See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/26870161

Hyperthyroidism during pregnancy: etiology, diagnosis and management

Article  in  Women s Health · July 2005

DOI: 10.2217/17455057.1.1.97 · Source: PubMed

CITATIONS READS
8 1,467

1 author:

John H Lazarus
Cardiff University
434 PUBLICATIONS   14,700 CITATIONS   

SEE PROFILE

Some of the authors of this publication are also working on these related projects:

EUGOGO View project

USI and IDD in CEE/CIS View project

All content following this page was uploaded by John H Lazarus on 23 November 2016.

The user has requested enhancement of the downloaded file.

For reprint orders, please contact:
[email protected]

R EVIEW

Hyperthyroidism during pregnancy: etiology,

diagnosis and management
John H Lazarus
Pregnancy has marked effects on thyroid physiology and autoimmune thyroid disease
Cardiff University, Centre for
tends to ameliorate through gestation due to the general immunosuppression seen in
Endocrine and Diabetes
Sciences, University Hospital pregnancy. There is a need for trimester-specific thyroid hormone reference ranges.
of Wales, Heath Park, Hyperthyroidism in pregnancy – usually due to Graves’ disease – is not common but, if the
Cardiff, CF14 4XN, patient is compliant, a good outcome can be expected for both mother and child if
Wales, UK
Tel.: +44 2920 716900; treatment with anti-thyroid drugs (propylthiouracil is preferred) is instituted. Thyroid-
Fax: +44 2920 712045; stimulating hormone receptor antibody should be measured at 36 weeks in such patients
E-mail: [email protected] in order to predict the possibility of neonatal hyperthyroidism. Transient gestational
hyperthyroidism is often associated with hyperemesis gravidarum and thyroid function
should be checked in patients severely affected by this condition. Radioiodine therapy is
contraindicated in pregnancy but thyroid surgery may be performed safely in the second
trimester. Autoimmune thyroiditis and Graves’ hyperthyroidism occur quite commonly in
postpartum women.

The prevalence of Graves’ disease is approxi- The placenta secretes human chorionic gona-
mately 3/1000 with an incidence of around dotropin (hCG), a glycoprotein hormone shar-
0.5/1000/year. The prevalence and incidence in ing a common α subunit with thyroid-
women during child bearing years is not known stimulating hormone (TSH) but having a
but hyperthyroidism is said to occur in 2/1000 unique β subunit, which confers specificity. Evi-
pregnancies and Graves’ disease would be dence derived both from in vitro studies on thy-
expected to account for at least 80% of these roid tissue, and on eukaryotic cells stably
cases. While these figures are low, untreated or expressing the human TSH receptor (TSHR),
poorly controlled hyperthyroidism can have a suggests that hCG, or a molecular variant, is able
deleterious effect on the mother as well as the to act as a TSH agonist. The impact of the phys-
fetus. The thyroid hormone changes and immu- iologic changes on thyroid function is shown in
nologic effects of normal pregnancy will be Table 1 [6].
reviewed as a background to the management of
hyperthyroidism during pregnancy. The subject Immune changes
has been reviewed previously [1–3]. Pregnancy has a profound effect on the
immune system, in order to maintain the fetal–
Pregnancy & the thyroid maternal allograft, which is not rejected despite
Hormonal changes displaying paternal histocompatability antigens
It has been known for some time that pregnancy [7]. While there is no overall immunosupression
has an appreciable effect on thyroid economy [4]. during pregnancy, dramatic clinical improve-
There are significant changes in iodine metabolism ment usually occurs in patients with immuno-
characterized by increased excretion of iodine in the logic disorders such as rheumatoid arthritis
urine; this iodine loss may account for the increase (RA) when they become pregnant. T-cell subset
in thyroid volume even in areas of moderate dietary studies in pregnancy are discrepant, as periph-
iodine intake and the substantially greater increase eral blood CD4+ and CD8+ cell levels have
Keywords: antibodies, anti-
in volume in iodine-deficient areas [5]. Thyroid been variously reported to decline, remain
thyroid drugs, breast feeding, hormone transport proteins, particularly thyroxine unchanged and increase during pregnancy [7].
Graves’ disease, hyperemesis, binding globulin (TBG), increase in the first tri- Although the distinction between T-helper cell
hyperthyroidism, postpartum,
thyroid function
mester due to enhanced hepatic synthesis and a (Th)1 and Th2 responses in humans remains
reduced degradation rate caused by oligosaccharide less clear than in the mouse, the general agree-
modification. Serum concentrations of thyroid ment is that in pregnancy there is a bias
hormones have been reported to be decreased, towards a Th2 response [8]. This seems to be
increased or unchanged during gestation. achieved by the fetal–placental unit producing

10.2217/17455057.1.1.97 © 2005 Future Medicine Ltd ISSN 1745-5057 Women's Health (2005) 1(1), 97-104 97
REVIEW – Lazarus

Table 1. Physiologic changes in pregnancy that influence thyroid function tests.

