Maternal Hypothyroxinemia-Induced Neurodevelopmental Impairments in the Progeny

Abstract

Maternal hypothyroxinemia can induce neurodevelopmental impairments in the developing fetus. We here review recent studies on the epidemiology and molecular mechanisms associated with this important public health issue. In 2011, the American Thyroid Association defined maternal hypothyroxinemia as low serum free thyroxine (FT4) levels (<5th or <10th percentile) existing in conjunction with normal serum free triiodothyronine (FT3) or thyroid stimulating hormone (TSH) levels during pregnancy. Compared to clinical or subclinical hypothyroidism, hypothyroxinemia is more commonly found in pregnant women. Hypothyroxinemia usually ensues in response to several factors, such as mild iodine deficiency, environmental endocrine disrupters, or certain thyroid diseases. Unequivocal evidence demonstrates that maternal hypothyroxinemia leads to negative effects on fetal brain development, increasing the risks for cognitive deficits and poor psychomotor development in resulting progeny. In support of this, rodent models provide direct evidence of neurodevelopmental damage induced by maternal hypothyroxinemia, including dendritic and axonal growth limitation, neural abnormal location, and synaptic function alteration. The neurodevelopmental impairments induced by hypothyroxinemia suggest an independent role of T4. Increasing evidence indicates that adequate thyroxine is required for the mothers in order to protect against the abnormal brain development in their progeny.

Maternal hormonal milieu influence on fetal brain development

“…The importance of thyroid hormone to fetal brain development has been less characterized, but it is well established that maternal thyroid status is also intricately involved in the developing fetal brain (Eayrs, ; Lavado‐Autric et al., ; Patel, Landers, Li, Mortimer, & Richard, ; Stenzel & Huttner, ). Maternal thyroid dysfunction generally ensues in response to several factors such as iodine deficiency, environmental endocrine disrupters, or intrinsic thyroid diseases (Min et al., ). World Health Organization (WHO) has declared that iodine deficiency is, after starvation, the single most important cause of preventable brain damage, by affecting thyroid function (Morreale de Escobar et al., ; WHO, ).…”

“…The importance of thyroid hormone to fetal brain development has been less characterized, but it is well established that maternal thyroid status is also intricately involved in the developing fetal brain (Eayrs, 1953;Lavado-Autric et al, 2003;Patel, Landers, Li, Mortimer, & Richard, 2011;Stenzel & Huttner, 2013). Maternal thyroid dysfunction generally ensues in response to several factors such as iodine deficiency, environmental endocrine disrupters, or intrinsic thyroid diseases (Min et al, 2015).…”

Effect of Thyroid Hormones on Neurons and Neurodevelopment

“…However, data on the later phases of pregnancy are less concordant [54]. A recent metanalysis concluded that there is a 3-fold increased risk of child cognitive impairment when hypothyroxinemia is detected in mothers during gestation, although the big heterogeneity among the definitions of cognitive delay, the tests performed, and the assessment periods limits these findings [59]. In terms of iodine supplementation, another metanalysis concluded that, at present, the literature data are undermined by low evidence and several limitations, and no clear benefits or risks of iodine supplementation on children’s outcomes can be summarized [60].…”

Maternal Different Degrees of Iodine Deficiency during Pregnant and Lactation Impair the Development of Cerebellar Pinceau in Offspring

“…Our previous research findings suggested that hypothyroxinaemia caused by mild ID affected dendritic development of cerebellar purkinje cells (PCs), the proliferation of cerebellar granule neuron precursors (CGNPs), and differentiation of cerebellar granular cells (Wang et al, 2014a,b; Dong et al, 2016; Min et al, 2016a). As the most important neuron in the cerebellum, PCs summate all of stimulations to the cerebellum and are the only efferent nerves of the cerebellum (Palay and Chan-Palay, 1974).…”