Introduction: Neonatal hyperthyroidism, often caused by maternal Graves’ disease (GD), carries potential neurodevelopmental risks for children. Excessive thyroid hormones during fetal development are linked to neurological issues like ADHD and epilepsy. However, the impact of transient neonatal hyperthyroidism is not well understood. Methods: In a retrospective study at the Royal Children’s Hospital in Melbourne, 21 neonates with hyperthyroidism from mothers with GD were examined. Of these, the parents of 10 children consented to participate; thus, questionnaires assessing executive functions, behavior, and social communication were completed. The outcomes were compared to those of control subjects recruited from the community using standardized tools (BRIEF, SDQ, SCQ). The results were analyzed against socio-demographic factors, maternal, and neonatal health. Results: No significant demographic or clinical differences were found between study participants (n = 10) and non-participants (n = 11). Participants, compared to controls, showed similar family demographics but a higher proportion of control parents had university-level education (p = 0.003). Patients displayed more social (SCQ scores: 12.1 ± 2.5 vs. 6 ± 1.07, p = 0.008) and behavioral difficulties (SDQ scores: 10.2 ± 2.17 vs. 6.14 ± 1.03, p = 0.03), with increased executive function challenges (BRIEF scores indicating problem-solving and self-regulation difficulties). Significant effects of family living situation and partner education level on neurodevelopmental measures were noted, underscoring the influence of socio-demographic factors. Conclusions: These findings suggest neonatal hyperthyroidism might lead to subtle neurodevelopmental variations, with socio-economic elements and family dynamics possibly intensifying these effects. While most children did not show severe impairments, early detection and intervention are recommended. The research emphasizes the necessity for inclusive care approaches that consider socio-economic factors for children affected by neonatal hyperthyroidism.

Researchers at the Royal Children’s Hospital in Melbourne studied babies with neonatal hyperthyroidism, a condition that can occur when a mother with Graves’ disease passes on antibodies to her child. These antibodies can cause the baby’s thyroid gland to be overactive. The study was interested in how these babies, when they grow older, might do in areas like behavior, social skills, and problem-solving compared to other children without this condition.

The study found that while the children with neonatal hyperthyroidism did not have severe problems, they did have more challenges with social interaction, behavior, and executive functions like problem-solving and self-control. These issues were more noticeable in children from single-parent households or those whose parents had less education. This suggests that family environment and parents’ education might influence these developmental areas.

The study could not do face-to-face assessments because of COVID-19, so they used questionnaires filled out by the parents. Even though most children were doing okay, the study suggests that early help and support could be beneficial for children with neonatal hyperthyroidism to ensure they have the best development and quality of life possible.

It is also highlighted that when taking care of children with this condition, healthcare providers should think about family and social factors, not just medical treatment. This is because the family and social environment could play a big role in the child’s development. More research is needed to understand this fully, but this study provides a good starting point for improving care for these children.

Neonatal hyperthyroidism usually results from the transfer of TSH receptor antibodies (TRAb) from mothers who have a history of GD and who remain TRAb positive even if treated and on thyroxine. The severity of maternal disease is linked to fetal and or neonatal hyperthyroidism. Affected babies may exhibit signs of hyperthyroidism in utero [1]. After birth, hyperthyroidism is rare but can affect 1–8% of children born to mothers who are TRAb positive with active GD or after thyroidectomy or radioactive iodine ablation. It can manifest as elevated thyroid hormone levels, with or without clinical symptoms, such as tachycardia, heart failure, respiratory distress, and liver dysfunction.

Thyroid hormones play a crucial role in various aspects of early brain development, encompassing the proliferation of neurons, their migration and differentiation, the formation of synapses, and the development of myelin [2]. Maternal hyperthyroidism is known to have deleterious effects on the fetal developing brain in rats, as it compromises the expression of neuronal cytoskeletal proteins in the late second and third trimesters, suggestive of a pattern of accelerated neuronal differentiation [3]. High maternal free thyroxine concentrations during pregnancy, but not hyperthyroidism, have been associated with lower child IQ and lower gray matter and cortex volume [4], which could reflect alterations in cerebral hemodynamics and cellular osmotic pressure [5]. Evidence from studies in animals and in humans supports the hypothesis that it may increase the risk of developing attention deficit hyperactivity disorder (ADHD) [6]. Moreover, craniosynostosis and microcephaly have been reported in small cohorts of severely affected and late-diagnosed patients [7, 8]. After birth, neuropsychological manifestations of hyperthyroidism such as hyperexcitability, hypertonia, and irritability disappear or revert to normal with the normalization of thyroid function using antithyroid drugs. However, whether hyperthyroidism treated early in life has any long-term consequences is currently not known. The clinical presentation of neonatal hyperthyroidism has been extensively reported in small series or case reports, but long-term follow-up of a cohort of infants with GD from a single center has not been previously reported.

