Gynecological Endocrinology

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Pitfalls in the assessment of gestational transient

thyrotoxicosis

Shigeo Iijima

To cite this article: Shigeo Iijima (2020): Pitfalls in the assessment of gestational transient
thyrotoxicosis, Gynecological Endocrinology, DOI: 10.1080/09513590.2020.1754391

To link to this article: https://doi.org/10.1080/09513590.2020.1754391

Published online: 17 Apr 2020.

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GYNECOLOGICAL ENDOCRINOLOGY
https://doi.org/10.1080/09513590.2020.1754391

REVIEW ARTICLE

Pitfalls in the assessment of gestational transient thyrotoxicosis

Shigeo Iijima
Department of Regional Neonatal-Perinatal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan

ABSTRACT ARTICLE HISTORY

Gestational transient thyrotoxicosis (GTT) is associated with direct stimulation of the maternal thyroid Received 19 November 2019
gland by human chorionic gonadotropin (hCG). It is characterized by slightly higher thyroid hormone and Revised 30 March 2020
lower thyroid-stimulating hormone (TSH) levels in early pregnancy and mild or no symptoms. While GTT Accepted 7 April 2020
must be distinguished from Graves’ disease (GD), which is associated with maternal and fetal complica- Published online 17 April
2020
tions, treated GD and new-onset GD in pregnancy are occasionally challenging to distinguish. Evaluating
serum hCG levels and TSH receptor antibody (TRAb) titers can help, but the results are not irrefutable KEYWORDS
due to pregnancy-related immunosuppression. Moreover, GTT can follow unusual clinical courses in rela- Gestational transient
tion to some pregnancy complications. Excessive hCG production can cause severe GTT symptoms in thyrotoxicosis; Graves’
patients with hyperemesis gravidarum, trophoblastic disease, or multiple pregnancies. Thyrotoxicosis can disease; human chorionic
emerge beyond the second trimester in patients with gestational diabetes mellitus and mirror syndrome, gonadotropin; pregnancy;
because of delayed elevations in the hCG levels. Detailed knowledge about GTT is necessary for correct thyroid-stimulating hor-
diagnoses and its appropriate management. This review focuses on the diagnosis of GTT, and, particularly, mone receptor antibody
its differentiation from GD, and unusual clinical conditions associated with GTT that require comprehen-
sive management.

Introduction levels, complications associated with hyperemesis gravidarum

(HG), spontaneous recovery during the latter half of pregnancy,
Pregnancy profoundly affects the thyroid gland and thyroid func-
negative antithyroid autoantibodies, the absence of a goiter, and
tion. Hyperthyroidism during pregnancy is rare, but given the
circulating human chorionic gonadotropin (hCG) with high lev-
adverse outcomes that can occur in the mother and the fetus,
els of biological activity. However, the clinical manifestations of
identifying hyperthyroidism is essential [1]. Graves’ disease (GD)
GTT are not always evident [6]. Given that GTT symptoms are
occurs in 0.1–1% of all pregnancies and is the most common
similar to those seen during normal pregnancies, GTT is under-
cause of hyperthyroidism during pregnancy [2,3]. In contrast,
diagnosed, and it is challenging to detect without assessing thy-
gestational transient thyrotoxicosis (GTT), which is characterized roid function [6].
by increased thyroid hormone levels and thyroid-stimulating The pathological mechanisms that contribute to GTT include
hormone (TSH) suppression during normal pregnancies, causes thyrotropic stimulation of the thyroid gland by placental hCG
thyrotoxicosis more frequently than GD. GTT occurs in 2–11% [10], dysregulation of hCG production, hypersensitivity of the
of all pregnancies [4]. As other causes of thyrotoxicosis during TSH receptor to hCG [8], and heightened sensitivity of the thy-
pregnancy are rare, the differential diagnosis is usually GD or roid gland to thyroid hormone stimulation [11]. Strong positive
GTT [5]. However, as the symptoms and signs of hyperthyroid- correlations are evident between the serum FT4 and hCG levels
ism can be seen in normal pregnancies, diagnosing hyperthyroid- during the first trimester [4,12]. The serum hCG levels rise soon
ism that presents for the first time in pregnancy can be after fertilization and peak at 10–12 weeks of gestation, and when
challenging. While GTT usually has a short duration and they peak, the serum TSH levels fall (Figure 1) [13]; the TSH lev-
resolves spontaneously [6,7], it can be associated with unusual els were suppressed in 67% of women with hCG levels
manifestations, including a delayed onset, severe symptoms >2,00,000 IU/L and in 100% of women with hCG levels
requiring specific treatments, or a prolonged course [8]. This >4,00,000 IU/L [14,15]. Increases in serum thyroxine-binding
review focuses on diagnosing GTT, and, particularly, its differen- globulin (TBG) levels caused by a reduced TBG clearance as con-
tiation from GD, and unusual clinical conditions associated with sequences of estrogen and hCG-induced TSH receptor stimula-
GTT that require comprehensive management. tion, greatly affect thyroid function during pregnancy [16].
Alpha and beta subunits comprise the glycoprotein hCG. The
alpha subunit is almost identical to those found in TSH, luteiniz-
Overview of gestational transient thyrotoxicosis
ing hormone, and follicle-stimulating hormone [13]. The beta
Kimura et al. [9] were the first to describe ‘gestational thyrotoxi- subunits of hCG and TSH share an 85% sequence homology in
cosis’, and it was characterized in pregnant women as follows: the first 114 amino acids and they contain 12 cysteine residues
symptoms of thyrotoxicosis during early pregnancy, marked at highly conserved positions [10,17]. Hence, hCG can stimulate
increases in free thyroxine (FT4) and free triiodothyronine (FT3) TSH receptors to produce thyroid hormone and suppress TSH

