Folate, Folic Acid, and Autism: What Every Parent Needs to Know About Protecting Your Baby’s Brain

By Richard E Frye and Daniel Rossignol, the Autism Discovery and Treatment Foundation and the Rossignol Medical Center. 

Autism spectrum disorder (ASD) now affects approximately 1 in 31 children in the United States, and the number continues to climb [1]. While the causes of ASD are complex, a growing body of research is pointing to something that many pregnant women take every day as part of their prenatal routine: folic acid. But here is the crucial nuance — it is not folate itself that may be part of the problem, it is the specific form of folate you take that matters. 

Folate: Essential for a Healthy Baby 

Folate, also known as vitamin B9, is one of the most important nutrients during pregnancy. It is required for DNA synthesis, cell division, and proper development of your baby’s brain and spinal cord [2]. Folate deficiency during pregnancy has been firmly linked to neural tube defects like spina bifida and anencephaly, and supplementation around the time of conception has dramatically reduced these devastating birth defects worldwide [2]. 

Because the neural tube forms within the first 28 days of development — often before a woman even knows she is pregnant — public health authorities have mandated that grain-based foods be fortified with synthetic folic acid since 1998 in the United States and Canada [1]. On top of this food fortification, most prenatal vitamins also contain folic acid. The result has been a remarkable success story for preventing neural tube defects. But emerging science is exploring whether there may be unintended consequences to this well-meaning strategy. 

Folic Acid Is Not the Same as Folate 

This is one of the most important distinctions for parents to understand. The terms “folate” and “folic acid” are often used interchangeably, but they are chemically different. Folate is the natural form of vitamin B9 found in leafy greens, legumes, eggs, and liver. Folic acid is a synthetic, oxidized form of folate created in a laboratory and used in supplements and fortified foods. Folic acid is not metabolically active on its own; it must be converted into reduced forms before it can be used in the body. In contrast, leucovorin (also known as folinic acid) is a reduced metabolically active folate that enters this pathway downstream [2]. 

Here is the problem: folic acid requires a multi-step conversion process to become useful. The human enzymes dihydrofolate reductase (DHFR), which is responsible for this conversion, has relatively low, slow and variable activity [3]. When folic acid intake exceeds the body’s capacity to convert it, which can happen with the intake of fortified foods plus a prenatal vitamin, unmetabolized folic acid (UMFA) builds up in the bloodstream [3]. UMFA is biologically inactive and is increasingly being detected in both pregnant women and even in umbilical cord blood [4]. 

The Unmetabolized Folic Acid Problem 

Research from the Boston Birth Cohort reported an association between higher cord-blood UMA and later ASD diagnosis. Importantly, it is not total folate or the natural forms of folate but specifically UMFA [4]. Children with the highest cord blood UMFA were reported to have more than double the risk of a later ASD diagnosis compared to those with the lowest UMFA concentrations [4]. Data from the same cohort showed a “U-shaped” relationship between maternal folate levels and ASD risk, meaning that both very low and very high levels were associated with increased risk, with the high-level risk primarily driven by UMFA [1]. 

Animal studies reinforce these concerns. In mice, excess prenatal folic acid altered gene expression and DNA methylation in the developing brain, affecting pathways related to synapses, neurodevelopment, and neurotransmitter metabolism [5]. Another mouse study showed that excessive folic acid decreased the complexity of brain neurons and altered synaptic density. However, when folic acid was replaced with leucovorin (also known as folinic acid), these harmful changes did not occur [6]. 

Even breast milk is affected. A randomized trial found that mothers supplementing with synthetic folic acid had 14-fold higher levels of UMFA in their breast milk compared to mothers taking a natural reduced folate supplement, meaning infants continue to be exposed to this inactive form after birth [7]. 

Folate Receptor Alpha Autoantibodies: A Hidden Risk Factor 

Beyond the issue of UMFA, researchers have identified another important piece of the puzzle.  Some parents have autoantibodies against an important protein called the folate receptor alpha (FRα). The FRα is the primary gateway through which folate crosses the placenta to reach the developing baby and crosses the blood-brain barrier from the blood to the brain to nourish the brain [8]. 

Some individuals produce autoantibodies that attack this receptor. These FRα autoantibodies (FRAAs) come in two forms: blocking autoantibodies prevent folate from binding to the receptor, and binding autoantibodies can trigger inflammation and receptor destruction [8]. When a pregnant woman has these autoantibodies, folate delivery to her developing baby’s brain can be severely impaired, even if her blood folate levels are perfectly normal [8]. 

Research has shown that FRAAs are remarkably common in families affected by ASD. In a study of 82 children with ASD, their siblings, and their parents, 76% of affected children, 75% of unaffected siblings, 69% of fathers, and 59% of mothers tested positive for one or both types of FRAAs, compared to just 29% of controls [9]. A more recent study found that FRAA levels tend to increase across generations, especially in families with multiple children with ASD (multiplex families) and that these autoantibodies can be transmitted from parents to offspring in a pattern resembling what geneticists call “anticipation.” Anticipation describes the worsening of a disorder with each generation [10]. 

These findings suggest that FRAAs may represent a heritable, non-genetic risk factor for ASD that could potentially be addressed prenatally through targeted intervention. 

Leucovorin: A Promising Solution 

Leucovorin (also known as folinic acid) is a reduced and metabolically active form of folate. Unlike synthetic folic acid, leucovorin does not need to be activated and does not produce UMFA in the bloodstream [6]. Just as important, leucovorin can bypass the FRα receptor entirely by using an alternative transporter called the reduced folate carrier (RFC), which is not affected by FRAAs [8]. This means that even in women with autoantibodies blocking the FRα, leucovorin can still deliver this essential nutrient to the developing baby’s brain. 

