7
Impact of mild thyroid hormone deficiency in pregnancy on cognitive function in children: Lessons from the Generation R Study

https://doi.org/10.1016/j.beem.2013.04.008Get rights and content

Animal models and epidemiological studies suggest that mild maternal thyroid hormone deficiency in early gestation has adverse consequences on the cognitive abilities of the children. However, methodological problems, lack of a consistent definition for mild thyroid hormone deficiency, and short follow-up of the children reduce the confidence in the conclusion of existing studies. In this review, we summarize the main findings of a series of studies performed in Generation R, a population-based birth cohort in Rotterdam, the Netherlands. In this iodine sufficient region, we aimed to investigate the relation between mild maternal thyroid hormone deficiency in early gestation and children's verbal and nonverbal cognitive function and executive function. We discuss the main findings of these studies, present recommendations for clinicians and formulate suggestions for future research.

Introduction

For more than a century, severe thyroid hormone deficiency in new-borns, termed as congenital hypothyroidism, was known to cause irreversible damages to the brain and lead to intellectual disabilities in children.1 Yet, the critical role of thyroid hormones in brain development during early gestation remained less clear for a long time.[2], [3] Findings from animal models revealed that nuclear thyroid hormone receptors appear in the brain before mid-gestation, indicating a prominent role of thyroid hormones in the brain development, even before the function of the foetal thyroid gland fully begins.4

During prenatal development, the thyroid gland appears firstly as an epithelial proliferation in weeks 3–4 of gestation, and completes its formation at the end of the first trimester. Foetal secretion of thyroid hormones reaches clinically significant levels in the second trimester (around 16–20 weeks of gestation), and the full regulatory feedback system of hypothalamus, pituitary, and thyroid is achieved at birth.[4], [5], [6], [7] Before 12–14 weeks of gestation, that the foetal thyroid gland is not fully mature, maternal free thyroxine (T4) serves as the only source of thyroid hormones for the developing foetus.8 Given the low levels of triiodothyronine (T3) in foetal fluids, T3 is generated locally from maternal T4 in the foetal brain before mid-gestation.9 In line with this molecular evidence, clinical and epidemiological studies demonstrated that the children of pregnant women with untreated hypothyroidism in early pregnancy [low free T4 and high thyrotropin (TSH) levels] had poor neuropsychological outcomes.[10], [11]

Our knowledge on the mechanisms of action of thyroid hormones in the brain is derived mainly from experimental studies in animals. In early gestation, maternal thyroid hormones are necessary for neural proliferation and migration.6 From mid-gestation onwards both maternal and foetal thyroid hormones are crucial for neurogenesis, neuron migration, axonal growth, dendritic arborizations and synaptogenesis.[6], [9], [12] Further, the onset of myelination at later stages of gestation depends largely on thyroid hormones.6 The structural and functional abnormalities in response to thyroid hormone insufficiency occur in multiple brain regions including the neocortex, medial ganglionic eminence, the cerebellum, the hippocampus and myelinated white matter tracts such as the corpus callosum.[13], [14], [15] Thyroid deficiency at different stages of pregnancy affects different brain regions. For example, basal ganglia are affected by early thyroid hormone deficiency and cerebellar and hippocampal development is influenced by late thyroid dysfunction.[4], [6] Based on these animal studies, various neuropsychological abnormalities could occur in the child in response to thyroid hormone deficiency in pregnancy, such as impairment in general intelligence, language function, visuospatial and memory problems or neurodevelopmental disorders such as autism.[16], [17]

During normal pregnancy, the maternal hypothalamic-pituitary-thyroid system undergoes physiological changes to adapt to the high demand for both mother and child.18 An increase in the serum thyroxine binding globulin (TBG) causes a transient decrease in the free thyroid hormones and therefore a rise in serum TSH levels within the normal range. The increase in TSH levels provokes a rise of T4 levels in maternal serum. In parallel, in the first trimester of pregnancy, human chorionic gonadotropin (hCG) rises considerably, binds to the TSH receptors and stimulates the thyroid gland to produce T4. This adaption leads to an increase in the production of T4 in iodine sufficient women. Nonetheless, pregnant women with normal TSH levels may have low levels of free T4 specific for the stage of pregnancy, even in areas in which iodine intake is typically sufficient in the general population. This condition, i.e. maternal hypothyroxinaemia, has first been described by Man et al. in the 1970s[19], [20], [21] and has been defined as a normal maternal TSH concentration in conjunction with free T4 concentrations in the lower 5th or 10th percentile of the reference range for gestation.22 Although this condition was long thought as being without major consequences for mother and child, recent studies confirm the reports of Man and colleagues and show that maternal hypothyroxinaemia in early pregnancy may have adverse consequences for the child including psychomotor delay and attention deficit/hyperactivity disorders (ADHD).[23], [24] However, methodological problems such as small sample size, confounding, time of thyroid hormone assessment, lack of a consistent definition for maternal hypothyroxinaemia, lack of reference values for normal TSH in pregnancy, and short follow-up of the children of hypothyroxinaemic mothers remain concerns and temper the inferences possible.