CONTACT Shigeo Iijima [email protected] Department of Regional Neonatal-Perinatal Medicine, Hamamatsu University School of Medicine, 1–20–1
Handayama, Hamamatsu, 431–3192, Shizuoka, Japan
ß 2020 Informa UK Limited, trading as Taylor & Francis Group
2 S. IIJIMA

When patients receive antithyroid drugs, evaluating the effects

of pregnancy on the thyroid and on the course of GD is chal-
lenging. GD is aggravated during the first trimester, and amelio-
rates gradually during the latter half of pregnancy [21].
Moreover, hCG stimulation mildly aggravated thyrotoxicosis dur-
ing early pregnancy in patients with GD who were near remis-
sion [23]. Greater thyroid hormone elevations occur during early
pregnancy in many patients with GD [21], however, whether
hCG or TRAb causes these elevations remains unclear.
Evaluating the serum hCG and TRAb levels may help elucidate
such patients’ diagnoses. However, pregnancy profoundly affects
the maternal immune system, leading to general immunosup-
pression (e.g. reduced helper T-cell function) [24], which reduces
the TRAb levels [25]. A previous study showed that the TRAb
levels did not increase during early pregnancy in women with
confirmed GD who were in remission before pregnancy [23].

Figure 1. The pattern of changes in thyroid function and human chorionic New-onset Graves’ disease during pregnancy
gonadotropin. hCG: human chorionic gonadotropin; TSH: thyroid-stimulating hor-
mone; T4: thyroxine; TBG: thyroxine-binding globulin. Ide et al. [26] reported that among patients with thyrotoxicosis
during pregnancy and postpartum, 7% had new-onset GD during
levels. TSH levels increase gradually during the second and third pregnancy. The mechanism underlying the development of new-
onset GD during pregnancy is unclear; however, many immuno-
trimesters, because the hCG levels are lower.
logical factors contribute to maternal autoimmunity.
GTT is usually transient, has a short duration, and resolves
Thyrotoxicosis in a woman with no evidence of hyperthyroidism
spontaneously as the hCG levels decline [7]. Most patients with
before pregnancy favors a GTT diagnosis rather than a GD diag-
GTT do not require specific treatment, and it is not associated
nosis. Regarding the differential diagnosis of new-onset GD dur-
with unfavorable pregnancy or perinatal outcomes [5,18]. ing pregnancy and GTT, Ide et al. [26] reported significant
delays in the onset of thyrotoxicosis, significantly higher FT4
Distinction between gestational transient thyrotoxicosis and FT3 levels, and higher FT3/FT4 ratios in new-onset GD.
and Graves’ disease Moreover, these researchers used ultrasonography and found
that the thyroid volume and blood flow were significantly greater
Most patients with GTT have no or mild symptoms of hyperthy- in patients with GD than in those with GTT. However, the
roidism, such as palpitations only [3], whereas GD manifests as investigators suggested that these parameters may not be suffi-
palpitations, anxiety, hand tremors, and heat intolerance [2]. In ciently sensitive to differentiate between GD and GTT and rec-
addition, accurate clinical history, physical examination, and, ommended determining the TRAb levels as a more sensitive and
occasional ultrasonography can distinguish these two conditions. specific method. Physiological immunosuppression tends to sup-
For example, the absence of a history of thyroid disease and clin- press the TRAb levels during pregnancy, and they are often
ical signs of GD, such as goiter and ophthalmopathy, may favor undetectable in patients with new-onset GD and in those whose
a diagnosis of GTT [19]. However, differentiating between GTT GD is in remission [25]. Final diagnoses should be confirmed
