Perinatal/Neonatal Case Presentation

A case of fetal hyperthyroidism treated with maternal administration of methimazole

Abstract

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.

Introduction

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.

Case

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.

Figure 1
figure1

Ultrasound images of transverse view of the fetal neck at 31 weeks gestation. (a) The thyroid gland is located within the region of the ellipse. The trachea (arrow) is seen in the middle of the thyroid gland. Fetal goiter was diagnosed based on the bilobed, solid anterior neck mass, and a neck circumference greater than the 95th percentile. (b) Color Doppler showing central vascularization is suggestive of fetal hyperthyroidism.

Table 1 Fetal blood sampling at 31 weeks’ gestation and cord blood sampling at birth

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.

Discussion

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.

References

  1. 1

    Zimmerman D . Fetal and neonatal hyperthyroidism. Thyroid 1999; 9 (7): 727–733.

    CAS  Article  Google Scholar 

  2. 2

    Polak M, Van Vliet G . Therapeutic approach of fetal thyroid disorders. Horm Res Paediatr 2010; 74 (1): 1–5.

    CAS  Article  Google Scholar 

  3. 3

    Laurberg P, Bournaud C, Karmisholt J, Orgiazzi J . Management of Graves' hyperthyroidism in pregnancy: focus on both maternal and foetal thyroid function, and caution against surgical thyroidectomy in pregnancy. Eur J Endocrinol 2009; 160 (1): 1–8.

    CAS  Article  Google Scholar 

  4. 4

    Moore TR, Cayle JE . The amniotic fluid index in normal human pregnancy. Am J Obstet Gynecol 1990; 162 (5): 1168–1173.

    CAS  Article  Google Scholar 

  5. 5

    Ranzini AC, Ananth CV, Smulian JC, Kung M, Limbachia A, Vintzileos AM . Ultrasonography of the fetal thyroid: nomograms based on biparietal diameter and gestational age. J Ultrasound Med 2001; 20 (6): 613–617.

    CAS  Article  Google Scholar 

  6. 6

    Spremovic-Radjenovic S, Gudovic A, Lazovic G, Marinkovic J, Radunovic N, Ljubic A . Fetal free thyroxine concentrations in pregnant women with autoimmune thyroid disease. J Clin Endocrinol Metab 2012; 97 (11): 4014–4021.

    CAS  Article  Google Scholar 

  7. 7

    Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011; 21 (10): 1081–1125.

    Article  Google Scholar 

  8. 8

    Guibourdenche J, Noel M, Chevenne D, Vuillard E, Volumenie JL, Polak M, et al. Biochemical investigation of foetal and neonatal thyroid function using the ACS-180SE analyser: clinical application. Ann Clin Biochem 2001; 38 (Part 5): 520–526.

    CAS  Article  Google Scholar 

  9. 9

    Zakarija M, McKenzie JM, Hoffman WH . Prediction and therapy of intrauterine and late-onset neonatal hyperthyroidism. J Clin Endocrinol Metab 1986; 62 (2): 368–371.

    CAS  Article  Google Scholar 

  10. 10

    Luton D, Le Gac I, Vuillard E, Castanet M, Guibourdenche J, Noel M, et al. Management of Graves' disease during pregnancy: the key role of fetal thyroid gland monitoring. J Clin Endocrinol Metab 2005; 90 (11): 6093–6098.

    CAS  Article  Google Scholar 

  11. 11

    Aslam M, Inayat M . Fetal and neonatal Graves disease: a case report and review of the literature. South Med J 2008; 101 (8): 840–841.

    Article  Google Scholar 

  12. 12

    Heckel S, Favre R, Schlienger JL, Soskin P . Diagnosis and successful in utero treatment of a fetal goitrous hyperthyroidism caused by maternal Graves' disease. A case report. Fetal Diagn Ther 1997; 12 (1): 54–58.

    CAS  Article  Google Scholar 

  13. 13

    Wenstrom KD, Weiner CP, Williamson RA, Grant SS . Prenatal diagnosis of fetal hyperthyroidism using funipuncture. Obstet Gynecol 1990; 76 (3, Part 2): 513–517.

    CAS  PubMed  Google Scholar 

  14. 14

    Rivkees SA . Propylthiouracil versus methimazole during pregnancy: an evolving tale of difficult choices. J Clin Endocrinol Metab 2013; 98 (11): 4332–4335.

    CAS  Article  Google Scholar 

  15. 15

    Mortimer RH, Cannell GR, Addison RS, Johnson LP, Roberts MS, Bernus I . Methimazole and propylthiouracil equally cross the perfused human term placental lobule. J Clin Endocrinol Metab 1997; 82 (9): 3099–3102.

    CAS  PubMed  Google Scholar 

  16. 16

    Nakamura H, Noh JY, Itoh K, Fukata S, Miyauchi A, Hamada N . Comparison of methimazole and propylthiouracil in patients with hyperthyroidism caused by Graves' disease. J Clin Endocrinol Metab 2007; 92 (6): 2157–2162.

    CAS  Article  Google Scholar 

  17. 17

    Bahn RS, Burch HS, Cooper DS, Garber JR, Greenlee CM, Klein IL, et al. The role of propylthiouracil in the management of Graves' disease in adults: report of a meeting jointly sponsored by the American Thyroid Association and the Food and Drug Administration. Thyroid 2009; 19 (7): 673–674.

    CAS  Article  Google Scholar 

  18. 18

    Huel C, Guibourdenche J, Vuillard E, Ouahba J, Piketty M, Oury JF, et al. Use of ultrasound to distinguish between fetal hyperthyroidism and hypothyroidism on discovery of a goiter. Ultrasound Obstet Gynecol 2009; 33 (4): 412–420.

    CAS  Article  Google Scholar 

  19. 19

    Nachum Z, Rakover Y, Weiner E, Shalev E . Graves' disease in pregnancy: prospective evaluation of a selective invasive treatment protocol. Am J Obstet Gynecol 2003; 189 (1): 159–165.

    Article  Google Scholar 

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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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