Prenatal ultrasonography of a pregnant woman with a past history of total thyroidectomy for Graves’ disease detected fetal tachycardia, fetal growth restriction and oligohydramnios at 30 weeks gestation. Because a high titer of thyroid-stimulating hormone receptor antibody was noted in maternal serum and the fetal goiter was detected on ultrasonography, fetal hyperthyroidism was strongly suspected and subsequently confirmed with cordocentesis at 31 weeks gestation. After treatment of fetal hyperthyroidism through oral maternal administration of methimazole (MMI) starting at 33 weeks gestation, fetal heart rate and amniotic fluid volume returned to normal ranges. Complete resolution of the fetal goiter was observed at 35 weeks gestation. A male infant was born at 35 weeks 6 days gestation via cesarean section in the absence of thyrotoxic findings; however, cord blood chemical analysis at birth indicated iatrogenic fetal hypothyroidism. In the present report, maternal therapy using MMI to resolve symptoms of fetal thyrotoxicosis, including fetal tachycardia and oligohydramnios, was successfully conducted.
Approximately 1 to 5% of mothers with Graves’ disease have offspring with hyperthyroidism.1 Fetal hyperthyroidism may cause fetal tachycardia, growth restriction, goiter and oligohydramnios,2 and can be treated with maternal administration of anti-thyroid medication. In most reported cases of fetal therapy for thyrotoxicosis, propylthiouracil (PTU) has been used.3 Presented is a report of successful treatment of fetal hyperthyroidism using oral maternal administration of methimazole (MMI) as a first-line drug.
A 45-year-old primigravid woman was referred to our hospital at 8 weeks gestation. She had undergone total thyroidectomy 7 years previously, and was taking hormone replacement therapy with levothyroxine at 50 μg per day. Her physical examination revealed only mild exophthalmos. Thyroid function tests revealed a euthyroid status, but a markedly high titer of thyroid-stimulating hormone receptor antibody (TRAb) (second-generation assay using recombinant human thyroid-stimulating hormone (TSH) receptor, reference range <1.0 U l−1) was found at 24.7 U l−1. She also had a diagnosis of rheumatoid arthritis and was treated with prednisolone at 10 mg per day.
At 30 weeks gestational age, estimated fetal weight was 1200 g (corresponding to the 3.5th percentile of Japanese fetal growth charts). Additionally, oligohydramnios (amniotic fluid index: 4.2 cm; reference range at 30 weeks: 9.0 to 23.4 cm)4 and fetal tachycardia (fetal heart rate, 180 b.p.m.) were detected at 31 weeks gestation. Through detailed ultrasound examination of the fetal neck, a diagnosis of fetal goiter was made because of a bilobed, solid anterior neck mass with hypervascularity (Figure 1). The thyroid circumference was 6.23 cm, which was greater than the 95th percentile (reference range at 31 weeks: 3.3 to 5.2 cm).5 In addition, accelerated bone maturation was detected with the presence of the distal femoral ossification center. No additional anomalies, including hydropic signs, were detected. Taking these findings together, fetal hyperthyroidism was strongly suspected. Cordocentesis was performed at 31 weeks gestation and demonstrated fetal serum TSH of <0.010 μU ml−1 (reference range: 2.65 to 11.03 μU ml−1), FT4 of 3.42 ng dl−1 (reference range: 0.63 to 1.29 ng dl−1)6 and TRAb of 28.8 U l−1, thus confirming the diagnosis of fetal hyperthyroidism (Table 1). To treat the fetus transplacentally, oral maternal administration of MMI at 20 mg per day was started after informed consent was obtained.
At 33 weeks gestation, the fetal heart rate and amniotic fluid volume returned to normal ranges. At 34 weeks gestation, out of consideration of the risk of fetal hypothyroidism, the dose of MMI was reduced to 15 mg per day. However, because of maternal hypothyroidism (FT4: 0.54 ng dl−1; TSH: 5.794 μU ml−1; reference range: FT4, 0.62 to 1.20 ng dl−1; and TSH: 0.3 to 3.0 μU ml−1)7 subsequent to the fetal anti-thyroid therapy, the maternal dose of levothyroxine was increased to 100 μg per day at 34 weeks gestation. The circumference of fetal thyroid returned to the normal range at 35 weeks gestation.
