Periconceptional Folic Acid Supplementation on Neurodevelopment of Offspring

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This entry is adapted from the peer-reviewed paper 10.3390/nu16050755

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].

Figure 1. A simplified illustration of FA metabolism and the impact of maternal intake on offspring. Folate from food or folic acid (FA) from fortified food/supplements are converted by dihydrofolate reductase to form dihydrofolate (DHF) and then tetrahydrofolate (THF). THF is then converted to 5,10-methylenetetrahydrofolate (5,10-MTHF), which is required for nucleic acid synthesis. 5,10-MTHF is further converted by methylenetetrahydrofolate reductase to form 5-methyltetrahydrofolate (5-MTHF), which is necessary for neurotransmitter (NT) and nitric oxide (NO) synthesis. 5-MTHF is converted by methionine synthase back to THF. The methyl group is transferred from 5-MTHF to homocysteine to form methionine. Methionine can be converted to S-adenosylmethionine (SAM) and acts as the methyl donor in the methylation reactions. SAH, S-adenosylhomocysteine. Excess maternal FA intake induces changes at molecular, cellular, tissue, and organism levels in offspring.

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.

Reference	Country	Sample Size	Research Type	Assessment of Folic Acid Use (Dosage and Stage)	Measurements	Folate Level (nmol/L)	Key Findings
McNulty et al., 2013 ^[30]	United Kingdom	59 women in the folic acid group, 60 women in the placebo group	Randomized controlled trial (RCT)	All women took 400 μg/d of FA in the first trimester, and received 400 μg/d folic acid or placebo during the second and third trimesters.	Serum and red blood cell folate, serum vitamin B-12, and plasma homocysteine were analyzed.	Serum folate: 45.7 ± 21.3 in placebo group and 47.0 ± 21.0 in treatment group. Red blood cell folate: 1106 ± 746 in placebo group and 1203 ± 639 in treatment group.	Continued FA supplementation during the second and third trimesters significantly increased the levels of maternal and cord red blood folate, and decrease the level of plasma homocysteine.
Cochrane et al., 2023 ^[31]	Canada	60 mother–child pairs	Randomized control trials (RCT)	Pregnant women were enrolled at 8–21 weeks of gestation and randomized to 0.6 mg/day folic acid or an equimolar dose (0.625 mg) of (6S)-5-methyltetrahydrofolic acid [(6S)-5-MTHF].	Folate and cord blood unmetabolized folic acid (UMFA) in human milk collected 1 week postpartum were quantified via LC–MS/MS.	Total folate in human milk: 47 ± 20 in (6S)-5-MTHF group and 61 ± 28 in folic acid group. UMFA in human milk: 0.6 in (6S)-5-MTHF group and 12 in folic acid group.	Compared to natural folate, folic acid supplementation showed similar levels of total folate, but significantly higher levels of UMFA in the milk.
Timmermans et al., 2009 ^[32]	Netherlands	6353 pregnancies	Prospective birth cohort	Self-reported questionnaires on folic acid use.	Fetal growth measured in mid- and late pregnancy by ultrasound; birth weight, small for gestational age (SGA), and preterm birth were recorded at birth.	NA	Periconceptional folic acid use was associated with increased fetal growth resulting in higher placental and birth weight, and decreased risks of low birth weight and small for gestational age (SGA).
Eryilmaz et al., 2018 ^[33]	United States	292 youths 8–18 years of age	Retrospective clinical cohort	None, partial, or full prenatal folic acid fortification exposure.	Cortical thickness was measured by brain MRI scans.	NA	Prenatal exposure of folic acid was associated with cortical thickness increase in the bilateral, frontal, and temporal regions, as well as delayed age-associated cortical thinning in the temporal and parietal regions.
Yusuf et al., 2019 ^[34]	United States	345 smoking pregnant women	Randomized control trials (RCT)	Participants were randomly assigned to receive either 0.8 mg folic acid/d or 4 mg folic acid/d.	Fetal growth was assessed by intrauterine ultrasound.	NA	Infants of mother who received high dose folic acid showed no difference in brain weight, but were 0.33 percentage points lower in brain/body weight ratio compared to standard dose group.
Henry et al., 2018 ^[35]	United Kingdom	22 mother–child pairs in the folic acid group and 17 mother–child pairs in the placebo group	Randomized controlled trial (RCT)	All women took 400 μg/d of FA in the first trimester, and received 400 μg/d folic acid or placebo during the second and third trimesters.	Emotional intelligence and resilience were assessed in children at 6–7 years.	NA	Children of folic-acid-treated mothers had higher scores in emotional intelligence and resilience at 6–7 years old.
