Volume 65, Number 12

OBSTETRICAL AND GYNECOLOGICAL SURVEY

Copyright © 2011
by Lippincott Williams & Wilkins CME REVIEWARTICLE 34
CHIEF EDITOR’S NOTE: This article is part of a series of continuing education activities in this Journal through which a total
of 36 AMA/PRA Category 1 CreditsTM can be earned in 2011. Instructions for how CME credits can be earned appear on the
last page of the Table of Contents.

What the Obstetrician/Gynecologist

Should Know About Thyroid Disorders
Trimble L. Bailey Spitzer, MD
Clinical Fellow, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California,
San Francisco, CA

Thyroid disease is a common disorder faced by women of all ages. Because of its high incidence
in women, recognizing and treating thyroid dysfunction often becomes the responsibility of the
obstetrician/gynecologist. It is important that women’s healthcare providers understand how the
thyroid’s function changes as a woman enters her reproductive years, as well as during pregnancy
and menopause. Current guidelines for diagnosing and managing thyroid dysfunction and recom-
mended treatment strategies are discussed in this review.
Target Audience: Obstetricians & Gynecologists, Family Physicians
Learning Objectives: After completion of this educational activity, the obstetrician/gynecologist should
be better able to evaluate normal thyroid physiology and pathophysiology of thyroid dysfunction; assess
appropriate screening options for their patients; and diagnose and manage thyroid disorders common
among reproductive-aged women.

The prevalence of hypothyroidism in women of
reproductive age (12–49 years) is approximately
3.1%, with autoimmune thyroid disease being the
most common underlying cause (1). In 2007, the
Endocrine Society released “Guidelines on the Man-
agement of Thyroid Dysfunction during Pregnancy
and Postpartum.” However, respondents to a subse-
quent large survey initiative revealed that only 11.5%
of members of the American College of Obstetrics
and Gynecology or American Academy of Family
Physicians read the Endocrine Society guidelines (2)
despite the fact that thyroid dysfunction is a common
problem faced by women’s healthcare providers.
This review will cover normal thyroid physiology
and pathophysiology of thyroid dysfunction, diagno-
sis and management of thyroid disease, and provide
obstetricians/gynecologists and generalists with
up-to-date guidelines and information on thyroid
disorders as it relates to all phases of a woman’s life.
After completing this CME activity, obstetrician/
gynecologists should be better able to evaluate
normal thyroid physiology and pathophysiology of
thyroid dysfunction; assess appropriate screening
options for their patients; and diagnose and manage
thyroid disorders common among reproductive-aged
women.

Unless otherwise noted below, the author and any staff in a

position to control the content of this CME activity and their
spouses/life partners (if any) have disclosed that they have no
financial relationships with, or financial interests in, any commer-
cial organizations pertaining to this educational activity.
Correspondence requests to: Trimble L. Bailey Spitzer, MD,
Department of Obstetrics, Gynecology and Reproductive Sci-
ences, University of California, San Francisco, 2356 Sutter St, 7th
Floor, San Francisco, CA 94115–0916. E-mail: Trimble.Spitzer@
ucsfmedctr.org.
www.obgynsurvey.com | 779
HYPOTHALAMUS-PITUITARY-THYROID
AXIS
The thyroid gland is part of a classic endocrine
feedback control loop that involves the hypothalamus
and anterior pituitary. This autoregulatory mecha-
nism controls the rate of thyroid hormone synthesis
despite fluctuations in iodine availability. The parvo-
780 Obstetrical and Gynecological Survey
Fig. 1. Hypothalamic-pituitary-thyroid axis. H indicates hypothalamus; P, anterior pituitary; I, iodine transport.
cellular region of the paraventricular nuclei of the
hypothalamus secretes thyrotropin-releasing hor-
mone (TRH) and regulates thyroid-stimulating hor-
mone (TSH) release from the anterior pituitary. TRH
travels along the axons of the peptidergic neurons
across the median eminence and is released close to
the hypothalamic-pituitary portal plexus. When TRH
reaches the anterior pituitary, it stimulates thyrotrope
cells to release TSH (Fig.).
