Maternal thyroid hormones early in pregnancy and fetal brain development

doi:10.1016/j.beem.2004.03.012

Best Practice & Research Clinical Endocrinology & Metabolism

Volume 18, Issue 2, June 2004, Pages 225-248

https://doi.org/10.1016/j.beem.2004.03.012 Get rights and content

Abstract

During the last few decades our understanding of the possible role of thyroid hormones during brain development has increased and contributed to resolve previously discordant hypotheses, although much remains to be clarified. Thyroid hormones of maternal origin are present in the fetal compartment, despite the very efficient uterine-placental ‘barrier’, necessary to avoid potentially toxic concentrations of free T4 and T3 from reaching fetal tissues before they are required for development. T3 remains low throughout pregnancy, whereas FT4 in fetal fluids increases rapidly to adult levels, and is determined by the maternal availability of T4. It is present in embryonic fluids 4 weeks after conception, with FT4 steadily increasing to biologically relevant values. T3, generated from T4 in the cerebral cortex, reaches adult values by mid-gestation and is partly bound to specific nuclear receptor isoforms. Iodothyronine deioidinases are important for the spatial and temporal regulation of T3 bioavailability, tailored to the differing and changing requirements of thyroid hormone-sensitive genes in different brain structures, but other regulatory mechanism(s) are likely to be involved. Maternal transfer constitutes a major fraction of fetal serum T4, even after onset of fetal thyroid secretion, and continues to have an important protective role in fetal neurodevelopment until birth.

Prompt treatment of maternal hypothyroidism, identified by increased TSH, is being advocated to mitigate a negative effect on the woman and her child. However, even a moderate transient period of maternal hypothyroxinemia at the beginning of rat neurogenesis disrupts neuronal migration into cortical layers. These findings reinforce the epidemiological evidence that early maternal hypothyroxinemia—when neuronal migratory waves are starting—is potentially damaging for the child. Detection of an inappropiate first trimester FT4 surge that may not result in increased TSH, may be crucial for the prevention of learning disabilities in a significant number of unborn children.

Section snippets

Foreword: human rights

Every child has the right to an adequate supply of iodine to ensure his (or her) normal development.

Of particular importance in this context is the right of the unborn child.

‘Every mother has the right to an adequate iodine nutrition to ensure that her unborn child experiences normal mental development.’

These are Declarations emanating from the Convention on the Rights of the Child, United Nations Assembly, New York, 1989; World Summit for Children, United Nations, New York, 1990: Declaration

Thyroid hormones and their nuclear receptors in the human fetal brain

As already summarized, during most of the second half of the 20th century, the prevalent idea was that the early embryo and fetus actually developed in the absence of thyroid hormones. Supporting this conclusion was evidence of a placental ‘barrier’ system that limited drastically their transfer from the mother.27., 39., 40., 41. Recent information regarding the activity and expression of different iodothyronine deiodinases has confirmed the widespread distribution, mostly of D2 and D3, in the

The maternal surge of ft4 before mid-gestation

There is at present a widespread consensus that maternal hypothyroidism, both clinical and subclinical, requires early detection and prompt treatment, because of its significant negative effect for the woman, the pregnancy and her child. Confirmation of clinical and detection of subclinical hypothyroidism usually rely on an elevated maternal circulating TSH. Attainment of normal TSH levels is mostly used for follow-up during treatment, as is customary for non-pregnant women.⁸⁶ This practice,

Summary

Contrasting hypotheses prevalent for most of the second half of the last century regarding the existence, or not, of the transfer of maternal thyroid hormones to the fetus and its possible relevance for neurodevelopment have now been largely reconciled: maternal thyroid hormones do reach the human fetus in biologically relevant amounts during the first trimester, enabling occupation of the nuclear receptors that are already expressed in the cerebral cortex. The high activities of several

Acknowledgements

We are grateful for the financial support of the Instituto de Salud Carlos III, RCMN (03/08) of Spain.

