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

J Clin Invest. 2003 Apr;111(7):1073-82. doi: 10.1172/JCI16262.


Epidemiological studies from both iodine-sufficient and -deficient human populations strongly suggest that early maternal hypothyroxinemia (i.e., low circulating free thyroxine before onset of fetal thyroid function at midgestation) increases the risk of neurodevelopmental deficits of the fetus, whether or not the mother is clinically hypothyroid. Rat dams on a low iodine intake are hypothyroxinemic without being clinically hypothyroid because, as occurs in pregnant women, their circulating 3,5,3'-triiodothyronine level is usually normal. We studied cell migration and cytoarchitecture in the somatosensory cortex and hippocampus of the 40-day-old progeny of the iodine-deficient dams and found a significant proportion of cells at locations that were aberrant or inappropriate with respect to their birth date. Most of these cells were neurons, as assessed by single- and double-label immunostaining. The cytoarchitecture of the somatosensory cortex and hippocampus was also affected, layering was blurred, and, in the cortex, normal barrels were not formed. We believe that this is the first direct evidence of an alteration in fetal brain histogenesis and cytoarchitecture that could only be related to early maternal hypothyroxinemia. This condition may be 150-200 times more common than congenital hypothyroidism and ought to be prevented both by mass screening of free thyroxine in early pregnancy and by early iodine supplementation to avoid iodine deficiency, however mild.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Weight
  • Brain / embryology*
  • Brain / metabolism
  • Cell Movement
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology*
  • Female
  • Fetal Diseases / blood
  • Fetal Diseases / etiology
  • Hippocampus / embryology
  • Hippocampus / metabolism
  • Hypothyroidism / etiology
  • Hypothyroidism / metabolism*
  • Immunohistochemistry
  • Iodine / deficiency
  • Iodine / pharmacology
  • Maternal-Fetal Exchange*
  • Neurons / metabolism
  • Pregnancy
  • Pregnancy Complications / blood*
  • Rats
  • Rats, Wistar
  • Thyroid Gland / embryology
  • Thyroid Gland / metabolism
  • Thyroid Hormones / metabolism*
  • Thyroxine / blood*
  • Thyroxine / metabolism*
  • Thyroxine / physiology
  • Time Factors


  • Thyroid Hormones
  • Iodine
  • Thyroxine