Antenatal Diagnosis and Treatment ofa Dyshormonogenetic Fetal Goiter

Kathleen A. Mayor-Lynn, MD, Henry J. Rohrs, III, MD,Amelia C. Cruz, MD, Janet H. Silverstein, MD, Douglas Richards, MD

Received June 18, 2008, from the Department ofObstetrics and Gynecology, Division of Maternal-Fetal Medicine (K.A.M.-L., A.C.C., D.R.), andDepartment of Pediatric Endocrinology (H.J.R.,J.H.S.), University of Florida College of Medicine,Gainesville, Florida USA. Revision requested July14, 2008. Revised manuscript accepted for publica-tion August 4, 2008.

Address correspondence to Kathleen A. Mayor-Lynn, MD, Department of Obstetrics andGynecology, University of Florida College ofMedicine, 1600 SW Archer Rd, Box 100294,Gainesville, FL 32610-0294 USA.

E-mail: mayorlyn@obgyn.ufl.edu

AbbreviationsTSH, thyroid-stimulating hormone

Case Report

ongenital hypothyroidism is one of the most commoncongenital diseases, with an incidence of 1 per 4000 livebirths.1 The most serious complication of untreated con-genital hypothyroidism is profound mental retardation,

which can usually be prevented if diagnosed early and adequatelytreated. However, even with treatment beginning within the first fewdays of life, neonates with clinical features of congenital hypothy-roidism at birth may already have had substantial damage to the cen-tral nervous system.2

Fetal hypothyroidism, however, is usually not clinically apparent andis often unrecognized unless the mother has a history of a thyroid dis-order or antithyroid medication. However, both a fetal goiter andhypothyroidism can lead to serious sequelae. Long-term follow-up ofchildren with untreated fetal hypothyroidism reveals the presence ofmental retardation, delayed skeletal maturation, hearing defects, anddeficits in focusing, even with immediate postnatal screening and thy-roid replacement.1

Some fetuses, especially those with inborn errors of thyroid hormonesynthesis, may have large goiters in utero, which may result in polyhy-dramnios due to esophageal and tracheal compression, both of whichmay be compounded by neck hyperextension leading to dystocia.1

Respiratory impairment can also occur because of compression of thetrachea by the enlarged thyroid gland.

The fetal thyroid status can be accurately assessed by fetal blood sam-pling via cordocentesis, but the risk of fetal death with this procedure isreported to be about 1%, even in experienced hands. Fetal therapy isalso problematic; because limited thyroxine crosses the placenta,3

effective treatments include administration of thyroxine or triiodothy-ronine either into the amniotic cavity or by cordocentesis.4

We report a case of congenital hypothyroidism diagnosed by identifi-cation of a large fetal goiter on second-trimester sonography. Fetalhypothyroidism was documented by measuring amniotic fluid thyroidhormone levels and managed with weekly intra-amniotic injections oflevothyroxine and measurements of amniotic fluid thyroid hormonelevels.

C

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Case Report

A 16-year-old female patient, gravida 1, para 0,was referred to our prenatal diagnosis center at22 weeks’ gestation for counseling and target-ed sonography because her brother hadDiGeorge syndrome and a congenital heartdefect. Sonography showed a 40 × 15 × 22-mmfetal goiter (Figures 1 and 2) and a mildlyincreased quantity of amniotic fluid. Thesonographic findings were otherwise normal.She had no medical problems and was takingno medications. Thyroid antibody test resultswere negative. There was no family history of thy-roid disorders. On the basis of the absence ofmaternal thyroid antibodies and the large size ofthe fetal thyroid, a presumptive diagnosis of thy-roid dyshormonogenesis was made.

