The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 8 2630-2632
Copyright © 1999 by The Endocrine Society
Outcome of a Baby Born from a Mother with Acquired Juvenile Hypothyroidism Having Undetectable Thyroid Hormone Concentrations1
Toshiyuki Yasuda,
Hisashi Ohnishi,
Kunio Wataki,
Masanori Minagawa,
Kanshi Minamitani and
Hiroo Niimi
Department of Pediatrics, Chiba University School of Medicine,
Chiba 260-8670, Japan
Address correspondence and requests for reprints to: Toshiyuki Yasuda, M.D., Department of Pediatrics, Chiba University School of Medicine, 1–8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. E-mail:
toshi{at}med.m.chiba-u.ac.jp
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Abstract
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We report a baby born from a mother with strongly positive
thyroid stimulation blocking antibody (TSBAB) and nearly undetectable
T4 level. This case is a unique model of nearly complete
absence of thyroid hormones during fetal and early neonatal life in
humans. The infant girl was born by cesarean section, because of fetal
bradycardia, after 41 weeks gestation and received mechanical
ventilation for 3 days. The TSH level was more than 120 µU/mL in the
neonatal thyroid screening. At age 17 days, the results of a thyroid
function study showed undetectable free T3 and free
T4 concentrations, TSH 550 µU/mL, and TSH receptor
antibody (TRAB) 87%. Thyroxine at a dose of 30 µg/day was started at
age 17 days. The patient required thyroxine treatment until age 8
months. The brain magnetic resonance image at age 2 months revealed
reduced brain size. Her auditory brain stem response was absent at age
2 months. The audiogram at age 4 yr revealed sensorineural deafness of
70 dB. When she was 6 yr of age, motor development remained the same as
that at age 4 months. Her height was 106 cm (-1.5 SD). The results of
thyroid function study of the mother 23 days after delivery showed
undetectable free T3 and free T4, TRAB 84%,
and TSBAB 83%. In conclusion, the outcome of severe thyroid hormone
deficiency in utero and early in human neonatal life was
normal physical growth, fetal distress resulting in cesarean section,
difficulty in the onset of breathing, permanent deficit in auditory
function, brain atrophy, and severely impaired neuromotor development
despite the start of an adequate dose of thyroxine replacement during
the neonatal period.
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Introduction
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THE OUTCOME of transient hypothyroidism in
infants born to mothers with chronic thyroiditis is usually good, but
some are mentally retarded despite early neonatal treatment (1, 2).
Maternal hypothyroidism during pregnancy is thought to contribute to
the poor prognosis in these infants (3). We report a baby born from a
mother with a high thyroid stimulation blocking antibody (TSBAB) titer
and a nearly undetectable T4 level. This is a unique model
of the nearly complete absence of thyroid hormones during fetal and
early neonatal life in humans.
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Subjects and Methods
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Serum free T4, free T3, T4,
and TSH concentrations were measured with a Nippon DPC RIA kit (Nippon
DPC Corp., Tokyo, Japan), Daiichi RIA kit (Daiichi Pharmaceutical Company, Ltd.), and Dainabott immunoradiometric
assay kit (Dainbbott Co. Ltd., Tokyo, Japan), respectively. TSH
receptor antibody (TRAB) was measured with a Cosmic radio-receptor
assay kit (Cosmic Corp., Tokyo, Japan). TSBAB was
measured using the rat FRTL-5 cell line. In brief, we determined cAMP
production of the cells in the presence of 100 µU/mL bovine TSH with
an immunoglobulin preparation of the patient’s serum or of control
serum, and TSBAB was expressed by percent inhibition of cAMP production
by an immunoglobulin preparation of the patient’s serum compared with
the control, as previously described (4).
Case report
Infant. The girl was born by cesarean section because
of fetal bradycardia after 41 weeks gestation. She was intubated
because of poor spontaneous respiration and received mechanical
ventilation for 3 days. Cord arterial blood gas analysis was normal.
Her body weight and length were 2640 gm (-1.5 SD) and 49
cm (-1 SD), respectively. The TSH level was more than 120
µU/mL in the neonatal thyroid screening performed at age 8 days, and
the patient was referred to the Chiba University Hospital at the age of
17 days. Thyroxine at a dose of 30 µg/day was started at that
time. The epiphysis of the distal femur was not visible on the
knee x-ray film. The patient was inactive and had generalized edema,
peripheral coldness, and jaundice. The thyroid gland size was +1.5
SD by echosonography. The results of a thyroid function
study on admission were undetectable free T3, free
T4, and T4 concentrations, TSH 550 µU/mL, and
TRAB 87%. Both T4 and free T4 levels
normalized at age 24 days and have remained so since then. She received
medication until age 8 months. At that time, the patient’s TRAB became
negative (2.1%).
The brain magnetic resonance image (MRI) at age 2 months revealed
reduced brain size, most notably around the operculum (Fig. 1
). The auditory brain stem response was
less than 100 dB at age 2 months. The audiogram at age 4 yr revealed
sensorineural deafness of 70 dB. Her motor development at the age of 6
yr remained the same as that at age 4 months (head control and
roll-over). Her height was 106 cm (-1.5 SD).
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Figure 1. Brain T1-weighted MRI images at age 2
months. Three consecutive sections of brain MRI images are shown. There
is fluid accumulation in the bifrontal areas indicating mild brain
atrophy, which is most prominently noted around the operculum. There is
no significant ventricular enlargement.
