Prenatal Diagnosis of Resistance to Thyroid Hormone and Its Clinical Implications

Abstract

Context: Resistance to thyroid hormone-β (RTH-β) is an autosomal dominant disorder characterized by reduced sensitivity of target tissues to thyroid hormones (THs). Individuals with RTH-β have high TH levels usually due to mutations in the TH receptor-β (THRB) gene. The management of RTH-β during pregnancy is challenging, as wild-type (WT) fetuses born to RTH-β mothers have low birth weight and suppressed postnatal thyroid-stimulating hormone (TSH), due to intrauterine exposure to excess TH.

Objective: To determine birth weight and postnatal TSH of WT fetuses carried by mothers with RTH-β whose fT4 levels were maintained below 20% of the upper limit of normal (ULN).

Design: Retrospective chart review.

Setting: Academic institution in collaboration with off-site hospitals and private practices.

Patients: Thirteen women harboring THRB gene mutations were evaluated during 18 pregnancies.

Intervention: Prenatal genetic diagnosis by amniocentesis. Women carrying WT fetuses were given the option of treatment with antithyroid medication by their treating physicians with the aim to avoid serum fT4 levels above 20% of the ULN.

Results: No significant difference was found in birth weight corrected for gestational age and in serum TSH levels at birth between WT and RTH-β infants born to RTH-β mothers.

Conclusions: Prenatal diagnosis may play an important role in the management of RTH-β during pregnancy. Aiming for maternal fT4 levels not above 50% of the ULN in RTH-β mothers carrying WT fetuses seems to be a prudent approach that prevents the otherwise expected low birth weight and postnatal TSH suppression.

Figure 1.

(A) Birth weight of neonates born to mothers carrying a THRB gene mutation based on their genotype (RTH-β and WT). Birth weight is controlled for gestational age at delivery and expressed as Z score from the 50% percentile. Hatched symbols indicate neonates whose mothers received antithyroid treatment. (B) TSH levels at birth of neonates born to mothers carrying a THRB gene mutation based on their genotype (RTH-β and WT). (C) Free T₄ index (expressed as percent of the ULN) at birth of neonates born to mothers carrying a THRB gene mutation based on their genotype (RTH-β and WT). FTI: free T₄ index. Circles and vertical lines indicate, respectively, mean and SEM for the whole group of WT infants (open circles) and only those whose mothers were treated with antithyroid drugs (hatched circles).

Figure 2.

TFTs in three pregnant women with RTH-β (mutation in brackets) carrying WT fetuses. The arrow indicates initiation of antithyroid treatment. Subject 10 (P453T) received propylthiouracil requiring from 150 mg/d during the second trimester up to 450 mg/d during the third trimester. Subject 12 (M310L) received methimazole starting from 5 mg/d at gestational week 20 up to 10 mg/d during the third trimester. Subject 13 (R243Q) received propylthiouracil starting with a dose of 150 mg/d at gestational week 14, which was reduced to 100 mg/d after gestational week 20 and for the remaining gestational period.