Amniocentesis performed at 25 weeks’ gesta-tion confirmed fetal hypothyroidism (Table 1).Maternal thyroid study results were normal, andtest results for thyroglobulin antibody, thyroidperoxidase antibody, thyroid-binding–inhibitingimmunoglobulin, and thyroid-stimulating immu -no globulin were negative. At 26 weeks’ gestation,intra-amniotic injections of levothyroxine werestarted at a dose of 70 µg/kg estimated fetalweight, given as a weekly injection. This dosewas chosen on the basis of a case report byAbuhamad et al5 in 1995, in which hypothy-roidism was diagnosed on the basis of cordocen-tesis, and treatment was successfully performedwith weekly intra-amniotic injections of thyroidhormone. Before each treatment, amniotic fluid

was withdrawn and sent to the clinical laborato-ry at the University of Florida for measurement ofthyroid-stimulating hormone (TSH), free thy-roxine, and total thyroxine concentrations inthe amniotic fluid.6,7 Over the subsequent 5weeks, the amniotic fluid TSH, free thyroxine,and total thyroxine levels approached normal,with a slight reduction in goiter size. At thetime of the sixth intra-amniotic injection, thelevothyroxine dose was increased to 15 µg/kg/d(105 µg/kg/wk) because the goiter did notregress as quickly as expected, and the hormonelevels remained outside the normal range.Subsequently, the goiter regressed in size, andamniocentesis showed normalization of fetalthyroid function. A total of 11 intra-amnioticinjections were administered, with the lastinjection given at 37 weeks’ gestation.

At 38 weeks’ gestation the child’s mother wentinto active labor after spontaneous rupture ofthe membranes. She was delivered of a femaleneonate weighing 3012 g with Apgar scores of 9at 1 minute and 9 at 5 minutes and no evidenceof airway obstruction. On physical examination,there was a small palpable goiter with obviousredundancy of skin overlying the gland. Thyroidfunction tests performed on the first day of lifeshowed the neonate to be euthyroid. Theneonate was discharged on the second day of lifewith a levothyroxine dose of 37.5 µg/d. At 3 weeksof age, the neonate continued to be euthyroid,was gaining weight appropriately, and was toler-ating the levothyroxine without difficulty.

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Dyshormonogenetic Fetal Goiter

Figure 1. Sagittal view of the fetus at 23.9 weeks showing alarge goiter (arrow) preventing neck flexion.

Figure 2. Transverse view of the fetal neck at 23.9 weeks show-ing the large goiter (arrows). The spine (Sp) and trachea (Tr) arealso indicated.

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Discussion

Congenital hypothyroidism presenting with thy-roid enlargement is very rare (1 per 40,000) andcan be found in only 10% to 15% of all cases ofcongenital hypothyroidism.1 Dyshormono -genesis occurs with a frequency of 1 per 30,000neonates, accounting for approximately 15% ofall hypothyroid neonates. This disorder is causedby an autosomal recessive mutation in the genesencoding one or more of the steps in iodothyro-nine synthesis and secretion.2 Neonatal screen-ing programs for congenital hypothyroidismwere initiated in 1974 and have been successfulin making an early diagnosis and facilitatingtreatment within the first few weeks of life.8,9

Although the screen has substantially improvedthe outcome for children with a diagnosis of con-genital hypothyroidism, there are reports of spe-cific defects in hearing and speech and lower IQscores at 5 to 7 years of age in those children whohad evidence of hypothyroidism in utero, severechemical hypothyroidism at birth, or a delay intreatment.5

To avoid these possible adverse neurologicevents, we think that prenatal treatment is indi-cated when fetal hypothyroidism is diagnosed.Another potential benefit of treatment is that agoiter usually shrinks with treatment, avoidingthe complications associated with mechanicalobstruction of the esophagus and trachea.Additionally, normalization of fetal thyroid hor-mone levels may be beneficial to the developingfetal brain.4

The diagnosis of fetal hypothyroidism has tra-ditionally been made with direct measurementof fetal thyroid function via cordocentesis.Although this is a well-established method, cor-docentesis has a 0.5% to 9% complication rate,including fetal bleeding, infections, bradycardia,premature rupture of membranes, and fetaldeath, even when the procedure is performed byexperts.10–12 When complications occur at a veryearly gestational age, emergency delivery mayresult in severe iatrogenic prematurity. Giventhese concerns and the very high likelihood thatthe goiter was caused by dyshormonogenesis, wethought that presumptive treatment, with confir-mation by amniotic fluid thyroid function tests,carried the least chance of serious morbidity.