This study aimed to report long-term outcomes of children and adolescents with hyperthyroidism born to mothers with a history or active GD. It assessed parent reports of emotional symptoms, hyperactivity, conduct problems, peer problems, prosocial behavior, executive functioning, and social communication, using standardized psychological assessment measures. Secondary objectives included exploring associations between these outcomes and disease severity, antithyroid drug, and socio-demographic variables.

Participants

A retrospective review of all infants with neonatal hyperthyroidism referred to the endocrinology department of the Royal Children’s Hospital in Melbourne, Australia between 2008 and 2021 was undertaken. Children referred to the endocrinology clinic were identified by diagnosis through electronic medical records, and variables related to maternal, fetal, and neonatal outcomes were collected.

Parents and/or primary caregivers were invited to participate, and the clinical and biochemical characteristics of children who participated and declined to participate were compared. Among the 21 children identified with neonatal hyperthyroidism, in three contacts was not possible, 4 families declined to participate, and 4 agreed to participate; however, questionnaires were not returned at the deadline. In total, parents of 10 children responded and answered a socio-demographic questionnaire and neurodevelopmental questionnaires assessing executive functioning, behavior, and social communication; participant scores were compared to test normative data. For each included participant, one healthy control subject matched for age and gender was recruited from the comunity, and families answered the questionnaire battery. In total for the control group, 18 primary caregivers completed the questionnaire battery.

Due to the COVID-19 pandemic, face-to-face cognitive assessments were not possible, therefore, all questionnaires, and informed consent were distributed via email for completion at home and returned for the study. Any questions were addressed through phone or email support.

Measures

Neurodevelopmental Questionnaires

  • 1.

    Executive functioning: Behavior Rating Inventory of Executive Function – Preschool Version and School age parent versions (BRIEF-P/BRIEF-2; Gioia, Isquith, Guy & Kenworthy, 2015). A behavioral-based measure of executive functioning skills with 86 items. The preschool version for ages 2–5 years, contains the scales; inhibitory self-control, flexibility, and emergent metacognition. The school form, for ages 5 and over consists of the following scales: behavioral regulation, metacognition, and global executive function. T-scores above 65 are considered elevated and potentially clinically significant.

  • 2.

    Behavior: Strengths and Difficulties Questionnaire (SDQ; Goodman, 2003) – Parent form. A measure of parental perception of their child’s pro-social and difficult behaviors. The parent form has 25 items, rated on a 3-point Likert scale, measuring the frequency of positive and negative behaviors. The measure provides a Total Difficulties score and five subscale scores; Emotional Symptoms, Conduct Problems, Inattention/Hyperactivity, Peer Problems, and Prosocial Behavior. The SDQ provides information regarding children’s emotional and behavioral status. Higher scores indicate more difficulties, except on the Prosocial Behavior subscale where a higher score indicates better social skills.

  • 3.

    Social communication: Social Communication Questionnaire (SCQ) – Lifetime form. A measure of social communication for children older than 4 years old. It comprises 40 yes/no questions and focuses on the child’s entire developmental history. A score of 15 or above indicates an increased likelihood of an autism spectrum disorder (ASD) diagnosis.

Socio-Demographic Questionnaire

Information about family, pregnancy, development, school, and medical history was obtained. Data on maternal and paternal education was coded into six categories: Left school between 13 and 16 years, no formal qualifications, completed year 11, high school certificate, professional qualifications without a degree, university degree, and postgraduate degree. In this study, a higher value indicates lower education. Information regarding annual income was provided and divided into categories including less than Australian dollars (AUD) 25,000, AUD 25,000 to AUD 39,999, AUD 39,999 to AUD 55,000, AUD 55,000 to AUD 81,000, AUD 81,000 or more, and rather not say.

