Antenatal Diagnosis and Treatment of a Dyshormonogenetic Fetal Goiter

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1 Case Report Antenatal Diagnosis and Treatment of a Dyshormonogenetic Fetal Goiter Kathleen A. Mayor-Lynn, MD, Henry J. Rohrs, III, MD, Amelia C. Cruz, MD, Janet H. Silverstein, MD, Douglas Richards, MD Abbreviations TSH, thyroid-stimulating hormone Received June 18, 2008, from the Department of Obstetrics and Gynecology, Division of Maternal- Fetal Medicine (K.A.M.-L., A.C.C., D.R.), and Department of Pediatric Endocrinology (H.J.R., J.H.S.), University of Florida College of Medicine, Gainesville, Florida USA. Revision requested July 14, Revised manuscript accepted for publication August 4, Address correspondence to Kathleen A. Mayor- Lynn, MD, Department of Obstetrics and Gynecology, University of Florida College of Medicine, 1600 SW Archer Rd, Box , Gainesville, FL USA. mayorlyn@obgyn.ufl.edu Congenital hypothyroidism is one of the most common congenital diseases, with an incidence of 1 per 4000 live births. 1 The most serious complication of untreated congenital hypothyroidism is profound mental retardation, which can usually be prevented if diagnosed early and adequately treated. However, even with treatment beginning within the first few days of life, neonates with clinical features of congenital hypothyroidism at birth may already have had substantial damage to the central nervous system. 2 Fetal hypothyroidism, however, is usually not clinically apparent and is often unrecognized unless the mother has a history of a thyroid disorder or antithyroid medication. However, both a fetal goiter and hypothyroidism can lead to serious sequelae. Long-term follow-up of children with untreated fetal hypothyroidism reveals the presence of mental retardation, delayed skeletal maturation, hearing defects, and deficits in focusing, even with immediate postnatal screening and thyroid replacement. 1 Some fetuses, especially those with inborn errors of thyroid hormone synthesis, may have large goiters in utero, which may result in polyhydramnios due to esophageal and tracheal compression, both of which may be compounded by neck hyperextension leading to dystocia. 1 Respiratory impairment can also occur because of compression of the trachea by the enlarged thyroid gland. The fetal thyroid status can be accurately assessed by fetal blood sampling via cordocentesis, but the risk of fetal death with this procedure is reported to be about 1%, even in experienced hands. Fetal therapy is also problematic; because limited thyroxine crosses the placenta, 3 effective treatments include administration of thyroxine or triiodothyronine either into the amniotic cavity or by cordocentesis. 4 We report a case of congenital hypothyroidism diagnosed by identification of a large fetal goiter on second-trimester sonography. Fetal hypothyroidism was documented by measuring amniotic fluid thyroid hormone levels and managed with weekly intra-amniotic injections of levothyroxine and measurements of amniotic fluid thyroid hormone levels by the American Institute of Ultrasound in Medicine J Ultrasound Med 2009; 28: /09/$3.50

2 Dyshormonogenetic Fetal Goiter Case Report A 16-year-old female patient, gravida 1, para 0, was referred to our prenatal diagnosis center at 22 weeks gestation for counseling and targeted sonography because her brother had DiGeorge syndrome and a congenital heart defect. Sonography showed a mm fetal goiter (Figures 1 and 2) and a mildly increased quantity of amniotic fluid. The sonographic findings were otherwise normal. She had no medical problems and was taking no medications. Thyroid antibody test results were negative. There was no family history of thyroid disorders. On the basis of the absence of maternal thyroid antibodies and the large size of the fetal thyroid, a presumptive diagnosis of thyroid dyshormonogenesis was made. Amniocentesis performed at 25 weeks gestation confirmed fetal hypothyroidism (Table 1). Maternal thyroid study results were normal, and test results for thyroglobulin antibody, thyroid peroxidase antibody, thyroid-binding inhibiting immunoglobulin, and thyroid-stimulating immu - no globulin were negative. At 26 weeks gestation, intra-amniotic injections of levothyroxine were started at a dose of 70 µg/kg estimated fetal weight, given as a weekly injection. This dose was chosen on the basis of a case report by Abuhamad et al 5 in 1995, in which hypothyroidism was diagnosed on the basis of cordocentesis, and treatment was successfully performed with weekly intra-amniotic injections of thyroid hormone. Before each treatment, amniotic fluid was withdrawn and sent to the clinical laboratory at the University of Florida for measurement of thyroid-stimulating hormone (TSH), free thyroxine, and total thyroxine concentrations in the amniotic fluid. 