Maternal TSH-receptor antibodies predict fetal/neonatal hyperthyroidism in pregnancies with a history of Graves...

Transplacental transfer of thyrotropin receptor antibodies (TRAbs) during pregnancy may cause fetal/neonatal thyroid dysfunction. Current guidelines recommend a universal TRAb titer threshold, irrespective of gestational age or assay platform. However, evidence supporting trimester-specific and assay-specific thresholds is lacking.

This work aimed to determine whether trimester-specific TRAb levels predict fetal/neonatal thyroid dysfunction and to establish assay-specific cutoff values for clinical risk stratification.

In this prospective, multicenter, observational cohort study (2010-2023), maternal TRAb titers were measured using the TRAK human assay on the BRAHMS Kryptor Compact Plus analyzer. Settings were tertiary and secondary care centers (n = 44) across the Netherlands. Patients included women with a history of (n = 500) or active (n = 178) Graves disease. Main outcome measures included biochemically confirmed fetal/neonatal hyperthyroidism or hypothyroidism.

Trimester-specific TRAb titer thresholds predicted risk with high accuracy. In women with a history of Graves disease (n = 500), trimester-specific cutoffs of 25-, 19-, and 6-fold the upper limit of normal (ULN) showed a negative predictive value of 100%. In women with active Graves (n = 178), cutoffs of 10-, 12-, and 10-fold the ULN showed sensitivities of 89%, 86%, and 83%. Neonatal hyperthyroidism occurred despite low or declining maternal TRAb levels in mothers treated with antithyroid drugs.

Trimester-specific TRAb thresholds were higher than the universal ULN multipliers commonly applied in clinical practice, and differed by gestational age and disease status. Application of a single ULN-based threshold titer across different TRAb assays may result in misclassification (ie, overestimation of fetal and neonatal Graves disease) and consequently in unnecessary and resource-intensive fetal surveillance. This indicates that TRAb thresholds are assay specific and require platform-specific clinical validation, even when assays are calibrated against a common international standard.