Comment on “Maternal TSH-receptor Antibodies Predict Fetal/Neonatal Hyperthyroidism in Pregnancies With a History of Graves Disease”

Vollständiger Abstract

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Graves disease is an autoimmune disease characterized by thyrotropin receptor antibodies (TRAbs), which can cross the placenta and cause fetal or neonatal thyroid dysfunction. Neonatal hyperthyroidism is uncommon, but more likely when maternal TRAb levels are elevated. Therefore, monitoring this value is used for risk assessment, but guidelines are limited by small studies, differing TRAb assays, and a lack of trimester-specific thresholds, especially for patients with a history of Graves disease who became euthyroid following treatment. Because TRAb testing is often first performed in the third trimester, earlier fetal thyroid dysfunction may be missed. This study evaluated whether trimester-specific TRAb thresholds could improve the prediction of fetal and neonatal hyperthyroidism or hypothyroidism in pregnant patients with active or prior Graves disease. This prospective observational study was conducted at 44 Dutch centers and enrolled pregnant patients 18 years old or above with active Graves disease or a history of Graves disease. Patients with multiple gestations or missing fetal/neonatal diagnostic data were excluded. Participants received routine obstetric and endocrine care, including fetal heart rate monitoring and fetal thyroid ultrasound antenatally, and cord blood sampling, neonatal examination, and neonatal thyroid function testing after delivery. Maternal TRAb levels were measured during each trimester using a centralized chemiluminescence assay, and neonatal thyroid function was assessed via TSH and free T4 measurements. The primary outcome was overt fetal or neonatal hyperthyroidism, defined biochemically as suppressed TSH alongside elevated free T4 in the setting of elevated maternal TRAbs. Logistic regression and ROC analyses were used to assess the association between TRAb levels and fetal/neonatal thyroid dysfunction and to find thresholds that maximized sensitivity. The study included 678 pregnancies, of which 500 involved patients with a history of Graves disease and 178 involved active Graves disease. Fetal/neonatal hyperthyroidism was more common with active Graves than prior Graves disease (6.7% vs. 2.6%, P =0.01). Maternal TRAb titers were significantly higher in active cases across all trimesters, with titers declining at similar rates throughout pregnancy in both groups. Among patients with a history of Graves disease, thresholds of 27, 21, and 7 IU/L in the first, second, and third trimesters, respectively, achieved 100% sensitivity and 96% to 99% specificity. In patients with active Graves disease, trimester-specific thresholds of 11, 13, and 11 IU/L identified most cases of fetal/neonatal hyperthyroidism, but positive predictive value varied, with only 29% of patients above the first-trimester threshold later developing hyperthyroidism. In a subset of patients, assay comparison showed that TRAb values differed between testing platforms. These findings demonstrate the value of trimester-specific TRAb titer measurements and suggest that TRAb thresholds may be most useful for ruling out fetal/neonatal complications in patients with a history of Graves disease. This could reduce unnecessary repeat testing following subthreshold values in the first trimester. In contrast, for patients with active Graves disease, neonatal hyperthyroidism still occurred in some cases below the identified thresholds, particularly in those receiving antithyroid drugs with low TRAb levels. Continued fetal and neonatal surveillance throughout pregnancy remains warranted in patients with active Graves disease. The findings also caution against using a single TRAb threshold for all assays and instead support the creation of assay-specific standards. Strengths include the large multicenter cohort, prospective design, centralized testing, and trimester-specific analysis. Limitations include missing TRAb measurements in some trimesters and limited assay comparison data. (Summarized from Saleh L, Schreurs MWJ, Boersma E, et al. Maternal TSH-receptor antibodies predict fetal/neonatal hyperthyroidism in pregnancies with a history of Graves disease. J Clin Endocrinol Metab. 2026; 111: e2161-e2170. doi:10.1210/clinem/dgag118).