Statistical Analysis

Fisher’s exact tests and two-sample t tests assuming equal variances were used to compare categorical and continuous variables. Continuous variables were analyzed for correlations using the Pearson correlation coefficient, while polychotomous variables were subjected to analysis utilizing the Bonferroni analysis with multiple variables. Statistical significance was present if the p value <0.05.

Twenty-one newborns, of whom 12 (57%) were females with neonatal hyperthyroidism, were born to 15 mothers with Graves’ disease (GD). Included in these were 5 siblings from 2 different mothers; one had 3 children and the other had two affected children. To avoid selection bias, the characteristics of children with neonatal hyperthyroidism (patients) were compared between those who participated and those who did not participate in the study. No statistically significant differences were found regarding demographic, clinical, fetal, newborn, biochemical, and treatment variables between both groups. The exception was participants exhibiting liver function test abnormalities more frequently (p = 0.01), as shown in online supplementary Table 1 (for all online suppl. material, see https://doi.org/10.1159/000539268).

Children with neonatal hyperthyroidism included in the study (n = 10) were compared to a control group (n = 18) (Table 1). Age at assessment was similar, and no significant differences in the relationship to the child, number of siblings, or adults living at home were found. However, there was a significant difference in the education level, with controls having a higher proportion of parents with university or postgraduate education (p = 0.003). No differences regarding complications during pregnancy, alcohol consumption, or tobacco use during pregnancy were observed. Similarly, no differences in language development, school learning and ability, and motor, social, and behavioral skills were reported between groups. A higher proportion of patients were receiving interventions (e.g., physiotherapy, speech therapy, occupational therapy and/or counseling) (p = 0.013), and patients’ parents were more concerned about their child’s functioning when compared to controls (e.g., thinking, behavior, emotions, social skills, etc.) (p = 0.04).

Table 1.

Comparative analysis of characteristics between children with neonatal hyperthyroidism (patients) and controls

