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Xu, X.; Zhang, Z.; Lin, Y.; Xie, H. Periconceptional Folic Acid Supplementation on Neurodevelopment of Offspring. Encyclopedia. Available online: (accessed on 20 April 2024).
Xu X, Zhang Z, Lin Y, Xie H. Periconceptional Folic Acid Supplementation on Neurodevelopment of Offspring. Encyclopedia. Available at: Accessed April 20, 2024.
Xu, Xiguang, Ziyu Zhang, Yu Lin, Hehuang Xie. "Periconceptional Folic Acid Supplementation on Neurodevelopment of Offspring" Encyclopedia, (accessed April 20, 2024).
Xu, X., Zhang, Z., Lin, Y., & Xie, H. (2024, March 11). Periconceptional Folic Acid Supplementation on Neurodevelopment of Offspring. In Encyclopedia.
Xu, Xiguang, et al. "Periconceptional Folic Acid Supplementation on Neurodevelopment of Offspring." Encyclopedia. Web. 11 March, 2024.
Periconceptional Folic Acid Supplementation on Neurodevelopment of Offspring

Folate, also known as vitamin B9, facilitates the transfer of methyl groups among molecules, which is crucial for amino acid metabolism and nucleotide synthesis. Adequate maternal folate supplementation has been widely acknowledged for its pivotal role in promoting cell proliferation and preventing neural tube defects. 

folate folic acid maternal neurodevelopment gene expression behavioral changes

1. Introduction

Folate is water-soluble vitamin B9 which includes the natural folate derived from food and the synthetic form. Folic acid (FA) is the synthetic form of folate and has been widely used in nutrient supplements and fortified food [1]. When consumed in our diet or supplements, folic acid is absorbed in the small intestine and then sequentially converted to dihydrofolate (DHF) and THF by dihydrofolate reductase (DHFR) in the cells [2]. Together with serine, THF can be reversibly converted to 5,10-methylene tetrahydrofolate (5,10-MTHF) and glycine by serine hydroxymethyltransferase (SHMT) [3][4]. With the aid of 5,10-methylenetetrahydrofolate reductase (MTHFR), 5,10-MTHF can be further catalyzed to 5-methyl THF (5-MTHF), a biologically active form of folate utilized in the synthesis of various molecules [5]. Food folate is the reduced form, and no reduction to dihydrofolate by DHFR is necessary [6]. More recently, another natural form (6S)-5-methyltetrahydrofolic acid (Metafolin®) has been used in place of the synthetic form folic acid, as it does not require either DHFR or MTHFR to form 5-MTHF [7]. 5-MTHF can be recycled back to THF via the re-methylation of homocysteine to form methionine and this process is crucial to maintaining an adequate supply of S-Adenosyl methionine (SAM), the key methyl donor in many biological methylation reactions (Figure 1). Additionally, 5-MTHF is required for nitric oxide synthesis via tetrahydrobiopterin and biogenic amine synthesis, producing some of the key neurotransmitters in the central nervous system [8][9].
Since folate is involved in the synthesis of nucleic acids and amino acids and is critical for cellular growth and differentiation [10], the demand for folate increases during pregnancy due to fetal/placental growth and uterus enlargement [11]. In addition, beyond the nervous system, the benefits of sufficient folate on reproductive and cardiovascular health have been demonstrated [12][13][14][15] and insufficient maternal folate further increases the risk of offspring overweight [16] and elevated blood pressure [17]. Additional adverse impacts of maternal folate deficiency have also been intensively reviewed in other research [18][19]. Due to food fortification and the relatively high use of multivitamin supplements, overall folate levels have significantly increased on a population-wide scale [20][21][22].

2. Human Studies on the Effect of Maternal Folic Acid Supplementation

Since the discovery of the association between folate deficiency and neural tube defects (NTDs), multiple clinical trials have confirmed the benefit of folate supplementation during pregnancy in reducing the incidence of NTDs [23][24][25]. As such, these studies have led to the recommendation of folic acid intake for pregnant women [26]. To increase compliance, the regulation of mandated fortification of grain products with folic acid was issued by the Food and Drug Administration in 1996 [27]. Current recommendations for folic acid supplementation for women are 400 μg/day before pregnancy, 600 μg/day during pregnancy, and 500 μg/day during lactation [28]. A significant reduction in NTD birth prevalence was achieved following the FA fortification of the US food supply [29], confirming the efficacy of food fortification in reducing NTD incidence in the population.
In the post-fortification era, serum and RBC folate levels have increased 2.5 times and 1.5 times, respectively, in the US population [21]. Periconceptional multivitamin or folic acid intake further increase folate levels in the pregnant women. In the Boston Birth Cohort, a wide range of plasma folate levels was shown in pregnant women, ranging from insufficient to excess levels [16]. The broad range of maternal folate intake enables dose–response studies to be conducted. Here, the researchers have compiled recent human studies examining the effects of folate supplementation in the developmental outcomes of offspring (Table 1).
Table 1. Human studies on the influence of folic acid supplementation during pregnancy in the offspring. NA—not available. Background colors categorize references into groups.

