Associations of prenatal PFAS exposure with offspring neurobehavioral outcomes by maternal folate supplementation and cord blood 5-MTHF levels: a prospective birth cohort study.

While prenatal exposure to per- and polyfluoroalkyl substances (PFAS) has been associated with adverse neurodevelopment, epidemiological evidence on the modifying role of maternal folate remains limited. This study included 1267 mother-child pairs from the Shanghai Birth Cohort. We measured ten PFAS in maternal plasma and 5-methyltetrahydrofolate (5-MTHF) in cord blood red blood cells (RBCs). Data on maternal folic acid supplementation during early and late pregnancy was collected using questionnaires. Offspring neurodevelopment was assessed at ages 2 and 4 years using the Bayley Scales of Infant Development-Third Edition (BSID-III) and the Strengths and Difficulties Questionnaire (SDQ). We employed multivariable linear regression to examine the associations between PFAS and neurodevelopmental outcomes, with additional stratified and interaction analyses by folate status Johnson-Neyman analyses were conducted to describe the range of 5-MTHF values associated with statistically significant PFAS-outcome associations. PFAS mixture effects were evaluated using complementary approaches including weighted quantile sum (WQS) regression and quantile g-computation (qgcomp). After adjusting for confounders, higher maternal levels of PFDA, PFNA, and PFUA were associated with lower cognitive and language scores, whereas PFDoA and PFBS showed positive associations with selected developmental domains. The magnitude of PFAS-neurodevelopment associations varied across folate strata, with weaker associations observed in higher folate groups. Johnson-Neyman analyses identified ranges of 5-MTHF associated with statistically significant PFAS effects. Mixture analyses using WQS regression and qgcomp showed results generally consistent with single-pollutant analyses, with no significant mixture effects observed. Overall, our findings suggest that prenatal exposure to PFDA, PFNA, and PFUA was associated with adverse cognitive and language development in offspring. Although maternal folate status may be related to heterogeneity in PFAS-neurodevelopment associations, these findings should be considered exploratory and require further confirmation.