Pregnancy

Folic Acid During Early Brain Development Is Important, but Too Much Is Not Good

This is an invited research digest contributed by Dr. Nafisa M. Jadavji at Carleton University and the University of Ottawa, Canada.

Folic acid is a B-vitamin and is well known for its role during early neurodevelopment. It promotes the closure of the neural tube in utero. The neural tube in the developing embryo is the first step to forming the brain and spinal cord during in utero neurodevelopment. If the neural tube does not close, it leads to neural tube defects (NTDs) in babies, such as spina bifida [1]. Women of child bearing age are recommended to take 0.4 -1 mg of folic acid supplements daily. Additionally, to reduce the number of NTDs mandatory folic acid fortification laws were put into place in 1998 in the US and Canada, as well as other countries. Since 1998, there has been a reduction in the number of NTDs in both Canada and the US [2].

The brain begins developing a few days after implantation and continues until the individual is in his or her mid-twenties. During neurodevelopment, the short-term impact of folic acid is well known, but the long-term effects are not well defined.  This article will describe recent data that shows long term effects of maternal deficiency on offspring memory function. On the other side, maternal over supplementation of folic acid has recently been reported to have negative effects on neurodevelopment. Over supplementation is defined as ingesting over 1 mg of folic acid daily.

Using a mouse model, we investigated the long-term effects of maternal deficiencies of folic acid on offspring memory function. Female mice were put on a diet deficient in folic acid prior to pregnancy [3]. The impact of maternal deficiency on offspring memory function was evaluated.  The offspring were ~3 weeks which is equivalent to young adults. Our research findings suggest that offspring from moms with a folic acid deficiency had impaired short-term visual memory. This may be a result of increased cell death and reduced cell proliferation within the hippocampus, a structure in the brain that is involved in memory.  Being folic acid deficient is not recommended for women of child bearing age, not only to avoid NTD, but also for neurodevelopment after birth.

Recently, there have been concerns about over supplementation of folic acid in countries like Canada where mandatory folic acid fortification laws are in place and supplement use is high [4]. In epidemiological studies, too much folic acid has been associated with increased risk of cancer [5]. Interestingly, too much maternal folic acid intake has been associated with autism spectrum disorder [6], but the data is not clear as other studies have reported the protective effects [7]. Furthermore, too much maternal folic acid has been reported to impair other neurodevelopmental aspects of the brain and behavior in offspring [8].

We recently published a study investigating whether too much maternal folic acid is associated with changes in the neurodevelopment of offspring [9]. Using a mouse model of maternal over supplementation of folic acid we report that male offspring from mothers that were fed high levels of folic acid had impaired memory and brain development.

The amount of folic acid in the diet of mothers was 20mg/kg to model over supplementation in humans. Mothers were supplemented for 6 weeks prior to pregnancy and throughout lactation. Once we weaned the pups from mothers they were maintained on supplemented diet until we collected experimental data. We assessed short-term memory of mice using a test called the novel object recognition, animals from mothers with too much folic acid did not remember seeing a familiar object as well as control animals did. Furthermore, they had reduced levels of a neurotransmitter that is important in learning and memory called acetylcholine. The pups from mothers over supplemented folic acid mothers had altered development of the cortex. This means that part of their brain did not follow normal development patterns. Interestingly the offspring from maternally over supplemented folic acid mother showed a similar phenotype to that of mice with a genetic deficiency in folic acid metabolism [10].

These are some of the first results showing how maternal over supplementation with folic acid may affect early neurodevelopment. More studies are required to further dissect the mechanisms as well as determine if the benefits continue into adulthood. As someone wise once said, everything in moderation.

References

[1] Lemire, R. J. (1988). Neural tube defects. Jama, 259(4), 558-62.

[2] Castillo-Lancellotti, C., Tur, J. A., & Uauy, R. (2013). Impact of folic acid fortification of flour on neural tube defects: a systematic review. Public health nutrition, 16(5), 901-911.

[3] Jadavji, N. M., Deng, L., Malysheva, O., Caudill, M. A., & Rozen, R. (2015). MTHFR deficiency or reduced intake of folate or choline in pregnant mice results in impaired short-term memory and increased apoptosis in the hippocampus of wild-type offspring. Neuroscience, 300, 1-9.

[4] Patel, K. R., & Sobczyńska-Malefora, A. (2017). The adverse effects of an excessive folic acid intake. European journal of clinical nutrition, 71(2), 159.

[5] Boyles, A. L., Yetley, E. A., Thayer, K. A., & Coates, P. M. (2016). Safe use of high intakes of folic acid: research challenges and paths forward. Nutrition reviews, 74(7), 469-474.

[6] Beard, C. M., Panser, L. A., & Katusic, S. K. (2011). Is excess folic acid supplementation a risk factor for autism?. Medical hypotheses, 77(1), 15-17.

[7] Wang, M., Li, K., Zhao, D., & Li, L. (2017). The association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders in children: a meta-analysis. Molecular autism, 8(1), 51.

[8] Roth, C., Magnus, P., Schjølberg, S., Stoltenberg, C., Surén, P., McKeague, I. W., … & Susser, E. (2011). Folic acid supplements in pregnancy and severe language delay in children. Jama, 306(14), 1566-1573.

[9] Bahous, R. H., Jadavji, N. M., Deng, L., Cosín-Tomás, M., Lu, J., Malysheva, O., … & Greene, N. D. (2017). High dietary folate in pregnant mice leads to pseudo-MTHFR deficiency and altered methyl metabolism, with embryonic growth delay and short-term memory impairment in offspring. Human molecular genetics, 26(5), 888-900.

[10] Jadavji, N. M., Deng, L., Leclerc, D., Malysheva, O., Bedell, B. J., Caudill, M. A., & Rozen, R. (2012). Severe methylenetetrahydrofolate reductase deficiency in mice results in behavioral anomalies with morphological and biochemical changes in hippocampus. Molecular genetics and metabolism, 106(2), 149-159.

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