Physiologic change Thyroid function test change
↑ Thyroid binding globulin ↑ Serum total T4 and T3 concentration
First trimester hCG elevation ↑ Free T4 and ↓TSH
↑ Plasma volume ↑ T4 and T3 pool size
↑ Type III 5-deiodinase (inner-ring deiodination) ↑ T4 and T3 degradation (resulting in requirement
due to increased placental mass for increased hormone production)
Thyroid enlargement (in some women) ↑ Serum thyroglobulin
↑ Iodine clearance ↓ Hormone production in iodine-deficient areas
Adapted from Brent [6]. hCG: Human chorionic gonadotropin; TSH: Thyroid-stimulating hormone.

Th2 cytokines, which inhibit Th1. Th1 mutation activated only during pregnancy
cytokines are potentially harmful to the fetus as resulting in familial recurrent gestational
interferon is a known abortifacient. thyrotoxicosis due to hypersensitivity to hCG
The high concentrations of estrogen produced of the mutant TSHR [11].
in normal pregnancy almost certainly contribute This latter unique case has drawn attention to
to the fall in autoantibody levels observed in the close association of gestational transient thy-
pregnant patients with autoimmune thyroid dis- rotoxicosis and hyperemesis gravidarum. Gesta-
ease (AITD) [9]. Despite the fall in autoantibod- tional transient hyperthyroidism is due to
ies, there are no significant changes reported in spillover of hCG onto the TSHR [12].
the number of B-cells in the circulation in nor-
mal human pregnancy. While progesterone may Clinical aspects & diagnosis
favor Th2 cells, evidence has indicated that The clinical presentation of hyperthyroidism
estrogen delivers a negative signal to B-cell func- may not be obvious, as the symptoms of tachy-
tion during pregnancy and this showed a slow cardia, sweating, dyspnea and nervousness may
reversal in the postpartum period. In keeping be seen in normal pregnancy. Cardiac systolic
with these observations, autoantibody titers and flow murmurs occur in normal pregnancy as
inflammation fall throughout pregnancy as well as hyperthyroidism.
observed in all autoimmune diseases investigated The diagnosis of hyperthyroidism in preg-
[10]. However, after most pregnancies, there is a nancy is made by routine measurement of circu-
marked increase in many different types of lating thyroid hormones and TSH by a sensitive
autoantibody secretion and an exacerbation of assay. Free T4 and T3 as opposed to total T4 and
diseases in the months after delivery, not just T3 assays are preferred by some as there is no
AITD but, for example, also in patients with interference resulting from the estrogen-stimu-
multiple sclerosis or RA. An outline of the lated increase in TBG concentrations. Recent
immunologic and hormonal changes during ges- national and internationally agreed guidelines [13]
tation in relation to autoimmune thyroid disease suggest that laboratories should be encouraged to
is shown in Table 2 [2]. develop normal ranges for levels of total, but
more particularly free, T4 and T3, as well as TSH
Causes of hyperthyroidism in pregnancy [14–16], all of which may change during the course
Etiology of gestation. As TSH may be suppressed in early
While the most common cause of hyper- pregnancy due to the secretion of hCG, serum
thyroidism in pregnancy (which affects up to TSH alone is usually not adequate to assess thy-
0.2% of pregnant women) is Graves’ disease roid status in early gestation but has a high specif-
(85–90%), other causes such as hyperemesis icity in later pregnancy. Radioiodine uptake
gravidarum, toxic multinodular goiter, toxic studies are contraindicated during pregnancy but
adenoma, and subacute thyroiditis may occur. thyroid ultrasound will indicate the diffuse
It should be noted that most women with nau- nature of the thyroid gland. The diagnosis of
sea and vomiting in pregnancy do not have Graves’ disease is made clinically by noting the
hyperthyroidism although the levels of TSH presence of a positive family history of auto-
may be below normal at this time of gestation. immune thyroid disease and/or by the finding of
Rarer causes include struma ovarii, hydatidi- a diffuse goiter together with extrathyroidal signs
form mole and one reported case of a TSHR of ophthalmopathy or dermopathy (not seen in

