Effects of maternal folic acid supplementation during the second and third trimesters of pregnancy on neurocognitive development in the child: an 11-year follow-up from a randomised controlled trial

Abstract Background Maternal folic acid (FA) supplementation before and in early pregnancy prevents neural tube defects (NTD), but it is uncertain whether continuing FA after the first trimester has benefits on offspring health. We aimed to evaluate the effect of FA supplementation throughout pregnancy on cognitive performance and brain function in the child. Methods Follow-up investigation of 11-year-old children, residing in Northern Ireland, whose mothers had participated in a randomised trial of Folic Acid Supplementation in the Second and Third Trimesters (FASSTT) in pregnancy and received 400 μg/day FA or placebo from the 14th gestational week. Cognitive performance (Full Scale Intelligence Quotient, Verbal Comprehension, Working Memory, Perceptual Reasoning, and Processing Speed) was assessed using the Wechsler Intelligence Scale for Children. Neuronal function was assessed using magnetoencephalographic (MEG) brain imaging. Results Of 119 mother-child pairs in the FASSTT trial, 68 children were assessed for neurocognitive performance at 11-year follow-up (Dec 2017 to Nov 2018). Children of mothers randomised to FA compared with placebo scored significantly higher in two Processing Speed tests, i.e. symbol search (mean difference 2.9 points, 95% CI 0.3 to 5.5, p = 0.03) and cancellation (11.3 points, 2.5 to 20.1, p = 0.04), whereas the positive effect on Verbal Comprehension was significant in girls only (6.5 points, 1.2 to 11.8, p = 0.03). MEG assessment of neuronal responses to a language task showed increased power at the Beta (13–30 Hz, p = 0.01) and High Gamma (49–70 Hz, p = 0.04) bands in children from FA-supplemented mothers, suggesting more efficient semantic processing of language. Conclusions Continued FA supplementation in pregnancy beyond the early period currently recommended to prevent NTD can benefit neurocognitive development of the child. MEG provides a non-invasive tool in paediatric research to objectively assess functional brain activity in response to nutrition and other interventions. Trial registration ISRCTN ISRCTN19917787. Registered on 15 May 2013.

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Effect of continued folic acid supplementation beyond the first trimester of pregnancy on cognitive performance in the child: a follow-up study from a randomized controlled trial (FASSTT Offspring Trial)

BMC Medicine ◽

10.1186/s12916-019-1432-4 ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 3

Author(s):

Helene McNulty ◽

Mark Rollins ◽

Tony Cassidy ◽

Aoife Caffrey ◽

Barry Marshall ◽

...

Keyword(s):

Folic Acid ◽

Cognitive Performance ◽

Controlled Trial ◽

First Trimester ◽

Folic Acid Supplementation ◽

Verbal Iq ◽

Acid Supplementation ◽

Randomized Controlled ◽

In Pregnancy

Abstract Background Periconceptional folic acid prevents neural tube defects (NTDs), but it is uncertain whether there are benefits for offspring neurodevelopment arising from continued maternal folic acid supplementation beyond the first trimester. We investigated the effect of folic acid supplementation during trimesters 2 and 3 of pregnancy on cognitive performance in the child. Methods We followed up the children of mothers who had participated in a randomized controlled trial in 2006/2007 of Folic Acid Supplementation during the Second and Third Trimesters (FASSTT) and received 400 μg/d folic acid or placebo from the 14th gestational week until the end of pregnancy. Cognitive performance of children at 7 years was evaluated using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III) and at 3 years using the Bayley’s Scale of Infant and Toddler Development (BSITD-III). Results From a total of 119 potential mother-child pairs, 70 children completed the assessment at age 7 years, and 39 at age 3 years. At 7 years, the children of folic acid treated mothers scored significantly higher than the placebo group in word reasoning: mean 13.3 (95% CI 12.4–14.2) versus 11.9 (95% CI 11.0–12.8); p = 0.027; at 3 years, they scored significantly higher in cognition: 10.3 (95% CI 9.3–11.3) versus 9.5 (95% CI 8.8–10.2); p = 0.040. At both time points, greater proportions of children from folic acid treated mothers compared with placebo had cognitive scores above the median values of 10 (girls and boys) for the BSITD-III, and 24.5 (girls) and 21.5 (boys) for the WPPSI-III tests. When compared with a nationally representative sample of British children at 7 years, WPPSI-III test scores were higher in children from folic acid treated mothers for verbal IQ (p < 0.001), performance IQ (p = 0.035), general language (p = 0.002), and full scale IQ (p = 0.001), whereas comparison of the placebo group with British children showed smaller differences in scores for verbal IQ (p = 0.034) and full scale IQ (p = 0.017) and no differences for performance IQ or general language. Conclusions Continued folic acid supplementation in pregnancy beyond the early period recommended to prevent NTD may have beneficial effects on child cognitive development. Further randomized trials in pregnancy with follow-up in childhood are warranted. Trial registration ISRCTN ISRCTN19917787. Registered 15 May 2013.