and GD is challenging when the clinical characteristics of GD during patient follow-up; however, some patients’ differential
are absent, because the manifestations of GTT are not always diagnoses may remain elusive.
apparent [6]. Estimating thyroid stimulation directly using, for
example, radioactive iodine uptake tests, or tests that examine Thyroid-stimulating hormone receptor antibody-negative
the distribution of functional tissue using, for example, thyroid Graves’ disease
scintigraphy, is contraindicated during pregnancy. Essentially,
GTT is nonautoimmune transient hyperthyroidism that occurs Thyroid autoantibodies are present in patients with GD, but not
in normal pregnancies, which differentiates it from GD; there- in those with GTT [20]; however, these autoantibodies are
fore, when a diagnosis is ambiguous, determining the TSH undetectable in some patients who appear to have typical GD.
receptor antibody (TRAb) level is indicated [20]. Some antibody-negative patients may have GD but remain
undiagnosed as the antibody levels may be below the detection
level initially, which is a consequence of pregnancy-related
Treated Graves’ disease immunosuppression [25].
Besides, false-negative thyroid antibody results are always pos-
Between 26 and 44% of patients with treated GD have GTT sible. First, second, and third generation thyroid binding inhibit-
[21,22]. As GTT occurs in 2–11% of women with normal preg- ing immunoglobulin assays have been developed, and each new
nancies [4], the prevalence of GTT among pregnant patients generation assay has greater sensitivity and specificity [27,28]
with GD is much higher than that in normal pregnancies. This (Table 1). Despite using the newest TRAb assays, sensitivity may
finding may be associated with the greater receptiveness of the vary according to the stage of the disease [23], and some patients
thyroid of patients with GD to stimulation, because it is primed with GD will test negative. However, some TRAb-negative
by TRAbs. A study reported that among patients with GD, the patients develop TRAb-positive GD during follow-up [29].
TRAb and hCG levels were higher in those with GTT compared Therefore, comparative follow-up studies are required.
with those without GTT [22]. Furthermore, Nishihara et al. [29] reported that 4.5% of their
 GYNECOLOGICAL ENDOCRINOLOGY 3

Table 1. Immunoassay methods for detecting/measuring thyroid-stimulating hormone receptor antibodies.

Clinical Clinical
sensitivity, specificity,
mean mean
Generation TSHR Phase Technology Tracer Assay time Procedure (range) (%) (range) (%)
First Solubilized Liquid RIA Labelled >1 day Manual 77.5 (52.2–94.0) 99.2 (97.5–100.0)
porcine bovine TSH
Second Immobilized Solid RIA Labelled >3 h Manual 95.9 (85.5–100.0) 97.9 (91.4–100.0)
porcine, bovine TSH
recombinant
human
Third Immobilized Solid ECLIA, FEIA, CLEIA Labelled M22 <30 min Fully automated 97.7 (96.0–100.0) 99.5 (98.9–100.0)
porcine
TSHR: thyroid-stimulating hormone receptor; RIA: radioimmunoassay; ECLIA: electrochemiluminescence immunoassay; FEIA: fluorescence enzyme immunoassay;
CLEIA: chemiluminescent enzyme immunoassay; TSH: thyroid-stimulating hormone; M22: thyroid-stimulating human monoclonal antibody.

patients with antibody-negative GD had activating mutations of Given the relatively high incidence of GTT in patients with
the TSH receptor that caused diffuse thyroid enlargements and HG, thyroid function should be evaluated routinely to avoid
clinical or subclinical hyperthyroidism. unnecessary antithyroid drug therapy and to detect excessively
high thyroid hormone levels [31].