98 Women's Health (2005) 1(1)

 Hyperthyroidism during pregnancy: etiology, diagnosis and management – REVIEW

in normal pregnancy. However, many of these

Table 2. Immunologic and hormonal features of pregnancy.
reports are relatively old. With better recognition
Clinical Improvement in Graves’ hyperthyroidism, of the treatment requirements of the pregnant
rheumatoid arthritis, psoriatic arthritis, and other Graves’ patient these complications should
autoimmune diseases
become less frequent. A recent confirmation of the
Trophoblast HLA-G expression occurrence of fetal loss associated with excess thy-
Fas ligand expression
roid hormone exposure was provided by Anselmo
Lymphocytes Th2 response and colleagues who studied this problem in
Th2 cytokines produced by the fetal/placental unit patients with thyroid hormone resistance thereby
Hormones Progesterone increase – reduction in B-cell activity avoiding any consideration of thyroid autoimmu-
Estrogen increase – fall in autoantibody levels nity [18]. Miscarriage rates were 22.9% in response
Cortisol (hydrocortisone), 1,25-dihydroxy vitamin D, and
to greatly elevated thyroid hormone levels in the
norephinephrine all affect the immune response
affected mother when the fetus did not have this
HLA: Human leukocyte antigen; Th: T-helper cell.
resistance compared with 2–4% in controls. There
Adapted from Lazarus [2].
is therefore no doubt that hyperthyroidism should
gestational hyperthyroidism) and biologically, if be treated although it is true to state that Graves’
necessary, by measurement of TSHRAb. disease may ameliorate during gestation in a similar
Due to the immune changes already referred fashion to other autoimmune diseases.
to, the titer of TSHR antibodies (TSHRAb – This gestational amelioration is often associ-
Table 3) will decline during gestation along with ated with a reduction in titer of TSHRAb and, as
that of anti-thyroid peroxidase antibody (anti- has been stated, a change from stimulatory to
TPO Ab). Thus, at 36 weeks TSHRAb may be blocking antibody activity is observed in Graves’
negative; if still positive at this time, the risk of disease during pregnancy in some cases [19]. It
neonatal hyperthyroidism due to the transpla- should also be noted that a variety of thyroid-
cental passage of maternal antibody is high. related antibodies may occur in patients with
Measurement of TSHRAb is particularly impor- Graves’ disease. Zakarij and colleagues, for exam-
tant in a woman previously treated for Graves’ ple, reported the presence of two species of stim-
hyperthyroidism by destructive therapy and ulating antibody in a patient who gave birth to
known to be euthyroid during gestation. In this three children with transient neonatal hyper-
situation a false sense of security in relation to thyroidism [20]. In addition to the classical
the development of neonatal hyperthyroidism TSHRAb another stimulating antibody whose
may be engendered if TSHRAb are not meas- in vitro stimulating activity was not inhibited by
ured at 36 weeks. Cases of neonatal hyperthy- TSH binding inhibitory antibody (TBIAb) was
roidism have been recorded whose mothers have found. In addition, this particular patient also
been treated by surgery for hyperthyroidism and had appreciable amounts of TBIAb. This report
who have been receiving thyroxine therapy for emphasizes the concept that patients with Graves’
postsurgical hypothyroidism while pregnant. hyperthyroidism often possess more than one
antibody directed against the TSHR. To empha-
Outcome of poorly treated or untreated size this, a recent report has documented the
Graves’ hyperthyroidism in pregnancy appearance of a blocking antibody to TSHR
Prompt diagnosis and treatment are essential to which was suggested to be the cause of the devel-
avoid both maternal and fetal complications. opment of primary hypothyroidism in a patient
Maternal complications include miscarriage, pla- with Graves’ disease in late pregnancy [21].
centa abruptio and preterm delivery. Congestive
heart failure and thyroid storm may also occur and Management
the risk of pregnancy-induced hypertension and Preconception
pre-eclampsia is significantly higher in women There is a good case for a preconception clinic for
with poorly controlled hyperthyroidism. From the patients with Graves’ hyperthyroidism who wish
fetal aspect, hyperthyroidism, neonatal hyper- to become pregnant. First, education about the
thyroidism, prematurity and intrauterine growth effects of the disease on maternal health and fetal
retardation may be observed. Hamburger cited 11 well-being can be given to allay fears that are
reports that collectively documented a 5.6% inci- commonly present in these women. The patient’s
dence of fetal death or stillbirth in 249 pregnancies thyroid status should be checked frequently to
and a further 5% fetal and neonatal abnormalities minimize risk of miscarriage should she be hyper-
[17]. These figures are greater than those expected thyroid at the time of conception. If treatment

www.futuremedicine.com 99
REVIEW – Lazarus

Table 3. Guidelines for measurements of TSH-receptor antibodies in a pregnant

women with Graves’ disease.
Patient status Measurement
Euthyroid – previous ATD Not necessary
Euthyroid ± T4 therapy Check in early pregnancy: if low or absent no further testing
Previous radioiodine therapy/surgery If high – check fetus and check antibodies in last trimester
Receiving ATD during pregnancy Measure in last trimester
TSH receptor antibodies may be measured by a ‘binding’ assay in which the result is expressed as the percentage
inhibition of TSH to thyroid membranes by the test serum. The antibodies may also be assayed by the ability of the
test serum to stimulate cyclic AMP in a thyroid slice assay. Hence values are not given in this table. (Reproduced from
Laurberg et al. [21], with permission of the Society of the European Journal of Endocrinology.
ATD: Anti-thyroid drug; TSH: Thyroid-stimulating hormone.

