Folic Acid During Pregnancy May Support Brain Development

It is recommended that daily folic acid supplements should be taken before pregnancy and during the first 12 weeks post conception to reduce risk of birth defects. However, it has also been hypothesised that a high folic acid intake may have beneficial effects on neurocognitive development. From a recent study by Valera-Gran et al. it was reported that taking higher intake of folic acid benefits cognition and behaviour in children, but that daily doses of folic acid during the periconception period may be detrimental [1]. From discussing their conclusions within wider research, it has been suggested that there is not sufficient evidence to make a recommendation regarding folic acid supplementation based solely on cognition, but that supplementation with 400μg/day should continue to be advised. It could also be said that pregnant women should consume high quantities of folic acid from food during all three trimesters to prevent deficiency and support brain development.

The human brain is the slowest organ to develop, beginning 18 days after fertilisation and continuing for many years post-birth [2], with rapid neurogenesis, synaptogenesis, myelination, axonal and dendritic growth and gliogenesis characterising early critical stages [3]. Nutrition influences neurodevelopment, with deficiencies potentially imparting long-term effects on brain structure and cognition. One nutrient of particular interest is folic acid (FA), of which elevated levels have been observed in the brain of a foetus [4].

FA is the oxidised and synthetic form of folate found in supplements and fortified foods. Upon absorption, it is reduced to tetrahydrofolate for incorporation into physiologically functional pools [5] and is used to transfer one carbon units, or methyl groups, for DNA replication and amino acid metabolism [6]. During pregnancy there is an increased requirement of FA due to rapid cell proliferation and tissue, placental and foetal growth [7]. FA also has a fundamental role in brain development [4], affecting neural stem cell proliferation and differentiation [8], neurotransmitter and receptor synthesis [2], and DNA methylation [7]. Its role as a cofactor for the methionine synthase enzyme that converts homocysteine (Hcy) to methionine means folate also prevents elevated Hcy levels, which is otherwise associated with its accumulation and enhanced apoptosis within regions of the brain affecting working memory and memory formation, motor and executive function, and neurogenesis [9].

Advice in the UK is for 400μg/day FA in supplemental form to be taken prior to conception and up to the 12^th week of pregnancy, in addition to consuming foods rich in FA, to reduce the risk of neural tube defects (NTD) such as spina bifida and anencephaly [10]. However, as approximately half of pregnancies are unplanned, it has become of increasing concern that there are limits to the effectiveness of this advice [11]. Mandatory fortification of flour with FA has been recommended by the Scientific Advisory Committee for Nutrition (SACN), with the optimal level of 300μg/100g flour having the potential to reduce risk of NTD affected pregnancies by 11-18% [11]. The effect of this action on cognitive development has not been quantified. A recent prospective cohort study by Valera-Gran et al. investigated the effect of maternal FA supplementation on neurocognitive development in children at age 4-5 years during both the periconception period and the entire pregnancy [1]. This review will relate their findings to wider research to evaluate the association between FA supplementation and subsequent neurodevelopment and to discuss whether there may be benefits obtained from flour fortification beyond that of preventing NTDs.

Method

Study population

Data was from the Infancia y Medio Ambiente Study, a multicentre mother-child cohort study. 1682 mother-child pairs were included who had data for the variables required when children reached age 4-5 years.

Assessment of dietary folate and supplement use

Two 101-item food frequency questionnaires (FFQs) were administered at 10-13 weeks and 28-32 weeks from conception and used to calculate dietary folate intake. Questions on FA supplementation were asked at each time point. Doses were categorised as <400μg/day, 400-999μg/day, and ≥1000μg/day.

Neuropsychological assessment

The McCarthy Scales of Children’s Abilities (MSCA) assessed neuropsychological development at median age 4.5 years, or 5.7 years in Valencia.

Statistical analysis

MSCA outcomes were standardised and multiple linear regression models used to analyse the association between MSCA scales and both intake of dietary folate and FA supplements in the periconception period, from the fourth to seventh month, and for the entire pregnancy.

Results

Subject characteristics

The recommended FA supplement dose was not taken by 54.8% of women. 29.8% took ≥1000μg/day in the periconception period, although this reduced in the second stage of pregnancy.