McNulty et al., 2019 ^[36]	United Kingdom	37 mother–child pairs in the folic acid group and 33 mother–child pairs in the placebo group	Randomized controlled trial (RCT)	All women took 400 μg/d of FA in the first trimester, and received 400 μg/d folic acid or placebo during the second and third trimesters	Cognitive performance was evaluated in children at 3 and 7 years.	NA	Children of folic-acid-treated mothers scored higher in cognition at 3 years old and had higher scores in word reasoning at 7 years old.
Caffrey et al., 2021 ^[37]	United Kingdom	68 mother–child pairs (37 in FA group, 31 in placebo group)	Randomized controlled trial (RCT)	All women took 400 μg/d of FA in the first trimester, and received 400 μg/d folic acid or placebo during the second and third trimesters.	Cognitive performance was assessed by the Wechsler Intelligence Scale in children at 11 years old.	NA	Children of folic-acid-treated mothers scored higher in two Processing Speed tests, and showed more efficient semantic processing of language at 11 years old.
Julvez et al., 2009 ^[38]	Spain	420 mother–child pairs	Prospective birth cohort	Interviewer-administered questionnaires at the end of the first trimester of pregnancy.	Psychological outcomes were assessed in children at age 4 years.	NA	Maternal use of folic acid supplements was positively associated with verbal, motor, verbal-executive function, social competence, and inattention symptoms.
Veena et al., 2010 ^[39]	India	536 mother–child pairs	Prospective Mysore Parthenon birth cohort	Folate levels were measured from maternal plasma samples collected at 30 weeks of gestation.	Cognitive function was measured in children at 9–10 years.	NA	It showed a positive association between maternal plasma folate levels and children’s cognitive performance.
Roth et al., 2011 ^[40]	Norway	38,954 mother–child pairs	Prospective mother–child cohort	Self-report 3-year follow-up questionnaires.	Children’s language competency at age 3 years measured by maternal report.	NA	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.
Chatzi et al., 2012 ^[41]	Greece	553 mother–child pairs	Prospective mother–child cohort	Interviewer-administered questionnaires at 14–18 weeks of gestation.	Neurodevelopment was assessed in children at 18 months.	NA	Children of mothers with reported doses of 5 mg/d or more folic acid had a 5-unit increase in receptive communication and a 3.5-unit increase in expressive communication.
Villamor et al., 2012 ^[42]	United States	1210 mother–child pairs	Prospective pre-birth cohort	Questionnaires on the use of food frequency during the first and second trimesters of pregnancy.	The cognition and visual-motor skills were assessed in children at age 3 years.	NA	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 PPVT-III scores in the children at age 3 years.
Wu et al., 2012 ^[43]	Canada	154 mother–child pairs	Prospective birth cohort	Folate levels were measured from maternal plasma samples collected at 16 and 36 weeks of gestation.	Neurodevelopment was assessed in children at 18 months of age.	NA	No association was found between maternal plasma folate concentrations and child cognitive development.
Boeke et al., 2013 ^[44]	United States	895 mother–child pairs	Prospective pre-birth cohort	Semiquantitative food frequency questionnaire (FFQ) at each of the first- and second-trimester study visits.	Visual memory and verbal and non-verbal intelligence were assessed in children at the age of 7 years.	NA	No associations were found between maternal folate intake and the cognitive outcomes in children aged 7 years.
Huang et al., 2020 ^[45]	China	180 mother–child pairs	Prospective birth cohort	Serum folate concentrations were measured in blood samples collected from pregnant women at early, middle and late stages of pregnancy.	Gross motor skills, fine motor skills, language, adaptive behavior, and social behavior were assessed in children at the age of 2 years.	NA	Maternal serum folate in late pregnancy was positively associated with children’s language development while maternal serum folate in early pregnancy was inversely related to fine motor development in the children at the age of 2 years.
Irvine et al., 2023 ^[46]	Canada	309 mother–child pairs	Prospective birth cohort	Maternal RBC folate status assessed during the second trimester of pregnancy.	Neurodevelopment was assessed in children at 3–5 years old.	NA	Maternal folate status during the second trimester of pregnancy was associated with improved executive function development, but not associated with children’s intelligence, language, memory, or motor outcomes at 3–5 years of age.
