Folic acid in pregnancy — are all forms equally good?

Aim of the study: Background: Mandatory folic acid (FA) fortification prevents neural tube defects but leads to unmetabolized folic acid (UMFA) in the blood, because the liver enzyme dihydrofolate reductase (DHFR) reduces FA only slowly. Whether UMFA itself, separate from high total folate, has biological effects remains unclear.

Results: For red blood cell folate, the two available trials showed conflicting directions of effect but were insufficient to establish equivalence or non-inferiority. For tHcy, no difference between forms was detected. With only two to three trials per outcome, no prespecified margins, and no trial designed for this purpose, the evidence cannot support a claim of equivalence or non-inferiority for either outcome, and clinical benefit remains unproven. Current evidence does not establish that UMFA independently causes harm.

Aim of the study: Folate (vitamin B9) and vitamin B12 are essential micronutrients for cell growth, DNA synthesis, methylation, and one-carbon metabolism, and are especially important for early development. This review begins with an overview of vitamins essential to development, with a focus on folate and B12, followed by a detailed examination of folate sources, chemical forms, absorption, bioavailability, and genetic influences on folate metabolism and transport.

Results: We then discuss neurodevelopmental disorders, focusing on autism spectrum disorder (ASD), and summarize evidence on folate's role in brain formation during pregnancy, maternal folate deficiency as a contributor to autism risk, and the critical periods when folate status may have the greatest influence on neurodevelopmental outcomes. We focus specifically on clinical trial evidence: the detection of folate deficiency or insufficiency in children with ASD and treatment with leucovorin (folinic acid), as well as the detection of folate deficiency risk in pregnancy, particularly through screening for folate receptor alpha autoantibodies (FRAA), and treatment with calcium folinate. Recent randomized, placebo-controlled trials suggest that reduced forms of folate may offer benefits over folic acid in selected groups, including children with ASD and FRAA-positive pregnancies, though larger confirmatory studies are needed.

Aim of the study: Folate compounds are crucial for DNA and RNA synthesis, homocysteine regulation, and epigenetic methylation. However, significant differences exist between 5-methyltetrahydrofolate (5-MTHF), folinic acid (CHO-THF), and synthetic folic acid (sFA).

Results: CHO-THF shows promise in managing autism spectrum disorders by affecting neurotransmission and neurometabolic pathways. Despite these advantages, sFA remains the only folate form with proven effectiveness in large randomized clinical trials for preventing neural tube defects (NTDs), and it continues to play a key role in public health strategies. Use of sFA at doses above 1000 µg/day requires monitoring to avoid masking B12 deficiency. For personalized care or high-risk cases, 5-MTHF and CHO-THF should be the preferred options, ideally combined with vitamin B12 supplementation.