had commenced with methimazole or carbima- highlighted the concern about fetal radiation risk
zole, a change to propylthiouracil (PTU) is rec- [25]. The maternal thyroid uptake, the gestational
ommended to reduce the admittedly rare age and the ability of the fetal thyroid to concen-
occurrence of aplasia cutis reported following the trate iodine are all vital in determining the radioio-
administration of the former drugs as well as the dine exposure in utero. The fetal thyroid
rarer and more serious embryopathy [22]. The concentrates iodide after 10 to 12 weeks gestation
management of the patient during gestation shall and is relatively more avid for iodine than the
be discussed below. maternal thyroid. The fetal tissues are also more
radio-sensitive. Administration of up to 15 mci
Previously treated patients with (555 MBq)131I for hyperthyroidism up to
Graves’ disease 10 weeks gestation does not compromise fetal thy-
These patients may have received anti-thyroid roid function and the low fetal whole-body irradia-
drugs, surgery or radioiodine therapy and be tion is not considered sufficient to justify
euthyroid on or off thyroxine therapy. The termination of pregnancy, although this is often
important concern here is that fetal and neonatal performed. However, from limited clinical data,
hyperthyroidism may still occur. Recent guide- 131I given after that gestational age results in bio-

lines state that if antithyoid drugs have been pre- chemical hypothyroidism and even cretinism in the
viously used there is no need to measure neonate [26]. In these circumstances termination of
TSHRAbs as the maternal thyroid function gives pregnancy may be advised but dosimetry studies
a reliable estimate of fetal thyroid status and the should be performed. If the pregnancy continues to
risk of neonatal hyperthyroidism is very low [23] term, intrauterine hypothyroidism may be diag-
(Table 3). TSHRAbs should be measured in a nosed by umbilical cord sampling. The neonate
euthyroid pregnant woman previously treated by should be evaluated at birth specifically for
either of the other modalities early in pregnancy. hypothyroidism and for malformations, which are
If the level is high at this time the fetus should be more common with higher doses of radiation. Nev-
evaluated carefully during gestation and the anti- ertheless some experience even with high adminis-
bodies measured again in the last trimester tered activity of radioiodine in the second trimester
(Box 1). In women with active Graves’ disease suggests that the total absorbed dose to the fetal
umbilical blood sampling may improve the con- body did not justify termination of pregnancy [27].
trol of fetal thyroid function in selected cases [24]
but this procedure has to be balanced against the Patients found to have hyperthyroid Graves’
potential risk. disease in early pregnancy
Medical therapy is preferred by most clinicians
Graves’ hyperthyroidism inadvertently as radioiodine is contraindicated and surgery
treated with radioiodine in early gestation requires pretreatment with anti-thyroid drugs
The practical procedures surrounding the adminis- to render the patient euthyroid. When there is
tration of radioiodine therapy for Graves’ disease not a combined antenatal clinic with an obste-
vary widely. In many clinics routine pregnancy test- trician together with a physician skilled in man-
ing is not performed before 131I administration. agement of patients with thyroid disorders,
Despite patient denial of pregnancy, several reports patients are usually treated by obstetricians,
of inappropriate radioiodine administration have although there is concern that some feel their

