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Thyroid
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© Mary Ann Liebert, Inc.

DOI: 10.1089/thy.2018.0098
1
Three consecutive pregnancies in a patient with chronic
Three consecutive pregnancies in a patient with chronic autoimmune thyroid disease associated with hypothyroidism and extremely high levels of anti‐TSH receptor antibodies (DOI: 10.1089/thy.2018.0098)
autoimmune thyroid disease associated with hypothyroidism and
This paper has been peer‐reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof.
extremely high levels of anti‐TSH receptor antibodies
Hervé GRULET (MD) (1), Sara BARRAUD (MD) (1,2), Karim CHIKH (PharmD, PHD) (3), Pierre
François SOUCHON (MD) (4), Olivier CLARIS (MD, PHD) (5), Raymonde BOUVIER (MD) (6),
Jacqueline TROUILLAS (MD, PHD) (6), René GABRIEL (MD, PHD) (7), Jean Paul BORY (MD)
(7), Claire SCHVARTZ (MD) (8), Jacques ORGIAZZI (MD) (9), Brigitte. DELEMER (MD, PHD)
(1,2)
Downloaded by Linkoping University Library from www.liebertpub.com at 04/13/19. For personal use only.
(1) Centre Hospitalier Universitaire de Reims, Service d'Endocrinologie ‐ Diabète ‐

Nutrition
Reims, Champagne‐Ardenne, FR
(2) Université de Reims Champagne‐Ardenne UFR de Médecine, Reims, FR
(3) Centre Hospitalier Universitaire de Lyon, Centre de Biologie du Centre Hospitalier Lyon‐
Sud, Lyon, Rhône‐Alpes, FR
(4) Centre Hospitalier Universitaire de Reims, Hôpital Américain ‐ Service de Pédiatrie
Thyroid
(5) Centre Hospitalier Universitaire de Lyon, Hôpital Mère Enfant, Service de Néonatalogie,
Lyon, Rhône‐Alpes, FR
(6) Centre Hospitalier Universitaire de Lyon, Laboratoire Central d’Anatomie et de
Cytologie Pathologiques, Lyon, Rhône‐Alpes, FR
(7) Centre Hospitalier Universitaire de Reims, Service de Gynécologie‐obstétrique
(8) Institut Jean Godinot, rue du Général KOENIG, Reims, FR 51100
(9) Centre Hospitalier Universitaire de Lyon, Service d'Endocrinologie, Lyon, Rhône‐Alpes,
FR
‐ Hervé. GRULET: hgrulet@ch‐chalonsenchampagne.fr
‐ Sara BARRAUD: sbarraud@chu‐reims.fr
‐ Karim CHIKH: karim.chikh@chu‐lyon.fr
‐ Pierre François SOUCHON: pfsouchon@chu‐reims.fr
‐ Olivier CLARIS: olivier.claris@chu‐lyon.fr
‐ Raymonde BOUVIER : [email protected]
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‐ Jacqueline TROUILLAS : jacqueline.trouillas@univ‐lyon1.fr
‐ René GABRIEL : rgabriel@chu‐reims.fr
‐ Jean Paul BORY : jpbory@chu‐reims.fr
‐ Claire SCHVARTZ: [email protected]
‐ Jacques ORGIAZZI: jacques.orgiazzi@chu‐lyon.fr
‐ Brigitte DELEMER (corresponding author): CHU de Reims – Hôpital Robert Debré – Service
d’Endocrinologie Diabétologie et Nutrition, Rue du Général Koenig, 51100 REIMS, France.
E‐mail: bdelemer@chu‐reims.fr
Running title:
3 pregnancies and very high maternal TRAb levels
Keywords: TRAb, fetal hyperthyroidism, fetal malformation, maternal Hashimoto’s
disease, TSAb, TBAb
Acknowledgments
We would like to thank José Grulet for his valuable contribution in creating the main
Thyroid
figure. We would also like to thank Prof. Sophie Collardeau‐Fracon for providing additional
autopsy information and Alpha Diallo for his corrections.
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Abstract
Background: Thyroid‐stimulating hormone (TSH) receptor (TSHR) antibodies (TRAb) can be
present in chronic autoimmune thyroiditis. Transplacental TRAb transfer can lead to fetal
thyroid dysfunction and serious complications.
Patient Findings: We report the case of a woman with autoimmune hypothyroidism and
extremely high TRAb levels, with blocking and stimulating activities (biological activities
characterized with Chinese hamster ovary cells expressing TSHR). At week 22 of her first
pregnancy, sonography detected fetal growth retardation and cardiac abnormalities

