REVIEW

CURRENT
OPINION Thyroid disorders in pregnancy
Swaytha Yalamanchi and David S. Cooper

Purpose of review
Recognition and management of thyroid disease during pregnancy is challenging with conflicting
recommendations from various professional organizations.
Recent findings
We review the literature related to the diagnosis and management of gestational hypothyroidism and
hyperthyroidism. We also discuss postpartum thyroiditis, thyroid nodules and thyroid cancer. The evidence
clearly demonstrates that both overt hypothyroidism and hyperthyroidism should be treated, but controversy
exists regarding the treatment of subclinical hypothyroidism and thyroid antibody positive euthyroidism,
and whether pregnant women should be screened for thyroid disease.
Summary
Appropriate management of thyroid disease during pregnancy is important for maternal and fetal health,
particularly the recognition and management of hypothyroidism and thyrotoxicosis.
Keywords
hyperthyroidism, hypothyroidism, pregnancy, thyroid cancer, thyroiditis

INTRODUCTION [3,4]. Only about 50% of prenatal vitamins in the

Effective management of thyroid disease during
pregnancy and the postpartum period is important
for optimal maternal and fetal health. We review the
changes in thyroid function during pregnancy and
highlight the diagnosis and management of gesta-
tional hypothyroidism and hyperthyroidism. We
also briefly discuss postpartum thyroiditis, thyroid
nodules and thyroid cancer.
United States contain iodine, with more consistent
content when iodine is in the form of potassium
iodide, rather than kelp [5]. The WHO [6], American
Thyroid Association (ATA) [7], and Endocrine
Society [8] recommend a daily intake of 250 mcg
in the form of potassium iodide during pregnancy
and lactation. Prenatal vitamins containing 150–
250 mcg of iodine preconception are recommended
&&
[7,8,9 ].

PHYSIOLOGIC CHANGES IN PREGNANCY

Thyroid-stimulating hormone (TSH), which is
released by the pituitary, stimulates the trapping
of iodine, and synthesis and secretion of thyroid
hormones (T4 and T3) from the thyroid.
Iodine
Iodine is required for thyroid hormone synthesis.
Pregnant women have higher iodine requirements
because of increased thyroid hormone production,
increased renal iodine excretion and fetal iodine
requirements [1]. Although iodine intake in the
United States is considered adequate, recent data
suggest that over 50% of US women have subopti-
mal urinary iodine concentrations, particularly
non-Hispanic blacks [2]. The WHO has classified
the United Kingdom as mildly iodine deficient
Thyroxine-binding globulin
Thyroxine-binding globulin (TBG) is the primary
carrier protein of T4 and T3. Total T4 and T3
levels reflect protein-bound serum hormone
levels, whereas free T4 and T3 reflect bioavail-
able levels.
Division of Endocrinology, Diabetes and Metabolism, Department of
Medicine, The Johns Hopkins University, Baltimore, Maryland, USA
Correspondence to David S. Cooper MD, Division of Endocrinology,
Diabetes and Metabolism, Department of Medicine, The Johns Hopkins
University School of Medicine, 1830 East Monument Street, Suite 333,
Baltimore, MD 21287, USA. Tel: +1 410 502 4926; fax: +1 410 955 8172;
e-mail: dscooper@jhmi.edu
Curr Opin Obstet Gynecol 2015, 27:406–415
DOI:10.1097/GCO.0000000000000226

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 Thyroid disorders in pregnancy Yalamanchi and Cooper

total T4 levels should be no greater than 18 mg/dl)

KEY POINTS and plateau mid-gestation [10].

Pregnancy necessitates unique interpretation of thyroid
function tests.
Human chorionic gonadotropin

Overt hypothyroidism should be treated, whereas Serum levels of maternal plasma human chorionic
recommendations regarding subclinical hypothyroidism,
gonadotropin (hCG), a placental glycoprotein
antibody positive euthyroidism and screening for
thyroid disease remain controversial. structurally homologous to TSH, peak at 10–12
weeks, gestation and gradually decline in the third

Multiple causes of gestational thyrotoxicosis exist. GTT trimester [13]. hCG binds to the thyroid TSH recep-
may be physiologic or more severe as in hyperemesis tor, and, when present in high levels typical of
gravidarum. Treatment is supportive.
pregnancy, causes a small increase in serum T4

PTU is recommended during the first trimester and MMI and a reciprocal drop in serum TSH (Fig. 1) [12].
or CMZ in the second and third trimesters for the Serum TSH concentrations are transiently subnor-
treatment of Graves’ disease. mal in 10–20% of normal women with the degree of

Women with antithyroid antibody positivity are at risk suppression related to the level of circulating hCG
for PPT. [15].

Thyroid function tests

Increased circulating estrogen levels during the The above changes necessitate trimester-specific
first trimester both increase hepatic production and reference ranges for thyroid function assessment
&&
decrease metabolism of TBG, resulting in a twofold (Table 1) [7,8,9 ]. TSH is the most sensitive
increase in TBG serum levels that lead to an increase indicator of thyroid function. Interpretation of free
in serum total T4 and T3 levels (Fig. 1) [10–14]. T4 and T3 levels during pregnancy is difficult, as
Serum total T4 and T3 levels should be less than higher TBG and lower albumin levels decrease
1.5 times the upper limit of nonpregnant reference accuracy of immunoassays, causing falsely low
range (i.e. if the upper limit for total T4 is 12 mg/dl, levels in the third trimester [11]. The most accurate

Weeks' gestation
10 20 30 40

100
% Change relative to non-pregnancy levels

TBG

Total T4
50

hCG
TV
0
TSH

Free T4

–50

1st Trimester 2nd Trimester 3rd Trimester

FIGURE 1. Changes in thyroxine-binding globulin (TBG) [10], total T4 [10], free T4 [11], TSH [12], hCG [13] and thyroid
volume (TV) [14] throughout pregnancy. The decline in measured free T4 levels during the second and third trimesters is likely
because of laboratory artifact [11]. Figure published with permission of Carole Spencer, PhD. hCG, human chorionic
gonadotropin.

