The effects of high maternal folate intake on the health outcomes of offspring

By Priyanjana Pramanik, MSc.Reviewed by Danielle Ellis, B.Sc.Mar 8 2024

In a recent review article published in Nutrients, researchers summarized what is known about the effects of excessive folic acid (FA) supplementation for mothers on children.

They conclude that while folate is a crucial nutrient, higher than necessary maternal FA intake may have adverse effects on their offspring.

Folate is an essential nutrient

Water-soluble vitamin B9, or folate, is needed for red blood cell (RBC) formation and to promote healthy cell growth and functioning. Doctors consider it necessary during pregnancy and lactation for fetal and placental growth, for the enlargement of the uterus, to reduce the risk of the child developing congenital disabilities in the brain and spine, and otherwise improve cardiovascular and reproductive health.

Folate can be found naturally in some foods, such as beans, peas, green leafy vegetables, and nuts. However, synthesized FA has been distributed widely in fortified food and nutrient supplements. Once consumed, it facilitates methyl group transfer among molecules, facilitating nucleotide synthesis and the metabolism of amino acids. Specifically, it is involved in methyl-donor metabolism.

Adequate FA supplementation has been associated with higher birth and placental weight and a lower risk of children being small for their gestational age and low birth weight. It also reduces the likelihood of neural tube defects (NTDs).

Continuing supplementation into the second and third trimesters has been shown to have sustained benefits for the neurocognitive development of children up to 11 years old. These included emotional intelligence, word reasoning, semantic processing, verbal-executive and motor function, attention, communication, and social competence.

Maternal deficiency of folate has been linked to numerous adverse outcomes, including elevated blood pressure and overweight in children. However, the availability of fortified foods and supplements has significantly raised folate levels in serum, RBCs, and overall, and recent studies have raised the possibility of adverse consequences of excess supplementation.

FA supplementation and ASD

Maternal intake of folate has been associated with autism spectrum disorder (ASD) incidence in addition to its neurodevelopmental benefits. A study in Norway found that FA intake starting four weeks before the pregnancy began and continuing for 12 weeks was protective against ASD.

However, a more recent study in the United States found a ‘U-shaped’ relationship between ASD  risk and the frequency of maternal multivitamin supplementation. This suggests that ASD risk is highest at very low and very high levels of supplementation.

Another analysis indicates that unmetabolized folic acid (UMFA) levels in the cord blood could 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 on the effects of high FA supplementation that cannot be ethically researched using human experiments, the timing and duration of supplementation, concentration of FA, how FA was administered, and the possibility of differential effects depending on the sex of the offspring must be considered.

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.

Results from some studies indicate that mice exposed to an intermediate level 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 differential effects in the placenta, embryonic brain, and early postnatal brain. There were also indications that FA could affect brain development early in life but lead to lasting changes in behavior into adulthood.

While maternal FA deficiency has been implicated in NTD, excess supplementation has been associated with reduced placental and embryonic weights, smaller hippocampal areas, and increased weight gain in male but not female offspring. Observed neurodevelopmental impacts included short-term memory impairment, hyperactivity-like and repetitive behavior, and increased anxiety in mouse pups.

Findings varied across studies, but there is clear evidence that excess maternal FA intake can have long-term influences on physical and behavioral outcomes. It may also be implicated in glucose metabolism and reproductive disorders, but there are no indications that there are transgenerational inheritance effects.

Conclusions

Concerns about maternal folate deficiency, but FA supplements and fortified foods are now widely available, and excess intake may have widespread effects on the central nervous system.

While there is now growing evidence of detrimental effects in addition to benefits, there is a need to translate learnings from mouse models to studies on humans and explore the sex-linked impacts. Additionally, focus should be given to new forms of FA supplementation that can mitigate the potential harms of currently available supplements.