100 Women's Health (2005) 1(1)

 Hyperthyroidism during pregnancy: etiology, diagnosis and management – REVIEW

Box 1. Management of Graves' during pregnancy and after delivery, together

hyperthyroidism in pregnancy with methimazole, was claimed to be effective in
reducing the incidence of postpartum recurrence
• Confirm diagnosis. of hyperthyroidism but these results have not
• Start propylthiouracil. been confirmed. PTU should be continued at a
• Render patient euthyroid; continue with low dose throughout gestation and up to, and
low-dose anti-thyroid drug (ATD) up to and
through labor, although some clinicians stop the
during labor.
drug before delivery. Common complications of
• Monitor thyroid function regularly throughout
gestation (4–6 weekly) adjust ATD if necessary.
thionamide therapy include skin rash, arthralgia
• Check thydroid-stimulating hormone receptor and nausea in about 2% of patients. Methima-
antibodies at 36 weeks'gestation. zole (or carbimazole) may be used as an alterna-
• Discuss treatment with patient. tive in this situation with only a 33% chance of
• Effect on patient. crossreaction. Agranulocytosis is rare and is an
• Effect on fetus. indication for immediate withdrawal of the drug
• Breastfeeding. and possible treatment with granulocyte colony-
• Inform obstetrician and pediatrician. stimulating factor, although the results are not
• Check infant for thyroid dysfunction always satisfactory in non-pregnant patients; it
if indicated.
has not been used in pregnant patients. There is
Review postpartum – check for exacerbation.
no benefit in routine monitoring of the white
blood count as the fall in whole blood count may
training to be inadequate with low confidence be very rapid. β-adrenergic blocking agents such
in managing the condition [28]. It may not be as propranolol may be used for a few weeks to
appropriate for obstetricians to be managing ameliorate the peripheral sympathomimetic
Graves’ disease in pregnancy. Treatment is actions of excess thyroid hormone but prolonged
essential to minimize the adverse outcomes use can result in retarded fetal growth and
associated with Graves’ disease. General man- impaired response to anoxic stress together with
agement is outlined in Box 1. PTU should be postnatal bradycardia and hypoglycemia.
given in a dose of 100–150 mg three-times
daily until the patient becomes euthyroid (with Fetal evaluation
normal thyroid function tests) at which time As indicated, the fetus is at risk of thyroid dysfunc-
the dose should be reduced to the lowest tion if the mother has TSH receptor antibodies
amount to maintain the euthyroid state. The and/or is taking anti-thyroid drugs during the third
preference for PTU rather than methimazole trimester. Demonstration of fetal goiter by ultra-
(or carbimazole) administration relates firstly to sonography is an important predictor of fetal thy-
the occurrence of aplasia cutis with methima- roid dysfunction. It has been reported that fetal
zole but not with PTU [29]. Second, the inci- thyroid function is normal if there is no goiter but
dence of methimazole embryopathy (a severe fetal hyperthyroidism or hypothyroidism may be
midline deformity characterized by choanal diagnosed if there is thyroid enlargement [32]. Fetal
atresia and facial abnormalities), although rare, hypothyroidism is seen in mothers taking anti-
can be devastating [30]. There is only one thyroid drugs. Further fetal thyroid status evalua-
reported case resulting from PTU administra- tion may be obtained from an estimate of bone
tion [31] and many clinicians feel that PTU is maturation at the distal femoral center and fetal
the preferred drug. However, in terms of rapid- heart rate as well as fetal growth. Fetal blood sam-
ity of action and potential to induce fetal pling should be reserved for those cases in which
hypothyroidism, there is probably little reason fetal hypothyroidism requires intra-amniotic injec-
to choose PTU over methimazole. The so- tion of levothyroxine or where doubt exists between
called ‘block and replace’ regimen in which thy- fetal hyper- and hypothyroidism.
roxine is given with an anti-thyroid drug
should not be used because the dose of anti- Lactation & thyrotoxicosis
thyroid drug would inevitably be too high and Available evidence suggests that there is no signif-
cause fetal goiter and hypothyroidism. The aim icant effect of anti-thyroid drugs in utero on the
of treatment should be to maintain the serum long-term health of the neonate or child assuming
T4 concentration at the upper end of the nor- the dose during gestation has not caused iatro-
mal range for pregnancy. T4 administration to genic fetal hypothyroidism. PTU has a shorter
pregnant women with Graves’ hyperthyroidism half-life than methimazole and is more bound to