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The long-term impact of folic acid in pregnancy on offspring DNA methylation: follow-up of the Aberdeen Folic Acid Supplementation Trial (AFAST)

International Journal of Epidemiology ◽

10.1093/ije/dyy032 ◽

2018 ◽

Vol 47 (3) ◽

pp. 928-937 ◽

Cited By ~ 21

Author(s):

Rebecca C Richmond ◽

Gemma C Sharp ◽

Georgia Herbert ◽

Charlotte Atkinson ◽

Caroline Taylor ◽

...

Keyword(s):

Dna Methylation ◽

Folic Acid ◽

Folic Acid Supplementation ◽

Acid Supplementation ◽

Long Term Impact ◽

In Pregnancy

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Effect of folic acid supplementation during pregnancy on brain health of the child at 11 years: the FASSTT Offspring trial

Proceedings of The Nutrition Society ◽

10.1017/s0029665120004553 ◽

2020 ◽

Vol 79 (OCE2) ◽

Author(s):

Aoife Caffrey ◽

Kristina Pentieva ◽

Helene McNulty ◽

Pramod Gaur ◽

Joel B. Talcott ◽

...

Keyword(s):

Folic Acid ◽

Cognitive Performance ◽

Processing Speed ◽

Brain Function ◽

Folic Acid Supplementation ◽

Full Scale ◽

Brain Health ◽

Acid Supplementation ◽

Lower Power ◽

High Gamma

AbstractPericonceptional folic acid (FA) has an established role in the prevention of neural tube defects (NTDs), leading to global recommendations for FA supplementation before and in early pregnancy. However, it is unclear whether there are any benefits for offspring brain health arising from continued maternal FA supplementation beyond the first trimester. The aim of this study was to investigate the role of maternal folate nutrition during pregnancy in relation to cognitive performance and brain function in the offspring at 11 years. The children of mothers who had participated in a randomised trial of Folic Acid Supplementation in the Second and Third Trimesters (FASSTT) were investigated, providing a unique opportunity to examine offspring brain health in relation to maternal folate (the FASSTT Offspring trial; n = 68). Cognitive performance was assessed using the Wechsler Intelligence Scale for Children, Fourth UK Edition (WISC-IV). The WISC-IV measures Full Scale IQ and specific domains of cognitive performance: Verbal Comprehension, Perceptual Reasoning, Working Memory and Processing Speed. Brain function was measured using magnetoencephalography (MEG) in a subset of the child participants (n = 33). The results showed no significant difference in Full Scale IQ between the children of mothers who had received folic acid versus placebo during pregnancy (P = 0.993). Processing Speed subtest scores were however significantly higher in the folic acid group compared with placebo (Symbol Search: P = 0.046 and Cancellation: P = 0.011). The application of MEG analysis showed that at rest, there were differences in brain functioning with significantly lower overall power at Broad band [1–48Hz] (P = 0.041) and a trend (not significant) towards lower power in all other frequency bands (Theta, Mu, Beta, Low Gamma and High Gamma) in children from the FA group compared with placebo. Results for the responses to the language task (congruent and incongruent sentences) in children from the FA group showed significantly lower power within the Theta band [4–8Hz] and significantly higher power within high frequency bands i.e. Beta [13–30 Hz] and High Gamma [49–70 Hz]. This suggested more efficient language processing abilities in these children compared to children of mothers in the placebo group. The findings provide scientific evidence that continuing FA supplementation beyond the periconceptional period that is protective against NTDs, may be beneficial for brain health in the offspring. Furthermore, this study demonstrates that MEG is a useful tool for objective assessment of functional brain activity in healthy children in response to nutrition intervention.

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