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Women’s health

Table 1. Trimester-specific thyroid-stimulating hormone common causes include prior total or subtotal
goals based on professional organization thyroidectomy, radioiodine therapy, head and neck
recommendations if trimester-specific laboratory reference radiation, and thyroid dysgenesis [19].
ranges are unavailable
Organization TSH (mU/l) Isolated hypothyroxinemia
Isolated hypothyroxinemia, defined as low serum
American Thyroid Association [7]
free T4 levels in the setting of normal serum TSH
1st trimester 0.1–2.5
levels, has been attributed to mild dietary iodine
2nd trimester 0.2–3.0
deficiency. The clinical significance of these labora-
3rd trimester 0.3–3.0 tory findings is unclear, although limited data
Endocrine Society [8] suggest an association with reduced intelligence,
1st trimester <2.5 including nonverbal IQ, cognitive delay, fetal dis-
2nd trimester <3.0 tress, small for gestational age, musculoskeletal mal-
3rd trimester <3.0 formations, slower/less stable reaction speed, and
European Thyroid Association [9 ]
&&
attention deficit and hyperactivity disorders [20–
1st trimester <2.5 24]. However, multiple other studies have shown no
2nd trimester <3.0 association with adverse perinatal outcomes and
3rd trimester <3.5
infant development [25,26]. Current guidelines
recommend correcting iodine deficiency if present,
but do not recommend levothyroxine treatment [7].

assessment of free T4 levels during pregnancy is by

online extraction liquid chromatography/tandem
mass spectrometry, which is not widely available
[16]. Either the free T4 index or total T4 levels 1.5
times the upper limit of the reference range may also
&&
be used [7,8,9 ].
Thyroid size
Maternal goiters during pregnancy may be seen in
regions with marginal/low iodine intake. However,
women with sufficient iodine intake generally
develop only a small increase in thyroid volume,
likely due to increased intrathyroidal blood flow,
and only detectable by ultrasound [14].
HYPOTHYROIDISM
Subclinical hypothyroidism is defined as supra-
normal serum TSH in the setting of normal
T4 levels. In contrast, overt hypothyroidism
occurs when serum TSH levels are elevated in
the setting of low serum free T4. The prevalence
of subclinical and overt hypothyroidism in preg-
nancy is 2.5 and 0.3% in the United States and
higher in mildly iodine-deficient countries
[17,18]. Prevalence estimates depend on diagnos-
tic criteria, trimester of pregnancy and maternal
iodine status.
Complications
Overt maternal hypothyroidism is associated with
adverse maternal, fetal and obstetrical outcomes,
including gestational hypertension, preeclampsia
and anemia. Low fetal birth weight, miscarriage,
congenital circulation system malformations,
respiratory distress and fetal death have also been
described [17,20]. There is an increased risk of pla-
cental abruption, postpartum hemorrhage, spon-
taneous abortion and premature delivery [19,27,28].
Adverse events associated with subclinical hypo-
thyroidism are more controversial and less severe
than that seen in overt hypothyroidism. Subclinical
hypothyroidism has been reported to be associated
with an increased risk of miscarriage, preterm deliv-
ery and reduced IQ in offspring. It has also been
associated with fetal distress and poor vision devel-
opment, and maternal gestational diabetes [29,30].
There have been limited data to suggest that
pregnant euthyroid women whose serum TSH is
in the upper half of the reference range may be at
increased risk for complications. Negro et al. [31]
reported that women with negative thyroid anti-
body titers with serum TSH levels 2.5–5.0 mU/l had
significantly higher rates of miscarriage (6.1%) vs.
women with serum TSH less than 2.5 mU/l (3.6%;
P ¼ 0.006).

Cognition in the offspring

Causes The neurocognitive data in hypothyroidism are con-
Hashimoto’s thyroiditis is the most frequent cause flicting. Haddow et al. [32] retrospectively identified
of hypothyroidism in pregnant women. Other less 62 gravid women with subclinical and overt