www.futuremedicine.com 101
REVIEW – Lazarus

serum proteins; hence it is not present in as high a The diagnosis of subacute thyroiditis is sug-
concentration in breast milk. Women receiving gested by the presentation of a painful thyroid in
PTU can breast-feed without significant risk to the presence of hyperthyroidism. As radionuclide
the neonate [33,34]. In addition, comprehensive evaluation (which would demonstrate a low iodine
studies have shown that thyroid function and uptake) is contraindicated, diagnosis may be made
physical and intellectual development of breast- with a fine needle aspiration biopsy of the thyroid
fed infants up to 86 months is not affected by associated with an elevation in systemic markers of
maternal methimazole therapy [35,36], even if the inflammation. Treatment is firstly with analgesics
mothers had developed hypothyroidism due to for pain and oral predinosolone therapy if inflam-
drug therapy [37]. The overall conclusions from mation is severe. Frequent monitoring of thyroid
these and other studies are encouraging and sug- function is required as a small number of patients
gest that with maternal doses of up to PTU will develop hypothyroidism.
750 mg or methimazole 20 mg (or equivalent)
there are no significant alterations in neonatal Surgery
thyroid hormone concentrations. Subtotal thyroidectomy is indicated if control
of the hyperthyroidism is poor on account of
Other causes of hyperthyroidism poor compliance or inability to take drugs.
Hyperemesis gravidarum is common and Patients with a very large goiter may also require
around 5% of cases require hospital admission surgery because of pressure symptoms. Surgery
because of dehydration and ketosis. The syn- is preferred in the second trimester as there is a
drome of transient hyperthyroidism of hyper- higher risk of associated abortion at an earlier
emesis gravidarum should be considered in any stage of gestation. In general, surgery should be
woman presenting with biochemical evidence avoided if it is considered that medical therapy
of hyperthyroidism in early pregnancy. Thyroid has a reasonable chance of success.
function should be checked in these patients; a
correlation has been established between the Severe hyperthyroidism
severity of the hyperemesis and thyroid func- This refers to patients who have been non-
tion with an elevated FT4 and FT3 with sup- compliant with previously prescribed drug ther-
pressed TSH. The FT3 may be normal in a apy as well as patients presenting for the first time
patient with poor nutrition presumably due to late in gestation with severe hyperthyroidism.
reduced T4 to T3 conversion. In those patients Rarely, an episode of infection or the develop-
who are hyperthyroid anti-thyroid drugs may ment of pre-eclampsia may precipitate thyroid
be given, although the hyperthyroidism is self- storm. This is a medical emergency requiring the
limiting and usually disappears with the cessa- use of thionamides, iodides, β-blockers, fluid
tion of vomiting. The diagnosis of gestational replacement and possibly steroid therapy and
thyrotoxicosis will be confirmed by noting the plasmapheresis to achieve euthyroidism [35].
absence of TSHR-stimulating antibodies, nega-
tive anti-TPO antibodies, usually an absence of Postpartum Graves’ disease
goiter and circulating hCG with high biologic Patients with Graves’ disease may develop
activity. As noted, a woman with low TSH in Graves’ hyperthyroidism during the early post-
the first trimester is almost certainly not hyper- partum period. Occasionally this is followed
thyroid, especially if the FT4 and FT3 are nor- immediately by transient hypothyroidism due to
mal. The TSH concentration falls as a normal co-existing destructive autoimmune thyroiditis
physiologic response to the increase in hCG despite increasing TSHRAb activity [39]. This
between 8 and 12 weeks gestation. Hence no may be important when considering postpartum
further investigation is required if thyroid hor- relapse of the disease.
mone concentrations are normal. The pathogenesis is related to what is know as
With regard to toxic multinodular goiter and ‘immune rebound phenomenon’ in which the
toxic adenoma, radioiodine, which may be the immune system, depressed during gestation,
treatment of choice, is absolutely contraindi- becomes activated postpartum with an accompa-
cated in pregnancy. The conditions may be man- nying elevation of thyroid antibodies. TSHRAbs
aged with anti-thyroid drugs during gestation; if tend to decrease during late gestation in Graves’
necessary surgery may be performed during the disease patients but there is a significant rebound
second trimester but if possible it is better to in the early postpartum period. Individual
postpone this till the postpartum period. patients at high risk of postpartum onset of

102 Women's Health (2005) 1(1)

 Hyperthyroidism during pregnancy: etiology, diagnosis and management – REVIEW

Graves’ disease can be found in early pregnancy feeding. Prevention of postpartum Graves’
by the detection of TSHRAb and up to 40% of hyperthyroidism may be achieved by adequate
women of child-bearing age may have developed treatment of the condition before the onset of
their disease during the postpartum period. gestation, which, in some cases, may include
It is important to differentiate postpartum destructive therapy.
Graves’ disease with accompanying hyperthy-
roidism from postpartum thyroiditis with hyper- Future perspective
thyroidism [40]. PPT occurs almost exclusively in The improvement in the management of thyrotox-
women who are found to have circulating anti- icosis in pregnancy, particularly that due to Graves’
TPO antibodies in early gestation. The presenta- disease, over the next decade will depend on:
tion of the hyperthyroid phase is at around
• Refinements in the ability to accurately assess
13 weeks post partum. Treatment of this
thyroid function during gestation
destructive thyroiditis is usually not necessary
(anti-thyroid drugs would not be helpful), but if • Exploration of the possibility of maternal thy-
tachycardia or palpitations are significant β- roid function screening in early gestation if
adrenoreceptor blocker therapy may be given. this becomes cost effective
The condition spontaneously resolves in 1– • Further elucidation of the immunology of
4 weeks but may be followed by a hypothyroid Graves’ disease with emphasis on the TSH
phase. The presence of circulating TSHRAb, receptor and its interaction with stimulating
radioiodine uptake, together with clinical exami- antibodies and artificial designer compounds.
nation and thyroid scintiscanning will usually This will provide a rational immunologic ther-
resolve any diagnostic difficulty although the apy for the condition instead of merely a block-
two conditions may occur together. Radioiodine ing agent with modest immunosuppressive
uptake testing is contraindicated during breast characteristics.

Executive summary
• Graves’ hyperthyroidism occurs in up to 2/1000 pregnancies.
• Thyroid hormone changes during gestation are due to an increase in thyroxine binding globulin (TBG) and the action of human
chorionic gonadotropin.
• There is a general immune suppression during pregnancy with an abrupt switch to the prepregnant state after delivery.
• The main cause of hyperthyroidism in pregnancy is Graves’ disease. Other important causes include hyperemesis gravidarum,
associated with gestational transient hyperthyroidism.
• Diagnosis of Graves’ disease is made clinically and by assay of thyrotropin receptor antibodies if necessary.
• Untreated or poorly treated Graves’ disease results in an increase in miscarriage, fetal death and neonatal abnormalities.
• Management of Graves’ hyperthyroidism in pregnancy should ideally be with propylthiouracil. Thyroid-stimulating hormone
receptor antibodies should be measured to predict neonatal hypothyroidism.
• Radioiodine therapy is totally contraindicated. If inadvertently administered in early gestation, termination is not indicated. If given
later, fetal and neonatal hypothyroidism should be carefully checked.
• There is a risk of exacerbation of Graves’ hypothyroidism in the postpartum period.
• Postpartum thyroiditis with a destructive hyperthyroidism occurs in 5–9% of women with positive anti-thyroid peroxidase
antibodies.

