Case Report
PREGNANCY AND AUTOIMMUNE THYROID DISEASE:
ALTERNATING BETWEEN HYPOTHYROIDISM AND HYPERTHYROIDISM
AND THE ROLE OF THYROTROPIN-RECEPTOR ANTIBODIES
Sara Awad, MBBS, FRCPC1; Heidi Dutton, MD, FRCPC1;
Julie Shaw, PhD, FCACB2; Erin Keely, MD, FRCPC1
ABSTRACT
Objective: To report the case of a female patient with
hypothyroidism who spontaneously developed Graves
hyperthyroidism during pregnancy and then reverted back
to hypothyroidism in a subsequent pregnancy.
Methods: The pertinent clinical features, laboratory
data, and clinical course of the case are reported, along
with a brief literature review.
Results: A 30-year-old female with hypothyroidism
diagnosed at age 20 years unexpectedly required decreased
levothyroxine dosing during her second pregnancy. She
was taking levothyroxine 12.5 µg daily when she became
pregnant a third time. In the first trimester, levothyroxine
was discontinued, and she presented in the third trimes-
ter with clinical and biochemical hyperthyroidism and a
diffusely enlarged goiter. Propylthiouracil (PTU) was initi-
ated. Thyroid-stimulating hormone–receptor antibodies
(TRAbs) were positive. After delivery, her baby developed
transient neonatal Graves disease. She was continued on
a stable dose of PTU for 10 months postpartum and then
became pregnant a fourth time. PTU was discontinued and
she remained euthyroid off medications until the second
Submitted for publication November 2, 2016
Accepted for publication December 18, 2016
From the 1Department of Medicine, Division of Endocrinology and
Metabolism, and 2Department of Pathology and Laboratory Medicine,
University of Ottawa, Ottawa, Ontario, Canada.
Address correspondence to Dr. Sara Awad, The Ottawa Hospital, Riverside
Campus, 1967 Riverside Drive, Room 4-12, Ottawa, ON, Canada K1H 7W9
E-mail: saraawad87@gmail.com
DOI: 10.4158/EP161660.CR
To purchase reprints of this article, please visit: www.aace.com/reprints.
Copyright © 2017 AACE.
e340 AACE CLINICAL CASE REPORTS Vol 3 No. 4 Autumn 2017
This is an Open Access article under the CC-BY-NC-ND license.
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trimester, when she presented with clinical and biochemi-
cal hypothyroidism, requiring levothyroxine initiation.
TRAb level was elevated. Thyroid-stimulating immuno-
globulin (TSI) bioassay was elevated. Despite elevated TSI
in her fourth pregnancy, her child did not develop neonatal
Graves disease. She remains euthyroid on levothyroxine.
Conclusion: Spontaneous transformation from hypo-
thyroidism to hyperthyroidism during pregnancy is rare but
can occur. The balance between the activity of stimulating
and blocking TRAbs may impact the clinical presentation
for both the mother and the fetus. (AACE Clinical Case
Rep. 2017;3:e340-e343)
Abbreviations:
AITD = autoimmune thyroid disease; FT3 = free
triiodothyronine; FT4 = free thyroxine; GD = Graves
disease; LT4 = levothyroxine; PTU = propylthiouracil;
TBAb = thyroid-blocking antibody; TRAb = thyroid-
stimulating hormone–receptor antibody; TSAb =
thyroid-stimulating antibody; TSH = thyroid-stimulat-
ing hormone
INTRODUCTION
Graves disease (GD) and Hashimoto hypothyroidism
represent extremes on the spectrum of autoimmune thyroid
disease (AITD) (1). The course of AITD is altered during
pregnancy. Patients with Hashimoto hypothyroidism have
a 20 to 40% increase in levothyroxine (LT4) requirements,
achieved safely by a two-tablet increase per week, to
maintain euthyroidism in early pregnancy (1,2). GD often
improves during pregnancy due to immune tolerance, but
there is an increased risk of relapse postpartum (1,3,4).
Spontaneous transformation from Hashimoto hypothyroid-
ism to GD and back to hypothyroidism during pregnancy is
rare but has been reported (5).