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hypothyroidism and demonstrated that the full scale
IQ was 4 points lower in their children (7–9 years old)
as compared with euthyroid controls. Fifteen percent
of children of hypothyroid women had IQ scores of
less than 85, and also had mean IQ scores 7 points
lower than that of children born to euthyroid
women. However, other studies have not found a
relationship between hypothyroidism and offspring
cognition. In a randomized-controlled trial, Lazarus
et al. [33] demonstrated no difference in the IQ of
children aged 3.5 years born to women with serum
TSH levels more than 3.65 mU/l who were initiated
on levothyroxine at a mean gestational age of 13
weeks to maintain a TSH level 0.1mU/l–1 mU/l, as
compared with an untreated control group (mean IQ
100 vs. 99.2). A National Institute of Health spon-
sored study assessing the effects of early screening
and treatment of mild thyroid dysfunction in preg-
nancy is ongoing [34].
Treatment
Treatment of hypothyroidism in pregnant women is
essential. The fetus is dependent on maternal thy-
roid hormone during the first trimester, and only
begins to produce thyroid hormone at 12–15 weeks.
Treatment of existing hypothyroidism
Women being treated with levothyroxine should
have their dosage optimized to maintain serum
TSH level of less than 2.5 mU/l preconception
[7,8]. Pregnancy increases levothyroxine dose
requirements and the dosage usually plateaus at
approximately 20 weeks [35]. Women with serum
TSH levels more than 1.2 mU/l should have their
levothyroxine dose increased by 25–30%, or two
extra tablets/week, once pregnancy is confirmed
[36,37]. Thyroid function tests should be repeated
after confirming pregnancy, every 4–6 weeks during
the first and second trimesters, and every 6–8 weeks
in the third trimester [19]. Dose requirements
decrease to prepregnancy needs after delivery and
are not impacted by lactation [35].
Treatment of newly discovered
hypothyroidism
In women diagnosed with overt hypothyroidism
during pregnancy, initiation of levothyroxine is
essential with achievement of trimester-specific
TSH goals (Table 1) [7,8]. Treatment of subclinical
hypothyroidism is more controversial. The ATA
recommends treating women with subclinical
hypothyroidism with positive antibody titers with
levothyroxine, but does not recommend for or
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Thyroid disorders in pregnancy Yalamanchi and Cooper
against treatment in women with negative thyroid
peroxidase (TPO) titers [7]. In contrast, the Ameri-
can College of Obstetrics and Gynecology (ACOG)
does not recommend the treatment of subclinical
hypothyroidism regardless of antibody status [38]
and the Endocrine Society recommends treating all
women with subclinical hypothyroidism [8]. The
European Thyroid Association recommends the
treatment of subclinical hypothyroidism in preg-
nancy with initiation of levothyroxine at a dose
&&
of 1.2 mcg/kg [9 ].
Treatment of antibody positive euthyroidism
The treatment of euthyroid women with positive
TPO antibodies is controversial. Negro et al. [39]
stratified euthyroid women into three groups: A)
TPO antibody positive treated with levothyroxine
(n ¼ 57); B) TPO antibody positive and untreated
with levothyroxine (n ¼ 57); and C) a control group
of antibody negative euthyroid women (n ¼ 869).
Group B had higher serum TSH and lower serum
free T4 levels. Group B also had significantly higher
rates of miscarriage (13.8%) as compared with
groups A [3.5%; P < 0.05, relative risk (RR) 1.7]
and C (2.4%, P < 0.01, RR 5.0). Group B also had
the highest rate of premature deliveries (22.5%), as
compared with groups A (7%, P < 0.05; RR ¼ 1.7) and
C (8.2%; P < 0.01, RR ¼ 12.2). Overall, the findings
suggest that euthyroid women with TPO antibody
positivity are at increased risk of miscarriage and
preterm delivery and that this risk may be reduced
by initiation of levothyroxine. However, most pro-
fessional groups do not currently recommend uni-
versal screening. In women who are aware of their
antibody status, the ATA and Endocrine Society
have found insufficient evidence to recommend
for or against treatment with levothyroxine [7,8].
If untreated, women should have repeat thyroid
tests every 4 weeks during the first half of pregnancy
and at least once during the third trimester.
Screening
Screening for thyroid disorders during pregnancy is
controversial with conflicting recommendations.
The ACOG recommends testing high-risk women
who are symptomatic or have a personal history of
autoimmune disease [38]. The Endocrine Society
supports case-finding in the following situations:
age above 30 years, family history of thyroid disease,
symptoms/signs of thyroid disease, history of thy-
roid disease/surgery, prior head or neck irradiation,
positive TPO antibody testing, history of auto-
immune disease, infertility, history of miscarriage
or preterm delivery, or residence in an iodine-
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Women’s health
deficient area [8]. The ATA recommendations are
similar to that of the Endocrine Society, additionally
recommending screening women with morbid
obesity (BMI  40 kg/m2) and women who have
used amiodarone, lithium or received recent iodi-
nated contrast [7].
HYPERTHYROIDISM
Hyperthyroidism occurs in 0.4–1.7% of pregnant
women, with the most common cause being Graves’
disease [40].
Differential diagnosis
Gestational thyrotoxicosis (GTT) includes various
forms of hCG-mediated hyperthyroidism including
normal pregnancy, hyperemesis gravidarum and,