Bibliography 3. Glinoer D: Thyroid disease during 5. Berghout A, Wiersinga W: Thyroid size and
Papers of special note have been highlighted as pregnancy. In: Werner and Ingbar’s The thyroid function during pregnancy: an analysis.
either of interest (•) or of considerable interest (••) Thyroid A Fundamental and Clinical Text. Euro. J. Endo. 138(5), 536–542 (1998).
to readers. Braverman LE, Utiger RD (Eds), Lippincott, 6. Brent GA: Maternal thyroid function:
1. Mestman JH: Hyperthyroidism in Williams and Wilkins, Philadelphia, PA, interpretation of thyroid function tests in
pregnancy. Best Prac. Res. Clin. Endocrinol. USA, 1086–1108 (2005). pregnancy. Clin. Obs. Gynecol. 40, 3–15
Metab. 18, 267–288 (2004). •• Clinical review. (1997).
•• Current overview of the subject. 4. Glinoer D: The regulation of thyroid •• Emphasis on problems with thyroid
2. Lazarus JH: Thyroid disorders associated function in pregnancy: Pathways of function tests in pregnancy.
with pregnancy. Treat. Endocrinol. 4, 31–41 endocrine adaptation from physiology to 7. Burns DN, Nourjah P, Wright DJ et al.:
(2005). pathology. Endo. Rev. 18, 404–433 (1997). Changes in immune activation markers
•• Wide-ranging review including •• Definitive review of iodine metabolism and during pregnancy and postpartum. J. Reprod.
hypothyroidism. other thyroid changes during pregnancy. Immunol. 42, 147–165 (1999).

