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
TSH, thyroid-stimulating hormone
Received June 18, 2008, from the Department of
Obstetrics and Gynecology, Division of MaternalFetal 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, 2008. Revised manuscript accepted for publication August 4, 2008.
Address correspondence to Kathleen A. MayorLynn, MD, Department of Obstetrics and
Gynecology, University of Florida College of
Medicine, 1600 SW Archer Rd, Box 100294,
Gainesville, FL 32610-0294 USA.
E-mail: [email protected]
ongenital 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
© 2009 by the American Institute of Ultrasound in Medicine • J Ultrasound Med 2009; 28:67–71 • 0278-4297/09/$3.50
Dyshormonogenetic Fetal Goiter
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 40 × 15 × 22-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 immunoglobulin 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 al5 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
Figure 1. Sagittal view of the fetus at 23.9 weeks showing a
large goiter (arrow) preventing neck flexion.
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 2. Transverse view of the fetal neck at 23.9 weeks showing the large goiter (arrows). The spine (Sp) and trachea (Tr) are
J Ultrasound Med 2009; 28:67–71
Mayor-Lynn et al
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
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
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.10–12 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.
J Ultrasound Med 2009; 28:67–71
Table 1. Thyroid Function as Measured in Amniotic
Gestational Age, wk
25 (before fetal treatment)
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 al10 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 al13
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
Gronowski7 in 2007. 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
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
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 al16 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.
Simsek M, Mendilcioglu I, Mihci E, Karagüzel G, Taskin O.
Prenatal diagnosis and early treatment of fetal goitrous
hypothyroidism and treatment results with two-year followup. J Matern Fetal Neonatal Med 2007; 20:263–265.
Setian N. Hypothyroidism in children: diagnosis and treatment. J Pediatria (Rio J) 2007; 83(suppl):S209–S216.
Calvo RM, Jauniaux E, Gulbis B, et al. Fetal tissues are
exposed to biologically relevant free thyroxine concentrations
during early phases of development. J Clin Endocrinol Metab
Agrawal P, Ogilvy-Stuart A, Lees C. Intrauterine diagnosis
and management of congenital goitrous hypothyroidism.
Ultrasound Obstet Gynecol 2002; 19:501–505.
Abuhamad AZ, Fisher A, Warsof SL, et al. Antenatal diagnosis and treatment of fetal goitrous hypothyroidism: case
report and review of the literature. Ultrasound Obstet
Gynecol 1995; 6:368–371.
Singh PK, Parvin CA, Gronowski AM. Establishment of reference intervals for markers of fetal thyroid status in amniotic
fluid. J Clin Endocrinol Metab 2003; 88:4175–4179.
Baumann NA, Gronowski AM. Establishment of reference
intervals for thyroid-stimulating hormone and free thyroxine
in amniotic fluid using the Bayer ADVIA Centaur. Am J Clin
Pathol 2007; 128:158–163.
Rovet J, Daneman D. Congenital hypothyroidism: a review of
current diagnostic and treatment practices in relation to neuropsychologic outcome. Pediatr Drugs 2003; 5:141–149.
Medeiros-Neto G, Bunduki V, Tomimori E, et al. Prenatal
diagnosis and treatment of dyshormonogenetic fetal goiter
due to defective thyroglobulin synthesis. J Clin Endocrinol
Metab 1997; 82:4239–4242.
Perrotin F, Sembely-Taveau C, Haddad G, Lyonnais C, Lansac
J, Body G. Prenatal diagnosis and early in utero management
of fetal dyshormonogenetic goiter. Eur J Obstet Gynecol
Reprod Biol 2001; 94:309–314.
Liao C, Wei J, Li Q, Li L, Li J, Li D. Efficacy and safety of cordocentesis for prenatal diagnosis. Int J Gynaecol Obstet
Tongsong T, Wanapirak C, Kunavikatikul C, Sirirchotiyakul S,
Piyamongkol W, Chanprapaph P. Cordocentesis at 16-24
weeks of gestation: experience of 1,320 cases. Prenat Diagn
Mirsaeid Ghazi AM, Ordookhani A, Pourafkari M, et al.
Intrauterine diagnosis and management of fetal goitrous
hypothyroidism: a report of an Iranian family with three consecutive pregnancies complicated by fetal goiter. Thyroid
Nath CA, Oyelese Y, Yeo L, et al. Three-dimensional sonography in the evaluation and management of fetal goiter.
Ultrasound Obstet Gynecol 2005; 25:312–314.
Johnson RL, Finberg HJ, Perelman AH, Clewell WH. Fetal
goitrous hypothyroidism: a new diagnostic and therapeutic
approach. Fetal Ther 1989; 4:141–145.
J Ultrasound Med 2009; 28:67–71
Mayor-Lynn et al
Sagot P, David A, Yvinec M, et al. Intrauterine treatment of
thyroid goiters. Fetal Diagn Ther 1991; 6:28–33.
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; 16:47–51.
J Ultrasound Med 2009; 28:67–71