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.

Folic acid intervention during pregnancy alters DNA methylation, affecting neural target genes through two distinct mechanisms

“…In contrast, supplementation served only to prevent the decrease in serum folate between GW 12 and GW 36 seen in the women receiving placebo. Preventing a drop in maternal folate levels and increasing folate concentration in foetal circulation is firmly associated with positive effects on cognitive and psychosocial outcomes both in this cohort [ 29 – 31 ] and in others [ 27 , 55 , 56 ].…”

“…In addition, these children showed significantly elevated scores on the Resiliency Attitudes and Skills Profile (RASP) and Trait Emotional Intelligence Questionnaire Child Short Form (TEIQue‐CSF) [ 30 ]. Most recently, we showed more efficient semantic processing of language (demonstrated using magnetoencephalographic brain imaging) in the same cohort at 11 years [ 31 ]. Our studies to date have not fully addressed, however, the biological mechanisms underpinning the relationship of maternal FA exposure during pregnancy with neurodevelopment.…”

Dietary Supplement Use during Pregnancy: Perceptions versus Reality

“…The same patterns of folic acid supplementation decline were observed in studies conducted in northwestern China and some other countries [ 4 , 36 , 42 ]. In addition to NTDS, studies found that taking folic acid throughout pregnancy benefited pregnant women and babies in other ways, such as reduction in recurrent pre-eclampsia and better child cognitive development [ 43 , 44 , 45 ]. As recommended by the Chinese Dietary Guidelines, folic acid supplementation should continue throughout pregnancy [ 4 ].…”

Nutritional Opportunity and Brain Development among Fetus and Infant

“…9 According to a recent study, folic acid supplementation in the second and third trimester of pregnancy, as recommended in the first trimester, can affect children's cognitive ability and brain function as young as 11 years of age. 10…”