Two main causes of thyroid hormone deficiency in women of reproductive age are known as iodine deficiency and thyroid autoimmune diseases.3 Iodine is a micronutrient essential for biosynthesis of thyroid hormones, and an adequate amount of this micronutrient in the diet is needed for the normal function of the thyroid gland and thyroid hormone secretion. In a recent report published by the World Health Organization (WHO) on iodine status of the population in industrialized countries, Europe is reported to have the highest prevalence of iodine deficiency, with specific concern regarding iodine insufficiency during pregnancy.25 Because of high requirement as well as high clearance during pregnancy, pregnant women are the most susceptible to iodine deficiency among all age groups.

In iodine sufficient areas, thyroid autoimmunity is the main known cause of thyroid hormone deficiency. Among thyroid autoantibodies, thyroid peroxidise antibodies (TPO-Abs) are the most sensitive and specific marker of thyroid autoimmunity.26 In pregnancy, the presence of TPO-Abs is commonly associated with subclinical hypothyroidism in the mother and can also lead to hypothyroxinaemia.22 However, even with normal thyroid function, thyroid autoimmunity can happen in 10% of pregnant women and is related to pregnancy complications and poor child outcomes.[27], [28]

Against this background, we aimed to examine the effect of early pregnancy thyroid hormone levels across the entire range on children's cognitive functioning and behavioural problem. Thyroid autoimmunity and iodine insufficiency, as the two main underlying factors of low thyroid function in pregnant women, were investigated in relation to maternal and neonatal thyroid function as well as children's cognitive and behavioural outcomes. For this aim, we used the data on maternal and neonatal thyroid function and the children's cognition and behaviour from an ongoing population-based birth cohort in Rotterdam, the Netherlands: the Generation R Study.

Section snippets

The Generation R Study

The Generation R Study (R for Rotterdam) is a population-based birth cohort in Rotterdam, the Netherlands, which tracks children from foetal life onwards to identify early environmental and genetic determinants of children's growth, diseases, behaviour and cognition.[29], [30] Briefly, all pregnant women living in Rotterdam with an expected delivery date between April 2002 and January 2006 were invited to participate. In total, 9778 pregnant women participated in the study, including 8879 women

Maternal thyroid function in pregnancy and verbal and nonverbal cognitive function

In a sample of 3659 pregnant women and their children, we found that maternal TSH and free T4 levels during early pregnancy were not related to the different measures of language functioning with one exception: higher levels of maternal free T4 predicted a lower risk of expressive language delay in the children at 2½ years. In contrast, mild hypothyroxinaemia before 18 weeks of gestation was significantly related to children's expressive language delay at 1½ and 2½ years (OR = 1.44, 95%CI:

Discussion and conclusions

To summarize, we found that prenatal exposure to maternal hypothyroxinaemia increased the risk of expressive language delay and nonverbal cognitive delay in preschool age children. The results were less consistent regarding the behavioural outcomes. In addition, maternal hypothyroxinaemia was associated with a larger head circumference during postnatal period. However, the relation between maternal thyroid status and children's cognitive delay was not explained by head size. Based on the

Summary (focus on the conclusions reached in the review, including unanswered and unanswerable questions)

In the Generation R Study, we found a relation between maternal hypothyroxinaemia and children's verbal and nonverbal cognitive abilities. Children's head size, although increased in children exposed to hypothyroxinaemia prenatally, did not explain the association with cognitive function. Moreover, in this iodine-sufficient sample, low maternal urinary iodine secretion was related to children's executive function. The results regarding children's behaviour were less consistent. These findings

Conflict of interest statement

No competing financial interest exists for the authors.

Practice points: recommendations for clinicians:

  • Await ongoing randomized controlled trial of the effectiveness of thyroid screening before adapting thyroid screening at population level.

  • Verbally screen all pregnant women in the first prenatal visit, for history of thyroid disease and thyroid medication.