TSH is the major direct pituitary regulator of the
thyroid gland. It is a glycoprotein composed of 2
subunits as follows: an ␣ subunit, which is common
to human chorionic gonadotropin (hCG), follicle-
stimulating hormone, and luteinizing hormone; and a
␤ subunit specific to TSH. TRH increases and thy-
roid hormones suppress the transcription of both
subunits.
In response to TRH, TSH is released into the
bloodstream and reaches the thyroid follicular epi-
thelial cells via its surrounding capillary network.
The TSH receptor is a G protein-coupled receptor.
When the TSH receptor is activated, cyclic adenosine
monophosphate is synthesized, stored thyroglobulin
protein is released, and new protein is synthesized.
By its reaction with thyroperoxidase enzyme, iodine
is covalently bound to tyrosine residues in thyroglob-
ulin, forming the molecules that make up thyroxine
and triiodothyronine (T4 and T3). Small globules of
the follicular colloid undergo endocytosis and di-
gested by proteases which releases T4 and T3 into
the circulation.
EMBRYOLOGIC DEVELOPMENT
The human thyroid gland is a derivative of the
primitive buccopharyngeal cavity and begins to de-
velop at the fourth week of gestation along the mid-
line of the floor of the primitive pharynx. As the cells
migrate caudally through the anterior midline of the
neck, they rapidly multiply so that when they reach
their final position around 7 weeks of gestation, they
have formed a bilobed organ. At 12 weeks of gesta-
tion, the fetal thyroid gland weighs approximately 80
mg and will reach a weight of 1 to 1.5 g by term.
Pituitary and plasma TSH levels increase during
the second trimester, around the same time of devel-
opment of the pituitary portal vasculature. Plasma
thyroid-binding globulin (TBG) and total T4 levels
increase from their lowest levels at 16 to 18 weeks of
gestation to maximal levels at term. Free T4 (fT4)
levels also increase as a result of increasing T4
production. Studies of preterm infants have shown
that hypothalamic-pituitary control of the thyroid
gland fully matures late in the third trimester and in
the early neonatal period (1).
ADOLESCENCE
Thyroid hormones are necessary for normal puber-
tal growth, sexual development, and reproductive
function. The changes that occur in total and free
thyroid hormone levels are poorly defined. Dunger et
al performed a longitudinal study of 39 normal pu-
bertal adolescents (20 girls and 19 boys) aged 10 to
 What the Obstetrician/Gynecologist Should Know About Thyroid Disorders Y CME Review Article 781
15 years (2). There was a decrease in serum free
thyroxine (fT4) began at 12.5 years for girls and 13.5
years for boys that continued until approximately 15
years old. Total T4 measurements had a similar pat-
tern with a slight delay in its lowest point. Free T3
levels decreased in girls after age 12.5 years, but
showed no change with age in boys.
The volume of the thyroid gland increases during
adolescence, with a maximum growth occur between
ages 11 and 15 years. This growth is correlated with
body surface area for both genders (P ⬍ 0.05). Thy-
roid growth is nearly constant throughout puberty in
boys and similar in girls until menarche, when
growth becomes 14.5% larger in girls (P ⬍ 0.01) (3).
It is likely that this timely increase in growth is due
to the influence of growth hormone and sex steroid
secretion around the time of puberty.
THE THYROID AND INFERTILITY
Thyroid dysfunction can be associated with a wide
range of menstrual irregularities and infertility con-
cerns. Menstrual flow abnormalities related to thyroid
dysfunction were first reported in 1952 by Goldsmith et
al (4). Since that time, multiple studies have confirmed
the relationship between thyroid dysfunction and men-
strual patterns (5–7).
Ovulatory dysfunction and the subsequent men-
strual irregularities associated with hypothyroidism
often are due to a secondary hormone disruption.