(extreme tachycardia, right ventricular dilatation, pericardial effusion). The mother’s TRAb
level, assayed later, was 4030 IU/L (N<10). Delivered via caesarean section gestational
week 30, the newborn girl had several malformations, signs of malnutrition, goiter and
hyperthyroidism associated with elevated TRAb (1200 IU/L). The newborn died 26 days
after delivery. Faced with persistently high TRAb levels and a desire to become pregnant
again, the woman was treated with three consecutive 740‐MBq activities of iodine‐131,
Thyroid
which resulted in a decrease in TRAb to 640 IU/L. The patient had two subsequent
pregnancies 16 and 72 months after the radioiodine administration. During the close
follow‐ups, fetal development was normal, and initial TRAb levels during the two
pregnancies were 680 and 260 IU/L, respectively, which initially decreased but then
increased in late pregnancy. In both cases, labor was induced at 34 weeks. The newborns,
mildly hyperthyroid at birth, required carbimazole treatment at days 5 and 2, respectively.
The mild hyperthyroidism despite high TRAb levels was likely due to the concomitant
presence of stimulating and blocking TRAb. The two girls, now aged 12 and 8 years, are in
good health. The mother has no detectable thyroid gland tissue and is euthyroid on
levothyroxine (175 µg/d). Her TRAb level gradually decreased to 136 IU/L.
Summary and conclusions: This remarkable case illustrates the severe consequences of
untreated fetal hyperthyroidism and the need to assay and follow‐up TRAb levels in
women of reproductive age with autoimmune thyroiditis.

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Introduction
The presence of thyroid‐stimulating hormone (TSH) receptor antibodies (TRAb) in patients
with chronic autoimmune thyroid disease associated with hypothyroidism (Hashimoto’s