  • Screen pregnant women at high risk for thyroid dysfunction by determining TSH level in serum:

    • 1

      In the first trimester of pregnancy, and

    • 2

      Using

Acknowledgement

The work of Dr Tiemeier and Dr Ghassabian was supported by a research grant from the European Community's 7th Framework Programme (FP7/2008–2013) under grant agreement 212652 (NUTRIMENTHE project, “The Effect of Diet on the Mental Performance of Children”).

References (68)

  • L.I. Gardner

    Historical notes in cretinism

  • G.M. de Escobar et al.

    Maternal thyroid hormones early in pregnancy and fetal brain development

    Best Practice and Research. Clinical Endocrinology and Metabolism

    (2004)
  • R.D. Utiger

    Maternal hypothyroidism and fetal development

    The New England Journal of Medicine

    (1999)
  • J. Bernal

    Thyroid hormone receptors in brain development and function

    Nature Clinical Practice. Endocrinology & Metabolism

    (2007)
  • G. Morreale de Escobar et al.

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

    The Journal of Clinical Endocrinology and Metabolism

    (2000)
  • G.R. Williams

    Neurodevelopmental and neurophysiological actions of thyroid hormone

    Journal of Neuroendocrinology

    (2008)
  • G. Szinnai et al.

    Sodium/iodide symporter (NIS) gene expression is the limiting step for the onset of thyroid function in the human fetus

    The Journal of Clinical Endocrinology and Metabolism

    (2007)
  • G. Morreale de Escobar et al.

    Role of thyroid hormone during early brain development

    European Journal of Endocrinology/European Federation of Endocrine Societies

    (2004)
  • J.E. Haddow et al.

    Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child

    The New England Journal of Medicine

    (1999)
  • V.J. Pop et al.

    Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy

    Clinical Endocrinology

    (1999)
  • E. Auso et al.

    A moderate and transient deficiency of maternal thyroid function at the beginning of fetal neocorticogenesis alters neuronal migration

    Endocrinology

    (2004)
  • S.M. Wheeler et al.

    Hippocampal size and memory functioning in children and adolescents with congenital hypothyroidism

    Journal of Clinical Endocrinology and Metabolism

    (2011)
  • E.B. Man

    Thyroid function in pregnancy and infancy. Maternal hypothyroxinemia and retardation of progeny

    CRC Critical Reviews in Clinical Laboratory Sciences

    (1972)
  • A. Stagnaro-Green et al.

    Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum

    Thyroid

    (2011)
  • F. Vermiglio et al.

    Attention deficit and hyperactivity disorders in the offspring of mothers exposed to mild-moderate iodine deficiency: a possible novel iodine deficiency disorder in developed countries

    Journal of Clinical Endocrinology and Metabolism

    (2004)
  • V.J. Pop et al.

    Maternal hypothyroxinaemia during early pregnancy and subsequent child development: a 3-year follow-up study

    Clinical Endocrinology

    (2003)
  • M.B. Zimmermann

    Iodine deficiency in industrialized countries

    Clinical Endocrinology

    (2011)
  • S. Mariotti et al.

    Antithyroid peroxidase autoantibodies in thyroid diseases

    Journal of Clinical Endocrinology and Metabolism

    (1990)
  • T. Mannisto et al.

    Perinatal outcome of children born to mothers with thyroid dysfunction or antibodies: a prospective population-based cohort study

    Journal of Clinical Endocrinology and Metabolism

    (2009)
  • M.F. Prummel et al.

    Thyroid autoimmunity and miscarriage

    European Journal of Endocrinology/European Federation of Endocrine Societies

    (2004)
  • H. Tiemeier et al.

    The Generation R Study: a review of design, findings to date, and a study of the 5-HTTLPR by environmental interaction from fetal life onward

    Journal of American Academy of Child and Adolescent Psychiatry

    (2012)
  • V.W. Jaddoe et al.

    The Generation R Study: design and cohort update 2012

    European Journal of Epidemiology

    (2012)
  • A. Ghassabian et al.

    Maternal thyroid function during pregnancy and behavioral problems in the offspring: the Generation R Study

    Pediatric Research

    (2011)
  • M. Abalovich et al.

    Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline

    Journal of Clinical Endocrinology and Metabolism

    (2007)
  • Cited by (0)

    e

    Tel.: +31 10 703 7071; Fax: +31 10 704 3447.

    f

    Tel.: +31 13 4662949; Fax: +31 13 4662067.

    View full text