Unusual clinical manifestations of gestational transient

thyrotoxicosis Gestational trophoblastic disease
GTT is generally associated with subclinical or mild hyperthy- Gestational trophoblastic disease is a rare complication that
roidism. However, some patients with GTT, including those with ranges from hydatidiform mole (HM) to choriocarcinoma, and
HG, gestational trophoblastic disease, and multiple pregnancies, HM, which is also known as a molar pregnancy, is the most
have severe symptoms requiring treatment. Thyrotoxicosis in common form. The incidence of HM in Europe and North
GTT occurs temporarily from 10–15 weeks of pregnancy, which America is approximately 0.1% of all pregnancies [36]. Molar
corresponds with the peak serum hCG levels [6], but it can per- pregnancies are present in 7% of patients with hyperthyroidism
sist beyond 20 weeks of pregnancy, for example, during multiple and rarely in patients with severe thyrotoxicosis [37]. Women
pregnancies, and it can develop during and beyond the second with molar pregnancies may present with pathologically high
trimester, for example, in patients with gestational diabetes melli- hCG levels. The thyrotropic activity of hCG from HMs is aug-
tus (GDM) and mirror syndrome. mented compared with that associated with hCG from normal
placentas. Indeed, cyclic adenosine monophosphate (cAMP) pro-
duction is exacerbated by hCG in the serum from women with
Hyperemesis gravidarum gestational trophoblastic disease when it is incubated with
The incidence of HG is 0.3–1%, and it is a complication of early Chinese hamster ovary cells transfected with the human TSH
pregnancy characterized by persistent vomiting, >5% weight receptor [38]. The severity of thyroid disease in patients with
loss, ketonuria, electrolyte abnormalities, and dehydration [30]. HMs increases with age, parity, the beta-hCG level, and mole
GTT occurs in 30–60% of patients with HG [13,31–33]. The size [39].
mechanism underlying HG and the role of hyperthyroidism in Surgically removing the HM rapidly ameliorates hyperthyroid-
HG are unclear. However, hCG may be involved in the patho- ism and, if possible, surgery should occur during early pregnancy
genesis of GTT and HG, because higher hCG levels are found in [40]. Nevertheless, uncontrolled hyperthyroidism may develop
both conditions [34]. The hCG levels correlate positively with into a thyroid crisis or cause serious arrhythmias perioperatively
the vomiting severity and the degree of thyroid stimulation [32]. [41]. Patients require close observation for the first 24–48 h post-
Sun et al. [31] reported that the overall incidence of GTT operatively, preferably in a high-dependency unit. Further, to
increased significantly if the serum hCG levels were >80,000 IU/ exclude the presence of persistent trophoblastic tissue, thyroid
L, subclinical GTT was present if the serum hCG level was function and beta-hCG levels should be monitored regularly
80,000–1,40,000 IU/L, and clinical GTT was present if the serum until the hCG levels normalize.
hCG level was >1,80,000 IU/L.
Patients with HG complicated by GTT usually complain of
Multiple pregnancies
nausea, vomiting, and weight loss by 4–9 weeks of gestation, and
they present with tachycardia, fine tremors, and mild proximal Gr€un et al. [42] reported that compared with single pregnancies,
weakness. Patients with high serum FT3 levels present with twin pregnancies were associated with more frequent and pro-
shortness of breath, heat intolerance, and palpitations. found serum TSH level reductions. Moreover, they found that
Hyponatremia, hypokalemia, mild hyperbilirubinemia, and mild- the mean peak serum hCG levels at 9–11 weeks were significantly
to-moderate liver enzyme elevations are also described [35]. The higher in twin pregnancies compared with those in single preg-
most appropriate treatment for HG with GTT includes fasting nancies (1,71,000 U/L vs. 65,500 U/L), and that hCG levels
and intravenous hydration to maintain the water and electrolyte >75,000 U/L lasted for <1 week in single and 6 weeks in twin
balance, and thyroid function elevations should be conducted. pregnancies. Higuchi et al. [43] described a patient with GTT
Antithyroid drugs might be warranted for patients with severe who had severe symptoms, and they suggested that the overpro-
clinical symptoms; treatment usually lasts for a few weeks, duction of hCG (359,900 mIU/mL at 12 weeks’ gestation) caused
because thyroid function normalizes by the second trimes- by the triplet pregnancy led to severe GTT. Ogueh et al. [44]
ter [6,7]. found that maternal thyroid activity levels increased with the
4 S. IIJIMA

