Evaluation and management of neonatal Graves' disease
- Stephen LaFranchi, MD
Stephen LaFranchi, MD
- Professor of Pediatrics
- Oregon Health & Sciences University
Neonatal Graves' disease refers to the hyperthyroidism that is seen in a small percentage of infants born to mothers with Graves' disease. Although neonatal Graves' disease is usually self-limited, it can be severe, even life-threatening, and have deleterious effects on neural development. Maternal Graves' disease is by far the most common cause of neonatal hyperthyroidism. Active Graves' disease in a pregnant woman can lead to either hyper- or hypothyroidism in the fetus and neonate, depending on the balance of the maternal stimulatory and inhibitory antibody and antithyroid drug effect . Babies destined to develop neonatal Graves' disease, however, are almost always hyperthyroid at or within one week of birth. (See "Hyperthyroidism during pregnancy: Treatment".)
Graves' hyperthyroidism occurs in approximately 0.2 percent of women, and it occurs in approximately one to five percent of infants born to these mothers [2-4]. Thus, neonatal Graves' hyperthyroidism would be expected to occur in approximately 1:25,000 neonates, and affects males and females equally.
Why only 1 to 5 percent of infants of mothers with Graves' hyperthyroidism are affected is explained by the level of the maternal serum stimulatory thyrotropin receptor antibody (TSHR-Ab). The higher the maternal stimulatory TSHR-Ab concentration is during the third trimester, the greater is the likelihood of neonatal Graves' hyperthyroidism. In practice, neonatal hyperthyroidism is most likely when the TSHR-Ab activity of maternal serum is above 500 percent of the values in serum of normal subjects [5,6]. This was illustrated in a study of 29 pregnant women with a history of Graves' disease that confirmed the relationship of high TSHR-Ab and neonatal thyrotoxicosis. In the 35 live births, there were six cases of neonatal Graves' disease, all of whom had a TSHR-Ab level above 500 percent of normal; in addition, six other babies with a TSHR-Ab above 500 percent of normal did not develop hyperthyroidism. In this study, measurement of the TSHR-Ab had a 100 percent sensitivity, with 50 percent specificity. The incidence of neonatal Graves' disease in this study was 17 percent, which is a higher rate than previously reported .
Neonatal (and fetal) Graves' hyperthyroidism results from the transplacental passage of maternal stimulatory thyrotropin receptor antibody (TSHR-Ab) [3,8,9]. Most neonatal Graves' disease occurs in the setting of active Graves' hyperthyroidism in the mother. However, the disorder also can occur in infants of women with a history of Graves' hyperthyroidism treated with thyroidectomy or radioactive iodine in the past . After a woman with Graves' disease undergoes one of these treatments, the risk of having an infant affected by neonatal Graves' disease falls over time, in conjunction with decreases in TSHR-Ab levels. The risk of neonatal Graves' disease is low five years after radioactive iodine, but some mothers still have persistent TSHR-Ab elevation and will deliver babies with neonatal Graves' disease . As described above, measurement of maternal serum TSHR-Ab may be helpful in predicting whether a newborn will be affected. (See "Hyperthyroidism during pregnancy: Treatment".)
Serial in utero ultrasonography with measurement of fetal thyroid size has also been reported to help determine which neonates are likely to manifest neonatal hyperthyroidism . In a report of 20 pregnant women with Graves' disease treated with an antithyroid drug, the fetal thyroid gland was enlarged in five pregnancies. In these five patients, the maternal antithyroid medication dose was decreased resulting in a reduction of the fetal thyroid gland to a normal size in three cases but in the other two cases the gland remained enlarged. These latter two infants both developed neonatal Graves' disease . Thus, care must be taken because fetal goiter may be a feature of in utero hypothyroidism or hyperthyroidism. Another study using ultrasonography reported that a hyperthyroid fetus was more likely to have a goiter with central vascularization, along with other findings, including fetal tachycardia, increased fetal movement, and advanced bone maturity .