PatientsControlsp value
mean±SD, n (%)mean±SD, n (%)
Sample size 10 (35.7) 18 (100)  
Age at assessment 5.6±0.97 6.7±0.86 0.39 
Mother responding 8 (80) 17 (94.4) 0.28 
Child living with mother 7 (70) 18 (100) 0.037 
Number of siblings 
 0 0.06 
 1 
 2 
 3 
 4  
Primary caregiver’s (PC) age, years 40.1±2.17 39.8±1.18 0.92 
PC highest level of education 
 1 (highest) 10 0.003 
 2 
 3 
 4 (lowest)  
PC does not work outside the home 3 (30) 12 (66.6) 0.11 
PC is living with a partner 9 (90) 18 (100) 0.35 
Partner’s age, years 40.4±2 41±1.2 0.78 
Partner’s highest level of education 3 (30) 2 (11.1) 0.01 
Partner working outside the home 3 (30) 2 (11.1) 0.14 
Income 
 1 (<25,000 AUD/year) 13 0.13 
 2 (25,000–39.999 AUD/year) 
 3 (39.999–55,000 AUD/year) 
 4 (>55,000 AUD/year)  
Complications during pregnancy (no GD) 1 (10) 2 (11.1) 0.71 
Alcohol consumption during pregnancy 0 (100) 0 (100)  
Tobacco use during pregnancy 1 (10) 0.35 
Complications during labor 4 (40) 4 (22.2) 0.4 
Delayed language development: expressive 2 (20) 2 (11.1) 0.6 
Delayed language development: receptive 1 (10) 0.35 
Delayed motor skills: gross 1 (10) 1 (5.5) 0.59 
Delayed motor skills: fine 0 (100) 0 (100)  
Delayed school learning and ability 3 (30) 1 (5.5) 0.11 
Delayed social skills 1 (10) 0.35 
Delayed behavioral skills 2 (20) 0.11 
Child in a remedial class 1 (5.5) 0.57 
Teacher’s aid 1 (10) 0.42 
Have they repeated a grade?  
Have they previously received any extra help? 2 (20) 1 (5.5) 0.55 
Funding for support 1 (10) 0.45 
Family history of learning, hearing, and/or mental health problems 5 (50) 2 (11.1) 0.17 
Child receiving intervention or help (e.g., physiotherapy, speech therapy, occupational therapy, counseling, etc.) 5 (50) 1 (5.5) 0.013 
Child on any medication 2 (20) 2 (11.1) 0.6 
Concerns about child’s current functioning (e.g., thinking, behavior, emotions, social skills, etc.)? 4 (40) 1 (5.5) 0.04 
Disabling conditions 0 (100) 0 (100)  
Other medical conditions 2 (20) 2 (11.1) 0.6 
Child with thyroid problems 0 (100) 0 (100)  
PatientsControlsp value
mean±SD, n (%)mean±SD, n (%)
Sample size 10 (35.7) 18 (100)  
Age at assessment 5.6±0.97 6.7±0.86 0.39 
Mother responding 8 (80) 17 (94.4) 0.28 
Child living with mother 7 (70) 18 (100) 0.037 
Number of siblings 
 0 0.06 
 1 
 2 
 3 
 4  
Primary caregiver’s (PC) age, years 40.1±2.17 39.8±1.18 0.92 
PC highest level of education 
 1 (highest) 10 0.003 
 2 
 3 
 4 (lowest)  
PC does not work outside the home 3 (30) 12 (66.6) 0.11 
PC is living with a partner 9 (90) 18 (100) 0.35 
Partner’s age, years 40.4±2 41±1.2 0.78 
Partner’s highest level of education 3 (30) 2 (11.1) 0.01 
Partner working outside the home 3 (30) 2 (11.1) 0.14 
Income 
 1 (<25,000 AUD/year) 13 0.13 
 2 (25,000–39.999 AUD/year) 
 3 (39.999–55,000 AUD/year) 
 4 (>55,000 AUD/year)  
Complications during pregnancy (no GD) 1 (10) 2 (11.1) 0.71 
Alcohol consumption during pregnancy 0 (100) 0 (100)  
Tobacco use during pregnancy 1 (10) 0.35 
Complications during labor 4 (40) 4 (22.2) 0.4 
Delayed language development: expressive 2 (20) 2 (11.1) 0.6 
Delayed language development: receptive 1 (10) 0.35 
Delayed motor skills: gross 1 (10) 1 (5.5) 0.59 
Delayed motor skills: fine 0 (100) 0 (100)  
Delayed school learning and ability 3 (30) 1 (5.5) 0.11 
Delayed social skills 1 (10) 0.35 
Delayed behavioral skills 2 (20) 0.11 
Child in a remedial class 1 (5.5) 0.57 
Teacher’s aid 1 (10) 0.42 
Have they repeated a grade?  
Have they previously received any extra help? 2 (20) 1 (5.5) 0.55 
Funding for support 1 (10) 0.45 
Family history of learning, hearing, and/or mental health problems 5 (50) 2 (11.1) 0.17 
Child receiving intervention or help (e.g., physiotherapy, speech therapy, occupational therapy, counseling, etc.) 5 (50) 1 (5.5) 0.013 
Child on any medication 2 (20) 2 (11.1) 0.6 
Concerns about child’s current functioning (e.g., thinking, behavior, emotions, social skills, etc.)? 4 (40) 1 (5.5) 0.04 
Disabling conditions 0 (100) 0 (100)  
Other medical conditions 2 (20) 2 (11.1) 0.6 
Child with thyroid problems 0 (100) 0 (100)  

Assessment of social communication (Table 2) using the SCQ revealed that patients had significantly higher total scores compared to controls (12.1 ± 2.5 vs. 6 ± 1.07, p = 0.008) but within normal ranges, with 3 (30%) presenting abnormal results (at risk of social deficits), indicating greater difficulty in social communication, which can be a characteristic of autism spectrum disorders. On the SDQ, the total behavior difficulties score was higher in patients than controls (10.2 ± 2.17 vs. 6.14 ± 1.03, p = 0.03), indicating greater overall difficulties in behavioral functioning, with 2 patients (20%) exhibiting abnormal scores (clinically significant) compared to controls (0%) (p = 0.02). Furthermore, patients scored significantly higher in the BRIEF global executive functioning index, a summary measure that suggests difficulty in one or more areas of executive function. Similarly, patients scored higher on the working memory (p = 0.003), and behavioral regulation index (p = 0.01), indicating difficulties in successfully guiding active systematic problem-solving and appropriate self-regulation, and in the emotion regulation index subscales (p = 0.03), respectively, suggesting an inability to modulate emotional responses.