Results of statistical analysis

For the periconception period, maternal dietary folate was associated with an increase in global memory and in visual and verbal span scores in children at age 4-5 years. Compared with 400-999μg/day, FA supplementation of ≥1000μg/day was associated with a reduction in global verbal score, and verbal memory, cognitive function of the posterior cortex, and cognitive function of the left posterior cortex. A significantly lower verbal memory score was observed for FA supplement intake <400μg/day.

For the fourth to the seventh month of pregnancy, dietary folate intake was positively associated with verbal memory score but negatively associated with visual executive function. There was no association between cognition and FA supplementation ≥1000μg/day.

Throughout the entire pregnancy, higher dietary folate intake was positively associated with verbal memory, and tended to be associated with global verbal, global memory, visual and verbal span and cognitive function of the left posterior cortex. However, there were no associations between cognition and FA supplementation ≥1000μg/day.

Discussion

The study by Valera-Gran et al. concluded that FA intake of ≥1000μg/day in the periconception period was associated with reduced cognitive function and that supplementation of <400μg/day adversely affected verbal memory [1]. As FA intake is correlated with circulating concentrations [4], the results reinforce the biological effects of FA on brain development but suggest that doses above the tolerable upper limit are detrimental. A systematic review by Gao et al. found that only 15 of 22 studies observed benefits from FA supplementation on neurodevelopment or autistic spectrum disorder (ASD) in children, with 6 reporting no statistically significant effect [6]. Although this does indicate a protective effect, inconsistencies within the literature should be considered. For example, Wu et al. reported no relationship between maternal folate and infant development [12], whereas an inverse association between FA supplementation and risk of autistic disorder, the most severe form of ASD, has been observed [13]. Similarly, Schmidt et al. found higher intake of FA to be associated with reduced risk of ASD during the periconceptual period [14]. The differences between studies may result from bias due to incomplete ascertainment of ASD cases in the cohort [13] or loss to follow up of those with lower cognitive function [1]. This may attenuate the effects or result in lower statistical power, causing null findings.

Many studies limit their analysis to advised levels of supplementation but Valera-Gran et al. observed a reduction in cognitive function for those with FA supplementation use ≥1000μg/day [1]. In contrast, it was also found for 5mg/day supplementation, as advised for those who have previously had a NTD-affected pregnancy, to be associated with increased fine motor development and receptive and expressive communication at 18 months [4]. Exceeding the upper limit of 1mg/day may result in unmetabolized FA in the circulation, of which the significance is unknown [5]. It is therefore likely that further research and monitoring may be essential to determine whether high dose FA supplementation should be avoided in the general population.

Recommendations for FA supplementation beyond the 12^th week of pregnancy are varied [15] and few studies consider its effects. Valera-Gran et al. observed higher FA intake between the fourth and seventh month to be positively associated with verbal memory score and, across the entire pregnancy, with verbal memory [1]. Maternal and cord red blood cell folate concentrations have been reported to increase as a consequence of supplementation continuing into the second and third trimester [15], which may have an indirect effect on cognitive development by preventing Hcy elevation and subclinical folate deficiency later in pregnancy when maternal folate declines [7]. Pre-pregnancy elevated tHcy has been associated with poorer psychomotor and mental performance at 4 months and lower IQ at 6 years [9] so if high tHcy during pregnancy has similar impacts it may be of value to continue supplementation. It is important to note that Valera-Gran et al. suggests there to be no additional benefits obtained from high doses, therefore it may be that folate from standard dietary sources could suffice.

Impacts

The conclusions reported by Valera-Gran et al., that higher FA intake during pregnancy is associated with improved cognition in children but doses in excess of 1mg may be detrimental [1], have been discussed within wider literature. Some inconsistencies between studies have been found and a limited amount of evidence. Nonetheless, it could be proposed that there may be beneficial effects of FA supplementation on neurodevelopment, with the potential for the reduction in ASD occurrence, but that high doses should be avoided unless medically prescribed. Consequently, without additional research, the current recommendation of 400μg/day should remain. The study by Valera-Gran et al., among most others, tests specific cognitive functions. However, to relate these factors to phenotypic behavioural characteristics, it has been suggested that low maternal folate status increases risk of mood instability, nervousness, somatic problems, phobias, apathy, disruptive behaviours, impulsiveness and aggressiveness [2]. 

