In a recent review article published in nutrientsresearchers summarized what is known about the effects of excessive maternal folic acid (FA) supplementation on children.
They concluded that while folic acid is an extremely important nutrient, higher-than-required maternal fatty acid intake may have adverse effects on their offspring.
Folate is an essential nutrient
Water-soluble vitamin B9, or folic acid, is needed for the formation of red blood cells (RBCs) and to promote healthy cell growth and function. Doctors believe that it is necessary during pregnancy and breastfeeding for the growth of the fetus and placenta, for the enlargement of the uterus, to reduce the risk of developing congenital damage to the brain and spine of the child, and otherwise to improve the cardiovascular and reproductive health.
Folic acid can be found naturally in some foods, such as beans, peas, green leafy vegetables and nuts. However, synthetic fatty acids are widely distributed in fortified foods and nutritional supplements. Once consumed, it facilitates the transfer of a methyl group between molecules, facilitating nucleotide synthesis and amino acid metabolism. Specifically, it is involved in methyl donor metabolism.
Adequate FA supplementation is associated with higher birth weight and placental weight and lower risk of children being small for gestational age and low birth weight. It also reduces the chance of neural tube defects (NTD).
Continuing supplementation through the second and third trimesters has been shown to have lasting benefits on neurocognitive development in children up to 11 years of age. These include emotional intelligence, word reasoning, semantic processing, verbal-executive and motor function, attention, communication, and social competence.
Maternal folate deficiency is associated with multiple adverse outcomes, including increased blood pressure and overweight in children. However, the presence of fortified foods and supplements significantly increased serum, red blood cell, and total folate levels, and recent studies have raised the possibility of adverse effects from excess supplementation.
Addition of FA and ASD
Maternal folate intake is associated with the onset of autism spectrum disorder (ASD) in addition to its neurodevelopmental benefits. A study in Norway found that fatty acid intake starting four weeks before pregnancy and continuing for 12 weeks protected against ASD.
However, a more recent study in the United States found a “U-shaped” relationship between the risk of ASD and the frequency of maternal multivitamins. This suggests that the risk of ASD is highest at very low and very high supplementation levels.
Another analysis suggests that cord blood levels of unmetabolized folate (UMFA) may be positively associated with ASD risk, particularly in black children, but further research is needed to shed light on these mechanisms.
Insights from mouse models
While well-designed mouse models can provide important information about the effects of high-FA supplementation that cannot be ethically investigated using human experiments, the timing and duration of supplementation, the concentration of FA, the mode of FA administration and the possibility of different effects depending on the gender of the offspring should be considered.
The researchers used microarrays, Western blotting, ribonucleic acid sequencing (RNA-seq), and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to analyze the effects of FA.
The results of some studies showed that mice exposed to medium levels of FA had more gene changes. In terms of sex-based differences, some genes were more affected in female mice, while others were more affected in male mice, leading to different effects in the placenta, embryonic brain, and early postnatal brain. There have also been indications that FA may affect early brain development but lead to lasting behavioral changes in adulthood.
While maternal FA deficiency has been implicated in NTDs, excess supplementation has been associated with reduced placental and embryo weights, smaller hippocampal areas, and increased weight gain in male but not female offspring. The observed neurodevelopmental effects included short-term memory impairment, as well as hyperactivity and repetitive behavior and increased anxiety in the pups.
Findings vary across studies, but there is clear evidence that excessive maternal fatty acid intake can have long-term effects on physical and behavioral outcomes. It may also be involved in glucose metabolism and reproductive disorders, but there is no indication that it has transgenerational heritable effects.
Conclusions
Maternal folate deficiency is a concern, but mass supplements and fortified foods are now widely available, and excessive intake can have widespread effects on the central nervous system.
Although there is now increasing evidence of harmful effects in addition to benefits, there is a need to translate knowledge from mouse models into human studies and to examine gender-related effects. In addition, attention should be paid to new forms of fatty acid supplementation that may mitigate the potential harms of currently available supplements.
