prenatal factors on children's health at birth as well as in later life, and to investigate the ethnic heterogeneity in both these risk factors and health outcomes. 

Cohort profile
Between January 2003 and March 2004, all pregnant women living in Amsterdam were asked to participate in the ABCD study during their first prenatal visit to an obstetric care provider (e.g. general practitioner or midwife). All 12373 approached women were registered and requested to complete a questionnaire, covering socio-demographic data, obstetric history, lifestyle, dietary habits, and psychosocial factors. The questionnaire was available in Dutch and in English, Turkish, or Arabic for immigrant women. Of the 12373 women approached, 8266 women filled out the pregnancy questionnaire (response rate 67%), in which 7863 women gave birth to viable singleton infants and 132 women gave birth to viable multiples. The remaining mothers experienced a miscarriage or fetal death (n=92), or were lost to follow-up (n=179).
To measure the maternal nutrient status, 6735 of the 8266 mothers gave permission for follow-up for the 5-years measurements of their child and 6161 mothers were actually approached for those measurements. (Phase III, 2008-2010).
During the third phase, participating mothers received two questionnaires, one to be filled out by the child's teacher, the other by themselves. The questionnaire was about family socio-demographics, maternal lifestyle, psychosocial conditions, family history of medical conditions, child's (school) performance and behaviour. The children were invited to participate in the ABCD health check, which took place at the child's primary school. Specially developed cartoons were used to explain the measurements to the 5-year-old children (15). The measurements included a blood sample for assessing glycaemic control and lipid profile as well as fatty acid profile, physical measurements and a cognitive test battery. This standardized, sensitive, neurocognitive test battery (the Amsterdam Neuropsychological Tasks; ANT) is designed to evaluate basic processes that underlie the performance of complex cognitive processes like attention, memory, and executive functions (16). 


DISCUSSION

The results of this community-based cohort study suggest that maternal n-3 fatty acid status during pregnancy affects cognitive functioning at age 5. 
In the unadjusted model, age and sex of the child are confounders in the relation between maternal fatty acid status and cognitive functioning. In this model, we found that children of mothers with a high fatty acid status during pregnancy have a better cognitive functioning at age 5, compared with children of mothers with a low fatty acid status during pregnancy. However, the fatty acid DHA did not demonstrate a significant association. The observed negative associations between the maternal fatty acid status and cognitive functioning mean positive reaction time outcomes. When the fatty acid status increases, the mean reaction time and intra-individuality time will reduce. This means a faster response and a longer concentration curve.   
Remarkable is the fact that not DHA, but EPA has the most influence on cognitive functioning. Nowadays, DHA is mainly seen as important omega-3 fatty acid, but this study showed EPA is most important. This could be explained due to the fact that DHA and EPA are correlated with each other, whereby the results of EPA and DHA as well. This means that the impact of EPA and DHA on cognitive functioning are equal to each other.

In the adjusted model for parity, computer skills of the child and maternal education en ethnicity, we found again a significant association, with a small change compared with the crude model. This change in outcomes is most likely due to the co variables maternal education and the computer skills of the child. Maternal education appears to be strongly related to the total omega-3 fatty acid status of the mother during pregnancy. When the maternal education following primary school takes 6 years or longer, the fatty acid status will be higher. Computer skills of the child are partly responsible for cognitive functioning. If children practice more on the computer, their cognitive functioning will be better.
The children's number of omissions showed no associations with the fatty acid status during pregnancy. After adjustment for parity, computer skills and maternal education and ethnicity, these associations did not change.
Previous studies have examined the relation between maternal fatty acid status and cognitive functioning. However, almost all studies investigated the potential importance of maternal fatty acid status and cognitive functioning in infancy. The present study investigated the association between maternal fatty acid status and cognitive functioning at age 5. Despite this, the results from this study corroborate findings in previous studies (11, 14), although it should be noted that EPA in this study plays a more important role than DHA.

Our study has some limitations. First, despite the large sample size, our results apply to a relatively healthy sample of pregnant women; our estimates may therefore be too conservative. We were able to measure the maternal fatty acid status in early pregnancy, but given the low-intrusive design, not thereafter. However, our results are not likely to be influenced by changes in fatty acid status in late gestation. Longitudinal studies have suggested that the early pregnancy profile well predicts the fatty acid profile later in pregnancy (17, 18).
Secondly, in this study, we investigated the effects of the omega-3 fatty acid status during pregnancy on later life. However, we did not distinguish the different ways of omega-3 intake. Nowadays, it is possible to get omega-3 fatty acids inside via a variety of ways. Fresh fish, canned fish and supplements with added fish oil are some of the many ways to get omega-3 fatty acids in their diet. The different ways may have a different function and/or other side effects that should be investigated. 
Besides the different ways of intake, the adverse effects of fish intake have to be investigated. Supplements are probably 'clean' and contain only pure omega-3 fatty acids. Fish also contain other nutrients, such as mercury and PCB's, which would also be harmful to the unborn child. (19).
Finally, we had no information on the children's fatty acid status. It could be relevant to investigate whether the child's fatty acid status influences their cognitive functioning or not.
Despite these limitations, our study was the first that has examined the association between omega-3 fatty acid status during pregnancy and cognitive functioning in their five-year-old offspring in a large community based cohort. More research is warranted to confirm the results of this study.


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