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Maternal thyroid function during pregnancy and child brain morphology: a time window-specific analysis of a prospective cohort

https://doi.org/10.1016/S2213-8587(19)30153-6Get rights and content

Summary

Background

Adequate thyroid hormone availability during pregnancy is necessary for optimal fetal brain development. During the first 18–20 weeks of gestation, fetal thyroid hormone availability largely depends on the placental transfer of maternal thyroxine. Although various studies have shown that maternal thyroid dysfunction is associated with suboptimal child neurodevelopmental outcomes, the most vulnerable time window remains to be identified. The aim of this study is to examine the association of maternal thyroid function with child brain morphology and to study whether any association depends on the timing of thyroid assessment.

Methods

This prospective cohort study was part of the Generation R Study in Rotterdam, Netherlands, with a prospective population-based birth cohort. Pregnant women living in Rotterdam with an expected delivery date between April 1, 2002, and Jan 1, 2006, were eligible. Other inclusion criteria were maternal serum thyroid-stimulating hormone (TSH) and free thyroxine (FT4) measurement in early or mid-pregnancy (≤18 weeks) and available brain MRI data for child at age 10 years. Exclusion criteria were pre-existing thyroid disorder, thyroid disorder treatment, twin pregnancy, in-vitro fertilisation-induced pregnancy, and suboptimal-quality MRI data or major incidental finding on MRI. The main outcome was the association between maternal TSH and FT4 concentrations with brain MRI outcomes of children. Regression analyses accounted for gestational age at blood sampling, maternal age, ethnicity, education level, smoking, thyroid peroxidase antibody positivity, child sex, age at MRI, and total intracranial volume. Effect modification by gestational age at blood sampling was also investigated.

Findings

Between Dec 1, 2001, and June 30, 2005, 7069 women were enrolled during early or mid-pregnancy (≤18 weeks of gestation), of whom 5088 were not included because they did not have available data on maternal serum TSH or FT4 concentrations (n=1175), their child did not have brain MRI done (n=3377), or they met exclusion criteria (n=536). Thus, 1981 mother–child pairs were included in the study, with TSH and FT4 concentrations measured during pregnancy at a median of 13·1 weeks of gestation (IQR 12·1–14·5) and offspring brain morphology assessed by MRI at a median age of 9·9 years (9·7–10·2). Maternal TSH had an inverted U-shaped association with offspring total grey matter volume (p=0·007) and with cortical grey matter volume (p=0·022). The association of maternal TSH with child total grey matter volume (pinteraction=0·053) and cortical volume (pinteraction=0·086) differed by the duration of gestation. Analyses stratified for gestational age at blood sampling showed an inverted U-shaped association of maternal TSH with child total grey matter volume and cortical grey matter volume, which was most evident at 8 weeks gestation. After about 14 weeks of gestation, TSH was no longer associated with child brain morphology. Maternal FT4 concentrations were not associated with child total grey matter volume after adjusting for total intracranial volume (p=0·75).

Interpretation

Here, we show that both low and high maternal thyroid function are associated with smaller child total grey matter and cortical volume. To the best of our knowledge, this study is the first to show that an association with a neurodevelopmental outcome is most evident when maternal thyroid function is measured early in pregnancy. These novel findings suggest that embryonic brain development is particularly vulnerable to altered maternal thyroid function.

Funding

Netherlands Organisation for Health Research and Development and the Sophia Children's Hospital Foundation.

Introduction

Adequate maternal thyroid function is required for optimal fetal brain development. Thyroid hormone regulates fundamental neurodevelopmental processes, including the proliferation, migration, and differentiation of neuronal cells that ultimately develop into the grey matter of the brain.1, 2, 3

Neurogenesis starts around the fifth week of gestation and thyroid hormone receptors are present in the fetal brain from 8 weeks of gestation onwards.4 Fetal thyroid hormone production starts around the 14th week, but the fetal thyroid is not fully functional until week 18–20.5 Therefore, fetal thyroid hormone availability during crucial phases of early brain development predominantly depends on the placental transfer of maternal thyroxine. Maternal hypothyroidism or hypothyroxinaemia during early pregnancy is associated with various child adverse neurodevelopmental outcomes, including a lower intelligence quotient (IQ) and a higher risk of autism, schizophrenia, and attention-deficit hyperactivity disorder.6, 7, 8, 9, 10, 11, 12, 13 Although it is generally accepted that maternal thyroid dysfunction during pregnancy is associated with suboptimal child neurodevelopmental outcomes, the most crucial period for maternal thyroid hormone to ensure optimal fetal brain development remains to be elucidated. Identification of this crucial period can have direct clinical implications related to risk assessment and the time window for potential treatment.

Research in context

Evidence before this study

In the past two decades, epidemiological studies have shown that overt maternal hypothyroidism and hypothyroxinaemia is negatively associated with adverse neurodevelopmental outcomes such as low IQ, autism, schizophrenia, and attention-deficit hyperactivity disorder. Furthermore, clinical studies suggest that maternal thyroid dysfunction might affect brain morphology, particularly grey matter. However, the most vulnerable time window during which maternal thyroid function is associated with offspring neurodevelopmental outcomes remains to be identified.

Added value of this study

In our study we identified an inverted U-shaped association of maternal thyroid-stimulating hormone with total grey matter and cortical grey matter volume as assessed by MRI scanning in the offspring, which was strongest if thyroid function was assessed in early pregnancy (<14 weeks). To the best of our knowledge, this study is the first to show that an association with a neurodevelopmental outcome is more evident if thyroid function is measured before the 14th week of pregnancy.

