Original Article in the Management of Neonatal Graves’ Disease

Sonja M. Earles, MD this condition (which includes many intrauterine deaths and Peter M. Gerrits, MD stillbirths), approaches 25%.1 We previously reported the successful David J. Transue, MD management of a newborn infant with thyrotoxicosis using the iopanoic acid and propranolol2 and we now report the successful management of five additional cases.

OBJECTIVE: Traditionally, neonatal thyrotoxicosis has been managed with antithyroid and/or as well as , propranol and digitalis when CASE SUMMARIES necessary. The purpose of this study was to evaluate the management of The initial maternal and infant clinical and laboratory data are neonatal thyrotoxicosis using the radio- iopanoic acid. summarized in Table 1. The maternal age was between 25 and 43 METHODS: years and maternal TSI levels ranged from 409 to 1431% (normal We managed five cases of neonatal thyrotoxicosis. All infants were treated <130%). Maternal TSI levels >500% are predictive of neonatal 3 initially with (1.7 mg/kg/day) and iopanoic acid 250 to Graves’ disease. There was a history of Graves’ disease in each of 500 mg every third or fourth day. the mothers. Three women had developed Graves’ disease during the pregnancy and one (the mother of cases 1 and 2) had RESULTS: previously had a ablation with radioactive iodine and was In all cases, clinical signs improved and T3 and T4 levels decreased taking . Antithyroid was administered to dramatically within 24 to 72 hours. No toxic side effects were noted. three women (and transplacentally to their fetuses) during their CONCLUSION: pregnancies. Neonatal thyrotoxicosis can be managed successfully using iopanoic acid. Two of the five infants were born before 37 weeks of gestation Iopanoic acid is essentially free of side effects and need only be and case 1 was delivered at 32-6/7 weeks with undiagnosed and administered every 3 to 4 days. When administered until (transplacental) untreated fetal . Tachycardia was present in three maternal TSI has been metabolized by the neonate, iopanoic acid infants and one infant was asymptomatic. Thyroid studies before maintains euthyroid status with no risk of . With treatment confirmed the diagnosis of hyperthyroidism (Table 2). T4 conventional therapy, (PTU) must be administered three and T3 levels were elevated in all infants and TSH was undetected times a day. PTU also carries a significant risk of toxic side effects and a in four. week or more of therapy is required to correct the hyperthyroid state and All infants were treated with propranolol and iopanoic acid. The may induce hypothyroidism. average mean starting dose of propranolol was 1.7 mg/kg/day, Journal of Perinatology (2004) 24, 105–108. doi:10.1038/sj.jp.7211046 which was then adjusted depending upon the patient response. Published online 22 January 2004 Iopanoic acid, 250 or 500 mg was given every third or fourth day as per the recommendations of Karpman et al.4 who administered 3000 mg/1.7m2 to adults every third day.4 The duration of treatment was 24 to 94 days based on the infant’s clinical response INTRODUCTION and the time to resolution appears to be directly related to maternal Abnormalities of thyroid function in the mother and an increase in TSI levels (r ¼ 0.914, p<0.05) (Figure 1). We decreased the dose maternal-thyroid-stimulating immune globulin (TSI) can lead to of propranolol when the resting heart rate was less than 120. fetal and neonatal Graves’ disease, a severe, usually transient, Iopanoic acid was decreased at approximately 6 weeks and T4 and derangement of thyroid function. The perinatal mortality rate in T3 levels were monitored. If the levels increased, we resumed the previous dose for another 7 to 14 days. TSI levels are useful to gauge therapy, but it may take 10 to 14 days to obtain results. No adverse effects were observed. Department of Pediatrics, William Beaumont Hospital, Royal Oak, MI, USA. The infant with the highest TSI did not normalize T3 for 50 Address for correspondence and reprint requests to Peter M. Gerrits, MD, 3535 W. 13 Mile Road, days, but was clinically asymptomatic and gaining weight Royal Oak, MI 48073, USA. normally. This infant was treated for 77 days.

Journal of Perinatology 2004; 24:105–108 r 2004 Nature Publishing Group All rights reserved. 0743-8346/04 $25 www.nature.com/jp 105 Earles et al. Management of Neonatal Graves’ Disease

Table 1 Maternal and Infant Data

Case study Maternal Maternal Maternal Gestational Birth Age at Symptoms age (years) TSI (%) age at birth weight (kg) diagnosis at (weeks) (days) diagnosis

1 25 1190 Levothyroxine 32–6/7 2.085 1 Irritable, tachycardic, tachypneic, exophthalmic 2 27 1431 PTU 38–1/7 2.947 2 Goiter 3 36 409 PTU 40–1/7 3.66 7 None 4 26 683 PTU, propranolol 33–5/7 1.742 6 Tachypneic, tachycardic 5 43 426 Methimazole 37 2.55 16 Tachycardic, poor growth

Table 2 Infant Response to Iopanoic Acid Therapy

Case study Pretreatment Iopanoic acid Propanolol Days to normalization Therapy duration dose (mg/days) dose (mg/kg/day) T3 (ng/dl) T4 (mcg/dl) TSH (mlU/ml) T3 T4 TSH (days)

1 314 25.6 ND 500/3 1.9 10 19 94 94 2 1000 23.5 ND 500/3 1.4 50 8 64 77 3 314 24.7 ND 500/3 1.6 5 13 19 34 4 315 >36.5 0.36 250/4 2.4 10 60 10 40 5 123 19.3 ND 500/4 1.2 7 24 15 24

ND ¼ not detected.

