Prenatal Folinic Acid in FRAA-Positive Pregnancies: Preschool Neurodevelopmental Outcomes from a Pilot RCT Follow-Up

Background

Folate receptor alpha autoantibodies (FRAAs) during pregnancy impair placental and cerebral folate transport, predisposing the developing brain to autism spectrum disorder (ASD) through cerebral folate deficiency (CFD). A previously published pilot randomised controlled trial (RCT) showed that prenatal calcium folinate (folinic acid), compared with standard folic acid, lowered ASD incidence in the offspring of FRAA-positive mothers at 24-30 months. Mechanistically, whereas folic acid depends largely on the antibody-blocked folate receptor alpha, folinic acid (a reduced folate) enters cells through the reduced folate carrier and proton-coupled folate transporter, restoring cerebral folate delivery despite receptor blockade. We investigated whether this benefit persists at preschool age (36-50 months); the primary endpoint was verification that children born without ASD remain ASD-free.