3. Influence of Periconceptional Folic Acid Supplementation in DNA Methylation in the Offspring

As a key player in methyl-donor metabolism, folic acid supplementation during pregnancy influences the DNA methylation profiles in offspring. Steegers-Theunissen et al. revealed the 4.5% higher methylation of the insulin-like growth factor 2 gene differentially methylation region (IGF2 DMR) in children born to mothers with periconceptional folic acid supplementation [51]. Moreover, the increased methylation level of IGF2 DMR was associated with decreased birth weight, indicating that FA-associated epigenetic changes in IGF2 in the child may affect intrauterine growth. Haggarty et al. also showed that folic acid use after 12 weeks of gestation was associated with higher methylation level in IGF2, and reduced methylation in both paternally expressed gene 3 (PEG3) and the long interspersed nuclear element 1 (LINE-1) [53]. Hoyo et al. assessed the association of maternal FA supplementation before and during pregnancy with aberrant DNA methylation at two DMRs regulating IGF2 and found decreased methylation levels at the IGF2/H19 DMR with increasing FA intake [52]. The inconsistent methylation changes at the IGF2 gene among different studies might be due to the different genomic regions studied. This also implies a complex relationship between maternal folic acid supplementation and the methylation alterations observed in offspring.

4. The Impact of Periconceptional Folic Acid Supplementation on the Neurodevelopment of Offspring

Adequate folate supplementation during pregnancy is considered positively associated with child neurodevelopment. Timmermans et al. revealed that periconceptional folic acid use was associated with higher placental and birth weight, and decreased risks of low birth weight and small for gestational age [32]. Eryilmaz et al. showed that the prenatal exposure of folic acid was associated with a cortical thickness increase in the bilateral, frontal, and temporal regions, as well as delayed age-associated cortical thinning in the temporal and parietal regions [33]. A randomized controlled trial (RCT) was performed to assess the effect of folic acid on fetal brain growth among pregnant women who smoke [34]. The results indicated that infants born to mothers who received high dose folic acid (4 mg/day) showed no difference in brain weight, but were 0.33 percentage points lower in brain/body weight ratio compared to those in the standard dose group (0.8 mg/day) [34].
In another RCT, known as the Folic Acid Supplementation in the Second and Third Trimesters trial, researchers found that continued FA supplementation during the second and third trimesters significantly increased the levels of maternal and cord RBC folate [30]. Compared to children born to mothers who only took 400 μg/day of FA during the first trimester, those whose mothers took 400 μg/day throughout the entire pregnancy achieved higher scores in cognition at 3 years old, and higher scores in word reasoning, emotional intelligence, and resilience at 6–7 years old [35][36]. Further follow-up investigations of this cohort showed that children from the latter group gained neurocognitive development benefits, as indicated by a higher score in two Processing Speed tests and more efficient semantic processing of language at 11 years old [37].
Multiple prospective cohort studies across different countries also support the beneficial effect of folate supplementation during pregnancy on child neurodevelopment. Julvez et al. showed that the maternal use of folic acid supplements was positively associated with verbal, motor, verbal-executive function, social competence, and inattention symptoms [38]. Veena et al. indicated a positive association between maternal plasma folate levels and children’s cognitive performance [39]. Roth et al. revealed that maternal use of folic acid in early pregnancy was associated with a reduced risk of severe language delay in children at the age of 3 years [40]. Chatzi et al. showed that children of mothers with reported doses of 5 mg/day or more folic acid had a 5-unit increase for receptive communication and a 3.5-unit increase in expressive communication [41]. Villamor et al. estimated that for every 600 ug/day increase in total folate intake during the first trimester of pregnancy, there was a 1.6-point increase in the cognition level measured by Peabody Picture Vocabulary Test III (PPVT-III) scores in the children at age 3 years [42].
Despite several studies supporting the benefit of periconceptional FA supplementation, some other prospective birth cohort studies have yielded inconsistent results. Wu et al. found no association between maternal plasma folate concentrations and child cognitive development at 18 months of age [43]. Boeke et al. found no association between maternal folate intake and cognitive outcomes in children aged 7 years [44]. Huang et al. revealed that maternal serum folate levels in late pregnancy were positively associated with children’s language development. Conversely, maternal serum folate levels in early pregnancy were inversely related to fine motor development in children at the age of 2 years [45]. Irvine et al. showed that maternal folate levels during the second trimester of pregnancy were linked to improved executive function development, but not associated with children’s intelligence, language, memory, or motor outcomes at 3–5 years of age [46]. A few retrospective cohort studies were performed, as well, to assess the benefit of maternal FA supplementation. Wehby and Murray showed that folic acid supplementation was associated with improved gross motor development. However, they showed a marginally significant negative association with performance in the personal–social domain [48]. Tamura et al. found no association between children’s cognitive development and maternal plasma or erythrocyte folate concentrations [47].


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