Hypothyroidism increases TRH production from the
hypothalamus, resulting in elevated prolactin secre-
tion and altered gonadotropin-releasing hormone pul-
satile secretion. This leads to a delay in luteinizing
hormone response and an inadequate corpus luteum
(8). Hypothyroidism additionally influences ovarian
function by decreasing levels of sex-hormone-binding
globulin, thereby increasing the number of bioavailable
androgens (9).
TSH in the rat also has a direct effect on the ovaries
by stimulating progesterone secretion during the initial
luteinization of granulosa cells (10–12). Thyroid hor-
mone receptors exist on the human ovary, although
their full role has yet to be elucidated completely (13).
There is a surprising paucity of studies on the
incidence of infertility among women with hypothy-
roidism. A retrospective review of 399 women (244
infertile and 155 fertile controls) indicated a higher
incidence of subclinical hypothyroidism in their in-
fertile group than in fertile controls (13.9% vs. 3.9%
respectively) (14). Subclinical hypothyroidism and
autoimmune thyroid disorders both have been re-
ported to be independently associated with early
pregnancy loss (crown-rump length ⱕ10 mm) (15).
For those undergoing infertility treatment, admin-
istering exogenous gonadotropins, such as those used
for in vitro fertilization, may cause an increase in
serum TBG, T4 and T3 levels, a decrease in fT4, and
a slight rise in serum TSH (usually in the high normal
range) (16). Study of the rat ovary has shown that
gonadotropins periodically regulate expression of
TSH receptors by ovarian granulosa cells (17).
SCREENING
In its Committee Opinion published in October
2007, the American College of Obstetrics and Gyne-
cology recommended against routine screening for
all pregnant women (18). However, since that time,
multiple clinical studies support universal testing of
pregnant women for thyroid dysfunction as a cost-
effective screening tool (19,20).
In both pregnant and nonpregnant low-risk popu-
lations, TSH is sufficient as a screening test. It is
recommended that high-risk women, those with au-
toimmune disease, thyroid nodules or goiter on phys-
ical examination, exposure to radiation, or personal
or family history of thyroid cancer, should be
screened using both TSH and thyroid peroxidase
(TPO) antibodies. All women with TSH values ⬎5
should be evaluated for the presence of TPO anti-
bodies. If TPO antibodies are positive, the physician
should treat the patient with thyroid replacement for
her elevated TSH. If they are negative, antibodies
should be repeated in 3 months.
Medications, such as amiodarone, dopamine,
levodopa, bromocriptine, glucocorticoids (⬎0.5 mg/d
dexamethasone, 100 mg/d hydrocortisone), octreotide,
and amphetamines alter various thyroid function tests
(21). Time of sampling also can impact results. TSH is
secreted in a pulsatile manner with circadian variation,
leading to a nightly surge and physiological dampening
of pulse amplitude throughout the day.
By physical examination alone, the prevalence of
palpable thyroid nodules in the general population
can be estimated at approximately 5% (22). Based on
ultrasound studies however, the presence of thyroid
nodules increase with age, so that 10% of 25-year
olds have nodules, while nearly 55% of women over
70-years have nodules notable on ultrasound. Tradi-
tionally, only 5% of nodules are malignant. Biopsy
and management of thyroid nodules in a pregnant
woman are typically delayed until after she has
delivered.
782 Obstetrical and Gynecological Survey
It is recommended that all patients with a palpable
nodule undergo ultrasound evaluation. Ultrasound is
the ideal imaging modality of the neck and best
radiologic assessment of the thyroid gland. Accord-
ing to the American Thyroid Association guidelines,
those with nodules ⬎1 cm should undergo fine nee-
dle aspiration (23). Any abnormal findings on ultra-
sound should be referred promptly to a thyroid
specialist.
The value of evaluating total T4 is limited. It may
be useful in women who are pregnant or receiving
high doses of thyroid replacement because of possi-
ble confounding TBG effects. Normal values for
total T4 in nonpregnant women are approximately 5
to 12 ␮g/dL, whereas normal values are slightly
higher in the pregnant women (11–14 ␮g/dL).