disease) (1) has been documented for decades (2, 3) and can combine stimulatory and/or
blocking activity (TSAb and TBAb) (4). Fetal hypothyroidism due to the presence of
maternal blocking TRAb has been reported, representing approximately 1% of congenital
hypothyroidism cases (5). Fetal hyperthyroidism may also occur in patients with
autoimmune thyroiditis (6, 7, 8). We report an exceptional case of a woman treated for
hypothyroidism since adolescence with dramatically high TRAb levels, which were
presumably responsible for the neonatal death of her first child. In contrast, the
subsequent two pregnancies progressed favorably after radioiodine ablation of thyroid
tissue and a significant reduction of the TRAb levels.
Patient
Thyroid
The patient was diagnosed at 14 years of age with Hashimoto’s thyroiditis and presented a
firm goiter, high TSH (52.4 mIU/L), antithyroperoxidase (TPO) and antithyroglobulin (Tg)
antibody levels, and a positive TRAb assay (83%, N<15%; commercial radio‐receptor assay,
TRAK‐Henning).
Her first pregnancy (at 26 years of age) was considered normal until the 22nd week when a
fetal ultrasound indicated severe growth retardation, tachycardia of >220 bpm, right
ventricular dilatation and pericardial effusion. The mother was then closely monitored in a
tertiary center. At 27 weeks, the fetal thyroid gland was enlarged [22 x 17 mm; estimated
thyroid perimeter, 6.2 cm; reference range, 2.7–4.4 cm (9)]. The mother’s TRAb levels
were 2800 and 4030 IU/L (TRAK Human, Thermo Fisher Scientific, Clinical Diagnostics,
B.R.A.H.M.S GmbH, Hennigsdorf, Germany; reference level <10 IU/L) at 26 and 29 weeks of
gestation, respectively. The mother was clinically euthyroid throughout the pregnancy,
although the typical initial levothyroxine dosage (125 µg/d) was reduced to 50 µg/d
because serum TSH levels decreased from 0.4 to 0.05 mU/L.
At 30 weeks and 2 days, an unplanned caesarian delivery was performed due to full
cervical dilation and breech presentation. The newborn girl had the following
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characteristics: Apgar score, 1/1/8; weight, 1240 g (25th percentile for age); height, 35.5 cm
(10th percentile); head circumference, 24.5 cm (10th percentile); markedly reduced anterior
fontanelle; microcephaly; dysmorphic facies; abnormal ear folding; microretrognathia; and
apparent microphthalmia. The newborn presented markedly underdeveloped
subcutaneous adipose tissue, enlarged liver and spleen, jaundice, elevated conjugated
bilirubin levels, thrombopenia, anemia and disseminated intravascular coagulation. The
infant’s thyroid gland was significantly enlarged, and blood glucose was undetectable.
Cardiac ultrasonography revealed cardiomyopathy and an interatrial septal aneurysm
bulging into the right atria, while a brain MRI showed a triventricular hydrocephalus
related to cortical atrophy. The electroencephalogram showed low voltage and poorly
differentiated activity, and thyroid function tests confirmed the newborn’s
hyperthyroidism (Table 1), with a TRAb level of 1200 IU/L (TRAK Human, B.R.A.H.M.S
GmbH). Antithyroid drug treatment was not initiated because the hyperthyroidism did not
appear predominant, given the clinical malformation and lack of marked tachycardia. The
mother’s thyroid parameters were normal (TSH, 2.6 mU/L; FT4, 12.6 pmol/L; FT3, 5.8
Thyroid
pmol/L), with TRAb unchanged at 2520 IU/L.
The newborn’s neurological and cardiorespiratory status worsened progressively, with

