brain development

A new study published in the British Journal of Nutrition suggests that folate insufficiency in early pregnancy has a longstanding, overall effect on brain development and is linked to poorer cognitive performance.


Folate is an essential B-vitamin that is required for replication and growth of cells, as well as for DNA methylation and synthesis. It is widely recognized that maternal folate deficiency during the critical phase of early pregnancy is associated with an increased risk of neural tube defects – that is, severe abnormalities of the brain, skull, and spine. Along with the well-known risks of neural tube defects, low levels of folate in pregnancy could have long-term effects on brain development and cognitive function during childhood. Accordingly, folate supplementation is recommended during the peri-conceptional period, which includes the period from 1 month before conception to 3 months after conception.

Previous studies have provided evidence showing that prenatal maternal folate deficiency is linked to a reduction in prenatal brain growth and psychological issues in offspring. However, the longstanding consequences of prenatal folate deficiency on brain development are not well understood. A group of researchers at the Erasmus University Medical Center, in the Netherlands, conducted a study primarily to assess the connection between prenatal maternal plasma folate status in early pregnancy and brain anatomy of school-aged children. They also wanted to examine whether brain volume explained any association between prenatal folate status and the existence of behavioral and emotional problems or cognitive performance in the same study sample. As a result of the correlation between folate, total homocysteine (tHcy) and vitamin B12 levels – and the association between tHcy, vitamin B12 and cognitive effects in children – brain volume, psychological and cognitive outcomes were also examined with respect to maternal plasma B12 and tHcy levels. The study is a part of the Generation R Study, which examined approximately 10,000 pregnant Dutch women between 2002 and 2006, and consisted of 256 Dutch children between the ages of 6 and 8 years from whom structural brain scans were gathered using MRI. Insufficient (<8nmol/l) plasma folate levels was found in the mothers of sixty- two children in early pregnancy. Snijders-Oomen Niet-verbale intelligentie test – Revisie and the NEPSY-II-NL were used to assess cognitive development. Moreover, the parent report of the Child Behavior Checklist was used to assess psychological problems at age 6 years.

The findings, published in the British Journal of Nutrition, suggest that prenatal maternal folate deficiency at mild-to-moderate levels (defined as plasma folate <8 nmol/l) during pregnancy is associated with an overall reduced brain volume (rather than in certain brain regions). There was no evidence to show effects of plasma B12 or tHcy levels on child brain volumes.

brain development

Additionally, the researchers found that both a lower prenatal plasma folate concentration and higher plasma tHcy concentration were associated with poorer performance on numerous cognitive domains. Among children of mothers with high levels of plasma tHcy during pregnancy, intelligence at 6 years of age was found to be significantly lower (7 points), compared with children of mothers with normal tHcy levels. Likewise, high prenatal plasma tHcy concentrations were linked to poorer functioning on the visuospatial and language subdomains of the NEPSY-II. An association between low prenatal folate and a lower child intelligence score at 6 years of age was also found, although the link was not significant.

In addition, the results did not show a significant relationship between total NEPSY-II score and low maternal folate concentrations; yet, there appeared to be differences in performance on several individual NEPSY-II domains. Low prenatal plasma folate levels were associated with poorer performance on several of the subdomains of the NEPSY-II. Children with lower levels of prenatal plasma folate had lower scores on the language, visuospatial and the learning/memory subdomains.

Lastly, there was no evidence to show that children of mothers with low folate levels had more behavioral or emotional issues than the children of mothers with normal folate levels at 6 years of age. This finding indicates that effects of prenatal folate deficiency on the psychological functioning of adolescents might fade throughout development, perhaps due to compensating environmental influences, such as sufficient family functioning and nutrition, or support and social stimulation.

The overall study findings suggest that mild-to-moderate folate deficiency in early pregnancy has a long-term and overall effect on brain development in offspring, as indicated by a reduced brain volume in 6 to 8-year-old adolescents. This effect may partly explain the poorer test scores seen on several of the cognitive domains in kids with low prenatal plasma folate concentrations. Greater concentrations of maternal tHcy (>9μmol/l) were linked to decreased performance on some of the cognitive subdomains and lower child intelligence scores. However, the researchers could not prove that differences in brain volume related to folate levels explained any long-term risk of behavioral or emotional problems in children. Further studies are needed to confirm the results and to examine the underlying mechanisms by which prenatal folate, tHcy and vitamin B12 status affects brain development, in addition to their effects on the well-being and daily functioning of the child. Nonetheless, the study emphasizes the significance of prenatal nutrition, particularly folate supplementation.




Written by: Nigar Celep, BASc

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