PHYSIOLOGIC HORMONE CHANGES IN
PREGNANCY
Thyroid-Binding Globulin
TBG is synthesized in the liver and binds 75% of
circulating T4 (24). Increased endogenous estrogen
(pregnancy) and exogenous estrogen (controlled
ovarian hyperstimulation) increase TBG production
as well as TBG sialylation, decreasing its clearance
(25). In pregnancy, this results in a nearly 2-fold
increase in serum TBG concentration. TBG excess
leads to a rise in total T4 and T3 concentrations, but
does not affect the physiologically important serum
fT4 and free T3 levels. Additionally, with advancing
gestation, there is an increase in renal blood flow and
glomerular filtration, leading to increased iodine
clearance, thereby modifying peripheral metabolism
of thyroid hormones (7).
Thyrotropin-Releasing Hormone
TRH levels do not increase in the systemic circu-
lation in pregnancy. Even so, the human placenta
does synthesize low levels of immunologically active
TRH. In vitro and in vivo data have shown maximal
placental TRH synthesis at 7 to12 weeks of gestation
and a decline as gestation advances further (26).
Thyrotropin-Stimulating Hormone
There is a modest reduction in TSH secretion from
the anterior pituitary in response to rising hCG levels
in the first trimester of pregnancy (27). Near term,
however, TSH concentrations may be slightly ele-
vated due to increased renal clearance of iodine and
placental degradation of thyroid hormone. Through-
out pregnancy, TSH maintains its normal circadian
rhythm.
It is important to note that despite changes in
associated hormone concentrations, the size of the
thyroid stays relatively unchanged throughout preg-
nancy. Therefore, any enlargement or the presence of
a goiter should be investigated appropriately.
TREATMENT
Throughout normal pregnancy, thyroid hormone
requirements increase 20% to 40%. Recent prospec-
tive randomized trials have shown a significant de-
crease in maternal hypothyroidism during the first
trimester with an increase dose of 2 tablets per week
of a woman’s current dosage of levothyroxine, start-
ing from the beginning of pregnancy (28). For those
newly diagnosed with hypothyroidism and starting
medication, a general guideline is to start levothy-
roxine 0.8 ␮g/lb (1.76 ␮g/kg) and recheck TSH
levels in 4 to 6 weeks.
In the United States, treatment of hyperthyroidism
typically involves medical management with propy-
lthiouracil (PTU) or methimazole. Both PTU and
methimazole cross the term placenta with equal
transfer kinetics (29). Rare case reports of aplasia
cutis, a scalp defect in newborns of mothers exposed
to methimazole, caused many practitioners to give
PTU during the first 3 months of pregnancy to min-
imize this risk (30,31). Other congenital malforma-
tions such as tracheoesophageal and choanal atresias
have been associated with methimazole, but not with
PTU (32). Because of these concerns, the American
Thyroid Association and the Food and Drug Admin-
istration have officially recommended limiting PTU
use to the first trimester. In the second trimester, the
patient should be switched to an equivalent dose of
methimazole for the remainder of the pregnancy
(33). Clinical experience has shown that methima-
zole is 20 to 30 times more potent than PTU; there-
fore, 300 mg of PTU would roughly equal 10 to 15
mg methimazole.
COMPLICATIONS IN PREGNANCY
Symptoms of thyroid dysfunction may be exacer-
bated in the first trimester of pregnancy. Hypereme-
sis gravidarum is a poorly understood syndrome
classified as nausea and vomiting, accompanied by
the loss of at least 5% body weight during pregnancy.
While evaluating thyroid function in women with
severe hyperemesis is a reasonable approach, mild or
 What the Obstetrician/Gynecologist Should Know About Thyroid Disorders Y CME Review Article 783
moderate nausea and vomiting during early preg-
nancy is common and does not typically require
thyroid testing.