less commonly, TSH receptor mutations and cho-
riocarcinoma/molar pregnancy. As noted above,
hCG levels peak at 12 weeks, resulting in subnormal
TSH levels in approximately 20% of women. This
may be more extreme in twin pregnancies due to
higher hCG levels. This ‘physiologic’ GTT typically
resolves within 2–3 months of diagnosis. Hyperem-
esis gravidarum, in contrast, is characterized by
markedly higher hCG levels, for unknown reasons,
resulting in a marked increase in thyroid hormone
and estradiol production. Excess estradiol contrib-
utes to excessive nausea and vomiting, which may
lead to weight loss and electrolyte disturbances. The
severity of hyperemesis correlates with the magni-
tude of serum TSH suppression and free T4 increase.
Overt clinical findings of hyperthyroidism are
uncommon. Hyperemesis-related GTT is typically
treated with supportive care only, without the use
of antithyroid drugs (ATDs) (Table 2) [12].
Table 2. Differences in the presentation, diagnosis and management of Graves’ disease versus gestational transient
thyrotoxicosis
Graves’ disease
Clinical features Personal/family history of autoimmune disease
þOrbitopathy
þGoiter
Duration Diagnosis prior to pregnancy
Variable course
HCG No increase above physiologic levels
Thyroid function tests Increased T3/T4 ratio
Antibody status þTSH-receptor antibodies
Treatment PTU in the 1st trimester MMI in 2nd and 3rd trimesters
hCG, human chorionic gonadotropin; MMI, methimazole; PTU, propylthiouracil; TSH, thyroid-stimulating hormone.
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Graves’ disease, in contrast, is due to circulating
anti-TSH receptor antibodies (TRAb) (Table 2). Toxic
multinodular goiters or solitary toxic nodules are far
less common in women under the age of 40, particu-
larly in iodine replete areas [41]. Thyroiditis, extra-
thyroidal sources of thyroid hormone production
(including, but not limited to, excessive levothyr-
oxine dosing, factitious intake of thyroid hormone,
functional thyroid cancer metastases and struma
ovarii) and TSH-producing pituitary adenomas are
rare causes of thyrotoxicosis in pregnancy [40].
Complications
Hyperthyroidism has important implications for
maternal and fetal health including an increased
risk of preeclampsia, congestive heart failure, pre-
term labor, stillbirth and small for gestational age
babies [42,43].
Diagnosis
Many of the symptoms of hyperthyroidism overlap
with physiologic hypermetabolic features of preg-
nancy, making diagnosis challenging. Women with
suggestive clinical findings such as goiter, weight loss
(rather than weight gain), palpitations, diaphoresis,
heat intolerance, severe anxiety or prominence of the
eyes should be assessed with thyroid function tests
[40].
The laboratory diagnosis of hyperthyroidism
may also be difficult in early pregnancy because
hCG-mediated subnormal serum TSH levels and
TBG-mediated increased serum total T4 and total
T3 may be seen in normal women. However, in
‘physiologic’ GTT, it is rare that free T4 would be
elevated (Table 2). In hyperemesis gravidarum,
Gestational transient thyrotoxicosis
Self-limited
More common with multiple gestations
Hyperemesis
Mild/absent clinical signs of hyperthyroidism
Most common in first trimester, self-limited
Often >100 000 IU/l
Increased FT4, T3 can be normal
Negative antibody status
Supportive
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decreased deiodination of T4 to T3 may result in low
serum T3 levels due to caloric deprivation, whereas
serum T3 would be expected to be elevated in true
hyperthyroidism. When abnormalities in thyroid
function tests persist beyond 20 weeks, it is sugges-
tive of Graves’ disease or another cause of
true hyperthyroidism.
Thyroid receptor antibody testing
TRAb levels, which are elevated in Graves’ disease,
may be helpful to differentiate between causes of
hyperthyroidism in pregnancy. TRAb titers are more
commonly utilized to assess the risk of fetal hyper-
thyroidism prior to midpregnancy and neonatal
Graves’ disease during the third trimester [7,8].
Assessing TRAb titers every 2 months may addition-
ally be used to titrate ATDs by allowing an assessment
of Graves’ disease activity. If titers are threefold above
the upper limit of normal during the third trimester,
fetal ultrasound to assess for goiter, and evaluation
for accelerated bone maturation, fetal tachycardia,
intrauterine growth restriction and congestive heart
failure should be considered because of a higher risk
of fetal/neonatal Graves, disease due to transplacen-
tal passage of TRAb [44].
Treatment
ATDs are the treatment of choice for Graves’ disease
in pregnancy. In women diagnosed before preg-
nancy, radioiodine ablation at least 6 months prior
to pregnancy or surgical management, particularly
in women with high TSAb titers, is an alternative
modality of treatment that will obviate the need for
ATD therapy in pregnancy [7,8]. However, during
pregnancy radioiodine is contraindicated and
surgery is reserved for women with poorly con-
trolled thyrotoxicosis despite large doses of ATDs,
allergy to ATDs, poor treatment adherence or goiter
resulting in compressive symptoms.
Propylthiouracil (PTU) and methimazole (MMI)
are equally effective in the treatment of thyrotoxi-
cosis during pregnancy. Carbimazole (CBZ), used in
the United Kingdom and some former British Com-
monwealth countries, is a precursor to MMI. In
nonpregnant women, MMI or CBZ is used almost
exclusively, but in pregnant women, PTU is pre-
ferred in the first trimester because of potential
teratogenicity of MMI and CBZ.
Adverse events associated with antithyroid