is believed to cause mirror syndrome, and excessive shedding of

the placental trophoblast and/or placenta-derived angiogenic fac-
tors are related to its etiology [53]. The hCG levels are often
markedly higher in mirror syndrome [54]. Given that the placen-
tal trophoblast releases hCG, the hCG elevations could indicate
the level of placental disturbance [55].
Some patients have mirror syndrome complicated by
thyrotoxicosis [56,57], which may be caused by excessive hCG
production, because abnormal hCG has an even greater thyroid-
stimulating ability than normal hCG. Maternal symptoms of mir-
ror syndrome are likely to emerge beyond the second trimester
and disappear shortly after the fetal symptoms have been suc-
cessfully treated or the pregnancy has been terminated [58].
Therefore, the onset of thyrotoxicosis in this condition might be
later than that in typical GTT. Assessing maternal hCG levels
Figure 2. Serum median human chorionic gonadotropin levels by pregnancy
type. hCG: human chorionic gonadotropin.
and thyroid function should be part of the evaluation of fetal
hydrops associated with mirror syndrome.
fetal number. Figure 2 shows the median serum hCG levels by
pregnancy type [45]. In multiple pregnancies, the peak hCG lev-
Familial nonautoimmune hyperthyroidism
els are significantly higher and the peaks are of much longer
durations than those in single pregnancies [6,42]. Compared Rodien et al. [59] reported a patient with GTT who had similar
with single pregnancies, the placenta may produce larger hCG levels to those seen in normal pregnancies. The patient
amounts of hCG for longer periods during multiple pregnancies. developed persistent thyrotoxicosis that required antithyroid
Conversely, Sakaguchi et al. [46] reported that the serum hCG drugs during pregnancy, and her condition improved rapidly
levels in multiple pregnancies did not correlate positively with postpartum. The researchers found a mutation in the gene
the thyroid hormone levels and differed from the results from encoding the TSH receptor that resulted in the replacement of a
normal single pregnancies. These investigators suggested that lysine residue with an arginine residue at position 183
hCG circulating during multiple pregnancies may comprise var- (Lys183Arg) in the patient and her mother. The mutant receptor
iants with lower levels of thyrotropic activity that were likely was more sensitive to hCG than the wild-type receptor; it caused
related to the molecular heterogeneity of hCG. a four-fold increase in cAMP production that increased the thy-
roid hormone level [60]. Subsequently, Coulon et al. [61]
Gestational diabetes mellitus described another patient with prolonged and severe GTT whose
TSH receptor gene sequence had a mutation that caused the
GDM affects 2–5% of pregnant women [47]. Oguz et al. [48] replacement of lysine 183 with asparagine (Lys183Asn), resulting
reported a significantly higher frequency of GDM among women in greater sensitivity to hCG.
with GTT (13.4%) compared with that among healthy pregnant
women without GTT (4%); patients with GTT had significantly
higher hemoglobin A1c (HbA1c) levels at 6–12 weeks of preg- Conclusions
nancy and the TSH levels correlated negatively with the HbA1c
levels in the thyrotoxic state. Furthermore, Artner et al. [49] As GTT and GD during pregnancy can show similar clinical
found that compared with women with healthy pregnancies, symptoms, it is important to differentiate these diseases.
women with GDM had similar serum hCG levels during the first However, gold standard investigative methods have not yet been
trimester, their hCG levels increased from the twenty-fifth week established. Although GTT tends to be associated with subclin-
of gestation until the end of the pregnancy, and they had signifi- ical or mild hyperthyroidism, it can lead to unusual manifesta-
cantly higher serum hCG levels after 30 weeks of gestation. A tions, including a delayed onset, worse symptoms, or a
recent study’s findings demonstrated that the serum beta-hCG prolonged clinical course, in women with particular complica-
levels in women with GDM increased with gestational age [50]. tions. Hence, thyroid function should be routinely tested and fol-
Hence, women with GDM may have GTT during the second or lowed in patients with conditions likely to cause GTT.
third trimester because of a potential association between the
excessive production of hCG and low levels of progesterone pro-
duction caused by reduced placental function [51]. Acknowledgement
Thyroid hormones may increase gluconeogenesis and glycoge-
The author received no specific funding.
nolysis rates, elevate insulin degradation rates, increase the secre-
tion of and exacerbate the effects of glucagon, and increase the
plasma free fatty acid concentrations [52]. Therefore, GTT itself
Disclosure statement
may adversely affect glucose tolerance until late pregnancy.
No potential conflict of interest was reported by the author(s).

Mirror syndrome
ORCID
Mirror syndrome is characterized by maternal edema, fetal
hydrops, and placental hypertrophy [53]. The hydropic placenta Shigeo Iijima http://orcid.org/0000-0003-3391-3757
 GYNECOLOGICAL ENDOCRINOLOGY 5

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