100

90

80

70

60

50

40

30

Duration of Therapy (days) 20

10

0 0 200 400 600 800 1000 1200 1400 1600 Maternal TSI (%) Figure 1. Linear regression plot of maternal TSI levels against the total duration of therapy showing a significant correlation y ¼ 0.0596: þ 4.473, r ¼ 0.9140 (p<0.05).

DISCUSSION levels of TSI and thus bear hyperthyroid neonates. Zakarija and McKenzie3 studied 20 infants with neonatal Graves’ disease The fetal thyroid gland begins to produce thyroid hormone by and found that a maternal TSI greater than 500% basal activity 18 to 20 weeks of gestation,5,6 at which time the maternal TSI in the third trimester was always associated with a hyperthyroid that crosses the placenta can stimulate thyroid hormone infant. production. Mothers who have been treated for Graves’ disease The diagnosis of neonatal Graves’ disease is based on the by surgical or chemical ablation of their thyroid glands, and maternal history of Graves’ disease, the clinical findings in the fetus who are euthyroid, may nevertheless have persistently elevated and neonate, and elevated neonatal T3 and T4 levels and a

106 Journal of Perinatology 2004; 24:105–108 Management of Neonatal Graves’ Disease Earles et al.

suppressed TSH. Signs of thyrotoxicosis in the fetus include days. Furthermore, hypothyroidism is frequently induced with PTU tachycardia, excessive fetal activity, heart failure, and fetal death as and there is a significant risk of toxic side effects with thionamides early as 24 weeks of gestation. After birth, thyrotoxicosis may present including rash, nausea, and agranulocytosis. In addition, at any time during the first weeks of life. If the mother is receiving correction of the hyperthyroid state with PTU may take a week or antithyroid treatment with a thionamide, enough may cross more. Nevertheless, whether iopanoic acid or conventional therapy the placenta to delay the onset of symptoms for up to a week.1 is used, the total duration of therapy is typically 6 to 12 weeks. The signs and symptoms of neonatal Graves’ disease include No toxic side effects have been reported with iopanoic acid in irritability, flushing, tachycardia, poor weight gain, weight loss in adults.2,4,10,11,14–18 We have observed no toxic effects in infants. 16,17 the face of a lusty appetite, thyroid enlargement, and Thyroid hormone levels decrease more rapidly and T3 levels exophthalmos. Craniosynostosis is a less common complication. often normalize within 24 to 72 hours. There is no risk of These clinical signs may present suddenly and progress rapidly. In treatment-induced hypothyroidism4,14,16,17,19 and the drug is normal newborns, there is an abrupt increase in the peripheral administered every 3 to 4 days as opposed to TID. Since 7–9 conversion of T4 to T3 and, when coupled with a large pool of cardiovascular thyrotoxic effects are common in neonates with T4 available in the hyperthyroid newborn, this phenomenon may hyperthyroidism (Table 1), we recommend propranolol at the time contribute to the rapid progression of clinical findings. In the of diagnosis to control or prevent cardiovascular symptoms. absence of exophthalmos, however, the signs and symptoms can be Iopanoic acid does not appear to be adequate therapy for long- nonspecific, cardiac arrhythmias and congestive heart failure term treatment of Graves’ disease in all patients19 but, because the accounting for the high mortality rate.1 disease is self-limiting in neonates, iopanoic acid is appropriate for With proper monitoring, the thyrotoxic fetus can be identified the management of neonatal Graves’ disease. The radiocontrast and treated transplacentally with thionamides. The effect of agents may prove effective in the management of other causes of therapy is assessed by using serial ultrasonography to monitor fetal transient hyperthyroidism such as thyroxine overdose and subacute heart rate, growth and goiter development, and fetal thyroid thyroiditis11 and the use of these agents could also be considered in function can be monitored directly using sampled by the management of . cordocentesis. The signs of neonatal hyperthyroidism abate over several weeks (typically 6 weeks) as the maternally derived TSI is metabolized. References TSI half-life in the infant is approximately 12 days.4 1. Fisher DA. The thyroid. In: Kaplan SA, editor. Clinical Pediatric Iopanoic acid is a negatively charged iodinated molecule. It Endocrinology. Philadelphia; PA:WB Saunders; 1990. p. 114–5. consists of a benzene ring substituted with three iodine atoms, an 2. Transue D, Chan J, Kaplan M. Management of neonatal Graves’ disease amino group, and an isovaleric acid side chain. It was developed with iopanoic acid. J Pediatr 1992;121:472–4. for use as a contrast agent to visualize the gallbladder. Both 3. Zakarija M, McKenzie JM. Pregnancy–associated changes in the thyroid– iopanoate and ipodate (a similar radiocontrast agent) inhibit stimulating antibody of Graves’ disease and the relationship to neonatal peripheral deiodination of T to T .10–13 molecules are hyperthyroidism. J Clin Endocrinol Metab 1983;57:1036–40. 4 3 4. Karpman BA, Rapoport B, Filetti S, Fisher DA. Treatment of neonatal released as iopanoate is degraded, which probably accounts for the hyperthyroidism due to Graves’ disease with sodium ipodate. J Clin observed inhibition of colloid formation and release of T4 and T3 Endocrinol Metab 1987;64:119–23. 10,14,15 from the thyroid. 5. Petersen S, Serup J. Neonatal thyrotoxicosis. Acta Paediatr Scand The dose of iopanoic acid was extrapolated from the dose used 1977;66:639–42. 2 in adults (3 g/1.7 m every 3 days) as recommended by Karpman 6. Cove DH, Johnston P. Fetal hyperthyroidism: experience of treatment in four et al.4 Tablets are crushed and spoon fed. The dose (250 to siblings. Lancet 1985;1:430–2. 500 mg) and frequency (every 3 to 4 days) were adjusted based on 7. Erenberg A, Phelps D, Lam R, Fisher DA. Total and free thyroid hormone clinical judgment. We used iopanoic acid because it was concentrations in the neonatal peroid. Pediatrics 1974;53:211–6. immediately available and shares the antithyroid properties of the 8. Abuid JL, Klein AH, Foley Jr TP, Larson PR. Total and free similar radiocontrast agent, sodium ipodate, which was not and thyroxine in early infancy. J Clin Endocrinol Metab 1974;39:263–8. available at our hospital. 9. Fisher DA, Klein AH. Thyroid development and disorders of thyroid function In contrast to the use of iopanoic acid, standard treatment of in the newborn. N Engl J Med 1981;304:702–2. 10. Wu S, Chopra IJ, Solomon DH, Bennett LR. Changes in circulating neonatal hyperthyroidism has included symptomatic management iodothyronines in euthyroid and hyperthyroid subjects given ipodate with sedatives, propranolol, and digitalis as well as antithyroid (Oragrafin), an agent for oral cholecystography. J Clin Endocrinol Metab drugs and/or iodide. Owing to the short half-life of antithyroid 1978;46:691–7. medication, this approach to management is cumbersome and 11. Chopra IJ, Van Herle AJ, Koreman SG, Viosca S, Younai S. Use of sodium inconvenient. Propylthiouracil (PTU) is administered T.I.D., but is ipodate in management of hyperthyroidism in subacute thyroiditis. J Clin unstable in solution and requires pharmacy formulation every 10 Endocrinol Metab 1995;80:2178–80.