Table 2.

Comparative analysis of neurodevelopmental parent report questionnaire results between children with neonatal hyperthyroidism (patients) and controls

PatientsControlsp value
mean±SD, n (%)mean±SD, n (%)
Social communication (SCQ) 
 Total score 12.1±2.5 6±1.07 0.008 
  At risk of social deficits* 3 (30) 1 (5.5) 0.11 
Behavior (SDQ) 
 Emotional problems scale 2.8±0.84 1.64±0.53 0.23 
 Conduct problems scale 2.2±0.62 1.28±0.28 0.15 
 Hyperactivity scale 3.9±3.6 2.71±0.4 0.07 
 Peer problems scale 1.1±0.4 0.5±0.2 0.08 
 Prosocial scale 8.1±0.64 8.6±0.3 0.79 
 Internalizing (emotional + peer probs) 1.12±3.5 2.14±0.65 0.08 
 Externalizing (conduct + hyperactivity) 6.3±1.29 4±0.67 0.05 
 Total SDQ difficulties score 10.2±2.17 6.14±1.03 0.03 
  Abnormal range 2 (20) 0.02 
Executive functioning (BRIEF) 
 Inhibit 52.3±3.96 48.07±1.94 0.15 
 Self-monitoring 62.16±5.62 46.6±2.08 0.005 
 Shift 55.7±5.7 47.15±1.93 0.06 
 Emotional control 53.5±4.2 49±2.2 0.16 
 Initiate 51±3.7 45.5±1.6 0.07 
 Working memory 60.8±4.86 47.07±1.7 0.003 
 Plan/organize 51.4±3.9 46.23±1.68 0.1 
 Task monitor 48.83±4.06 46.6±3.2 0.34 
 Organization of materials 51.3±4.87 47±1.7 0.17 
 Behavioral regulation index 56.83±5.43 45.6±1.79 0.01 
 Emotion regulation index 58.6±5.12 48.2±2.47 0.03 
 Cognitive regulation index 53.16±3.98 47.2±2.07 0.08 
 Global executive functioning index 54.6±4.5 47.07±1.67 0.05 
PatientsControlsp value
mean±SD, n (%)mean±SD, n (%)
Social communication (SCQ) 
 Total score 12.1±2.5 6±1.07 0.008 
  At risk of social deficits* 3 (30) 1 (5.5) 0.11 
Behavior (SDQ) 
 Emotional problems scale 2.8±0.84 1.64±0.53 0.23 
 Conduct problems scale 2.2±0.62 1.28±0.28 0.15 
 Hyperactivity scale 3.9±3.6 2.71±0.4 0.07 
 Peer problems scale 1.1±0.4 0.5±0.2 0.08 
 Prosocial scale 8.1±0.64 8.6±0.3 0.79 
 Internalizing (emotional + peer probs) 1.12±3.5 2.14±0.65 0.08 
 Externalizing (conduct + hyperactivity) 6.3±1.29 4±0.67 0.05 
 Total SDQ difficulties score 10.2±2.17 6.14±1.03 0.03 
  Abnormal range 2 (20) 0.02 
Executive functioning (BRIEF) 
 Inhibit 52.3±3.96 48.07±1.94 0.15 
 Self-monitoring 62.16±5.62 46.6±2.08 0.005 
 Shift 55.7±5.7 47.15±1.93 0.06 
 Emotional control 53.5±4.2 49±2.2 0.16 
 Initiate 51±3.7 45.5±1.6 0.07 
 Working memory 60.8±4.86 47.07±1.7 0.003 
 Plan/organize 51.4±3.9 46.23±1.68 0.1 
 Task monitor 48.83±4.06 46.6±3.2 0.34 
 Organization of materials 51.3±4.87 47±1.7 0.17 
 Behavioral regulation index 56.83±5.43 45.6±1.79 0.01 
 Emotion regulation index 58.6±5.12 48.2±2.47 0.03 
 Cognitive regulation index 53.16±3.98 47.2±2.07 0.08 
 Global executive functioning index 54.6±4.5 47.07±1.67 0.05 

*SCQ scores above 15 indicate social communication difficulties and risk of autism spectrum disorder; SDQ higher scores indicate more difficulties except for Prosocial subscale; and BRIEF index scores above 65 indicate elevated range.