Early reports on amniotic fluid concentrationsof thyroid hormone and TSH suggested that theydo not reliably predict the fetal thyroid status;however, more recent reports have shown thatamniotic fluid TSH values could reflect the fetalrather than maternal thyroid status. In 2001,Perrotin et al10 reported a case in which evalua-tion of the thyroid status in a fetus with a goiterwas performed via amniocentesis, measuringlevels of TSH. They treated the fetus with levothy-roxine and showed a gradual decrease in theamniotic fluid TSH levels. Their diagnosis wassubsequently confirmed with neonatal cordblood, showing an elevated serum TSH level. Inanother report in 2005, Mirsaeid Ghazi et al13

described an Iranian family with 3 consecutivepregnancies complicated by fetal goiters; in thefinal pregnancy, amniocentesis was performedfor assessment of TSH and thyroxine values, andthe fetus received treatment with intra-amnioticlevothyroxine. The diagnosis of fetal hypothy-roidism was confirmed by neonatal and infantileelevated serum TSH levels, supporting the con-cept that amniotic fluid TSH could be an accept-able marker for the diagnosis of hypothyroidismin the goitrous fetus when serum fetal TSH deter-mination by cordocentesis might be hazardousor impractical. Reference ranges have beenestablished for thyroid concentrations in amni-otic fluid, most recently by Baumann andGronowski7 in 2007. Factors that could alteramniotic fluid thyroid hormone levels are thedifferential dilution from different quantities ofamniotic fluid and, for repeated testing, the fact

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Table 1. Thyroid Function as Measured in AmnioticFluid

Gestational Age, wk TSH, mIU/La

25 (before fetal treatment) 3.7426 3.427 3.0929 1.9830 1.4231 132 0.7433 0.3934 0.2335 0.2436 0.2037 0.13

aNormal, 0.04 to 0.51 mIU/L.

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that thyroxine levels could reflect hormoneremaining in the amniotic fluid from the priortreatment. Some authors have suggested thatmeasurement of TSH and iodothyronines inamniotic fluid is unreliable because of theunknown relative contributions from the motherand fetus.14 In our case, however, because thematernal TSH level was normal, the increasedamniotic fluid TSH level was the result of fetalhypothyroidism. This conclusion is consistentwith previous reports and supports the sugges-tion that amniotic fluid TSH levels reflect fetalhypothalamic-pituitary-thyroid function.

Prior reports of prenatal treatment of fetal thy-roid dyshormonogenesis helped guide ourmanagement. We found 9 reported cases of fetalgoitrous hypothyroidism treated with intra-amniotic injections of thyroxine.1,4,5,9,10,13,15–17

Amniocentesis was used for diagnosis in 3 of the9 reports,10,13,16 and fetal blood sampling was themethod for diagnosis in the other 6 reports. Sagotet al16 described a case in which the diagnosis wasmade at 23 weeks’ gestation with a TSH assay inamniotic fluid. In this case, they subsequentlyperformed cordocentesis at 27 weeks to assessthe fetal thyroid status.16 That may be anotheroption in cases in which the physician may behesitant to perform cordocentesis at the thresh-old of viability. We think that we were able tomonitor the fetal status adequately with amnio-centesis and did not need to subject the patient tothe increased risk of cordocentesis. The numberof injections ranged from 1 to 9. There are 4 casesin the literature in which early treatment wasundertaken, the earliest at 26 weeks, as in thiscase.1,5,10,17 In all but 1 pregnancy, the fetal goiterdecreased rapidly in size with the treatment.10 Allwomen were delivered at term via either sponta-neous vaginal delivery or cesarean delivery. Nonerequired cesarean delivery for dystocia, one of thepotential consequences of a fetal neck mass.

In summary, fetal thyroid dyshormonogenesisshould be suspected when a fetal goiter is diag-nosed in the absence of any maternal thyroiddisease. The disease can be effectively treated byintra-amniotic thyroxine administration. Thistreatment has the potential to prevent impair-ment of the developing fetal brain and to preventthe neonatal airway problems that may becaused by a large fetal goiter.

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