Moreover, it could be said that there may be some benefits of continuing supplementation throughout pregnancy, but this advice could not be extended beyond preventing deficiency. Consequently, the fortification of UK flour with FA may be an optimum way to ensure high maternal FA intake during the whole pregnancy to prevent FA deficiency, tHcy elevation, and adverse effects on neurocognitive development. If this does not occur, it would be important for pregnant women to include a variety of folic acid rich foods in their diet such as leafy green vegetables, beans and legumes, yeast extract, poultry and liver. Despite this, FA supplementation of 400μg/day during the pre- and periconception periods should still be recommended in order to reduce risk of NTDs.

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[1] Valera-Gran, D., Navarrete-Munoz, E. M., Garcia de la Hera, M., Fernandez-Somoano, A., Tardon, A., Ibarluzea, J., Balluerka, N., Murcia, M., Gonzalez-Safont, L., Romaguera, D., Julvez, J., Vioque, J. & Project, I. (2017). Effect of maternal high dosages of folic acid supplements on neurocognitive development in children at 4-5 y of age: the prospective birth cohort Infancia y Medio Ambiente (INMA) study. American Journal of Clinical Nutrition, 106 (3), 878-887.

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[3] Vazir, S. & Boindala, S. (2016). Nutrition, Brain Development and Cognition in Infants, Young Children and Elderly. Proceedings of the Indian National Science Academy, 82 (5), 1495-1506.

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[5] Selhub, J. & Rosenberg, I. H. (2016). Excessive folic acid intake and relation to adverse health outcome. Biochimie, 126, 71-78.

[6] Gao, Y., Sheng, C., Xie, R.-H., Sun, W., Asztalos, E., Moddemann, D., Zwaigenbaum, L., Walker, M. & Wen, S. W. (2016). New Perspective on Impact of Folic Acid Supplementation during Pregnancy on Neurodevelopment/Autism in the Offspring Children - A Systematic Review. Figshare.

[7] McGarel, C., Pentieva, K., Strain, J. J. & McNulty, H. (2015). Emerging roles for folate and related B-vitamins in brain health across the lifecycle. Proceedings of the Nutrition Society, 74 (1), 46-55.

[8] Nyaradi, A., Li, J., Hickling, S., Foster, J. & Oddy, W. H. (2013). The role of nutrition in children's neurocognitive development, from pregnancy through childhood. Frontiers in Human Neuroscience, 7.

[9] Murphy, M. M., Fernandez-Ballart, J. D., Molloy, A. M. & Canals, J. (2017). Moderately elevated maternal homocysteine at preconception is inversely associated with cognitive performance in children 4 months and 6 years after birth. Maternal and Child Nutrition, 13 (2).

[10] NICE (2014). Maternal and child nutrition. URL: https://www.nice.org.uk/guidance/ph11. [19th September 2017]

[11] SACN (2006). Folate and Disease Prevention. London:TSO.

[12] Wu, B. T. F., Dyer, R. A., King, D. J., Richardson, K. J. & Innis, S. M. (2012). Early Second Trimester Maternal Plasma Choline and Betaine Are Related to Measures of Early Cognitive Development in Term Infants. Plos One, 7 (8).

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[14] Schmidt, R. J., Tancredi, D. J., Ozonoff, S., Hansen, R. L., Hartiala, J., Allayee, H., Schmidt, L. C., Tassone, F. & Hertz-Picciotto, I. (2012). Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. American Journal of Clinical Nutrition, 96 (1), 80-89.

[15] McNulty, B., McNulty, H., Marshall, B., Ward, M., Molloy, A. M., Scott, J. M., Dornan, J. & Pentieva, K. (2013). Impact of continuing folic acid after the first trimester of pregnancy: findings of a randomized trial of Folic Acid Supplementation in the Second and Third Trimesters. American Journal of Clinical Nutrition, 98 (1), 92-98.