An analysis of variance (ANOVA) was conducted to assess the impact of various factors on neurodevelopmental measures. Regarding the SCQ total score, maternal-level education exhibited a trend but did not yield statistically significant group differences. In contrast, partner-level education demonstrated a significant effect, with an overall F-value of 4.40 (p = 0.0063), indicating an association between partner education and the SCQ Total Score. Furthermore, the mean SCQ total score for children living with both parents (n = 25) was 7.16 (SD = 4.99), while for those living only with their mother (n = 3), it was substantially higher at 16.67 (SD = 12.90). The ANOVA showed a significant effect of living arrangement on SCQ total scores, F(1, 26) = 6.75, p = 0.0152. A Bonferroni post hoc analysis revealed that the mean SCQ total score was significantly higher for children living only with their mothers compared to those living with both parents, with a mean difference of 9.51 (p = 0.015).

For the SDQ Total Difficulties Score, the family living situation also revealed a statistically significant difference between groups, F(1, 22) = 9.09, p = 0.0064, with children living only with their mother showing a higher mean difficulties score (M = 15.67, SD = 4.51) compared to those living with both parents (M = 6.71, SD = 4.84). A Bonferroni post hoc comparison revealed an adjusted mean difference of 8.95 between the two groups (p = 0.006), suggesting that living only with the mother is associated with an increased SCQ Total Difficulties Score compared to living with both parents. Maternal-level education showed a significant impact on the SDQ (F = 3.85, p = 0.0252), whereas partner-level education did not lead to significant differences.

Finally, concerning the BRIEF global executive function, the family living situation had a significant effect (F = 6.49, p = 0.0187). Maternal education showed a trend without significant group differences, while partner education significantly influenced outcomes (F = 3.08, p = 0.0367) (online suppl. Table 2).

This study aimed to investigate the long-term neurodevelopmental outcomes in children with neonatal hyperthyroidism born to mothers with GD. One notable finding was the significant differences observed between the mean neurodevelopmental questionnaire results: parents of children affected by neonatal hyperthyroidism reported being more concerned about their children’s measures of social communication, behavior, and executive functioning.

There is limited evidence regarding the effect of maternal hyperthyroidism on the developing fetal brain. Results from animal studies appear not to be comparable to humans, due to differences regarding embryonic development times, duration of pregnancy, and timing at which neurodevelopmental stages occur. Additionally, the assessment of brain development with standardized measurements is not comparable. Despite this, evidence suggests that maternal hyperthyroidism during pregnancy might negatively affect fetal brain development in laboratory animals [9]. This impact is observed through changes in how neurons develop and organize themselves, variations in the brain’s neurochemical conditions, and modifications in the expression of brain proteins. In humans, a meta-analysis observed an association between maternal hyperthyroidism, ADHD, and epilepsy in offspring [10]. However, the included studies were mostly register-based, which are large but assessment of exposure in pregnancy is indirectly performed from hospital diagnoses and/or redeemed prescriptions of drugs. A Danish case-control study showed that overt hyperthyroidism in pregnancy was a risk factor for epilepsy and autistic spectrum disorder in the child [11], however, the definition of developmental disorders and seizures relied on hospital diagnosis and not cognitive or electrophysiological testing results. Another German study compared 17 children of hyperthyroid mothers receiving antithyroid drug treatment during their pregnancies with 25 children of mothers who were euthyroid without any antithyroid treatment during their pregnancy. The assessment of the psychomotor and intellectual capacity of the children showed no abnormalities at different ages [12]. Interestingly, none of the mentioned studies provide information on whether neonates were affected by hyperthyroidism after birth. This consideration is important since only a small proportion of children born to mothers with GD are affected by hyperthyroidism postnatally.

