Abstract Maternal thyroid dysfunction and gestational disturbances in glucose regulation are each well-established determinants of altered fetal development. However, their combined effects and shared placental pathways have seldom been explored within an integrated framework. To address this gap, we conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses-guided, structured literature synthesis examining how perturbations along the maternal thyroid–glucose axis during pregnancy may intersect at the placental level to influence fetal endocrine programming. Systematic searches of PubMed, Scopus, and Embase yielded 1329 records; of these, 40 studies fulfilled predefined inclusion criteria for qualitative synthesis, encompassing human observational studies, placental mechanistic research, epigenetic investigations, and integrative reviews. Rather than performing a quantitative meta-analysis, findings were evaluated thematically across biological domains to identify mechanistic convergence. Across heterogeneous study designs, recurring associations were observed between maternal thyroid and glycemic dysregulation and alterations in placental thyroid hormone transporters, including MCT8 and members of the organic anion transporting polypeptide family, as well as adaptive changes in deiodinase activity (DIO2 and DIO3). These disturbances frequently coincided with modifications in placental glucose transport, nutrient-sensing pathways, and metabolic signaling. Moreover, many studies reported accompanying epigenetic alterations, most notably changes in DNA methylation and microRNA expression, in key genes regulating energy metabolism, stress responses, and endocrine function, such as peroxisome proliferator–activated receptor gamma coactivator 1-alpha, leptin gene, insulin-like growth factor 2, and 11β-hydroxysteroid dehydrogenase type 2. Collectively, the evidence supports a conceptual model in which the placenta functions as an active endocrine and epigenetic mediator, translating maternal metabolic and hormonal signals into fetal adaptations that affect the thyroid axis, pancreatic development, and hypothalamic–pituitary–adrenal function. Although much of the existing literature is associative and mechanistic, the consistency of findings across independent lines of inquiry enhances biological plausibility and underscores critical knowledge gaps. Integrated evaluation of thyroid and metabolic function during pregnancy, together with placental and epigenetic research, may be essential for advancing understanding of fetal endocrine programming and its long-term health consequences.
Andonotopo et al. (Thu,) studied this question.
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