Congenital Hypothyroidism in Children Confers Neurocognitive Impairment Risk

Crop of child lying on bed, during ultrasound of thyroid. Little girl, wearing in dress, courteously follows instructions of female doctor with ultrasound probe in hand and scanning her neck.
Researchers sought to discover whether children with either temporary or permanent congenital hypothyroidism have a higher risk of neurocognitive impairment and abnormalities.

Children with congenital hypothyroidism may face a higher risk of neurocognitive impairment and abnormalities in white matter, even with timely and adequate treatment, according to research results published in the Journal of Clinical Endocrinology and Metabolism.

Through a retrospective, prospective, observational cohort study, researchers sought to evaluate the cognitive performances in children with either permanent or transient congenital hypothyroidism. Researchers also intended to characterize brain anatomy, analyze microstructural white matter characteristics, and correlate these findings with disease severity.

Patients were identified between 2007 and 2012 through a systematic neonatal screening program at a tertiary academic center in Italy. A total of 39 children with permanent or transient congenital hypothyroidism (n=29 and n=11) and 39 healthy controls were enrolled between 2017 and 2019.

Clinical and biochemical evaluations began 2 weeks after levothyroxine initiation and took place every 2 weeks until thyroid-stimulating hormone (TSH) level normalization. Clinical examinations and serum TSH and free thyroxine 4 (FT4) measurements were also conducted every 2 to 3 months for 12 months. Between age 12 months and 3 years, evaluation frequency was reduced to every 3 to 4 months and levothyroxine dose was adjusted to keep serum FT4 above man and median reference interval values.

Cognitive evaluations were performed using the Total Intelligence Quotient (IQ), Verbal Comprehension Index (VCI), Perceptional Reasoning Index (PRI), Working Memory Index (WMI), and Processing Speed Index (PSI). Normal scores were between 85 and 115; intellectual functioning limitation scores were between 71 and 84, and intellectual disability scores were ≤70.

Thirty-five of the participants also underwent a brain magnetic resonance imaging study. Images were reviewed by 2 board-certified pediatric neuroradiologists to evaluate macroscopic brain and pituitary injuries.

Median participant age was 9.5 years (range, 6.7-11.8 years). At baseline, 25.6% of participants had neonatal jaundice and 3 underwent phototherapy.

On neonatal screening, investigators found that the mean TSH value was significantly lower in children with transient vs permanent congenital hypothyroidism, with a diagnosis confirmed via THS and FT4 serum evaluation, thyroid ultrasound, and scintigraphy at a median age of 12.5 days (range, 5-32 days) and 21 days (range, 7-35 days) in the permanent and transient congenital hypothyroidism groups.

Significantly higher serum TSH levels were noted in children with permanent congenital hypothyroidism (245.52±278.68 vs 58.14±53.97). Thirty-five participants began levothyroxine treatment at a median age of 14.1 and 18.6 days in the permanent and transient congenital hypothyroidism groups, respectively.

No significant between-group differences were noted in terms of auxological data or serum TSH levels; FT4 was significantly lower in children with transient congenital hypothyroidism (12.66±1.79 vs 14.35±1.55).

Over follow-up through age 5, mean TSH and FT4 levels every 6 months were 4.29±1.3 and 12.34±2.27 pg/mL, respectively.

During the first 3 years of life, neurodevelopmental milestones were normal, excluding 3 children who demonstrated a mild speech delay.

Eighteen children with permanent congenital hypothyroidism came from families with a positive history of thyroid disorders, compared with 6 children in the transient hypothyroidism group. No assisted reproductive techniques were used, although 2 cases of oligohydramnios, 1 case of preeclampsia, 1 case of gestosis, 1 case of gestational diabetes, 1 case of thrombophlebitis, and 1 case of fetal ovarian cyst were reported. Twelve children were delivered via cesarean section.

In terms of cognitive evaluation, children with transient congenital hypothyroidism demonstrated, on average, higher scores on all scales compared with those with permanent congenital hypothyroidism. With the exception of PRI and Numerical Knowledge, no results were statistically significant.

In the transient and permanent congenital hypothyroidism groups, 1 and 8 children demonstrated an intellectual functioning limitation, respectively, and 3 children with permanent congenital hypothyroidism had an IQ ≤70.

PSI was significantly lower in children with permanent congenital hypothyroidism; other tests also showed significantly lower values and significant differences in terms of visual sustained attention, speed in reading, and arithmetic tests.

IQ and VCI scores were also significantly lower in children with a positive family history for thyroid disorders.

Results of the imaging analysis showed a trend toward higher axial diffusivity in the splenium of the corpus callosum, the posterior limbs of the internal capsule, and posterior thalamic radiations in those with transient vs permanent congenital hypothyroidism. After controlling for age and gender, there were no significant differences in fractional anisotropy, mean diffusivity, and radial diffusivity between the 2 groups.

Study limitations include the small number of children with transient congenital hypothyroidism.

“We found a significant association of permanent hypothyroidism with cognitive ability and brain structure, thus improving our understanding of the role of thyroid hormones and brain vulnerability,” the researchers wrote. “The results of this study suggest that, despite early diagnosis and timely treatment…neonates with thyroid dysgenesis, and particularly those born from mothers with thyroid diseases, show significant structural abnormalities in their white matter tracts and a higher risk of adverse neurodevelopmental function.”

“Although universal screening of healthy mothers before pregnancy is not currently recommended, a history of maternal thyroid dysfunction should alert physicians in order to prevent or attenuate early and irreversible neurological harm from thyroid hormone deficiency,” they concluded.


Perri K, De Mori L, Tortora D, et al. Cognitive and white matter microstructure development in congenital hypothyroidism and familial thyroid disorders. J Clin Endocrinol Metab. Published online ahead of print June 9, 2021. doi: 10.1210/clinem/dgab412