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Mother. The mother was 33 yr old when she delivered the
patient. She had delivered a normal son when she was 28 yr old. Two or
three years after delivery of the first baby, she experienced
intolerance to cold, loss of hair, and fatigability. The results of a
thyroid function study 23 days after delivery of the patient were
undetectable free T3 and free T4,
T4 0.12 µg/mL, TSH 123 µU/mL, and TRAB 84% with the
property of TSBAB (83% inhibition of cAMP production by the patient’s
immunoglobulin preparation compared with the control). The thyroid
gland was small. A thyroid scan revealed no notable accumulation of
123I around the neck. She has been treated with thyroxine
since then, and both TRAB and TSBAB have remained strongly
positive.
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Discussion
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Because T4 crosses the placenta, hypothyroid fetuses
that cannot synthesize the hormone at all usually receive
T4 (5, 6). Thus, maternal T4 may partially
compensate for the fetal thyroid deficiency, and the effect of thyroid
hormone deficiency on human fetal brain development in these babies may
be difficult to assess. Because, in this case, the mother’s thyroid
hormone concentration was nearly undetectable, transfer of maternal
thyroxine to the fetus was likely to be absent. The baby had received
TRAB with the property of the TSH blocking type to give rise to
inhibition of the biological actions of TSH that synthesize thyroid
hormones. As a consequence, this patient is a unique model of nearly
complete absence of thyroid hormones during fetal and early neonatal
life in humans.
The role of maternal thyroid hormones in fetal brain development is an
important but complex issue (7). The placental permeability to thyroid
hormones and the degree of development in the nervous system and the
TSH-thyroid axis during fetal life vary among species. Dussault
and Coulombe (8) estimated that placental transfer of maternal
T4 is less than 1% of the fetal T4 production
rate in the rat. Subsequent studies, also in rats, revealed that
T4 and T3 are in fact transferred to the fetus
from the earliest stages of gestation, but at this time the
physiological significance remains unknown (9). A recent study by
Vulsma et al.(5) suggested that in human fetuses with
congenital hypothyroidism, maternal-fetal transfer of T4
may result in neonatal plasma levels of 25–50% of those in normal
infants. Because type II 5'-deiodinase activity in the brain increases
in response to lowered concentrations of T4, these levels
of T4 might suffice as a substrate to maintain a normal or
near normal T3 concentration in brain (10). In contrast,
our patient did not receive or produce any significant amount of
thyroid hormone at all.
Severe hypothyroidism early in pregnancy is reported to be complicated
by fetal distress in labor, leading to cesarean section in most cases
(11), as in this report. The cause may be that inadequate thyroid
hormone levels early in pregnancy produce irreversible changes in the
fetoplacental vascular beds, impairing subsequent circulatory responses
to the stress of labor. As for the roles of thyroid hormones in brain
development, thyroid hormones appear to regulate those processes
associated with terminal differentiation such as dendritic and axonal
growth, synaptogenesis, neuronal migration, and myelination (7).
Thyroid hormone deprivation in neonatal rats has long been known to
result in a diminished rate of myelin production and the concentration
of each of its component proteins, which is associated with reduced
levels of mRNA for myelin-associated genes (7, 12). These rats have
reduced brain size. Thus, the brain atrophy in our patient may be due
to extreme thyroid hormone deficiency or fetal distress probably
induced by maternal hypothyroidism early in pregnancy. Cord blood gas
analysis was normal, therefore the contribution of the fetal distress
to brain atrophy may be minor. Thyroid hormones, as well as
glucocorticoids, promote pulmonary surfactant production (13). A
deficiency in the surfactant causes neonatal respiratory distress
syndrome. However, our patient did not suffer from respiratory distress
syndrome, despite severe thyroid hormone deficiency in
utero.
Hearing problems are a feature of endemic goiter, and of some patients
with thyroid hormone resistance due to the thyroid hormone receptor
(TR)ß gene deletion (Reffetoff syndrome) (14), but are rarely found
in congenital hypothyroidism (15). TRß knockout mice have a
functional cochlear defect (14). Evidence in rats suggests that
cochlear development occurs early in gestation (16), so it is possible
that, in humans, similarly, deafness is a feature of babies in whom the
hypothyroidism was present earlier in gestation.
The birth weight and length in this patient were normal, which may
indicate that thyroid hormone is not essential for physical growth
during human fetal life and also that maternal hypothyroidism does not
impair physical growth of the fetus (1).
In conclusion, the outcome of severe thyroid hormone deficiency in
humans in utero and early in neonatal life was fetal
distress resulting in cesarean section, difficulty in the onset of
breathing, a permanent deficit in auditory function, brain atrophy, and
severely impaired neuromotor development despite starting thyroxine
replacement during the neonatal period.
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Acknowledgments
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The authors would like to thank Drs. A. Honda, Asahi General
Hospital, A. Suzuki, Chiba Rehabilitation Center, and Y. Kobayashi,
Kobayashi Clinic, for initial management and later follow-up of this
patient.
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Footnotes
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1 This study was supported by grants from the Ministry of Health and
Welfare, Japan. 
Received May 27, 1998.
Revised August 8, 1998.
Revised April 28, 1999.
Accepted May 5, 1999.
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Abstract
Introduction
