Maternal Thyroid Dysfunction and Neuropsychological Development in Children

Yuanzhi Chen; Zhong-Cheng Luo; Ting Zhang; Pianpian Fan; Rui Ma; Jun Zhang; Fengxiu Ouyang


J Clin Endocrinol Metab. 2023;108(2):339-350. 

In This Article

Abstract and Introduction


Context: Thyroid hormones are essential for fetal brain development. The potential effects of maternal gestational thyroid dysfunction on offspring neuropsychological development remain inconclusive.

Objective: This work aimed to estimate effects of maternal thyroid dysfunction during pregnancy on offspring neuropsychological development in the first 2 years.

Methods: We prospectively examined 1903 mothers and their children from the Shanghai Birth Cohort. Thyroid hormones were assessed at about 12 gestational weeks. Maternal thyroid function was classified into 7 categories: euthyroid, overt/subclinical hyperthyroidism, overt/subclinical hypothyroidism, hyperthyroxinemia, and hypothyroxinemia. Neuropsychological development was assessed by the Ages and Stages Questionnaire at age 6 months, and Bayley Scales at age 24 months.

Results: Compared with children of euthyroid mothers, maternal overt hypothyroidism was associated with 7.0 points (95% CI, 1.7–12.4) lower scores in personal-social domain in girls aged 6 months, 7.3 points (95% CI, 2.0–12.6) lower in motor domain, and 7.7 points (95% CI, 1.1–14.2) lower social-emotional scores in boys at age 24 months; maternal subclinical hypothyroidism was associated with 6.5 points (95% CI, 1.0–12.1) poorer social-emotional domain in boys at age 6 months, and 7.4 points (95% CI, 0.1–14.8) poorer adaptive behavior domain in boys at age 24 months; maternal hypothyroxinemia was associated with 9.3 points (95% CI, 3.5–15.1) lower motor scores in boys at age 24 months; and maternal subclinical hyperthyroidism was associated with 6.9 points (95% CI, 0.1–13.7) lower language scores in girls at age 24 months.

Conclusion: Maternal overt hypothyroidism, subclinical hypothyroidism/hyperthyroidism, and hypothyroxinemia during early pregnancy were associated with weakened neuropsychological development in infancy, and some effects may be sex specific.


Thyroid hormones are essential for fetal growth and brain development. Fetal thyroid function is not well developed before 20 weeks of gestation, thus the thyroid hormones required for fetal brain development depend completely or mostly on the supply from mother during this critical window.[1] Maternal-origin thyroxine (T4) is converted to 3,5,3'-triiodothyronine (T3) by type 2 deiodinase in the fetal brain, and T3 regulates the neuronal proliferation processes and the initiation of neuronal migration.[2] Thyroid dysfunction is a common endocrine disorder in pregnancy, with hypothyroidism, hyperthyroidism, and thyroid autoimmunity occurring in 3%, 0.4%, and 17% of pregnant women, respectively.[3] Pregnancy itself is a specific physiological period that induces endocrine changes in thyroid hormones levels. Total thyroxine and free thyroxine (FT4) levels rise,[1] and thyrotropin (TSH) levels drop in the first 10 weeks of gestation, while TSH levels gradually increase and FT4 levels decrease over the later gestational ages.[1] Therefore, trimester-specific reference ranges of TSH and FT4 have been recommended for assessment of maternal thyroid function during pregnancy.

The potential effects of maternal thyroid dysfunction (subclinical hypothyroidism and hyperthyroidism, and hyperthyroxinemia/hypothyroxinemia) in pregnancy on offspring neuropsychological development remain inconclusive. Some studies suggest that subclinical hypothyroidism during pregnancy increases the risk of neurodevelopmental delay in infancy,[4] impairs intellectual and mental development in early childhood,[5] and affects academic performance in school.[6] A study also reported an inverted U-shaped association between maternal TSH and the child's total gray matter in the brain.[7] However, studies from the Generation R birth cohort have reported no association between maternal subclinical hypothyroidism or TSH levels and offspring cognitive development.[8,9] Recent studies have shown that maternal hypothyroxinemia may increase the risk of lower IQ, speech delay, reduced motor function, autism, and attention-deficit/hyperactivity disorder in the offspring.[10–12] However, 2 studies with infant neuropsychological development assessments at multiple time points reported no association between maternal hypothyroxinemia and cognitive outcomes.[13,14] Few studies have examined the effect of maternal subclinical hyperthyroidism and hyperthyroxinemia on offspring neuropsychological development, and have not found any association.[15,16] Also, there is no conclusive evidence of the benefits of treating maternal hypothyroidism with levothyroxine (LT4) on child neurodevelopment.[17–19] The Controlled Antenatal Thyroid Screening (CATS) study compared scores of children of mothers with subclinical hypothyroidism only, either treated or not treated. However, there was no euthyroid control group that was compared.[19] Therefore, it is unknown if there is any difference in neurodevelopment between children of treated subclinical hypothyroid mothers and children of euthyroid mothers. In addition, sex dimorphism in offspring neuropsychological development has been related to early adverse environmental exposures.[20] However, findings on sex dimorphism on the associations between maternal thyroid dysfunction and offspring neuropsychological development have been inconsistent both in animal and population studies[6,15,21]

In this prospective cohort study, we aimed to examine the associations between the entire spectrum of maternal thyroid dysfunction and neuropsychological development indices in infancy at 2 time points in infancy (age 6 months and 24 months) in a population with high-quality prenatal care, and stratified by infant sex to examine sex dimorphism.