The neonate (weight, 1836 g) was born via cesarean section at 35 weeks and 6 days gestation because of a maternal hip-joint disorder due to her rheumatoid arthritis and onset of labor. Apgar scores were 8 and 9 at 1 and 5 min, respectively. No abnormalities were detected on the neonatal physical examination, and no goiter was palpable in the neonatal anterior neck. Cord blood analysis showed neonatal hypothyroidism (TSH: 0.421 μU ml−1; FT4: 0.31 ng dl−1), and a high TRAb titer (36.2 U l−1).8 After observation for 2 days, neonatal administration of levothyroxine at 15 μg per day was started owing to worsening of fetal hypothyroidism. At 5 days of life, the neonate became hyperthyroidic and required cessation of levothyroxine and initiation of MMI at 1 mg kg−1 per day and propranolol at 1 mg kg−1 per day. The neonate was euthyroid with medication from the ninth day of life onward and was discharged home on the 18th day of life. At 15 days of life, propranolol was stopped. MMI was reduced gradually from 1 month of life, and stopped at 3 months. The infant has since been able to maintain euthyroid status with normal growth and development.
Maternal TRAb crossing the placental barrier may stimulate fetal thyroid follicular TSH receptors and cause fetal hyperthyroidism. It has been reported that the concentration of TRAb in the fetal circulation increases by the end of the second trimester, reaching a level similar to that of the mother at about 30 weeks gestation.3 Untreated fetal thyrotoxicosis may result in heart failure, which is associated with a perinatal mortality rate of approximately 20%.9 Fetal hyperthyroidism can be associated with various unspecific ultrasound findings such as fetal tachycardia, fetal growth restriction and abnormal amniotic fluid volume.2 Fetal goiter and accelerated bone maturation have also been reported.10 Fetal hyperthyroidism cannot be diagnosed solely based on ultrasound findings; therefore, percutaneous umbilical blood sampling was performed to determine the maternal dosage of anti-thyroid medication needed for fetal therapy in the present study.
In the present case, MMI was selected as a first-line drug against fetal hyperthyroidism. In 2008, Aslam and Inayat11 reported a case of fetal thyrotoxicosis treated with MMI; however, PTU has been used12 in most other reported cases.11,13 PTU has historically been preferred over MMI during pregnancy because PTU is considered to have slower placental transfer kinetics and a lower teratogenic risk than MMI. However, recent studies have demonstrated that these two drugs have similar placental permeability and teratogenic risk.14,15 In addition, the risk of serious hepatic toxicity due to PTU has been recently revisited.16 The United States Food and Drug Administration and the American Thyroid Association have recently recommended use of PTU only in the first trimester of pregnancy, and recommended MMI in the second and third trimesters.17 Also, a case of fetal anti-thyroid therapy has been reported, in which maternal administration of PTU had to be replaced by MMI owing to drug-induced maternal hepatitis.13 Therefore, maternal MMI may become the preferred drug for treatment of fetal hyperthyroidism.
Optimal monitoring of the fetal response to anti-thyroid therapy has not yet been well established. Some investigators state that normalization of fetal heart rate1 and resolution of fetal goiter correlate with improvement of fetal thyroid status during fetal therapy.18 On the other hand, a recent review demonstrated that assessment of fetal heart rate, fetal growth and fetal thyroid size is inadequate for prediction of fetal thyroid status.12 In the present case, after treatment with MMI, the fetus regained a normal heart rate and amniotic fluid volume, but neonatal thyroid function was unexpectedly suppressed. There has also been a report of serial cordocentesis performed for evaluation of fetal thyroid function during fetal therapy;19 however, that report did not include a discussion concerning adverse events owing to repeated cordocentesis. Thus, it is unclear whether serial cordocentesis during fetal anti-thyroid therapy is able to improve outcomes of thyrotoxic fetuses.
The present case of fetal hyperthyroidism in a pregnant woman with remote total thyroidectomy for Graves’ disease was treated using oral maternal MMI. This therapy effectively and safely resolved symptoms of fetal thyrotoxicosis, including fetal tachycardia, oligohydramnios and fetal goiter.
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The authors declare no conflict of interest.
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Sato, Y., Murata, M., Sasahara, J. et al. A case of fetal hyperthyroidism treated with maternal administration of methimazole. J Perinatol 34, 945–947 (2014). https://doi.org/10.1038/jp.2014.163
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