Copyright © 2017 AACE
Copyright © 2017 AACE Autoimmune Thyroid in Pregnancy, AACE Clinical Case Rep. 2017;3(No. 4) e341

The thyroid-stimulating hormone (TSH)-receptor
(TSH-R) is the primary antigen targeted in AITD (6).
TSH-R antibodies (TRAbs) are heterogeneous antibod-
ies and may have stimulatory (TSAb), inhibitory/blocking
(TBAb), or neutral actions on the TSH-R, which predicts
the biochemical and clinical presentation (7). When TRAb
biologic action is stimulatory (TSAb), there is increased
gland growth and hormone synthesis and release. This
constitutes the basis of GD. When TRAb biologic action is
blocking (TBAb), there is a reduction or complete block-
age of the action of TSH on TSH-R. Also, TRAb can have
a neutral action such that there is no influence on TSH-R
activity (4,7).
TRAb measurements are routinely made by immuno-
assay, which measures the concentration of TRAbs present
but does not discern whether the antibodies are stimula-
tory or inhibitory. The presence of stimulatory TRAbs can
be determined using a bioassay, which detects the ability
of TRAbs to activate the TSH-R. The presence of thyroid
inhibitory antibodies can also be measured using a bioas-
say, but these assays are not widely available.
We report the case of a patient with known hypothy-
roidism who spontaneously developed GD during preg-
nancy and then reverted back to hypothyroidism in a subse-
quent pregnancy. Clinical implications for her offspring are
also discussed.
CASE REPORT
A 30-year-old female was diagnosed with Hashimoto
hypothyroidism at age 20 years. She was treated with
LT4 112 µg daily until age 23, when she became preg-
nant (December 2009-September 2010) and required an
expected increase in LT4 to 125 µg daily, with a return to
pre-pregnancy dose postpartum. This was followed by a
second pregnancy (July 2011-March 2012), during which
there was an unexpected decrease in LT4 to a minimum
dose of LT4 25 µg by the third trimester. Subsequently,
LT4 was reduced to12.5 µg daily by 6-months postpartum.
She then became pregnant a third time (January-
October 2013) and was on LT4 12.5 µg daily until late
first trimester, when LT4 was discontinued (see Fig. 1
for details of thyroid indices and clinical course). She
presented to our clinic at 30+6 weeks gestation with symp-
toms of hyperthyroidism, including palpitations, tremors,
weight loss, and heat intolerance. Thyroid exam revealed
a diffusely enlarged goiter, and bloodwork was consistent
with hyperthyroidism (TSH <0.03 mIU/L; reference, 0.3
to 5.6 mIU/L; free thyroxine [FT4], 43.4 pmol/L; refer-
ence, 7.2 to 21 pmol/L). TRAb was positive at 30.2 IU/L
(reference <1.0 IU/L), confirming the diagnosis of GD.
Propylthiouracil (PTU) and propranolol were initiated,
and she improved clinically and biochemically. Fetal ultra-
sound performed at 31+6 weeks gestation revealed normal
growth, no tachycardia, goiter, or advanced bone age. Her
baby boy was delivered at term and developed transient
neonatal GD. His bloodwork on day 2 revealed a suppressed
TSH of 0.03 mIU/L (reference, 0.8 to 8 mIU/L), FT4 21.4
pmol/L (reference, 9.8 to 23 pmol/L), and positive TRAb.
He was followed by pediatrics and did not require treat-
ment. Hyperthyroidism resolved by 4 months of age, and
antibodies became undetectable.

Fig. 1. Clinical course during the patient’s third pregnancy: 1. Not pregnant. On levothyroxine 12.5 µg daily.
2. Gestational age 30+6 weeks. Hyperthyroid, tachycardia, diffuse goiter. Graves disease diagnosed. Positive
thyroid-stimulating hormone (TSH)-receptor antibodies 30.2 U/L (normal <1.0 U/L), started on propylthio-
uracil (PTU) 50 mg three times a day. 3. Fetal ultrasound 31+6 weeks: normal growth, no tachycardia or
goiter. 4. Delivered October 1, 2013; baby developed transient neonatal Graves disease, managed conserva-
tively. Resolved by 4 months of age. 5. Postpartum 6 weeks; stable on PTU. The reference intervals for the
labs provided in the chart are: TSH, 0.3 to 5.6 mIU/L; free thyroxine (FT4), 7.2 to 21.0 pmol/L. The reference
intervals for labs on August 22 and November 14, 2013 were: TSH, 0.3 to 5.6 mIU/L; FT4, 7 to 17 pmol/L.