Hyperthyroidism is second only to diabetes as the
most common endocrinopathy in pregnancy, (34)
with Graves disease as the most common underlying
cause. Graves disease is an autoimmune disease
caused by autoantibodies to the TSH-receptor that
activate the receptor and stimulate the thyroid to
produce an excessive amount of thyroid hormone.
Poorly controlled hyperthyroidism increases rates of
spontaneous abortion, premature labor, preeclamp-
sia, low birth weight and stillbirth, as well as in-
creases in maternal morbidity of toxemia and cardiac
failure (35).
Transient subclinical hyperthyroidism during preg-
nancy occurs in 10% to 20% of previously euthyroid
women. As previously mentioned, hCG has weak
thyroid-stimulating activity. Serum fT4 and T3 con-
centrations increase slightly, paralleling the time of
the hCG peak (10–12 weeks gestation); however,
these hormones usually remain within the normal
range. Women with transient subclinical hyperthy-
roidism do not require treatment (36).
Hypothyroidism can be classified into overt (high
TSH and low fT4) and subclinical (high TSH and
normal fT4). Medical treatment of subclinical hypo-
thyroidism in pregnancy is a source of controversy.
In a large retrospective cohort study, results of serum
samples from 25,216 pregnant women, obtained over
a 2-year period were analyzed. In all, 62 women were
identified whose TSH levels were at or above the
98th percentile for pregnant women and matched to
124 normal controls. The children of these women
(aged 7–9 years) underwent IQ testing and scores
were compared between the 2 groups. Although not
statistically significant, the children of the 62 sub-
clinical hypothyroid women performed slightly less
well on all tests administered. Of the hypothyroid
group, 48 were not treated for their condition during
pregnancy. The full-scale IQ scores of the children of
this cohort averaged 7 points lower than those of the
control group (P ⫽ 0.005) (37). The mean TSH and
fT4 for the hypothyroid cohort were 13.2 mU/L
and 0.71 ng/dL, respectively, compared to 1.4 mU/L
and 0.97 ng/dL for controls.
Although we have known for years that thyroid
hormone is essential for normal neonatal neurodevel-
opment, its role in the fetus is not as well defined
(38). Many use these study findings as evidence that
thyroid hormone is essential for the neurodevelop-
ment of the fetus.
POSTPARTUM
Postpartum thyroid dysfunction has been reported
in up to 50% of women who have been found to have
TPO antibodies in early pregnancy. When TPO an-
tibodies are present, there is a lymphocytic infiltra-
tion into the thyroid, which may be exacerbated
following delivery. In all, 25% of women with dia-
betes mellitus type 1 also will experience postpartum
thyrotoxicosis. The hypothyroid phase of postpartum
thyrotoxicosis is symptomatic and requires T4 ther-
apy. A significant portion of these women (25%–
30%) go on to have permanent hypothyroidism. For
those with transient postpartum hypothyroidism,
monitoring for recurrent disease should be performed
more frequently, as there is a 50% risk of developing
hypothyroidism within the following 7 years (39).
As women with TPO antibodies are more likely to
develop postpartum thyroid dysfunction than those
without antibodies, Negro et al (40) studied postpar-
tum thyroid dysfunction prevention methods in
women positive for TPO antibodies. In the prospec-
tive placebo-controlled trial, 151 women positive for
TPO antibodies were randomized to receive either
placebo or 200 ␮g selenium throughout pregnancy
and postpartum and compared with the group to
TPO-negative matched controls. Results showed that
the selenium group had statistically significant fewer
episodes of postpartum thyrotoxicosis than the pla-
cebo group (29% vs. 49%). Although the study
showed great promise in the prevention of postpar-
tum thyroid dysfunction, the authors do not advise
initiating selenium treatment until further study is
completed.
There are mixed reports of an increased risk of
postpartum depression in women with postpartum
dysfunction. One large study found the incidence of
postpartum depression in an unselected population
was 1.7% with no increased risk for those positive
for TPO antibodies compared to controls (41).