drug treatment
Both minor and major reactions to ATDs have been
reported in pregnancy, including gastrointestinal
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Thyroid disorders in pregnancy Yalamanchi and Cooper
disturbances, rash, fever, hepatotoxicity, agranulo-
cytosis and antineutrophil cytoplasmic antibody
positive vasculitis.
MMI use in the first trimester is associated with
an increased risk of birth defects including aplasia
cutis congenita, choanal atresia, trachea-esophageal
fistula, omphalocele, hypothelia/athelia, develop-
mental delay and a distinctive facial phenotype
(together termed ‘methimazole embryopathy’),
compared with PTU (Fig. 2) [45,46]. In keeping with
these data, Andersen et al. [47] reported an excess of
2–4 birth defects per 100 live births among fetuses
born to women using MMI/CBZ. The Endocrine
Society and ATA recommend that pregnant women
treated with MMI/CBZ prior to pregnancy be tran-
sitioned to PTU, and that PTU be the ATD of choice
in the first trimester. It is recommended that women
transition back to MMI in the second and third
trimesters because of concern about hepatotoxicity
from PTU [7,8].
Data that justified these recommendations on
first trimester PTU use were made on the basis of
reported congenital malformations diagnosed at
&
birth. However, Andersen et al. [48 ] found that
PTU is also associated with birth defects, albeit more
minor abnormalities that may not be recognized at
birth (e.g. preauricular fistulas and cysts and hydro-
nephrosis). These data suggest that both ATDs are
associated with congenital malformations, but birth
defects associated with PTU use are milder than
those seen with MMI, and thus at this point in time,
transitioning from MMI to PTU in the first trimester
is still recommended [7].
Regardless of the drug used, patients should be
clinically and biochemically monitored every 4
weeks and the lowest possible dose of ATD should
be used to keep the free T4 above the upper third of
the reference range for nonpregnant women [49].
Starting doses for PTU range from 100–300 mg every
8 h and 5–30 mg daily for MMI, depending on bio-
chemical severity of thyrotoxicosis. TSH may
remain suppressed for months and thus may not
accurately reflect response to treatment. Because
pregnancy is often a time of autoimmune quies-
cence, most women can reduce their ATD dose every
1–2 months with as much as a 50% reduction after
2–3 months. In the third trimester, approximately
30% of women do not require ATDs to maintain free
T4 levels at the upper limit of the reference range,
and therapy may be discontinued if a woman is on a
small dose (50 mg PTU or 5 mg MMI daily).
Monitoring for neonatal hypothyroidism
PTU and MMI have equivalent transplacental pas-
sage and maternal monitoring is necessary to avoid
www.co-obgyn.com 411
Women’s health
(a)
FIGURE 2. (a) Aplasia cutis of the scalp; (b) Classic facial appearance seen in ‘methimazole embryopathy’ including upward
slanted palpebral fissures, small nose with broad nasal bridge and arched eyebrows. Figure is from [46].
fetal hypothyroidism [50]. Although ‘block and
replace’ treatments involving the use of a combi-
nation of ATD and levothyroxine have been utilized
in the past, this strategy is not recommended
because of potential use of unnecessarily high
ATD doses [7,8].
Breast feeding
PTU has less transfer into breast milk than MMI, but
milk concentrations of both drugs are low and both
have been shown to be safe in regard to neonatal
thyroid function. Although there is a theoretical risk
of hypothyroidism and drug allergies in neonates,
no cases have been reported in the literature to our
knowledge [51].
Symptomatic management
b-blockers may be used to treat adrenergic symp-
toms at the lowest effective dose and can often be
discontinued in 4–6 weeks when thyroid function
has normalized on ATDs (e.g. propranolol 20–40 mg
every 6 h). Limited data suggest an association of b-
blocker use with an increased risk of miscarriage,
small for gestational age infants, congenital defects
and when used late in pregnancy, neonatal brady-
cardia and hypoglycemia [52–54].
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(b)
POSTPARTUM THYROIDITIS
Postpartum thyroiditis (PPT) is defined as isolated
thyrotoxicosis (32%), isolated hypothyroidism
(43%) or thyrotoxicosis followed by hypothyroid-
ism (25%) in the first year postpartum in women
without clinical evidence of thyroid disease prior to
pregnancy [55]. PPT is an autoimmune process that
reflects a rebound of thyroidal autoimmunity after a
period of relative quiescence during pregnancy,
with thyroidal inflammation and passive release
of stored thyroid hormones into the circulation.
PPT may also occur after miscarriage or therapeutic
abortion [55]. Women on prepregnancy levothyr-
oxine replacement may also develop PPT if they
have residual endogenous thyroid function [56].
The prevalence of PPT partly depends on genetic
background and iodine intake, and reports range
from 1.1 to 16.7% [57]. PPT occurs much more
frequently in women with known positive thyroid
antibody titers early in pregnancy [PPT rate 33–
50%; relative risk 5.8 (95% confidence interval
5.3–6.1)] with higher titers associated with
increased risk [55,57]. A prior history of PPT also
increases the risk of recurrence in subsequent preg-
nancies (up to 70% in TPO antibody positive women
with a history of PPT) [58].
Thyrotoxicosis typically occurs 2–6 months
after delivery, though it has been reported up to 1
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December 2015