persistent hyperthyroidism (TSH <0.1; FT4, 24 pmol/L; FT3, 13 pmol/L), and she died 26
days after delivery. The autopsy revealed a fibrosing and necrotizing cholestatic liver
without inflammation or steatosis. The autopsy also revealed cardiomyopathy,
hypertrophy of the visceral brown fat surroundings the kidneys, adrenal glands, pancreas,
and in the mediastinum; her subcutaneous white fat was nearly absent. Polymicrogyria
affected the entire brain and was associated with astrocyte gliosis within the white matter
and atrophy of the pyramidal tract, while the basal ganglia were normal. The thyroid was
notably enlarged, very firm and homogeneous.
Five months post‐partum, the mother was clinically euthyroid, her goiter was small (30 mL)
firm and indolent. However, her levothyroxine dosage was increased from 50 to 100 µg/d
(TSH, 20 mIU/L). Her serum TRAb level was >40 IU/L at a 1/100 serum dilution. The TRAb
biological activity was assayed as previously described (Table 2) (10, 11). Both stimulating
and blocking activities were elevated up to a serum dilution of 1/400 (Table 2).
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Given the mother’s strong intention to conceive again, her TRAb levels were the main
concern. Given the steady elevated TRAb levels over 34 months (Table 2), we elected
thyroid tissue ablation (with the patient’s informed consent) to lower the TRAb level. We
chose to administer radioiodine (12), and the patient agreed to delay the pregnancy for at
least one year. At the age of 29 years, the patient was administered three consecutive 740‐
MBq iodine‐131 activities (uptake, 5.77%) at 3‐month intervals on an outpatient basis in
accordance with French nuclear medicine regulation. Although the patient showed no
signs of orbitopathy, she was administered oral prednisone at 1 mg/kg/day for one week,
tapered over 1 month, a dosage adapted from Bartalena et al. (13). The subsequent
decrease in thyroid volume and serum TRAb levels are shown in Figure 1.
The second pregnancy commenced nearly 2 years later, with an initial TSH level of 2.6
mIU/L and TRAb level of 680 IU/L, which decreased to 307 IU/L at 20 weeks and then
increased to 620 IU/L in late pregnancy (Figure 1). Biological assays showed both
stimulating and blocking activities (Table 2). Fetal development was normal, with no signs
Thyroid
(heart, growth, ossification points) of hyperthyroidism, and the cerebral MRI results were
normal. With the mother’s consent, labor was induced at 34 weeks and 2 days. The
newborn girl was healthy (weight, 2360 kg [+0.5 SD for gestational age]; height, 47 cm [+1
SD]; head circumference, 32 cm [+1 SD]), and her thyroid was moderately enlarged. She
initially had mild hyperthyroidism. Due to the increase in FT4 and FT3 (Table 1), the infant
was started on carbimazole treatment (3 mg/d) at day 5, resulting in a rapid correction of
FT4 and FT3, and the treatment was then tapered off and stopped at 9 weeks; TRAb was
then no longer detectable.
Similarly, the third pregnancy 4 years later progressed normally. The mother’s initial TRAb
level was 260 IU/L, which increased to 621 IU/L (Figure 1 and Table 2). Labor was once
again induced at 34 weeks and 2 days. The newborn girl was healthy, with anthropometric
indices at +1 SD for gestational age. At day 2, the infant’s FT4 level was markedly elevated
(Table 1), and she was treated with carbimazole for 10 weeks. The mother’s TRAb levels
further decreased to 116 UI/L, and her thyroid was undetectable on ultrasonography. The
daily levothyroxine dosage (initially 125 µg/d) was increased to 175 µg to maintain
euthyroidism.
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The two girls (now aged 12 and 8 years) are in good health, have no thyroid abnormality
and are doing well in school.
Discussion
This case of fetal hyperthyroidism illustrates the potential damage resulting from the
presence of TRAb in a woman with autoimmune thyroiditis and treated hypothyroidism.
Although this uncommon association is well‐known, assaying TRAb in this circumstance or,
as in our case, following‐up serum TRAb levels longitudinally, is not the rule. TRAb are
therefore likely to be discovered during pregnancy only in the context of fetal
hyperthyroidism or during neonatal hypothyroidism screening, depending on the
dominant biological TRAb activity. In our case, fetal hyperthyroidism was suspected during
the first pregnancy at 22 weeks of gestation, due to the combination of severe
manifestations likely related to the extremely high serum TRAb concentration. These
manifestations included extreme tachycardia, growth retardation and thyroid gland
enlargement, confirmed at birth by craniosynostosis‐related microcephaly, extreme
Thyroid
thinness, and the presence of a goiter. Cardiomyopathy, hepatosplenomegaly, jaundice,