POSTMENOPAUSE
Untreated thyroid disease substantially increases
the risks for both cardiovascular disease and osteo-
porosis in postmenopausal women. Prolonged thy-
roid dysfunction can result in cardiac diastolic
dysfunction, arrhythmia, and diastolic hypertension.
Symptoms of hypothyroidism in the elderly popula-
tion may be the same as symptoms in premenopausal
women, but complaints are generally less specific
than those reported by younger patients. Physical
findings may include bradycardia, diastolic hyperten-
784 Obstetrical and Gynecological Survey
sion, pallor, dry skin, dysarthria, and delayed re-
flexes. Voice and mental status changes also are
signs of hypothyroidism and often can be confused
with symptoms of clinical depression. Individuals
aged 80 years or older have a 5-fold greater chance of
developing hypothyroidism compared to 12 to 49
year olds (42).
The metabolic clearance rate of thyroid hormone
decreases with age. For euthyroid women, hormone
levels remain within the normal range; however, for
women with hypothyroidism receiving thyroid re-
placement, this decreased clearance may require a
decrease in thyroid replacement (43).
SUMMARY
Thyroid diseases are common in women of child-
bearing age and are influenced by a variety of
hormonal factors and autoimmune states. Thyroid dys-
function can present at any time in a woman’s life,
including mid to late puberty, and result in ovulatory
and menstrual flow irregularities. Prepregnancy is an
important time to regulate thyroid function, as abnormal
serum thyroid hormone levels during early pregnancy
negatively impact the developing fetus. Physiologic
hormone changes during pregnancy alter thyroid func-
tion and potentially can result in complications for both
the mother and infant. Obstetrician/gynecologists
should be aware of current best-practice guidelines for
diagnosing and managing thyroid dysfunction as it re-
lates to their patients.
Acknowledgment—The authors thank Francis S.
Greenspan, MD, Director of the UCSF Medical Cen-
ter Thyroid Clinic for providing valuable comments
and advice.
REFERENCES
1. Roti E. Regulation of thyroid-stimulating hormone (TSH) se-
cretion in the fetus and neonate. J Endocrinol Invest 1988;11:
145–158.
2. Dunger DB, Perkins JA, Jowett TP, et al. A longitudinal study
of total and free thyroid hormones and thyroxine binding
globulin during normal puberty. Acta Endocrinol (Copenh)
1990;123:305–310.
3. Fleury Y, Van Melle G, Woringer V, et al. Sex-dependent
variations and timing of thyroid growth during puberty. J Clin
Endocrinol Metab 2001;86:750–754.
4. Goldsmith RE, Sturgis SH, Lerman J, et al. The menstrual
pattern in thyroid disease. J Clin Endocrinol Metab 1952;12:
846–855.
5. Krassas GE, Pontikides N, Kaltsas T, et al. Disturbances of
menstruation in hypothyroidism. Clin Endocrinol (Oxf) 1999;
50:655–659.
6. Joshi JV, Bhandarkar SD, Chadha M, et al. Menstrual irregu-
larities and lactation failure may precede thyroid dysfunction
or goitre. J Postgrad Med 1993;39:137–141.
7. Poppe K, Velkeniers B, Glinoer D. Thyroid disease and female
reproduction. Clin Endocrinol (Oxf) 2007;66:309–321.
8. Faglia G. The clinical impact of the thyrotropin-releasing hor-
mone test. Thyroid 1998;8:903–908.
9. Poppe K, Velkeniers B, Glinoer D. The role of thyroid autoim-
munity in fertility and pregnancy. Nat Clin Pract Endocrinol
Metab 2008;4:394–405.
10. Csaba G, Shahin MA, Dobozy O. Effect of combined
gonadotropin-thyrotropin treatment on development of tes-
tis and ovarium in the chickling. Acta Physiol Acad Sci
Hung 1980;55:163–168.
11. Shahin MA, Csaba G, Dobozy O. Effect of gonadotropins and
thyrotropin on the testes and ovaries of the newly hatched
chicken. Acta Morphol Acad Sci Hung 1980;28:317–335.