- Polak M, Legac I, Vuillard E, et al. Congenital hyperthyroidism: the fetus as a patient. Horm Res 2006; 65:235.
- Ramsay I, Kaur S, Krassas G. Thyrotoxicosis in pregnancy: results of treatment by antithyroid drugs combined with T4. Clin Endocrinol (Oxf) 1983; 18:73.
- McKenzie JM, Zakarija M. Fetal and neonatal hyperthyroidism and hypothyroidism due to maternal TSH receptor antibodies. Thyroid 1992; 2:155.
- De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012; 97:2543.
- Zakarija M, McKenzie JM. Pregnancy-associated changes in the thyroid-stimulating antibody of Graves' disease and the relationship to neonatal hyperthyroidism. J Clin Endocrinol Metab 1983; 57:1036.
- McKenzie JM, Zakarija M. Clinical review 3: The clinical use of thyrotropin receptor antibody measurements. J Clin Endocrinol Metab 1989; 69:1093.
- Peleg D, Cada S, Peleg A, Ben-Ami M. The relationship between maternal serum thyroid-stimulating immunoglobulin and fetal and neonatal thyrotoxicosis. Obstet Gynecol 2002; 99:1040.
- Sunshine P, Kusumoto H, Kriss JP. Survival time of circulating long-acting thyroid stimulator in neonatal thyrotoxicosis: implications for diagnosis and therapy of the disorder. Pediatrics 1965; 36:869.
- Smallridge RC, Wartofsky L, Chopra IJ, et al. Neonatal thyrotoxicosis: alterations in serum concentrations of LATS-protector, T4, T3, reverse T3, and 3,3'T2. J Pediatr 1978; 93:118.
- Volpé R, Ehrlich R, Steiner G, Row VV. Graves' disease in pregnancy years after hypothyroidism with recurrent passive-transfer neonatal Graves' disease in offspring. Therapeutic considerations. Am J Med 1984; 77:572.
- Hamada N, Momotani N, Ishikawa N, et al. Persistent high TRAb values during pregnancy predict increased risk of neonatal hyperthyroidism following radioiodine therapy for refractory hyperthyroidism. Endocr J 2011; 58:55.
- Cohen O, Pinhas-Hamiel O, Sivan E, et al. Serial in utero ultrasonographic measurements of the fetal thyroid: a new complementary tool in the management of maternal hyperthyroidism in pregnancy. Prenat Diagn 2003; 23:740.
- Huel C, Guibourdenche J, Vuillard E, et al. Use of ultrasound to distinguish between fetal hyperthyroidism and hypothyroidism on discovery of a goiter. Ultrasound Obstet Gynecol 2009; 33:412.
- O'Connor MJ, Paget-Brown AO, Clarke WL. Premature twins of a mother with Graves' disease with discordant thyroid function: a case report. J Perinatol 2007; 27:388.
- Duprez L, Parma J, Van Sande J, et al. Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism. Nat Genet 1994; 7:396.
- Kopp P, van Sande J, Parma J, et al. Brief report: congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene. N Engl J Med 1995; 332:150.
- Holzapfel HP, Wonerow P, von Petrykowski W, et al. Sporadic congenital hyperthyroidism due to a spontaneous germline mutation in the thyrotropin receptor gene. J Clin Endocrinol Metab 1997; 82:3879.
- Chester J, Rotenstein D, Ringkananont U, et al. Congenital neonatal hyperthyroidism caused by germline mutations in the TSH receptor gene. J Pediatr Endocrinol Metab 2008; 21:479.
- Yoshimoto M, Nakayama M, Baba T, et al. A case of neonatal McCune-Albright syndrome with Cushing syndrome and hyperthyroidism. Acta Paediatr Scand 1991; 80:984.
- Mastorakos G, Mitsiades NS, Doufas AG, Koutras DA. Hyperthyroidism in McCune-Albright syndrome with a review of thyroid abnormalities sixty years after the first report. Thyroid 1997; 7:433.
- Weinstein LS, Shenker A, Gejman PV, et al. Activating mutations of the stimulatory G protein in the McCune-Albright syndrome. N Engl J Med 1991; 325:1688.