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12. DeGroot LJ, Rue PA. Roentgenographic contrast agents inhibit triiodothyr- 16. Wu S, Shyh T, Chopra IJ, Solomon DH, Huang H, Chu P. Comparison of onine binding to nuclear receptors in vitro. J Clin Endocrinol Metab sodium ipodate (oragrafin) and propylthiouracil in early treatment of 1979;49:538–42. hyperthyroidism. J Clin Endocrinol Metab 1982;54:630–4. 13. Kohrle J, Hesch RD, Loenard JL. Intracellular pathways of iodothyronine 17. Sharp B, Reed AW, Tamagna El, Geffner DL, Hershman JM. Treatment . In: Braverman LE, Utiger RD, editors. Werner and Ingbar’s the of hyperthyroidism with sodium ipodate (oragrafin) in addition Thyroid: a Fundamental and Clinical Text. 6th ed. Philadelphia, PA: JB to propylthiouracil and propranolol. J Clin Endocrinol Metab Lippincott; 1991. p. 144–89. 1981;53:622–5. 14. Wu S, Chopra IJ, Solomon DH, Johnson DE. The effect of repeated 18. Shen D, Wu S, Chopra IJ, et al. Long term treatment of Graves’ administration of ipodate (Oragrafin) in hyperthyroidism. J Clin Endocrinol hyperthyroidism with sodium ipodate. J Clin Endocrinol Metab Metab 1978;47:1358–62. 1985;61:723–7. 15. Bu¨rgi H, Wimpfheimer C, Burger A, Zaunbauer W, Ro¨sler H, Lemarchand– 19. Wang Y, Tsou C, Lin W, Hershman JM. Long term treatment of Graves’ Be´raud T. Changes of circulating thyroxine, triiodothyronine and reverse disease with iopanoic acid (telepaque). J Clin Endocrinol Metab triiodothyronine after radiographic contrast agents. J Clin Endocrinol Metab 1987;65:679–82. 1976;43:1203–10.

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