## 1 Introduction  
Folic acid is an oxidized form of folate (vitamin B9) used in pharmaceutical vitamin supplements that can be chemically synthesized in the laboratory, purified from natural food sources, or from microorganisms capable of synthesizing the molecule (reviewed in [PERSON] et al., 2018 [1]). Dietary folates derived from food sources are primarily reduced forms of folates. These can become oxidized during the cooking and processing of food to present as folic acid for intestinal absorption. During transport in the intestine, most of the dietary folate forms are converted to methylfolate (MTHF) in the folate cycle by methylenetetrahydrofolate reductase (MTHFR) and recycled by methionine synthase (MS) and dihydrofolate reductase (DHFR) [2, 3]. The transport of folate across the ileal enterocyte occurs primarily via the proton-coupled folate transporter (PCFT), which along with a proton, drives the transport of folates across the apical side of the ileal enterocyte; therefore, operates at a slightly acidic pH at the site of absorption [4, 5, 6]. This process occurs primarily in the jejunum where folateis converted to monoglutamate [7]. The high dihydrofolate reductase (DHFR) activity and other folate pathway enzymes in the ileal entrocyte rapidly convert folates to MTHF [8]. The basolateral transport of folate is purported to occur primarily via the reduced folate carrier (RFC) and to some extent via the ATP-binding-cassette dependent transporter, the multidrug-resistance-associated protein (MRP) [9]. Derived from intestinal absorption, liver metabolism, and exiting from tissue cells, MTHF accounts for more than 95% of circulating folate in the blood. In blood, it exists as the monoglutamate form of MTHF because of the conjugate activity in blood plasma, while intracellular forms have 5-8 glutamic acid residues coupled via peptide bonds [6; 10]. The polyglutamation of folates appears to help retain the vitamin in the cell and its participation in metabolic reactions [10]. Systemic folate deficiency leads rapidly to megaloblastic anemia, which can be readily diagnosed and treated [11; 12]. Subtle folate deficiency or disruption of folate metabolism in women has been linked to subfertility, miscarriage, and pregnancy-related complications including neural tube defects (NTD) in the fetus [13; 14; 15; 16]. Prenatal folic acid supplementation with 0.4 to 1 mg of folic acid daily has reduced the incidence of NTD by about 30-50% [17]. Some recent publications have suggested that unmetabolized folic acid may accumulate in blood and tissues with potential for deleterious effects [18]. Most published reports have suggested an association without connecting to metabolic pathways [19; 20; 21]. If such an issue exists, it may become significant with a daily intake of folic acid such as in pregnancy. However, there is no direct evidence of unmetabolized folic acid affecting folate absorption, transport, or intracellular folate pathways [22; 23]. Moderate folic acid supplementation in mice has produced behavioral deficits with a decrease in MTHFR pseudogene due to elevated folic acid [24]. The relevance of this observation, if any, to alteration in folate metabolism remains to be defined. Food fortification with folic acid in many countries has raised the folate status in the population and decreased the prevalence of pregnancy-related complications, but neurodevelopmental disorders persist. The identification of folate receptor alpha autoantibodies (FR\(\alpha\)AuAb) in women with NTD pregnancy prompted us to re-evaluate folate supplementation during pregnancy to determine if a specific form of folate would be preferable; especially since a significant number of women (60-70%) with a history of NTD pregnancy [16] or autism spectrum disorder (ASD) in the offspring [25] are positive for the FR\(\alpha\)AuAb [26; 27].