Folinic Acid Supplementation in Folate Receptor Alpha Autoantibodies‐Positive Pregnancy: A Pilot Randomized Study on Neurodevelopmental Outcomes

ABSTRACT Background Folate receptor alpha autoantibodies (FRAAs) during pregnancy may impair placental folate transport, contributing to cerebral folate deficiency and increasing the risk of neurodevelopmental disorders such as autism spectrum disorder (ASD). Folinic acid, an active form of folate, may bypass receptor‐mediated transport impairment. Objective To compare the effects of prenatal folinic acid versus folic acid supplementation on the incidence and severity of ASD and learning disorders in offspring of FRAA‐positive mothers. Methods In this single‐centre, double‐blind pilot randomized study, 210 women planning pregnancy were screened for FRAA. Thirty‐six ( n = 36/210, 17.1%) tested positive, of whom 29 consented to randomization after confirmation of pregnancy and were randomly assigned to receive either folinic acid daily ( n = 15) or folic acid daily ( n = 14) from the first trimester to delivery. Eighteen participants completed the trial (10 in the folinic acid group and 8 in the folic acid group). Children were assessed at 24–30 months for ASD (M‐CHAT‐R/F, DSM‐5, ADOS‐2 and ADI‐R) and cognitive performance (Bayley‐4, Mullen Scales and Vineland‐3). Results The incidence of ASD was significantly lower in the folinic acid group ( n = 1/10, 10%) than in the folic acid group ( n = 5/8, 62.5%) ( p = 0.043). Learning disorders were also less frequent (10% vs. 50%; p = 0.14). Children of mothers receiving folinic acid exhibited milder ASD symptoms and significantly higher cognitive scores ( p = 0.031 and p = 0.004, respectively). Conclusions In FRAA‐positive pregnancies, folinic acid supplementation is associated with a reduced incidence of ASD and learning disorders and with improved neurodevelopmental outcomes. These findings support the potential role of folinic acid as a preventive strategy in immunologically at‐risk pregnancies and warrant validation in larger‐scale trials. Trial Registration: ISRCTN Registry Identifier: ISRCTN96269039; Date of Registration, 22/05/2025; Date of Initial Participant Enrolment, 01/04/2023; URL of the Registration Site https://www.isrctn.com/ISRCTN96269039 .