Tamura et al., 2005 ^[47]	United States	335 mother–child pairs	Retrospective birth cohort	Both plasma and whole-blood folate concentrations were measured from maternal blood samples collected at 19, 26, and 37 weeks of gestation.	Six tests were performed in children at a mean of 5.3 years to assess their neurodevelopment.	NA	No association was found between maternal plasma and erythrocyte folate concentrations and children’s cognitive development.
Wehby and Murray, 2008 ^[48]	United States	6774 mother–child pairs	Retrospective birth cohort	The 1988 National Maternal Infant Health Survey (NMIHS) and its 1991 Follow-up Survey data.	16 Denver developmental screening items were measured in children at about 3 years of age.	NA	Folic acid use was associated with improved gross-motor development, but had marginally significant poorer performance for the personal–social domain.
Surén et al., 2013 ^[14]	Norway	85,176 children	Prospective birth cohort	The information of mothers’ supplement intake before conception and in early pregnancy was obtained through questionnaire report at week 18 of gestation.	Cases of ASD were diagnosed and confirmed by the health specialists.	NA	Prenatal folic acid supplementation around the time of conception was associated with a lower risk of ASD incidence.
Raghavan et al., 2018 ^[49]	United States	1257 mother–child pairs	Prospective birth cohort	A standard questionnaire was used to collect maternal data including supplement intake. Maternal plasma folate was measured from maternal blood samples collected 24–72 h post-delivery.	Children were diagnosed with ASD by the health specialists.	NA	It showed a “U shaped” relationship between maternal multivitamin supplementation frequency and ASD risk: moderate self-reported supplementation during pregnancy was associated with decreased risk of ASD, while low and high supplementation was associated with increased risk of ASD.
Raghavan et al., 2020 ^[50]	United States	567 mother–child pairs	Prospective birth cohort	A standard questionnaire was used to collect maternal data. Plasma and RBC folate levels were measured from umbilical cord blood samples collected at the time of delivery.	Children were diagnosed with ASD by the health specialists.	NA	Higher concentration of cord blood unmetabolized folic acid (UMFA) was associated with increased risk of ASD.
Steegers-Theunissen et al., 2009 ^[51]	Netherlands	120 mother–child pairs (86 mothers had used and 34 had not used folic acid periconceptionally)	Cross-sectional study	Questionnaire data via the mother on periconceptional folic acid use.	DNA methylation of IGF2 and folate levels in serum and red blood cells were measured using a mass spectrometry-based method in children between 12 and 18 months of age.	Serum folate in mothers: 15.3 in no FA group and 17.8 in yes FA group; Serum folate in children: 31.5 in no FA group and 32.1 in yes FA group; RBC folate in mothers: 687 in no FA group and 720 in yes FA group; RBC folate in children: 973 in no FA group and 1064 in yes FA group.	Children of mothers with periconceptional folic acid use had a 4.5% higher methylation of the IGF2 DMR and decreased birth weight.
Hoyo et al., 2011 ^[52]	United States	438 pregnancies	Prospective cohort study	Preconception and prenatal FA supplementation was assessed from the self-administered questionnaire.	The methylation levels of two IGF2 DMRs measured via pro-sequencing in umbilical cord blood leukocytes.	NA	The methylation level of the IGF2/H19 imprinted region decreased with increasing FA intake before and during pregnancy.
Haggarty et al., 2013 ^[53]	United Kingdom	913 mother–child pairs	Prospective cohort study	Folate levels were measured in maternal blood samples collected at 19 weeks of gestation and from cord blood samples.	DNA methylation level of 3 maternally methylated imprinted genes and 1 retrotransposon was measured in cord blood samples.	Maternal RBC folate: 456 Cord RBC folate: 657.	Folic acid supplement after 12 weeks of gestation was associated with a higher level of methylation in IGF2 and reduced methylation in both PEG3 and LINE-1.
Ondicova M et al., 2022 ^[54]	United Kingdom	86 cord blood DNA samples	Randomized controlled trial (RCT)	All women took 400 μg/d of FA in the first trimester, and received 400 μg/d folic acid or placebo during the second and third trimesters.	Methylation profiles of cord blood were measured by the EPIC array and validated using pyrosequencing.	NA	FA supplementation resulted in significant methylation changes at specific classes of neurodevelopmental genes in the cord blood.

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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