This study, with real-world data, explores possible associations between adverse neurocognitive outcomes and fetal/neonatal hyperthyroidism. Our findings suggest that neonatal hyperthyroidism may have subtle yet notable differences in social communication skills, behavioral functioning, and challenges related to executive functions. The lack of significant correlations between cognitive outcomes and maternal, fetal, and neonatal variables implies that neonatal hyperthyroidism’s effects on neurodevelopment may not be directly linked to specific clinical factors. Rather, it might be a result of subtle, but relevant, interactions between thyroid hormones and the developing brain. For instance, in some children affected by resistance to thyroid hormone beta (RTHβ), a syndrome of reduced responsiveness of peripheral tissue to thyroid hormone, a cognitive phenotype like ADHD is observed [13].

Whether these differences are truly explained by socioeconomic disparities needs to be confirmed, but childhood socioeconomic status has been associated with executive function abilities [14], and a higher risk of ADHD [15]. The finding that children living only with their mother had significantly higher SCQ and SDQ scores than those living with both parents is particularly noteworthy. This could reflect the impact of socio-economic and psychosocial factors associated with single parenting on children’s social communication skills and suggest they may face more challenges in emotional and behavioral domains. It is crucial to emphasize that these findings do not imply severe neurodevelopmental impairments, as all scores remained within the normal range, and most affected children did not face significant day-to-day problems. Nevertheless, these subtle differences should not be overlooked. Early identification and intervention for potential cognitive and executive functioning challenges in children with neonatal hyperthyroidism may prove beneficial in optimizing their overall development and quality of life.

This study has several strengths. We present for the first time the neurodevelopmental outcomes of the largest group of patients with neonatal hyperthyroidism studied to date. All patients were assessed at the same center, where the same criteria for treatment were used. Limitations to our study include a small sample size, which restricts the statistical power of our analysis, making it challenging to detect subtle differences and associations. As a result, findings should be interpreted cautiously. Although the observed trends and descriptive statistics provide valuable insights into the relationships under investigation, they may not represent the broader population accurately, and given the rarity of this disorder, this might be one of the biggest reported cohorts so far. Unfortunately, due to COVID-19, face-to-face neuropsychological assessments could not be conducted, and the outcomes are reported by parents, with a difference in parental education noted between cases and controls. This difference may affect the reporting/validity of the outcomes rather than the cognitive outcome itself. Additionally, despite efforts to minimize it, selection bias might be present. In that sense, while parental education level appears to be associated with cognitive and behavioral outcomes, the specific nature and extent of this influence may vary depending on the test and the groups being compared. Furthermore, most of the socio-demographic data is self-reported, such as maternal behaviors during pregnancy, among others, play a role in the obtained results that might be subject to bias. Moreover, the study did not evaluate other variables that could influence outcomes, such as environmental factors and neuroimaging. It is also possible that parents’ concerns about their child’s medical history may have heightened their perceptions of neurodevelopmental issues. Addressing these limitations in future research can strengthen the study’s findings and practical implications.

In conclusion, our study underscores the importance of considering familial and socio-economic factors when assessing development in children with neonatal hyperthyroidism. These findings provide valuable insights into potential areas of intervention and support to ensure optimal cognitive and behavioral outcomes in this population. Further research is warranted to explore the intricate interplay between socio-demographic variables and cognitive functioning in children with neonatal hyperthyroidism, to enhance their well-being and quality of life.

The authors thank Dr. Gabriel Cavada for statistical analyses and Mrs. Helena Poggi for the critical review of the manuscript.

The study was approved by the Royal Children’s Hospital Melbourne Human Research Ethics Committee (HREC 76169). Written informed consent was obtained from the participants’ parent/legal guardian/next of kin to participate in the study.

The authors have no conflicts of interest to disclose.

No funding was secured for this study.

Conceptualization, approval of final manuscript, and accountability for work: Francisca Grob, Amy Brown, and Margaret Zacharin. Writing – original draft: Francisca Grob. Writing – review and editing: Amy Brown and Margaret Zacharin.

All data generated or analyzed during this study are included in this article and its supplementary material files. Further inquiries can be directed to the corresponding author.