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Our patient continued on a stable dose of PTU 50 mg
twice daily for 10 months postpartum and subsequently
became pregnant a fourth time (see Fig. 2 for details of
thyroid indices and clinical course). At 5 weeks gestation,
her TSH was elevated at 9.84 mU/L, with low FT4 (<6.0
pmol/L); PTU was discontinued and LT4 100 µg daily was
initiated on a short-term basis to provide adequate thyroid
hormone levels to the developing fetus while the patient’s
endogenous thyroid hormone production recovered. LT4
was then discontinued at 8 weeks gestation when repeat
TSH was low (0.14 mIU/L). Thyroid indices were then
measured monthly, and she remained euthyroid off medi-
cations until 18 weeks gestation, when she became signifi-
cantly hypothyroid (TSH, 57.64 mIU/L; FT4 <6.0 pmol/L),
requiring re-initiation of LT4 100 µg daily. Repeat TRAb
measurement was elevated at 32.1 IU/L. In an attempt to
better clarify the function of the detectable TRAb, a thyroid-
stimulating immunoglobulin bioassay was performed and
was elevated at 311% (reference, <140%), indicating the
presence of TSAbs. This result was somewhat surprising,
given the biochemical hypothyroidism. We interpreted
this to mean that both TBAbs and TSAbs were present in
our patient, with the activity of TBAbs predominating to
produce an overall clinical picture of hypothyroidism.
Given the likely presence of both blocking and stimu-
lating antibodies, we were unsure as to whether the overall
TBAb predominance in the mother would also be mirrored
in the fetus. Fetal ultrasounds demonstrated no evidence
of goiter or hyperthyroidism. Therefore, we did not pursue
cordocentesis given the potential procedural risks. She
delivered a healthy baby at term who interestingly did not
develop neonatal GD. Cord blood TRAb concentrations
measured 9.0 IU/L (normal, <1.0 IU/L), which are elevated
compared to the reference interval for serum, suggesting
that maternal antibodies passed across the placenta to the
fetus. Unfortunately, a reference interval is not available
for cord blood TRAbs. Thyroid indices in cord blood were
also measured, and TSH was found to be 10.43 mIU/L,
with FT4 14.7 pmol/L and free triiodothyronine (FT3)
2.6 pmol/L. There are very limited data on normal thyroid
hormones and TSH concentrations in cord blood, making
interpretation difficult. However, a recent study by Mehari
et al (7) calculated cord blood reference intervals for TSH
(3.48 to 27.56 mIU/L), FT3 (1.83 to 3.86 pmol/L), and FT4
(11.5 to 19.7 pmol/L) measured on the Roche immunoassay
platform. Measurement of cord blood thyroid parameters
in our study was performed using the Beckman-Coulter
DXI platform. Based on local laboratory proficiency test-
ing data, TSH, FT3, and FT4 measurements agree relatively
well between the Roche and Beckman platforms, making it
possible to compare the cord blood measurements in our lab
with the reference intervals published by Mehari et al (7).
Therefore, cord blood values for TSH, FT3, and FT4 all fell
within the published normal reference intervals. The child
remained euthyroid, and our patient is now over 1 year
postpartum and remains euthyroid on LT4 100 µg daily.

Fig. 2. Clinical course during the fourth pregnancy. 1. Gestational age 3 weeks. Propylthiouracil stopped
and levothyroxine (LT4) 100 µg started. 2. Gestational age 8 weeks. LT4 stopped. 3. Gestational age 18
weeks. Hypothyroidism. Started on LT4 100 µg. Thyroid-stimulating hormone (TSH)-receptor antibod-
ies (TRAbs) positive, at 32.1 U/L (normal <1.0 U/L). 4. Gestational age 26 weeks. Euthyroid on LT4.
