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. Methods: Pre-planned longitudinal follow-up of the 18 mother-child pairs who completed the original pilot RCT. Sixteen families (88.9%) were re-evaluated at a mean age of 45.4 ± 3.8 months (folinic acid, n = 9; folic acid, n = 7) using DSM-5-TR diagnosis, ADOS-2, ADI-R, WPPSI-IV, and Vineland-3, alongside standardised language and learning-prerequisite batteries. Results: The pre-specified primary endpoint was met: none of the eight folinic acid-group children who were ASD-free at 24-30 months developed ASD (0/8; 95% CI 0-36.9%). With only eight children in this subgroup, the estimate is inevitably imprecise, and we read it as pilot evidence of stability rather than proof of complete protection. Confirmed ASD at preschool age was 1/9 (11.1%) versus 5/7 (71.4%; p = 0.024). Folinic acid-exposed children showed lower ADOS-2 scores (p = 0.008), higher WPPSI-IV Full Scale IQ (p < 0.001), and superior Vineland-3 Adaptive Behaviour Composite scores (p = 0.002). Trajectory analysis showed neurodevelopmental stability in the folinic acid group versus progressive worsening in the folic acid group (p = 0.043). Conclusions: Children born without ASD to FRAA-positive mothers prenatally supplemented with folinic acid remained ASD-free at preschool age; the single folinic acid-group ASD case was attributable to a pathogenic SHANK2 variant. These findings support prenatal folinic acid as a targeted neuroprotective strategy in FRAA-positive pregnancies and warrant confirmation in larger, multicentre randomised trials.