Leucovorin has shown therapeutic benefit in some studies of children diagnosed with ASD. Multiple clinical trials, including placebo-controlled studies, have demonstrated that leucovorin treatment improves communication, language, and social interaction in children with ASD, particularly those who test positive for FRAAs [10]. 

But what about prevention? Two groundbreaking recent studies from Italy raise the possibility that leucovorin given during pregnancy to FRAA-positive mothers may improve neurodevelopmental outcomesin their offspring. In the first report, two women who had previously given birth to children with ASD were found to be FRAA-positive. In their subsequent pregnancies, they received leucovorin supplementation beginning before conception and continuing throughout pregnancy. Both children had typical neurodevelopment at three years of age, with no signs of ASD [11]. 

The second study was a randomized controlled trial which screened 210 women planning pregnancy for FRAAs. The found that 36 (17.1%) tested positive for FRAAs. FRAA-positive women were randomly assigned to receive either leucovorin (15 mg/day) or standard folic acid (400 mcg/day) throughout pregnancy. The results were striking: only 1 of 10 children (10%) in the leucovorin group developed ASD, compared to 5 of 8 children (62.5%) in the folic acid group. Children whose mothers received leucovorin also had significantly higher cognitive scores [12]. 

What This Means for You 

This body of research is intriguing. While folate is absolutely essential during pregnancy, the form of folate matters enormously. Synthetic folic acid, though effective at preventing neural tube defects, can accumulate as UMFA in both the mother and baby, causing neurodevelopmental risks. Reduced forms of folate, such as leucovorin are metabolically active, do not produce UMFA, and can bypass autoantibody-blocked folate receptors to protect your baby’s developing brain. 

If you have a family history of ASD, a previous child with ASD, or are simply concerned about optimizing your baby’s neurodevelopment, consider discussing the evidence with your healthcare provider about testing for FRα autoantibodies and about using a reduced form of folate instead of synthetic folic acid during pregnancy. This article should not be read as advice to stop prenatal vitamins. Seek individualized medical guidance to get your questions answered.. 

The science is still evolving, and larger clinical trials are needed to confirm these promising findings. But the evidence so far is compelling: for women at risk, leucovorin supplementation during pregnancy may represent a safe, targeted strategy to help protect against ASD in the next generation. 

References 

1. Haghani V, Ali SM, Cannizzaro N, Green R, LaSalle JM, Zarbalis KS. Excess prenatal folic acid supplementation alters cortical DNA methylation and gene expression networks. Front. Nutr. 2025;12:1699376. 

2. Greenberg JA, Bell SJ, Guan Y, Yu Y. Folic acid supplementation and pregnancy: more than just neural tube defect prevention. Rev Obstet Gynecol. 2011;4(2):52-59. 

3. Wiens D, DeSoto MC. Is high folic acid intake a risk factor for autism? — A review. Brain Sci. 2017;7(11):149. 

4. Raghavan R, Selhub J, Paul L, Ji Y, Wang G, Hong X, Zuckerman B, Fallin MD, Wang X. A prospective birth cohort study on cord blood folate subtypes and risk of autism spectrum disorder. Am J Clin Nutr. 2020;112:1304-1317. 

5. Haghani V, Ali SM, Cannizzaro N, Green R, LaSalle JM, Zarbalis KS. Excess prenatal folic acid supplementation alters cortical DNA methylation and gene expression networks. Front. Nutr. 2025;12:1699376. 

6. Tat L, Cannizzaro N, Schaaf Z, Racherla S, Bottiglieri T, Green R, Zarbalis KS. Prenatal folic acid and vitamin B12 imbalance alter neuronal morphology and synaptic density in the mouse neocortex. Commun Biol. 2023;6:1133. 

7. Cochrane KM, Elango R, Devlin AM, Hutcheon JA, Karakochuk CD. Human milk unmetabolized folic acid is increased following supplementation with synthetic folic acid as compared to (6S)-5-methyltetrahydrofolic acid. Sci Rep. 2023;13:11298. 

8. Bobrowski-Khoury N, Ramaekers VT, Sequeira JM, Quadros EV. Folate receptor alpha autoantibodies in autism spectrum disorders: diagnosis, treatment and prevention. J Pers Med. 2021;11(8):710. 

9. Quadros EV, Sequeira JM, Brown WT, Mevs C, Marchi E, Flory M, Jenkins EC, Velinov MT, Cohen IL. Folate receptor autoantibodies are prevalent in children diagnosed with autism spectrum disorder, their normal siblings and parents. Autism Res. 2018;11:707-712. 

10. Frye RE, Cohen IL, Sequeira JM, Hill Z, Espinoza A, Brown WT, Mevs C, Marchi E, Flory M, Jenkins EC, Velinov MT, Quadros EV. Transgenerational effects and heritability of folate receptor alpha autoantibodies in autism spectrum disorder. Int J Mol Sci. 2025;26:8293. 

11. Giorlandino C, Margiotti K, Fabiani M, Mesoraca A. Folinic acid supplementation during pregnancy in two women with folate receptor alpha autoantibodies: potential prevention of autism spectrum disorder in offspring. Clin Transl Neurosci. 2025;9:30. 

12. Giorlandino C, Mesoraca A, Margiotti K, Fabiani M, Cupellaro M, Giorlandino F, Mastrandrea ML, Raffio R, Pignataro F, Mangiafico L, D’Emidio L, Coco C, Milite V. Folinic acid supplementation in folate receptor alpha autoantibodies-positive pregnancy: a pilot randomized study on neurodevelopmental outcomes. Reprod Female Child Health. 2026;5:e70053.