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8Maternal thyroid hormones early in pregnancy and fetal brain development

Abstract

Section snippets

Foreword: human rights

Thyroid hormones and their nuclear receptors in the human fetal brain

The maternal surge of ft4 before mid-gestation

Summary

Acknowledgements

Lancet

Lancet

Early Human Development

Brain Research

Molecular and Cellular Endocrinology

Biochimie

The Journal of Biological Chemistry

The Journal of Biological Chemistry

The story of iodine deficiency

Historical development of concepts of brain-thyroid relationships

The potential repercussions of maternal, fetal, and neonatal hypothyroxinemia on the progeny

Thyroid

Iodine deficiency as a cause of brain damage

Postgraduate Medical Journal

Iodine supplementation: benefits outweigh risks

Drug Safety

Endemic goiter in Western New Guinea II. Clinical picture, incidence and pathogenesis of endemic cretinism

The Journal of Clinical Endocrinology and Metabolism

Endemic cretinism: a continuous personal educational experience during 10 years

Postgraduate Medical Journal

Maternal thyroid function, iodine deficiency and fetal development

Clinical Endocrinology

Effect of chronic iodine deficiency on maternal and fetal thyroid hormone synthesis

Impairment of mental development by iodine deficiency and its correction. A retrospective view from studies in Peru

Timing of vulnerability of the brain to iodine deficiency in endemic cretinism

New England Journal of Medicine

Maternal thyroid hormone levels in pregnancy and the subsequent cognitive and motor performance of the children

Clinical Endocrinology (Oxf)

A metaanalysis of research on iodine and its relationship to cognitive development

Mild iodine deficiency in fetal/neonatal life and neuropsychological performances

Acta Medica Austriaca

Neuropsychological assessment in humans living in mild to moderate iodine deficiency

Endemic neonatal, infantile and juvenile hypothyroidism in Ubangi, Northern Zaı̈re: Clinical consequences and prevention

Thiocyanate induces cell necrosis and and fibrosis in selenium- and Iodine-deficient rat thyroids: a potential expedrimental model for myxedematous endemic cretinism in central Africa

Endocrinology

Is neuropsychological development related to maternal hypothyroidism, or to maternal hypothyroxinemia?

Journal of Clinical Endocrinology Metabolism

Iodine deficiency, the hidden scourge: The rat model of human neurological cretinism

Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases

Endocrine Reviews

Type 3 iodothyronine deiodinase is highly expressed in the human uteroplacental unit and in fetal epithelium

The Journal of Clinical Endocrinology and Metabolism

The role of thyroid hormones in prenatal and neonatal neurological developmental. Currents perspectives

Endocrine Reviews

Early maternal hypothyroxinemia alters histogenesis and cerebral cortex cytoarchitecture of the progeny

The Journal of Clinical Investigation

Homeostasis of brain T3 in rat fetuses and their mothers: effects of thyroid status and iodine deficiency

Acta Medica Austriaca

Observations on the neurology of endemic cretinism

The prenatal role of thyroid hormone evidenced by fetomaternal Pit-1 deficiency

The Journal of Clinical Endocrinology and Metabolism

Transient hypothyroidism in infants due to materanl TSH-receptor blocking antibodies-character of their IgG and long-term prognosis of their infants

Outcome of a baby born from a mother with acquired juvenila hypothyroidism having undetectable thyroid hormone concentrations

The Journal of Clinical Endocrinology and Metabolism

The placental transport, synthesis and metabolism of hormones and drugs which affect thyroid function

Endocrine Reviews

Maternal and fetal thyroid function

New England Journal of Medicine

Human placenta is an active site of thyroxine and 3,3′,5-triiodothyronine tyrosyl ring deiodination

The Journal of Clinical Endocrinology and Metabolism

Transfer of thyroid hormone across the human placenta at term

The Journal of Clinical Endocrinology and Metabolism

Passage of thyroxine and tri-iodo-thyronine from mother to foetus in pregnant women

Clinical Science

Tagged isomers and analogues of thyroxine (their transmission across the human placenta and other studies)

Journal of Nuclear Medicine

Ontogenesis of thyroid hormone receptor

Ontogenesis of the nuclear 3,5,3′-triiodothyroxine receptor in the human fetal brain

Endocrinology

Estimation of nuclear thyroid hormone receptor saturation in human fetal brain and lung during early gestation

The Journal of Clinical Endocrinology and Metabolism

8
Maternal thyroid hormones early in pregnancy and fetal brain development