No significant impact of levothyroxine treatment of maternal subclinical hypothyroidism on brain morphology in adolescence: insight from long-term follow up of Controlled Antenatal Thyroid Screening (CATS) study

Adequate thyroid hormone is essential in pregnancy, as thyroid hormone plays an important role in fetal development, especially neurodevelopment (1). The fetal thyroid gland does not start producing thyroid hormone until 18–20 weeks’ gestation. Thus, the fetus depends entirely on maternal thyroid hormone crossing the placenta during the critical period of development in early pregnancy. Maternal overt hypothyroidism is known to adversely affect pregnancy outcomes (2-4) and children’s neurodevelopment (5). However, impact of milder subclinical hypothyroidism in pregnancy is less clear. Although several well-designed cohort studies showed increased risks of preterm delivery (6), pregnancy loss (7), and impaired neurodevelopment in children (8-10), others reported no significant associations between maternal subclinical hypothyroidism in pregnancy and adverse obstetric or offspring outcomes (11). These conflicting results may be due to variability among studies in serum thyrotropin (TSH) level used in defining subclinical hypothyroidism and timing of TSH measurements. Given increasing evidence of adverse effects of maternal subclinical hypothyroidism in pregnancy, potential risk mitigation with levothyroxine treatment has been of interest. However, only three cohorts address impact of levothyroxine treatment of maternal subclinical hypothyroidism on children’s subsequent neurodevelopment (Table 1).

In the current study, Scholz et al. (16) assessed potential long-term effect of levothyroxine treatment of subclinical hypothyroidism in pregnancy on children’s brain morphology at adolescence utilizing the Controlled Antenatal Thyroid Screening (CATS) cohort. The CATS cohort included over 22,000 women who were randomized to either screening group (thyroid hormone levels assessed real-time with treatment of subclinical hypothyroidism) or control group (serum stored for measurements of thyroid hormone levels after delivery without treatment of subclinical hypothyroidism). Women with subclinical hypothyroidism in the screening group were treated with levothyroxine 150 mcg/day. Treatment was initiated at median of 13.3 weeks’ gestation with dose adjustment throughout pregnancy for goal TSH between 0.1 and 1 mIU/L. Previous follow-up studies of children from the CATS cohort at 3- and 9.5-years of age (CATS I and II, respectively) did not show significant benefit of levothyroxine treatment on children’s neurodevelopment (12,13). The current CATS III study aimed to evaluate long-term effects of intervention by assessing brain morphology of children between 10 and 16 years of age by magnetic resonance imaging (MRI). One of the limitations of CATS cohort was that about one-third of the women treated with levothyroxine reached free thyroxine (FT4) level >97.5^th percentile at 20–30 weeks’ gestation. Since both hypothyroidism and hyperthyroidism can adversely affect children’s neurodevelopment, CATS III took this into account in exposure categorization. Children were divided into four groups based on maternal thyroid status and treatment in pregnancy: (I) normal gestational thyroid function (GTF); (II) untreated suboptimal gestational thyroid function (SGTF); (III) optimally treated SGTF; and (IV) overtreated SGTF. Potential associations were assessed between exposure category as well as maternal TSH and FT4 levels and global brain volume measured by MRI.

A total of 85 children, including 24 in normal GTF, 21 in untreated SGTF, 20 in optimally treated SGTF, and 20 in overtreated SGTF groups, were enrolled in this study. There were no significant differences in global brain volume among the groups (P=0.37 for total gray volume, P=0.36 for cortical volume, P=0.75 for cerebral white matter volume, P=0.65 for subcortical gray matter volume, and P=0.53 for total intracranial volume). Although baseline maternal TSH level at 12 weeks’ gestation was positively correlated with global measures of brain volume, this association disappeared when adjusted for age, sex, and pubertal status (P=0.054 for total gray volume, P=0.07 for cortical volume, P=0.07 for cerebral white matter volume, P=0.18 for subcortical gray matter volume, and P=0.09 for total intracranial volume).

Scholz et al. concluded that mild maternal thyroid function abnormalities and its treatment with levothyroxine after 13 weeks’ gestation did not significantly affect brain morphology in children at adolescence. The findings of this study are in line with previous clinical trials (Table 1). Earlier follow-up studies of CATS I and CATS II showed no significant differences in mean intelligence quotient (IQ) or the number of children with IQ <85 points between treated SGTF and untreated SGTF groups at 3- and 9.5-years of age, respectively (12,13). A US-based randomized clinical trial by Casey and colleagues reported similar findings (14). In this study, 677 women with subclinical hypothyroidism were randomized to either levothyroxine 100 mcg/day or placebo treatment at median of 16.7 weeks’ gestation. There was no significant difference in children’s IQ assessed at 5 years of age between levothyroxine-treated or placebo-treated groups. Another cohort study in Iran recruited pregnant women at 11–12 weeks’ gestation, including 189 women with subclinical hypothyroidism treated with levothyroxine, 168 women with subclinical hypothyroidism not treated, and 737 euthyroid women (15). Notably, a lower TSH cutoff of 2.5 mIU/L was used for diagnosis of subclinical hypothyroidism in this study. There were no significant differences in neurodevelopmental test scores of children assessed at 3 years of age. However, in subgroup analysis using TSH cutoff of 4 mIU/L for subclinical hypothyroidism, children in levothyroxine treated group had slightly higher gross motor score compared to those in untreated group (60 vs. 57.5, respectively).

All currently available studies have limitations of starting levothyroxine either at the end of the first trimester (12,13,15,16) or well into the second trimester (14), possibly missing the critical time for intervention. In a population-based cohort study, Jansen et al. showed that association between maternal TSH level and children’s brain cortex volume differed by the gestational age of the TSH measurement (17). There was a clear inverse U-shaped association between maternal TSH and child’s cortex volume before 12 weeks’ gestation. However, such association was no longer present with maternal TSH measured beyond the 12 weeks’ gestation. This finding may partly explain the lack of association between maternal thyroid status or thyroid function and children’s brain morphology seen in the CATS III and other studies. Subclinical hypothyroidism likely results in milder symptoms that may be difficult to differentiate from those of normal pregnancy, such as fatigue, weight gain, and constipation. Yet, lack of clear data for benefit of levothyroxine treatment of maternal subclinical hypothyroidism argues against universal screening to detect mild thyroid dysfunction in pregnancy. The current American Thyroid Association’s guidelines recommend considering treatment of maternal subclinical hypothyroidism with TSH ≥4 mIU/L, especially if thyroid peroxidase (TPO) antibody titer is positive (18). However, it is unclear whether treatment would be needed if maternal subclinical hypothyroidism is diagnosed beyond the first trimester given lack of treatment benefit. Timing of diagnosis may need to be considered in treatment of maternal subclinical hypothyroidism in pregnancy. Although treatment may be beneficial if started in the first trimester, it may not result in meaningful benefit if started later in pregnancy. Furthermore, environmental or other factors may play more important role in children’s neurodevelopment than the potential adverse impact of maternal subclinical hypothyroidism beyond the first trimester. Further studies assessing impact of maternal subclinical hypothyroidism and its treatment in the first trimester on children’s neurodevelopment would be needed to answer this controversial question.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article did not undergo external peer review.

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-2026-1-0025/coif). The author has no conflicts of interest to declare.

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