1.
Samuels
SL
,
Namoc
SM
,
Bauer
AJ
.
Neonatal thyrotoxicosis
.
Clin Perinatol
.
2018
;
45
(
1
):
31
40
.
2.
Alcaide Martin
A
,
Mayerl
S
.
Local thyroid hormone action in brain development
.
Int J Mol Sci
.
2023
;
24
(
15
):
12352
.
3.
Evans
IM
,
Pickard
MR
,
Sinha
AK
,
Leonard
AJ
,
Sampson
DC
,
Ekins
RP
.
Influence of maternal hyperthyroidism in the rat on the expression of neuronal and astrocytic cytoskeletal proteins in fetal brain
.
J Endocrinol
.
2002
;
175
(
3
):
597
604
.
4.
Korevaar
TIM
,
Muetzel
R
,
Medici
M
,
Chaker
L
,
Jaddoe
VWV
,
de Rijke
YB
, et al
.
Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: a population-based prospective cohort study
.
Lancet Diabetes Endocrinol
.
2016
;
4
(
1
):
35
43
.
5.
Oatridge
A
,
Barnard
ML
,
Puri
BK
,
Taylor-Robinson
SD
,
Hajnal
JV
,
Saeed
N
, et al
.
Changes in brain size with treatment in patients with hyper- or hypothyroidism
.
AJNR Am J Neuroradiol
.
2002
;
23
(
9
):
1539
44
.
6.
Stohn
JP
,
Martinez
ME
,
Hernandez
A
.
Decreased anxiety- and depression-like behaviors and hyperactivity in a type 3 deiodinase-deficient mouse showing brain thyrotoxicosis and peripheral hypothyroidism
.
Psychoneuroendocrinology
.
2016
;
74
:
46
56
.
7.
Riggs
W
,
Wilroy
RS
,
Etteldorf
JN
.
Neonatal hyperthyroidism with accelerated skeletal maturation, craniosynostosis, and brachydactyly
.
Radiology
.
1972
;
105
(
3
):
621
5
.
8.
Daneman
D
,
Howard
NJ
.
Neonatal thyrotoxicosis: intellectual impairment and craniosynostosis in later years
.
J Pediatr
.
1980
;
97
(
2
):
257
9
.
9.
Andersen
SL
,
Andersen
S
.
Hyperthyroidism in pregnancy: evidence and hypothesis in fetal programming and development
.
Endocr Connect
.
2021
;
10
(
2
):
R77
86
.
10.
Ge
GM
,
Leung
MTY
,
Man
KKC
,
Leung
WC
,
Ip
P
,
Li
GHY
, et al
.
Maternal thyroid dysfunction during pregnancy and the risk of adverse outcomes in the offspring: a systematic review and meta-analysis
.
J Clin Endocrinol Metab
.
2020
;
105
(
12
):
dgaa555
.
11.
Andersen
SL
,
Andersen
S
,
Vestergaard
P
,
Olsen
J
.
Maternal thyroid function in early pregnancy and child neurodevelopmental disorders: a Danish nationwide case-cohort study
.
Thyroid
.
2018
;
28
(
4
):
537
46
.
12.
Messer
PM
,
Hauffa
BP
,
Olbricht
T
,
Benker
G
,
Kotulla
P
,
Reinwein
D
.
Antithyroid drug treatment of Graves’ disease in pregnancy: long-term effects on somatic growth, intellectual development and thyroid function of the offspring
.
Acta Endocrinol
.
1990
;
123
(
3
):
311
6
.
13.
Uter
J
,
Heldmann
M
,
Rogge
B
,
Obst
M
,
Steinhardt
J
,
Brabant
G
, et al
.
Patients with mutations of the Thyroid hormone beta-receptor show an ADHD-like phenotype for performance monitoring: an electrophysiological study
.
Neuroimage Clin
.
2020
;
26
:
102250
.
14.
Last
BS
,
Lawson
GM
,
Breiner
K
,
Steinberg
L
,
Farah
MJ
.
Childhood socioeconomic status and executive function in childhood and beyond
.
PLoS One
.
2018
;
13
(
8
):
e0202964
.
15.
Russell
AE
,
Ford
T
,
Russell
G
.
Socioeconomic associations with ADHD: findings from a mediation analysis
.
PLoS One
.
2015
;
10
(
6
):
e0128248
.