Longitudinal analysis of maternal exposure to phthalates and bisphenol A and their impact on infant neurodevelopment and autistic behavior: The potential mediating role of thyroid hormones

Abstract

This prospective cohort study investigated the impact of maternal exposure to endocrine-disrupting chemicals, specifically phthalates and bisphenol A (BPA), on infant neurodevelopment. From 2019 to 2022, 672 pregnant women consented to participate in the study during their initial prenatal appointments at the Obstetrics and Gynecology Clinic of King Faisal Specialist Hospital & Research Centre. Two urine samples were collected each trimester to measure seven phthalate metabolites and BPA levels. Neurodevelopmental performance was evaluated using the Ages & Stages Questionnaires® Third Edition at 6, 12, and 18 months of age, and the risk of autism was assessed with the Modified Checklist For Autism in Toddlers at 18 months. Linear mixed models and logistic regression were applied to evaluate trimester-specific and overall associations using natural log-transformed urinary concentrations of phthalates and BPA. Our results showed that each one-unit increase in the log-transformed concentration of specific phthalates and BPA was associated with significant changes in infant developmental scores. During the first trimester, elevated levels of mono-n-butyl phthalate (MnBP), mono-iso-butyl phthalate (MiBP), and BPA were associated with 4.3 %-5.6 % decreases in gross motor (GM) scores. In contrast, monoethyl phthalate (MEP) and low-molecular-weight (∑LMW) phthalates were linked to 4 %-4.5 % increases in communication (COMM) scores. In the third trimester, MECPP and Σ₃DEHP were positively associated with GM and fine motor (FM) scores, while MiBP was associated with reduced personal-social (PSoc) scores. Sex-stratified analyses revealed differences in susceptibility, with males showing stronger adverse associations in problem-solving and social domains and females more affected in gross and fine motor scores. Mediation analysis identified free thyroxine (FT4) as a partial mediator, accounting for 12.7 % of the effect of ∑LMW phthalates on COMM scores during the first trimester. However, most mediation effects through maternal thyroid hormones were small and not statistically significant. Additionally, some first-trimester exposures, such as MEP and mono-(2-ethyl-5-oxohexyl) phthalate, appeared to be associated with lower odds of a positive M-CHAT screen. At the same time, MnBP showed a potential increase in risk. However, these exploratory findings were based on crude models and a limited number of positive cases and should be interpreted cautiously. Our study also examined overall exposure to phthalates and BPA across pregnancy, revealing consistent yet subtle impacts across developmental domains. This study adds novel insights by assessing trimester-specific exposures and investigating maternal thyroid hormones as potential mediators of early neurodevelopmental outcomes.

Keywords: ASQ-3; Autism; Bisphenol A; Endocrine disruptors; M-CHAT; Neurodevelopment delays; Phthalates.