thrombocytopenia and intravascular disseminated coagulation could also be related to a
severe form of fetal hyperthyroidism (7, 14–16). Unfortunately, no antithyroid drug
treatment was administered to the levothyroxine‐treated mother to treat the fetus (17).
The mother was clinically euthyroid on levothyroxine despite a drop in TSH levels during
pregnancy in the absence of hyperemesis gravidarum, which resulted in a decrease in the
usual levothyroxine dosage. Unfortunately, (F)T4 readings were not performed; hence, it
cannot be determined whether the dose reduction was indeed appropriate. It should be
noted that the usual levothyroxine dosage had to be restored 5 months postpartum (18).
Whether the newborn’s facial malformation and cerebral abnormalities observed at
autopsy were related to the fetal hyperthyroidism remains uncertain (19).
Given the mother’s and neonate’s very high serum TRAb levels, it is surprising that the
neonate’s FT4 and FT3 levels on day 1 were only in the upper reference range and less
than twice the upper reference range, respectively. In autoimmune thyroiditis, as well as in
Graves’ disease, stimulating and blocking TRAb activities may coincide or their relative
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concentrations may vary over time (20, 21). In our patient, TRAb bioassays repeatedly
showed the presence of stimulating and blocking activities. While detecting blocking
activities is hampered by the presence of a concomitant potent stimulatory activity, the
patient’s serum still elicited a significant blocking activity (55%) at a 1/200 serum dilution
against a 782% stimulatory activity, a level that does not interfere with detecting the
blocking activity (22). It could be reasonably suggested that the moderate degree of
hyperthyroidism in the second and third child, despite still significant TRAb levels, and the
delayed neonatal hyperthyroidism, could be explained by the coexistence of stimulating
and blocking TRAb activities (7). The mother’s need for a higher levothyroxine dosage after
thyroid ablation could be explained by the persistence of functional thyroid tissue.
Given the strong desire for future pregnancies, the other main issue consisted in the
presence of persistently elevated TRAb levels of approximately 4000 IU/L for more than 2
years after the first pregnancy. Thyroid tissue ablation was therefore performed to lower
these levels. With the patient’s informed consent, a high‐school mathematics teacher, we
Thyroid
chose radioiodine over thyroidectomy to avoid the risk of surgical complications. Three
months after the last treatment, the TRAb level fell below 1000 IU/L and steadily declined
thereafter. Consequently, there were no signs of fetal hyperthyroidism and only mild initial
biological hyperthyroidism during the two subsequent closely monitored pregnancies,
consistent with the decrease of the elevated TRAb levels (range, 260–680 IU/L). In contrast
to Graves’ disease, the TRAb levels during these two pregnancies presented a biphasic
pattern, with a small initial dip followed by a significant rise during the second half of
pregnancy. Given the unfortunate outcome of the first pregnancy, labor induction at 34
weeks (with the patient’s informed consent) provided a satisfactory balance between the
risk of prematurity (23) and the development of fetal hyperthyroidism. The second and
third neonates, who had hyperthyroidism on days 1‐2, had a similar progression of FT4 and
FT3 levels, reaching higher values on days 4‐5, and requiring antithyroid drug treatment (7,
24).
In conclusion, this case illustrates the usefulness of detecting TRAb in women of
reproductive age with autoimmune thyroiditis, regardless of thyroid status, and illustrates
the impact of ablative therapy on consistently elevated TRAb levels.
Thyroid
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profit sector.

Author Disclosure Statement
All authors declare that they have no conflicts of interest.
The study received no specific grant from a funding agency in the commercial or not‐for‐
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Thyroid
5. Ilicki A, Larsson A, Karlsson FA 1991 Circulating thyroid antibodies in congenital
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receptor autoimmunity in Graves’ disease after therapy with anti‐thyroid drugs,
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158:69–75.
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Nardi M, Bartolomei MP, Lepri A, Rossi G, Martino E, Pinchera A 1998 Relation
between therapy for hyperthyroidism and the course of Graves’ ophthalmopathy. N
Engl J Med 338:73–78.
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14. Riggs W, Wilroy RS, Etteldorf JN 1972 Neonatal hyperthyroidism with accelerated
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17. Polak M, Leger J, Luton D, Oury JF, Vuillard E, Boissinot C, Czernichow P 1997 Fetal cord
blood sampling in the diagnosis and the treatment of fetal hyperthyroidism in the
offsprings of a euthyroid mother, producing thyroid stimulating immunoglobulins. Ann
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stimulating autoantibodies: potential mechanisms involved in the pendulum swinging
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Gynecol 99:1040–1043.

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Table 1: Postnatal thyroid hormone and TSH receptor antibodies levels in the three
children
Newborns TSH, mIU/L FT4, FT3, TRAb*,

age, days pmol/L pmol/L IU/L
Newborn 1 1 <0.1 25.4 11.8 1200
6 <0.1 21.6 21.2 420
Newborn 2 1 0.03 32.9 7.6 620

