Endocrine disruptor load in pregnancy and the thyroid–glucose axis: A mixture-aware systematic review and meta-analysis with mechanistic integration and a conceptual framework for the Pregnancy Disruptor Exposure Score

Abstract Background: Endocrine-disrupting chemicals are pervasive in contemporary environments, and biomonitoring data consistently demonstrate exposure during pregnancy. Experimental and epidemiological evidence increasingly suggests that these compounds do not act through single endocrine pathways. Instead, they may concurrently perturb thyroid regulation and glucose metabolism—two systems that are physiologically interdependent during gestation and central to placental function, fetal growth, and maternal metabolic adaptation. Existing reviews have largely addressed thyroid or glucose outcomes separately and have seldom accounted for real-world chemical mixtures. Methodology: We conducted a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. MEDLINE, Embase, Web of Science, Scopus, and CENTRAL were searched from inception to October 21, 2025. Eligible studies were human observational cohorts or case–control studies reporting measured maternal exposure to endocrine disruptors, including phthalates, bisphenols, per- and polyfluoroalkyl substances (PFAS), and metals, in relation to thyroid- or glucose-related outcomes. Two reviewers independently screened records, extracted data, and assessed risk of bias using design-appropriate tools. Findings from mixture-based analytical approaches were synthesized where available. Results: From 1,456 identified records, 39 studies met the inclusion criteria. Across populations and study designs, higher prenatal exposure to phthalates, bisphenols, and PFAS was consistently associated with altered maternal or neonatal thyroid hormone concentrations and impaired glucose regulation, including gestational diabetes mellitus. Studies applying mixture-aware methods generally reported stronger and more coherent associations than single-chemical models. Evidence for emerging exposures, such as microplastics, was limited and largely mechanistic. Overall certainty of evidence ranged from low to moderate. Conclusions: Current evidence indicates that exposure to endocrine disruptor mixtures during pregnancy is associated with perturbations of the coupled thyroid–glucose axis, with potential implications for both maternal metabolic adaptation and fetal development. To address the heterogeneity of existing findings, the Pregnancy Disruptor Exposure Score (PDES) is proposed as a conceptual, hypothesis-generating framework for summarizing cumulative exposure burden and supporting research stratification. The PDES is not intended for clinical application and requires further validation before any consideration of translational use. The review protocol was not registered.