Causes of Neonatal Thyrotoxicosis
The primary cause of neonatal thyrotoxicosis is transplacental passage of thyroid-stimulating immunoglobulins from mothers with Graves' disease, accounting for the vast majority of cases. 1, 2
Primary Causes
1. Maternal Graves' Disease-Related
Transplacental transfer of thyroid-stimulating immunoglobulins (TSAb/TRAb)
Important clinical consideration: The mother may be completely euthyroid due to previous treatment (surgery, radioiodine ablation, or medications) but still have circulating TSAb that can affect the fetus 3, 2
2. Genetic/Non-Immune Causes (Rare)
- Activating mutations of the TSH receptor 1
- Activating mutations of the stimulatory G protein (Gsα) in McCune-Albright syndrome 1
Clinical Presentation and Complications
Fetal Manifestations
- Fetal tachycardia (key diagnostic sign)
- Intrauterine growth retardation
- Fetal goiter
- Nonimmune hydrops fetalis
- Craniosynostosis
- Intrauterine death (mortality 12-20%) 2
Neonatal Manifestations
- Hyperkinesis
- Tachycardia
- Poor weight gain
- Diarrhea and vomiting
- Cardiac failure and arrhythmias
- Systemic and pulmonary hypertension (can be severe) 4
- Hepatosplenomegaly
- Jaundice
- Thrombocytopenia
- Hyperviscosity syndrome
- Craniosynostosis 1
Time Course and Prognosis
- Transient disease: Most cases of neonatal Graves' disease remit by 20 weeks of age; almost all cases resolve by 48 weeks 1
- Persistent disease: May occur in cases with:
- Strong family history of Graves' disease
- Activating mutations of the TSH receptor (characteristic) 1
Diagnostic Considerations
- Thyroid function tests (elevated free T4, suppressed TSH)
- Measurement of TSAb/TRAb levels in mother and infant
- Important caveat: Even low levels of TRAb by bioassay may still cause neonatal hyperthyroidism 5
- TSAb typically becomes undetectable in infants approximately 1 year after birth 6
Clinical Pitfalls to Avoid
Delayed presentation: Maternal antithyroid drugs can cross the placenta and suppress fetal thyroid function, masking thyrotoxicosis at birth. Symptoms may appear days to weeks after delivery when the drug effect wears off 6
Overlooking maternal history: All infants born to mothers with current or past Graves' disease should be monitored for thyrotoxicosis, even if the mother is currently euthyroid 3
Misdiagnosis of persistent pulmonary hypertension: Neonatal thyrotoxicosis can present with or exacerbate pulmonary hypertension, which may resolve with antithyroid treatment 4
Relying solely on TRAb levels: Bioassay TRAb measurements are not always reliable for predicting neonatal hyperthyroidism risk; clinical monitoring remains essential 5
Understanding these causes and mechanisms is crucial for early recognition and appropriate management of neonatal thyrotoxicosis, which can significantly reduce associated morbidity and mortality.