6,7 Over the subsequent 5 weeks, the amniotic fluid TSH, free thyroxine, and total thyroxine levels approached normal, with a slight reduction in goiter size. At the time of the sixth intra-amniotic injection, the levothyroxine dose was increased to 15 µg/kg/d (105 µg/kg/wk) because the goiter did not regress as quickly as expected, and the hormone levels remained outside the normal range. Subsequently, the goiter regressed in size, and amniocentesis showed normalization of fetal thyroid function. A total of 11 intra-amniotic injections were administered, with the last injection given at 37 weeks gestation. At 38 weeks gestation the child s mother went into active labor after spontaneous rupture of the membranes. She was delivered of a female neonate weighing 3012 g with Apgar scores of 9 at 1 minute and 9 at 5 minutes and no evidence of airway obstruction. On physical examination, there was a small palpable goiter with obvious redundancy of skin overlying the gland. Thyroid function tests performed on the first day of life showed the neonate to be euthyroid. The neonate was discharged on the second day of life with a levothyroxine dose of 37.5 µg/d. At 3 weeks of age, the neonate continued to be euthyroid, was gaining weight appropriately, and was tolerating the levothyroxine without difficulty. Figure 1. Sagittal view of the fetus at 23.9 weeks showing a large goiter (arrow) preventing neck flexion. Figure 2. Transverse view of the fetal neck at 23.9 weeks showing the large goiter (arrows). The spine (Sp) and trachea (Tr) are also indicated. 68 J Ultrasound Med 2009; 28:67 71

3 Mayor-Lynn et al Discussion Congenital hypothyroidism presenting with thyroid enlargement is very rare (1 per 40,000) and can be found in only 10% to 15% of all cases of congenital hypothyroidism. 1 Dyshormonogenesis occurs with a frequency of 1 per 30,000 neonates, accounting for approximately 15% of all hypothyroid neonates. This disorder is caused by an autosomal recessive mutation in the genes encoding one or more of the steps in iodothyronine synthesis and secretion. 2 Neonatal screening programs for congenital hypothyroidism were initiated in 1974 and have been successful in making an early diagnosis and facilitating treatment within the first few weeks of life. 8,9 Although the screen has substantially improved the outcome for children with a diagnosis of congenital hypothyroidism, there are reports of specific defects in hearing and speech and lower IQ scores at 5 to 7 years of age in those children who had evidence of hypothyroidism in utero, severe chemical hypothyroidism at birth, or a delay in treatment. 5 To avoid these possible adverse neurologic events, we think that prenatal treatment is indicated when fetal hypothyroidism is diagnosed. Another potential benefit of treatment is that a goiter usually shrinks with treatment, avoiding the complications associated with mechanical obstruction of the esophagus and trachea. Additionally, normalization of fetal thyroid hormone levels may be beneficial to the developing fetal brain. 4 The diagnosis of fetal hypothyroidism has traditionally been made with direct measurement of fetal thyroid function via cordocentesis. Although this is a well-established method, cordocentesis has a 0.5% to 9% complication rate, including fetal bleeding, infections, bradycardia, premature rupture of membranes, and fetal death, even when the procedure is performed by experts When complications occur at a very early gestational age, emergency delivery may result in severe iatrogenic prematurity. Given these concerns and the very high likelihood that the goiter was caused by dyshormonogenesis, we thought that presumptive treatment, with confirmation by amniotic fluid thyroid function tests, carried the least chance of serious morbidity. Table 1. Thyroid Function as Measured in Amniotic Fluid Gestational Age, wk TSH, miu/l a 25 (before fetal treatment) a Normal, 0.04 to 0.51 miu/l. Early reports on amniotic fluid concentrations of thyroid hormone and TSH suggested