Implications of all the available evidence

In line with previous studies, our study shows that both exposure to a low and a high maternal thyroid function is negatively associated with child total grey matter volume and cortical grey matter volume as assessed by MRI. The absence of association from the 14th week onwards is an important novel finding that should be considered during clinical risk assessment and when timing interventions during clinical practice, as well as in the design of future studies of the effects of levothyroxine treatment for mild thyroid disease in pregnancy.

Although of clinical relevance, clinical neurodevelopmental outcomes are less precise and more indirect measures of brain development. By contrast, brain imaging by MRI is an objective reproducible measure of brain development with detailed information on different brain structures. Imaging data can provide an indication of which neurogenesis processes depend on maternal thyroid function during specific stages of fetal brain development. Results of brain imaging studies suggest that maternal thyroid function might have a different effect on grey matter than on white matter: initial studies demonstrated that maternal hypothyroidism during pregnancy is associated with altered child brain morphology, including suboptimal hippocampal and cortical development.14, 15 Our group have previously shown an inverted U-shaped association of maternal free thyroxine (FT4) with total grey matter volume and cortical grey matter volume using data of 646 mother–child pairs.8 This result suggests that both a low and a high maternal thyroid function might have an adverse effect on fetal grey matter development. Although thyroid hormone also regulates white matter formation by stimulating myelination of neuronal cells, evidence from human imaging studies for adverse effects of maternal thyroid dysfunction on the development of white matter tracts is scarce.2, 16 The difference in the association of maternal thyroid function on grey matter versus white matter might be because myelination starts in the late second trimester, when the fetus has become increasingly dependent on its own thyroid hormone production.2, 17 Moreover, the effect of thyroid hormone on neuronal migration is largely mediated via the α-thyroid hormone receptor, which is expressed throughout fetal development, whereas myelination is largely regulated via the β-thyroid hormone receptor, which is expressed much later in fetal development.18

Based on models of fetal thyroid physiology and neurodevelopmental processes, maternal thyroid dysfunction might have a more deleterious effect in early gestation, yet no study has been able to demonstrate the crucial period. The aim of our study is to examine the association of maternal thyroid function with child brain morphology as a detailed and objective marker of brain development and to study whether this association with specific brain structures differs according to gestational age at blood sampling. We hypothesised that low maternal thyroid function, particularly in early pregnancy (first and early second trimester), is associated with a smaller grey matter volume in pre-adolescence.

Section snippets

Study design and participants

This prospective cohort study was part of the Generation R Study, a population-based prospective cohort from early fetal life onwards in Rotterdam, Netherlands.19 Pregnant women living in the municipality of Rotterdam with an expected delivery date between April 1, 2002, and Jan 1, 2006, were eligible and enrolled during visits to a midwife or the hospital.19 We included mother–child pairs if maternal thyroid-stimulating hormone (TSH) or FT4 serum measurements had been assessed during early or

Results

Between Dec 1, 2001, and June 30, 2005, 7069 women were enrolled during early or mid-pregnancy (≤18 weeks of gestation). Data on TSH or FT4 concentrations were available for 5894 mothers, and of these, 2517 had children who had brain MRI scanning. 536 mother–child pairs were excluded because they met exclusion criteria, thus, the final study population comprised 1981 mother–child pairs (figure 1). Non-response analyses showed that maternal TSH concentrations, FT4 concentrations, and TPO

Discussion

In this study, we show that both low and high maternal TSH concentrations, particularly in early pregnancy, are associated with a smaller volume of total grey matter and cortical grey matter in children aged 9–12 years. To the best of our knowledge, this study is the first to show that the association of maternal thyroid function with offspring neurodevelopment attenuates from early pregnancy onwards, suggesting that this is the most vulnerable period of the fetus for low or high maternal

References (42)

  • J Iskaros et al.

    Thyroid hormone receptor gene expression in first trimester human fetal brain

    J Clin Endocrinol Metab

    (2000)
  • JG Thorpe-Beeston et al.

    Maturation of the secretion of thyroid hormone and thyroid-stimulating hormone in the fetus

    N Engl J Med

    (1991)
  • J Henrichs et al.

    Maternal hypothyroxinemia and effects on cognitive functioning in childhood: how and why?

    Clin Endocrinol

    (2013)
  • JE Haddow et al.

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

    N Engl J Med

    (1999)
  • GC Roman et al.

    Association of gestational maternal hypothyroxinemia and increased autism risk

    Ann Neurol

    (2013)
  • T Modesto et al.

    Maternal mild thyroid hormone insufficiency in early pregnancy and attention-deficit/hyperactivity disorder symptoms in children

    JAMA Pediatr

    (2015)
  • A Ghassabian et al.

    Downstream effects of maternal hypothyroxinemia in early pregnancy: nonverbal IQ and brain morphology in school-age children

    J Clin Endocrinol Metab

    (2014)
  • 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

    J Clin Endocrinol Metab

    (2004)
  • KA Willoughby et al.

    Effects of maternal hypothyroidism on offspring hippocampus and memory

    Thyroid

    (2014)
  • JE Lischinsky et al.

    Preliminary findings show maternal hypothyroidism may contribute to abnormal cortical morphology in offspring

    Front Endocrinol

    (2016)
  • A Samadi et al.

    Children born to women treated for hypothyroidism during pregnancy show abnormal corpus callosum development

    Thyroid

    (2015)
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