year later, and invariably resolves. Hypothyroidism
typically occurs 3–12 months postpartum with
reversion to euthyroidism in 1 year. Thyrotoxic
symptoms include fatigue, palpitations and nerv-
ousness, whereas tiredness and impaired memory
are most common in the hypothyroid phase [55].
There is an unclear association between PPT and
postpartum depression. However, as thyroid dys-
function is a potentially reversible cause of depres-
sion, screening with TSH is appropriate in this
setting [8]. Ultimately, 20–40% of women with
PPT develop permanent primary hypothyroidism
within 3–12 years with risk factors including higher
titers of antithyroid antibodies and higher serum
TSH during initial hypothyroid phase [59–61].
It is important to distinguish the thyrotoxic
phase of PPT from postpartum Graves’ disease, as
the clinical course and management differ. Women
with PPT have milder thyrotoxicosis, TRAb nega-
tivity and an elevated T4:T3 ratio as compared with
those with Graves’ disease [62]. The 24-h radioio-
dine uptake with 131I cannot be used in women who
are breastfeeding or recently postpartum. Alterna-
tively, technetium and 123I have short half-lives and
thus, provided that breastfeeding is suspended for
48 h, may be utilized [7]. A recent study has shown
that these two conditions can be distinguished on
the basis of TRAb positivity and increased thyroid
blood flow on Doppler ultrasound in Graves’ disease
[63].
Some experts recommend that women with a
history of PPT who have another autoimmune dis-
ease or who have known TPO antibody positivity
prepartum have TSH and free T4 measured 3 months
postpartum. If a euthyroid woman has positive TPO
antibodies, serum TSH should also be obtained at 6
and 9 months [55].
ATDs are ineffective, as PPT is a destructive
thyroiditis. Symptoms of thyrotoxicosis may be
transiently treated with b-blockers. Once the thy-
rotoxic phase resolves, thyroid function tests
should be checked every 2 months until 1 year
postpartum and annually thereafter to monitor
for hypothyroidism. Treatment with levothyroxine
is recommended only for individuals with signifi-
cant hypothyroid symptoms, TSH more than
10 mU/l, or who have hypothyroidism longer than
2–3 months, as hypothyroidism is often mild and
transient [7,8]. A substantial fraction of patients
(25–50%) develop hypothyroidism later in life
[64].
THYROID NODULES/CANCER
The ATA recommends that women who have a
thyroid nodule detected on physical examination
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Thyroid disorders in pregnancy Yalamanchi and Cooper
be assessed for high-risk features including family
history of thyroid cancer, multiple endocrine neo-
plasia type 2, familial polyposis coli, history of child-
hood head/neck irradiation and rapidity of nodule
growth [7]. Women should also be screened with
thyroid function tests to rule out hyperthyroidism
[7,8]. Thyroid ultrasound should be performed to
look for suspicious nodule characteristics including
size more than 1–1.5 cm, hypoechogenecity, irreg-
ular margins, microcalcifications and being taller
than wide in the transverse view [65,66]. Fine needle
aspiration may be performed during any trimester
[7,8]. The overall reported malignancy rate during
pregnancy is approximately 15% [67]. There is no
evidence that pregnancy worsens differentiated thy-
roid cancer-related death or overall survival, though
there is conflicting evidence regarding the increased
risk of persistent/recurrent disease [68–72].
Women with cytopathology suspicious or diag-
nostic for papillary thyroid cancer should have thy-
roid ultrasounds every trimester. If the nodule grows
50% in volume (equal to a 20% increase in diameter
in two dimensions), or if lymph node metastases are
present by 24 weeks, gestation, surgery may be
performed in the second trimester. If the nodule
remains stable or is diagnosed in the second half of
the pregnancy, surgery may be performed after
delivery [7]. There is no evidence of improved sur-
vival by performing surgery during pregnancy, as
opposed to the postpartum period. Kuy et al. [73]
reported that pregnancy was an independent pre-
dictor of higher surgical complications, longer
adjusted length of stay and higher adjusted hospital
costs following thyroid and parathyroid surgery.
If surgery is deferred, levothyroxine suppressive
therapy with a TSH goal of 0.1–1.5 mU/l may be
considered [7]. Surgery during pregnancy should be
more strongly considered in the case of medullary
thyroid cancer, depending on the size of the primary
tumor and lymph node metastases [7].
CONCLUSION
Appropriate management of thyroid disease during
pregnancy is important for maternal and fetal
health. Further research is needed to address many
questions, including the utility of universal screen-
ing of pregnant women for thyroid dysfunction and
thyroid autoimmunity, and the efficacy of treat-
ment of subclinical hypothyroidism. Reexamina-
tion of the risk to benefit ratio of PTU as
compared with MMI in the treatment of Graves’
disease in the first trimester is also warranted.
Acknowledgements
None.
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Women’s health
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. Leung AM, Pearce EN, Braverman LE. Iodine nutrition in pregnancy and
lactation. Endocrinol Metab Clin North Am 2011; 40:765–777.
2. Caldwell KL, Pan Y, Mortensen ME, et al. Iodine status in pregnant women in
the National Children’s Study and in U.S. women (15–44 years), National
Health and Nutrition Examination Survey 2005–2010. Thyroid 2013;
23:927–937.
3. Rayman MP, Bath SC. The new emergence of iodine deficiency in the UK:
consequences for child neurodevelopment. Ann Clin Biochem 2015. [Epub
ahead of print]
4. Zimmermann MB, Gizak M, Abbott K, et al. Iodine deficiency in pregnant
women in Europe. Lancet Diabetes Endocrinol 2015; 3:672–674.
5. Leung AM, Pearce EN, Braverman LE. Iodine content of prenatal multivitamins
in the United States. N Engl J Med 2009; 360:939–940.
6. Secretariat WHO, Andersson M, de Benoist B, et al. Prevention and control of
iodine deficiency in pregnant and lactating women and in children less than 2-
years-old: conclusions and recommendations of the technical consultation.
Public Health Nutr 2007; 10 (12A):1606–1611.
7. Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the Amer-
ican Thyroid Association for the diagnosis and management of thyroid disease
during pregnancy and postpartum. Thyroid 2011; 21:1081–1125.
8. De Groot L, Abalovich M, Alexander EK, et al. Management of thyroid
dysfunction during pregnancy and postpartum: an Endocrine Society clinical
practice guideline. J Clin Endocrinol Metab 2012; 97:2543–2565.
9. Lazarus J, Brown RS, Daumerie C, et al. 2014 European Thyroid Association
&& guidelines for the management of subclinical hypothyroidism in pregnancy
and in children. Eur Thyroid J 2014; 3:76–94.
Guidelines from the European Thyroid Association on the management of sub-
clinical hypothyroidism.
10. Glinoer D. The regulation of thyroid function during normal pregnancy:
importance of the iodine nutrition status. Best Pract Res Clin Endocrinol
Metab 2004; 18:133–152.
11. Lee RH, Spencer CA, Mestman JH, et al. Free T4 immunoassays are flawed