that they do not reliably predict the fetal thyroid status; however, more recent reports have shown that amniotic fluid TSH values could reflect the fetal rather than maternal thyroid status. In 2001, Perrotin et al 10 reported a case in which evaluation of the thyroid status in a fetus with a goiter was performed via amniocentesis, measuring levels of TSH. They treated the fetus with levothyroxine and showed a gradual decrease in the amniotic fluid TSH levels. Their diagnosis was subsequently confirmed with neonatal cord blood, showing an elevated serum TSH level. In another report in 2005, Mirsaeid Ghazi et al 13 described an Iranian family with 3 consecutive pregnancies complicated by fetal goiters; in the final pregnancy, amniocentesis was performed for assessment of TSH and thyroxine values, and the fetus received treatment with intra-amniotic levothyroxine. The diagnosis of fetal hypothyroidism was confirmed by neonatal and infantile elevated serum TSH levels, supporting the concept that amniotic fluid TSH could be an acceptable marker for the diagnosis of hypothyroidism in the goitrous fetus when serum fetal TSH determination by cordocentesis might be hazardous or impractical. Reference ranges have been established for thyroid concentrations in amniotic fluid, most recently by Baumann and Gronowski 7 in Factors that could alter amniotic fluid thyroid hormone levels are the differential dilution from different quantities of amniotic fluid and, for repeated testing, the fact J Ultrasound Med 2009; 28:

4 Dyshormonogenetic Fetal Goiter that thyroxine levels could reflect hormone remaining in the amniotic fluid from the prior treatment. Some authors have suggested that measurement of TSH and iodothyronines in amniotic fluid is unreliable because of the unknown relative contributions from the mother and fetus. 14 In our case, however, because the maternal TSH level was normal, the increased amniotic fluid TSH level was the result of fetal hypothyroidism. This conclusion is consistent with previous reports and supports the suggestion that amniotic fluid TSH levels reflect fetal hypothalamic-pituitary-thyroid function. Prior reports of prenatal treatment of fetal thyroid dyshormonogenesis helped guide our management. We found 9 reported cases of fetal goitrous hypothyroidism treated with intraamniotic injections of thyroxine. 1,4,5,9,10,13,15 17 Amniocentesis was used for diagnosis in 3 of the 9 reports, 10,13,16 and fetal blood sampling was the method for diagnosis in the other 6 reports. Sagot et al 16 described a case in which the diagnosis was made at 23 weeks gestation with a TSH assay in amniotic fluid. In this case, they subsequently performed cordocentesis at 27 weeks to assess the fetal thyroid status. 16 That may be another option in cases in which the physician may be hesitant to perform cordocentesis at the threshold of viability. We think that we were able to monitor the fetal status adequately with amniocentesis and did not need to subject the patient to the increased risk of cordocentesis. The number of injections ranged from 1 to 9. There are 4 cases in the literature in which early treatment was undertaken, the earliest at 26 weeks, as in this case. 1,5,10,17 In all but 1 pregnancy, the fetal goiter decreased rapidly in size with the treatment. 10 All women were delivered at term via either spontaneous vaginal delivery or cesarean delivery. None required cesarean delivery for dystocia, one of the potential consequences of a fetal neck mass. In summary, fetal thyroid dyshormonogenesis should be suspected when a fetal goiter is diagnosed in the absence of any maternal thyroid disease. The disease can be effectively treated by intra-amniotic thyroxine administration. This treatment has the potential to prevent impairment of the developing fetal brain and to prevent the neonatal airway problems that may be caused by a large fetal goiter. References 1. Simsek M, Mendilcioglu I, Mihci E, Karagüzel G, Taskin O. 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5 Mayor-Lynn et al 16. Sagot P, David A, Yvinec M, et al. Intrauterine treatment of thyroid goiters. Fetal Diagn Ther 1991; 6: Grüner C, Kollert A, Wildt L, Dörr HG, Beinder E, Lang N. Intrauterine treatment of fetal goitrous hypothyroidism controlled by determination of thyroid-stimulating hormone in fetal serum: a case report and review of the literature. Fetal Diagn Ther 2001; 16: J Ultrasound Med 2009; 28: