Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental conditions that can be defined by impaired social communication and limited and repetitive behaviors. ASD manifests with a wide range of symptoms due to complex genetic and environmental interactions at critical developmental stages. The prenatal period is a critical period of fetal brain development, and disruptions in neurodevelopmental pathways during the prenatal period have been associated with increased risk of ASD. Several maternal exposures have been linked to a higher risk, with special attention given to maternal thyroid impairment.
Thyroid hormones play a crucial role in fetal neurogenesis, and the onset of fetal development depends on hormone transfer from the mother. Maternal thyroid levels have been linked to deviations that lead to negative offspring outcomes, including lower cognitive scores, expressive language delays, and nonverbal cognitive deficits.
Gestational overt or subclinical hypothyroidism has also been reported to be associated with worse child cognitive outcomes, and a meta-analysis of lower early-pregnancy free thyroxine (Free T4) FT4 levels was associated with multiple neurodevelopmental outcomes. The fetal neurodevelopment may also involve some autoimmune mechanisms that do not depend on hormone levels, but the results are inconsistent.
There is growing evidence that maternal thyroid dysfunction might be a risk factor for ASD. Certain studies have shown increased ASD rates in the children of mothers with hypothyroidism who were not treated. Several studies have found increased ASD rates in children born to mothers with untreated hypothyroidism, but the mechanism could be due to confounding and not to gestational hormone disruption. It is clinically significant to clarify this association, as thyroid dysfunction is common and treatment options are available. The current research thus investigated the existence of maternal thyroid dysfunction in pregnancy and its relationship with the diagnosis of ASD in children.
The Soroka University Medical Center (SUMC) followed a retrospective cohort of live singleton births from January 2011 to December 2017, until January 2021. Only the births in which both the mother and the child were registered in Clalit Health Services (CHS) were considered.
The demographic structure of the Negev area, where the proportion of Bedouin inhabitants exceeds 25% and the percentage of births among this group exceeds 50%, is conducive to extensive generalizability. The CHS electronic records, SUMC obstetric databases, and the Azrieli National Center of Autism and Neurodevelopment Research, which defines ASD according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria, were merged to obtain data.
Mother thyroid dysfunction was further classified as chronic, gestational, or both using International Classification of Diseases, Ninth Revision (ICD-9) codes for chronic disease and trimester-specific thyroid-stimulating hormone (TSH) and free T4 (FT4) levels for gestational diagnosis. To minimize transient fluctuations, trimester-specific median hormone values were used. The total number of mothers with abnormal thyroid functioning was 4409 (8.6%). The cumulative incidence of ASD did not differ significantly in the normal and abnormal thyroid (log-rank P =0.27).
Chronic hypothyroidism alone was not significantly associated with ASD (adjusted hazard ratio [aHR]: 0.47; 95% confidence interval [CI]: 0.15-1.48), but chronic and gestational hypothyroidism were (aHR: 2.61; 95% CI: 1.44-4.74). There was a dose response that increased across trimesters: 1, 2, and 3 trimesters resulted in aHR: 1.69 (95% CI: 1.19-2.83), aHR: 2.39 (95% CI, 1.24-5.78), and aHR: 3.25 (95% CI, 1.07-7.21), respectively.
Results are consistent with the previous studies that have associated abnormal levels of gestational thyroid hormone with ASD and with the hypothesis that both the magnitude and the duration of hypothyroid dysfunction are risk factors. Variations with another study in Israel are probably due to differences in the techniques used to determine exposure. The strengths are full-trimester levels of hormonal data and a heterogeneous cohort, and the ASD incidence (1.2%) is equivalent to national levels. Among them, there is limited power for trimester analyses, a lack of data on levothyroxine and iodine status, and possible residual confounding.
In general, the research indicates that maternal thyroid hormone disproportion, especially in cases of chronic disease comorbidity with gestational hypothyroidism, is linked to a higher risk of ASD in a dose-response model. ASD was not linked to chronic hypothyroidism alone, which confirms the need to monitor and treat hypothyroidism in pregnancy to ensure euthyroidism is maintained.
References: Elbedour L, Weinberg M, Meiri G, Michaelovski A, Menashe I. Maternal thyroid hormone imbalance and risk of autism spectrum disorder. J Clin Endocrinol Metab. 2025;dgaf596. doi:10.1210/clinem/dgaf596