- Farrehi C. Accelerated maturity in fetal thyrotoxicosis. Clin Pediatr (Phila) 1968; 7:134.
- Zakarija M, McKenzie JM, Hoffman WH. Prediction and therapy of intrauterine and late-onset neonatal hyperthyroidism. J Clin Endocrinol Metab 1986; 62:368.
- Weber G, Ielo V, Vigone MC, et al. Neonatal hyperthyoidism: Report of eight cases. Ital J Pediatr 2001; 27:757.
- Levy-Shraga Y, Tamir-Hostovsky L, Boyko V, et al. Follow-up of newborns of mothers with Graves' disease. Thyroid 2014; 24:1032.
- van der Kaay DC, Wasserman JD, Palmert MR. Management of Neonates Born to Mothers With Graves' Disease. Pediatrics 2016; 137.
- Skuza KA, Sills IN, Stene M, Rapaport R. Prediction of neonatal hyperthyroidism in infants born to mothers with Graves disease. J Pediatr 1996; 128:264.
- Besançon A, Beltrand J, Le Gac I, et al. Management of neonates born to women with Graves' disease: a cohort study. Eur J Endocrinol 2014; 170:855.
- Tajima T, Jo W, Fujikura K, et al. Elevated free thyroxine levels detected by a neonatal screening system. Pediatr Res 2009; 66:312.
- Rivkees SA, Szarfman A. Dissimilar hepatotoxicity profiles of propylthiouracil and methimazole in children. J Clin Endocrinol Metab 2010; 95:3260.
- U.S. Food and Drug Administration, update 4/21/2010: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm164162.htm (Accessed on September 09, 2010).
- Endocrine Society statement, April 14th, 2009. http://www.endo-society.org/advocacy/legislative/SocietyStatementontheNEJMLettetotheEditoronPTUUseInChildren.cfm.
- Bahn RS, Burch HB, Cooper DS, 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; 19:673.
- Daneman D, Howard NJ. Neonatal thyrotoxicosis: intellectual impairment and craniosynostosis in later years. J Pediatr 1980; 97:257.
- Mandel SH, Hanna CE, LaFranchi SH. Diminished thyroid-stimulating hormone secretion associated with neonatal thyrotoxicosis. J Pediatr 1986; 109:662.
- Kempers MJ, van Tijn DA, van Trotsenburg AS, et al. Central congenital hypothyroidism due to gestational hyperthyroidism: detection where prevention failed. J Clin Endocrinol Metab 2003; 88:5851.
- Kempers MJ, van Trotsenburg AS, van Rijn RR, et al. Loss of integrity of thyroid morphology and function in children born to mothers with inadequately treated Graves' disease. J Clin Endocrinol Metab 2007; 92:2984.
- Srisupundit K, Sirichotiyakul S, Tongprasert F, et al. Fetal therapy in fetal thyrotoxicosis: a case report. Fetal Diagn Ther 2008; 23:114.
- Miyata I, Abe-Gotyo N, Tajima A, et al. Successful intrauterine therapy for fetal goitrous hypothyroidism during late gestation. Endocr J 2007; 54:813.
- Bliddal S, Rasmussen ÅK, Sundberg K, et al. Graves' disease in two pregnancies complicated by fetal goitrous hypothyroidism: successful in utero treatment with levothyroxine. Thyroid 2011; 21:75.
- Natural history
- Other causes of neonatal hyperthyroidism
- - Thyrotropin-receptor activating mutations
- - Alpha subunit-G-protein activating mutation (McCune-Albright syndrome)
- CLINICAL MANIFESTATIONS
- Timing of symptoms
- Maternal Graves’ disease during pregnancy
- - Prenatal testing
- - Cord blood
- - Testing of the neonate
- Infants coming to attention after birth
- Neonatal Graves’ disease
- Hypothyroidism (transient)
- FETAL HYPERTHYROIDISM
- SUMMARY AND RECOMMENDATIONS