TRAb+, thyroid-stimulating antibodies (bioassay) 311% (normal <140%). Fetal ultrasound: normal
thyroid and growth. 5. Delivered April 26, 2015; transient neonatal Graves disease, resolved by 4 to 6
weeks of age. Cord blood: TRAb+ 9.0 IU/L. 6. Five months postpartum; continues on LT4 100 µg daily.
The reference intervals for all labs provided in the chart are: TSH, 0.3 to 5.6 mIU/L; free thyroxine
(FT4), 7.2 to 21.0 pmol/L. The reference intervals for the labs on January 29 and April 9, 2015: TSH,
0.3 to 5.6 mIU/L; FT4, 7 to 17 pmol/L. The reference intervals for the labs on September 29, 2015: TSH
0.3 to 4 mIU/L; FT4, 9 to 23 pmol/L.

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Copyright © 2017 AACE Autoimmune Thyroid in Pregnancy, AACE Clinical Case Rep. 2017;3(No. 4) e343
DISCUSSION
In our patient, we speculate that TRAb subtype serum
concentrations changed over time, causing varying effects
on both her and her fetuses’ thyroid glands. Pregnancy-
related immune changes presumably triggered a switch in
antibody properties and concentrations. In the third preg-
nancy, likely predominance of TSAbs resulted in GD, and
the neonate developed transient neonatal GD secondary
to transplacental transfer of stimulatory antibodies. In her
fourth pregnancy, clinical and biochemical patterns in the
mother and the fetus were conflicting. The patient’s TSAb
level was elevated, but she was clinically and biochemi-
cally hypothyroid. Interestingly, despite an elevated cord
blood TRAb, her neonate was biochemically euthyroid,
and thyroid hormone concentrations obtained in the cord
blood were within reference range, as per the study done
by Mehari et al (8). This indicates that although the bioac-
tivity of the TRAbs crossing the placenta matters, the rela-
tive proportion and affinity of the antibodies to the fetal
TSH-R is likely also important, and the fetal picture may
not mirror that of the mother.
The impact of maternal thyroid status on the devel-
oping fetus is significant. Inadequately treated maternal
hypothyroidism can cause fetal hypothyroidism, which
impairs neurocognitive development. Fetal goiter, brady-
cardia, growth restriction, and delayed bone age may
occur (9,10). Conversely, in maternal GD, elevated levels
of TSAbs, which freely cross the placenta after 20 weeks
gestation, can overstimulate the fetal thyroid gland, caus-
ing hyperthyroidism, goiter, tachycardia, heart failure,
advanced bone age, growth restriction, and hydrops (10).
The American Thyroid Association recommends serial
fetal ultrasound (US) for assessment of heart rate, growth,
amniotic fluid volume, and fetal goiter in patients with past
or current history of GD and positive TRAb (11). Fetal
thyroid function can be assessed by measuring thyroid
hormone levels via cordocentesis; however, this carries
risk of fetal morbidity and mortality (10,11). Furthermore,
measurements of cord blood hormone concentrations have
limitations; there are no well-established reference inter-
vals, and interpretation may be challenging. Thus, cordo-
centesis should be restricted to circumstances where clini-
cal and biochemical data are conflicting and results would
influence management (10,11).
It is prudent to closely monitor patients with AITD
who become pregnant, as the clinical course can be unpre-
dictable. When there is discrepancy between biochemistry
and antibodies, fetuses must be closely monitored with
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serial US. Cordocentesis should be considered if the diag-
nosis of fetal thyroid disease is not clear from the clinical
and sonographic data and the information obtained would
influence management (10,11).
CONCLUSION
The balance between the activity of stimulating and
blocking TRAbs may result in thyroid hormone fluctua-
tions. In our case, it appears that pregnancy was a trigger
for the shift in these antibody properties and concentra-
tions. Our case highlights the limitations of our current
laboratory assays to clarify the clinical implications of
TRAbs on the fetus; therefore, fetal monitoring is crucial.
DISCLOSURE
Dr. Shaw receives consulting and speaking honorar-
ia from Roche. The other authors have no multiplicity of
interest to disclose.
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