Sex-Specific Associations between Maternal Phthalate Exposure During Pregnancy and Neurodevelopmental Outcomes in Children at 2 Years of Age in the APrON Cohort

Abstract

There is inconsistent evidence regarding the sex-specific associations between prenatal phthalate exposure and children’s neurodevelopment; however, research suggests that these associations vary across neurodevelopmental domains and among phthalate metabolites. We evaluated the associations between prenatal phthalate exposure and sex-specific neurodevelopmental outcomes in children at 2 years of age using data from 448 mothers and their children (222 girls, 226 boys) included the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort. Nine phthalate metabolites were measured in maternal urine collected in the second trimester of pregnancy. Children’s cognitive, language, and motor outcomes were assessed using the Bayley Scales of Infant Development – Third Edition (Bayley-III). Parents completed measures of children’s executive function and behavior, the Behavior Rating Inventory of Executive Function- Preschool Version (BRIEF-P) and Child Behavior Checklist (CBCL). Sex-stratified robust multivariate regressions were performed.Higher MEOHP concentrations were associated with poorer performance on the Bayley-III Motor composite in boys (B = -0.07, 95% CI = -0.14, -0.01). Higher concentrations of DEHP and its metabolites were associated with higher scores (i.e., more difficulties) on the BRIEF-P Flexibility index in boys and girls (B’s = 0.03 to 0.07, 95% CI s= 0.01, 0.13) and Emergent Metacognition index in boys (B’s = 0.04 to 0.05, 95% CIs = 0.01, 0.10). Higher concentrations of DEHP and its metabolites were associated with more CBCL Externalizing Problems in girls and boys (B’s = 0.04 to 7.11, 95% CIs = 0.01, 12.30). Two phthalates, MBP and MMP, had sex-specific adverse associations with BRIEF-P and CBCL scores, while other metabolites (MEP and MiBP) were positively associated with boys’  performance on the Bayley-III.  These findings support the need for future research that specifically examines sex-specific effects of prenatal exposure to these endocrine disrupting chemicals.

Note: Funding Information: This cohort was established by an interdisciplinary team grant from Alberta Innovates Health Solutions (formally the Alberta Heritage Foundation for Medical Research). Additional funding from the Canadian Institutes of Health Research (MOP-123535), the U.S. National Institutes of Health (Exploration/ Development Grant 1R21ES021295-01R21), and the Alberta Children’s Hospital Foundation allowed for the collection and analysis of data presented in this manuscript. Salary support was provided to G. England-Mason through Postgraduate Fellowships in Health Innovation provided by Alberta Innovates, the Ministry of Economic Development, Trade and Tourism, and the Government of Alberta and the Canadian Institutes of Health Research.

Conflict of Interests: None to declare.

Ethical Approval: The research protocol was approved by the Conjoint Health Research Ethics Board at the University of Calgary. Written informed consent was provided prior to the collection of maternal urine samples, neurodevelopmental assessments, and completion of questionnaires. This work was carried out in accordance with the ethical principles for medical research involving human subjects (World Medical Association, 2013).

Keywords: Prenatal exposure, Phthalates, sex-specific outcomes, cognitive and executive function, motor, behavior