during pregnancy. Am J Obstet Gynecol 2009; 200:260.e1–260.e6.
12. Hershman JM. Physiological and pathological aspects of the effect of human
chorionic gonadotropin on the thyroid. Best Pract Res Clin Endocrinol Metab
2004; 18:249–265.
13. Taylor RN, Badell ML. The endocrinology of pregnancy. In: Gardner DG,
Shoback D, editors. Greenspan’s basic and clinical endocrinology, 9th ed.
China: McGraw-Hill Medical; 2011.
14. Nelson M, Wickus GG, Caplan RH, Beguin EA. Thyroid gland size in
pregnancy. An ultrasound and clinical study. J Reprod Med 1987;
32:888–890.
15. Glinoer D, de Nayer P, Bourdoux P, et al. Regulation of maternal thyroid during
pregnancy. J Clin Endocrinol Metab 1990; 71:276–287.
16. Sapin R, D’Herbomez M, Schlienger JL. Free thyroxine measured with
equilibrium dialysis and nine immunoassays decreases in late pregnancy.
Clin Lab 2004; 50 (9–10):581–584.
17. Allan WC, Haddow JE, Palomaki GE, et al. Maternal thyroid deficiency and
pregnancy complications: implications for population screening. J Med
Screen 2000; 7:127–130.
18. Moreno-Reyes R, Glinoer D, Van Oyen H, Vandevijvere S. High prevalence
of thyroid disorders in pregnant women in a mildly iodine-deficient country:
a population-based study. J Clin Endocrinol Metab 2013; 98:3694–
3701.
19. Teng W, Shan Z, Patil-Sisodia K, Cooper DS. Hypothyroidism in pregnancy.
Lancet Diabetes Endocrinol 2013; 1:228–237.
20. Su PY, Huang K, Hao JH, et al. Maternal thyroid function in the first twenty
weeks of pregnancy and subsequent fetal and infant development: a pro-
spective population-based cohort study in China. J Clin Endocrinol Metab
2011; 96:3234–3241.
21. Glinoer D. Regulation of thyroid function in pregnancy: maternal and neonatal
repercussions. Adv Exp Med Biol 1991; 299:197–201.
22. Henrichs J, Bongers-Schokking JJ, Schenk JJ, et al. Maternal thyroid function
during early pregnancy and cognitive functioning in early childhood: the
generation R study. J Clin Endocrinol Metab 2010; 95:4227–4234.
414 www.co-obgyn.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
23. Ghassabian A, Henrichs J, Tiemeier H. Impact of mild thyroid hormone
deficiency in pregnancy on cognitive function in children: lessons from the
generation R study. Best Pract Res Clin Endocrinol Metab 2014; 28:221–
232.
24. Finken MJ, van Eijsden M, Loomans EM, et al. Maternal hypothyroxinemia in
early pregnancy predicts reduced performance in reaction time tests in 5- to
6-year-old offspring. J Clin Endocrinol Metab 2013; 98:1417–1426.
25. Pakkila F, Mannisto T, Surcel HM, et al. Maternal thyroid dysfunction during
pregnancy and thyroid function of her child in adolescence. J Clin Endocrinol
Metab 2013; 98:965–972.
26. Craig WY, Allan WC, Kloza EM, et al. Mid-gestational maternal free thyroxine
concentration and offspring neurocognitive development at age two years.
J Clin Endocrinol Metab 2012; 97:E22–E28.
27. Abalovich M, Gutierrez S, Alcaraz G, et al. Overt and subclinical hypothyroid-
ism complicating pregnancy. Thyroid 2002; 12:63–68.
28. Benhadi N, Wiersinga WM, Reitsma JB, et al. Higher maternal TSH levels in
pregnancy are associated with increased risk for miscarriage, fetal or neonatal
death. Eur J Endocrinol 2009; 160:985–991.
29. Casey BM, Dashe JS, Wells CE, et al. Subclinical hypothyroidism and
pregnancy outcomes. Obstet Gynecol 2005; 105:239–245.
30. Casey B, de Veciana M. Thyroid screening in pregnancy. Am J Obstet
Gynecol 2014; 211:351–353.
31. Negro R, Schwartz A, Gismondi R, et al. Increased pregnancy loss rate in
thyroid antibody negative women with TSH levels between 2.5 and 50 in the
first trimester of pregnancy. J Clin Endocrinol Metab 2010; 95:E44–E48.
32. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during
pregnancy and subsequent neuropsychological development of the child. N
Engl J Med 1999; 341:549–555.
33. Lazarus JH, Bestwick JP, Channon S, et al. Antenatal thyroid screening and
childhood cognitive function. N Engl J Med 2012; 366:493–501.
34. Eunice Kennedy Shriver National Institute of Child Health and Human Devel-
opment (NICHD). Thyroid therapy for mild thyroid deficiency in pregnancy
(TSH). Bethesda, MD: National Library of Medicine. http://www.clinicaltrials.
gov/ct/show/NCT00388297. [Accessed 1 August 2015]
35. Alexander EK, Marqusee E, Lawrence J, et al. Timing and magnitude of
increases in levothyroxine requirements during pregnancy in women with
hypothyroidism. N Engl J Med 2004; 351:241–249.
36. Stagnaro-Green A, Pearce E. Thyroid disorders in pregnancy. Nat Rev
Endocrinol 2012; 8:650–658.
37. Yassa L, Marqusee E, Fawcett R, Alexander EK. Thyroid hormone early
adjustment in pregnancy (the THERAPY) trial. J Clin Endocrinol Metab
2010; 95:3234–3241.
38. Committee on Patient Safety and Quality Improvement, Committee on
Professional Liability. ACOG committee opinion no. 381: subclinical
hypothyroidism in pregnancy. Obstet Gynecol 2007; 110:959–960.
39. Negro R, Formoso G, Mangieri T, et al. Levothyroxine treatment in euthyroid
pregnant women with autoimmune thyroid disease: effects on obstetrical
complications. J Clin Endocrinol Metab 2006; 91:2587–2591.
40. Cooper DS, Laurberg P. Hyperthyroidism in pregnancy. Lancet Diabetes
Endocrinol 2013; 1:238–249.
41. Abraham-Nordling M, Bystrom K, Torring O, et al. Incidence of hyperthyroid-
ism in Sweden. Eur J Endocrinol 2011; 165:899–905.
42. Hamburger JI. Diagnosis and management of Graves’ disease in pregnancy.
Thyroid 1992; 2:219–224.
43. Andersen SL, Olsen J, Wu CS, Laurberg P. Spontaneous abortion, stillbirth
and hyperthyroidism: a Danish population-based study. Eur Thyroid J 2014;
3:164–172.
44. Luton D, Le Gac I, Vuillard E, et al. Management of Graves’ disease during
pregnancy: the key role of fetal thyroid gland monitoring. J Clin Endocrinol
Metab 2005; 90:6093–6098.
45. Yoshihara A, Noh J, Yamaguchi T, et al. Treatment of Graves’ disease with
antithyroid drugs in the first trimester of pregnancy and the prevalence of
congenital malformation. J Clin Endocrinol Metab 2012; 97:2396–2403.
46. Bowman P, Osborne NJ, Sturley R, Vaidya B. Carbimazole embryopathy:
implications for the choice of antithyroid drugs in pregnancy. QJM 2012;
105:189–193.
47. Andersen SL, Olsen J, Wu CS, Laurberg P. Birth defects after early pregnancy
use of antithyroid drugs: a Danish nationwide study. J Clin Endocrinol Metab
2013; 98:4373–4381.
48. Andersen SL, Olsen J, Wu CS, Laurberg P. Severity of birth defects after
& propylthiouracil exposure in early pregnancy. Thyroid 2014; 24:1533–1540.
This article demonstrates that birth defects may occur with any of the available
antithyroid drugs, including PTU. The severity of congenital defects with PTU is
milder than those associated with MMI/CMZ.
49. Momotani N, Noh J, Oyanagi H, et al. Antithyroid drug therapy for Graves’
disease during pregnancy. Optimal regimen for fetal thyroid status. N Engl J
Med 1986; 315:24–28.
50. Momotani N, Noh JY, Ishikawa N, Ito K. Effects of propylthiouracil and
methimazole on fetal thyroid status in mothers with Graves’ hyperthyroidism.
J Clin Endocrinol Metab 1997; 82:3633–3636.
51. Azizi F, Khoshniat M, Bahrainian M, Hedayati M. Thyroid function and
intellectual development of infants nursed by mothers taking methimazole.
J Clin Endocrinol Metab 2000; 85:3233–3238.
Volume 27
Number 6
December 2015