www.futuremedicine.com 103
REVIEW – Lazarus

8. Saito S, Sakai M, Sasaki K, Tanebe K, Tsuda 19. Kung AWC, Jones BM: A change from with prenatal methimazole exposure: three
H, Michimata T: Quantitative analysis of stimulatory to blocking antibody activity in new patients. Am. J. Med. Genet. A 129, 83–
peripheral blood Th0, Th1, Th2 and the Graves’ disease during pregnancy. J. Clin. 86 (2004).
Th1:Th2 cell ratio during normal human Endo. Metab. 83, 514–518 (1998). 31. Cheron RG, Kaplan MM, Larsen PR,
pregnancy and pre-eclampsia. Clin. Exp. 20. Zakarija M, De Forteza R, McKenzie JM, Selenkow HA, Crigler JF Jr: Neonatal
Immunol. 117, 550–555 (1999). Ghandur-Mnaymneh L: Characteristics and thyroid function after propylthiouracil
9. Davies TF: The thyroid immunology of the clinical correlates of a novel thyroid- therapy for maternal Graves’ disease. N.
postpartum period. Thyroid 9, 675–684 stimulating autoantibody. Autoimmunity 19, Engl. J. Med. 204, 525–528 (1981).
(1999). 31–37 (1994). 32. Polak M, Le Gac I, Vuillard E et al.: Fetal
• Useful review of the postpartum period 21. Ueta Y, Fukui H, Murakami H, and neonatal thyroid function in relation to
from an immunologic point of view. Yamanoughi Y, Yamamoto R: maternal Graves’ disease. Best Pract. Res.
10. Elenkov IJ, Wilder RL, Bakalov VK et al.: Development of primary hypothyroidism Clin. Endocrinol. Metab. 18, 289–302
IL-12, TNF-α, and hormonal changes with the appearance of blocking-type (2004).
during late pregnancy and early postpartum: antibody to thyrotropin receptor in 33. Momotani N, Yamashita R, Yoshimoto M,
implications for autoimmune disease activity Graves’ disease in late pregnancy. Thyroid Noh J, Ishikawa N, Ito K: Recovery from
during these times. J. Clin. Endo. Metab. 86, 9, 179–182 (1999) fetal hypothyroidism: evidence for the safety
4933–4938 (2001). 22. Cooper DS: Antithyroid drugs. New Engl. J. of breast feeding while taking
11. Rodien P, Jordan N, Lefevre A et al.: Med. 352, 905–917 (2005). propylthiouracil. Clin. Endo. 31, 591–595
Abnormal stimulation of the thyrotropin • Comprehensive overview of (1989).
receptor during gestation. Hum. Reprod. anti-thyroid drugs. 34. Momotani N, Noh JY, Ishikawa N, Ito K:
Update 10, 95–105 (2004). 23. Laurberg P, Nygaard B, Glinoer D, Effects of antithyroid drugs on fetal thyroid
• Fascinating and unique case report. Grussendorf M, Orgiazzi J: Guidelines for function during the treatment of pregnant
12. Yoshimura M, Hershman JM: Thyrotropic TSH-receptor antibody measurements in hyperthyroid women. J. Clin. Endocrinol.
action of human chorionic gonadotropin. pregnancy: results of an evidence-based Metab. 82, 3633–3636 (1997).
Thyroid 5, 425–434 (1995). symposium organized by the European 35. Azizi F, Khoshniat M, Bahrainian M,
13. Baloch Z, Carayon P, Conte-Devolx B et al. Thyroid Association. Eur. J. Endocrinol. 139, Hedayati M: Thyroid function and
Guidelines Committee, National Academy 584–590 (1998). intellectual development of infants nursed
of Clinical Biochemistry. Laboratory • Concensus guidelines for thyroid- by mothers taking methimazole. J Clin
medicine practice guidelines. Laboratory stimulating hormone receptor antibody Endocrinol Metab 85, 3233–3238 (2000).
support for the diagnosis and monitoring of measurement. 36. Azizi F, Bahrainian M, Khamseh ME,
thyroid disease. Thyroid 13, 3–126 (2003). 24. Nachum Z, Rakover Y, Weiner E, Shalev E: Koshniat M: Intellectual development and
14. Panesar NS, Li CY, Rogers MS: Reference Graves’ disease in pregnancy: Prospective thyroid function in children who were
intervals for thyroid hormones in pregnant evaluation of a selective invasive treatment breast-fed by thyrotoxic mothers taking
Chinese women. Ann. Clin. Biochem. 38, 329– protocol. Am. J. Obstet. Gynecol. 189, 159– methimazole. J. Pediatr. Endocrinol. Metab.
332 (2001). 165 (2003). 16, 1239–1243 (2003).
15. Sapin R, D’Herbonnez M, Schlienger JL: 25. Evans PMS, Webster J, Evans WD, Bevan 37. Azizi F: Thyroid function in breast-fed
Free thyroxine measured with equilibrium JS, Scanlon MF: Radioiodine treatment in infants is not affected by methimazole-
dialysis and nine immunoassays decreases in unsuspected pregnancy. Clin. Endocrin. 48, induced maternal hypothyroidism: results of
late pregnancy. Clin. Lab. 50(9–10), 581– 281–283 (1998) a retrospective study. J. Endocrinol. Invest.
584 (2004). 26. Gorman CA: Radioiodine and pregnancy. 26, 301–304 (2003).
16. Soldin OP, Tractenberg RE, Hollowell JG, Thyroid 9, 721–726 (1999). 38. Wartofsky L: Thyrotoxic storm. In: Werner
Jonklass J, Janicic N, Soldin SJ: Trimester- 27. Berg GE, Nystrom EH, Jacobsson L et al.: and Ingbar’s The Thyroid. (9th edition).
specific changes in maternal thyroid Radioiodine treatment of hyperthyroidism Braverman LE , Utiger RD (Eds),
hormone, thyrotropin, and thyroglobulin in a pregnant women. J. Nucl. Med. 39, Lippincott- Raven Philadelphia, PA, USA,
concentrations during gestation: trends and 2194–2195 (1998). 651–657 (2005).
associations across trimesters in iodine 28. Power ML, Milpatrick S, Schulkin J: 39. Lazarus JH, Ludgate ME: Prevention and
sufficiency. Thyroid 14, 1084–1090 (2004). Diagnosing and managing thyroid disorders treatment of postpartum Graves’ disease.
17. Hamburger JI: Diagnosis and management during pregnancy: a survey of obstetrician- Bailliere’s Clin. Endoc. Metab. 11, 549–560
of Graves’ disease in pregnancy. Thyroid 2, gynecologists. J. Reprod. Med. 49, 79–82 (1997).
219–224 (1992). (2004). • Good discussion of immunological changes
18. Anselmo J, Cao D, Karrison T, Weiss RE, 29. Karg E, Bereg E, Gaspar L, Katona M, Turi in pregnancy.
Refetoff S: Fetal loss associated with excess S: Aplasia cutis congenita after methimazole 40. Stagnaro-Green A: Postpartum Thyroiditis.
thyroid hormone exposure. JAMA 292, exposure in utero. Ped. Dermatol. 21, 491– Best Pract. Res. Clin. Endocrinol. Metab. 18,
691–695 (2004). 495 (2004). 303–316 (2004).
• Unique study in subjects with thyroid 30. Barbero P, Ricagni, C, Mercado G, Bronberg • Current clinical overview of the subject.
hormone resistance. R, Torrado M: Choanal atresia associated

104 Women's Health (2005) 1(1)

View publication stats