There is incontrovertible evidence that periconceptional folic acid (FA) supplementation can reduce the risk of neural tube defects (NTD) and some other congenital malformations. Research also suggests that continued maternal FA supplementation beyond the first trimester may have a long-term benefit for the neurocognitive development of the offspring, however, the evidence so far is inconclusive. We tested the hypothesis that children of mothers receiving FA supplementation during entire pregnancy would have better cognitive performance in childhood and early adolescence compared with those whose mothers have taken FA only until the end of the first trimester. As a potential biological mechanism linking maternal folate with differences in offspring cognitive abilities, we examined DNA methylation of targeted genes associated with brain growth and function. 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 400µg/d FA or placebo from the 14th gestational week until the end of pregnancy. The primary outcome was offspring cognitive performance which was evaluated at 7 years by the Wechsler Preschool and Primary Scale of Intelligence and at 11 years using the Wechsler Intelligence Scale for Children. From a total of 119 potential mother-child pairs, 70 children completed the assessment at age 7 years and 68 at age 11 years. The children of FA treated mothers scored significantly higher than the placebo group in Word Reasoning (13.3±2.6 vs 11.9±2.5; P=0.027) at 7 years and in Processing Speed subtests (Symbol Search: 27.44 ± 0.85 vs 24.86 ± 0.92; P 0.046 and Cancellation: 95.52 ± 3.11 vs 83.33 ± 3.36; P 0.011) at 11 years. Magnetoencephalography, used as an objective measure of brain function in a subset of participants at 11 years (n=33), showed more efficient language processing abilities in children of FA treated mothers compared to children of mothers in the placebo group. Analysis of cord blood showed significantly lower DNA methylation levels at LINE-1, IGF2 and BDNF genes in children of FA treated mothers compared with placebo. LINE-1 and IGF2 methylation was inversely associated with the cognitive scores of children at 7 years. Our results suggest that continued FA supplementation in pregnancy after the early period required to prevent NTD has beneficial effects on cognitive development in children. Further randomised trials in pregnancy with follow-up in childhood are warranted to confirm these findings.
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