52. Meidahl Petersen K, Jimenez-Solem E, Andersen JT, et al. Beta-blocker
treatment during pregnancy and adverse pregnancy outcomes: a nationwide
population-based cohort study. BMJ Open 2012; 2:e001185.
53. Magee LA, Duley L. Oral beta-blockers for mild to moderate hypertension
during pregnancy. Cochrane Database Syst Rev 2003; 3:CD002863.
54. Yakoob MY, Bateman BT, Ho E, et al. The risk of congenital malformations
associated with exposure to beta-blockers early in pregnancy: a meta-ana-
lysis. Hypertension 2013; 62:375–381.
55. Stagnaro-Green A. Approach to the patient with postpartum thyroiditis. J Clin
Endocrinol Metab 2012; 97:334–342.
56. Caixas A, Albareda M, Garcia-Patterson A, et al. Postpartum thyroiditis in
women with hypothyroidism antedating pregnancy? J Clin Endocrinol Metab
1999; 84:4000–4005.
57. Nicholson WK, Robinson KA, Smallridge RC, et al. Prevalence of postpartum
thyroid dysfunction: a quantitative review. Thyroid 2006; 16:573–582.
58. Lazarus JH, Ammari F, Oretti R, et al. Clinical aspects of recurrent postpartum
thyroiditis. Br J Gen Pract 1997; 47:305–308.
59. Stuckey BG, Kent GN, Ward LC, et al. Postpartum thyroid dysfunction and
the long-term risk of hypothyroidism: results from a 12-year follow-up study of
women with and without postpartum thyroid dysfunction. Clin Endocrinol
(Oxf) 2010; 73:389–395.
60. Lucas A, Pizarro E, Granada ML, et al. Postpartum thyroiditis: long-term
follow-up. Thyroid 2005; 15:1177–1181.
61. Sarvghadi F, Hedayati M, Mehrabi Y, Azizi F. Follow up of patients with
postpartum thyroiditis: a population-based study. Endocrine 2005; 27:279–
282.
62. Tagami T, Hagiwara H, Kimura T, et al. The incidence of gestational hyperthyr-
oidism and postpartum thyroiditis in treated patients with Graves’ disease.
Thyroid 2007; 17:767–772.
1040-872X Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Thyroid disorders in pregnancy Yalamanchi and Cooper
63. Ota H, Amino N, Morita S, et al. Quantitative measurement of thyroid blood
flow for differentiation of painless thyroiditis from Graves’ disease. Clin
Endocrinol (Oxf) 2007; 67:41–45.
64. Premawardhana LD, Parkes AB, Ammari F, et al. Postpartum thyroiditis
and long-term thyroid status: prognostic influence of thyroid peroxidase
antibodies and ultrasound echogenicity. J Clin Endocrinol Metab 2000;
85:71–75.
65. Brander A, Viikinkoski P, Tuuhea J, et al. Clinical versus ultrasound examina-
tion of the thyroid gland in common clinical practice. J Clin Ultrasound 1992;
20:37–42.
66. Papini E, Guglielmi R, Bianchini A, et al. Risk of malignancy in nonpalpable
thyroid nodules: predictive value of ultrasound and color-doppler features. J
Clin Endocrinol Metab 2002; 87:1941–1946.
67. Messuti I, Corvisieri S, Bardesono F, et al. Impact of pregnancy on prognosis
of differentiated thyroid cancer: clinical and molecular features. Eur J En-
docrinol 2014; 170:659–666.
68. Zhou YQ, Zhou Z, Qian MF, et al. Association of thyroid carcinoma with
pregnancy: a meta-analysis. Mol Clin Oncol 2015; 3:341–346.
69. Moosa M, Mazzaferri EL. Outcome of differentiated thyroid cancer diagnosed
in pregnant women. J Clin Endocrinol Metab 1997; 82:2862–2866.
70. Yasmeen S, Cress R, Romano PS, et al. Thyroid cancer in pregnancy. Int J
Gynaecol Obstet 2005; 91:15–20.
71. Herzon FS, Morris DM, Segal MN, et al. Coexistent thyroid cancer and
pregnancy. Arch Otolaryngol Head Neck Surg 1994; 120:1191–1193.
72. Vannucchi G, Perrino M, Rossi S, et al. Clinical and molecular features of
differentiated thyroid cancer diagnosed during pregnancy. Eur J Endocrinol
2010; 162:145–151.
73. Kuy S, Roman SA, Desai R, Sosa JA. Outcomes following thyroid and
parathyroid surgery in pregnant women. Arch Surg 2009; 144:399–406.
www.co-obgyn.com 415