5 0.02 58.3 13.3

Newborn 3 2 0.01 61.5 13.4 560
4 0.01 66.4 16.8 340
Reference ranges: Newborn 1: TSH 0.2‐4 mIU/L, FT4 10‐26 pmol/L, FT3 3‐7 pmol/L and
TRAb <10 IU/L. Newborn 2 and 3: TSH 0.27 – 4.2 mIU/L, FT4 12 – 21.9 pmol/L, FT3 3.08 –
6.8 pmol/L and TRAb <2 IU/L
Thyroid
*TRAK Human, Thermo Fisher Scientific, Clinical Diagnostics, B.R.A.H.M.S GmbH,

Hennigsdorf, Germany, normal < 10 IU/L
Abbreviations: D: days of life of the Newborns, FT3, free T3; FT4, free T4; TRAb: TSH
receptor antibodies

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Table 2: Maternal anti‐TSH receptor antibody biological activity
Biological Activities of TRAb**
TRAb, IU/L*
Stimulating, % Blocking, % Dilution

1029 84 1/50
1140 78 1/100

5 months after P1 > 40
782 55 1/200
547 38 1/400

24 months after P1 3600 644 99 undiluted
32 months after P1 4460 744 63 undiluted
P2 – 26 weeks 521 1054 50 undiluted

Thyroid
* TRAb values were quantified using a commercially available radioreceptor assay kit
(TRAK human, Thermo Fisher Scientific, Clinical Diagnostics, B.R.A.H.M.S GmbH,
Hennigsdorf, Germany)
** TRAb biological activities assays: TSHR‐expressing Chines hamster ovary (CHO) cells (11)
were incubated with test serum or control serum. For blocking activity assay, medium was
supplemented with bTSH (0.1 mIU/mL). After incubation, cAMP released from the cells
was measured by radioimmunoassay. Stimulating activity was expressed as a percentage
of the cAMP basal production. Blocking activity was calculated as follows: [1‐(a/b)] x100,
with a: cAMP generated in the presence of the patient’s serum + bTSH and b: cAMP
generated in the presence of normal sera + bTSH (10).
Abbreviations: bTSH, bovine TSH; cAMP, cyclic adenosine monophosphate; P1, first
pregnancy; P2, second pregnancy; P3 third pregnancy; TSH, thyroid‐stimulating hormone;
TSHR, thyroid‐stimulating hormone receptor.

Thyroid

Page 15 of 15
radioiodine administration.
doses of iodine‐131 three months apart.
P2 (shaded area): second pregnancy; P3 (shaded area): third pregnancy.
Figure 1 legend: Long‐term progression of serum level of TRAb (continuous line) and

Serum TRAb levels: notice the logarithmic scale. Abscissa (x‐axis), Months since the first
thyroid volume (dotted line) following the administration of three consecutive 740 MBq
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Thyroid

(1) Centre Hospitalier Universitaire de Reims, Service d'Endocrinologie ‐ Diabète ‐

pregnancy, sonography detected fetal growth retardation and cardiac abnormalities

with chronic autoimmune thyroid disease associated with hypothyroidism (Hashimoto’s

The newborn’s neurological and cardiorespiratory status worsened progressively, with

thinness, and the presence of a goiter. Cardiomyopathy, hepatosplenomegaly, jaundice,

surgery, or radioiodine: a 5‐year prospective randomized study. Eur J Endocrinol

Antibodies Are Highly Prevalent in Hashimoto’s Thyroiditis and Associated

21. McLachlan SM, Rapoport B 2013 Thyrotropin‐blocking autoantibodies and thyroid‐

Newborns TSH, mIU/L FT4, FT3, TRAb*,

6 <0.1 21.6 21.2 420

Newborn 2 1 0.03 32.9 7.6 620

5 0.02 58.3 13.3

4 0.01 66.4 16.8 340

*TRAK Human, Thermo Fisher Scientific, Clinical Diagnostics, B.R.A.H.M.S GmbH,

Stimulating, % Blocking, % Dilution

1140 78 1/100

547 38 1/400

24 months after P1 3600 644 99 undiluted

32 months after P1 4460 744 63 undiluted

P2 – 26 weeks 521 1054 50 undiluted

P3 – 24 weeks 653 470 50 undiluted

P3 – 30 weeks 738 526 46 undiluted

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