12. Grasso P, Crisp TM. In vitro responses of luteinizing rat gran-
ulosa cells to human thyroid-stimulating hormone. Biol Re-
prod 1985;32:935–945.
13. Rae MT, Gubbay O, Kostogiannou A, et al. Thyroid hormone
signaling in human ovarian surface epithelial cells. J Clin
Endocrinol Metab 2007;92:322–327.
14. Abalovich M, Mitelberg L, Allami C, et al. Subclinical hypothy-
roidism and thyroid autoimmunity in women with infertility.
Gynecol Endocrinol 2007;23:279–283.
15. De Vivo A, Mancuso A, Giacobbe A, et al. Thyroid function in
women found to have early pregnancy loss. Thyroid 2010;20:
633–637.
16. Muller AF, Verhoeff A, Mantel MJ, et al. Decrease of free
thyroxine levels after controlled ovarian hyperstimulation.
J Clin Endocrinol Metab 2000;85:545–548.
17. Sun SC, Hsu PJ, Wu FJ, et al. Thyrostimulin, but not thyroid-
stimulating hormone (TSH), acts as a paracrine regulator to
activate the TSH receptor in mammalian ovary. J Biol Chem
2010;285:3758–3765.
18. ACOG Committee Opinion No. 381: subclinical hypothyroid-
ism in pregnancy. Obstet Gynecol 2007;110:959–960.
19. Dosiou C, Sanders GD, Araki SS, et al. Screening pregnant
women for autoimmune thyroid disease: a cost-effectiveness
analysis. Eur J Endocrinol 2008;158:841–851.
20. Thung SF, Funai EF, Grobman WA. The cost-effectiveness of
universal screening in pregnancy for subclinical hypothyroid-
ism. Am J Obstet Gynecol 2009;200:267.e1–267.e7.
21. Dong BJ. How medications affect thyroid function. West
J Med 2000;172:102–106.
22. Mazzaferri EL. Management of a solitary thyroid nodule.
N Engl J Med 1993;328:553–559.
23. Cooper DS, Doherty GM, Haugen BR, et al. Revised American
Thyroid Association management guidelines for patients with
thyroid nodules and differentiated thyroid cancer. Thyroid
2009;19:1167–1214.
24. Schussler GC. The thyroxine-binding proteins. Thyroid 2000;
10:141–149.
25. Ain KB, Mori Y, Refetoff S. Reduced clearance rate of thyroxine-
binding globulin (TBG) with increased sialylation: a mechanism
for estrogen-induced elevation of serum TBG concentration.
J Clin Endocrinol Metab 1987;65:689–696.
26. Bajoria R, Babawale M. Ontogeny of endogenous secretion of
immunoreactive-thyrotropin releasing hormone by the human
placenta. J Clin Endocrinol Metab 1998;83:4148–4155.
27. Glinoer D. What happens to the normal thyroid during preg-
nancy? Thyroid 1999;9:631–635.
28. Yassa L, Marqusee E, Fawcett R, et al. Thyroid Hormone Early
Adjustment in Pregnancy (The THERAPY) Trial. J Clin Endo-
crinol Metab 2010;95:3234–3241.
29. Mortimer RH, Cannell GR, Addison RS, et al. Methimazole and
propylthiouracil equally cross the perfused human term pla-
cental lobule. J Clin Endocrinol Metab 1997;82:3099–3102.
30. Van Dijke CP, Heydendael RJ, De Kleine MJ. Methimazole,
carbimazole, and congenital skin defects. Ann Intern Med
1987;106:60–61.
 What the Obstetrician/Gynecologist Should Know About Thyroid Disorders Y CME Review Article 785
31. Martinez-Frias ML, Cereijo A, Rodriguez-Pinilla E, et al. Me-
thimazole in animal feed and congenital aplasia cutis. Lancet
1992;339:742–743.
32. Di Gianantonio E, Schaefer C, Mastroiacovo PP, et al. Adverse
effects of prenatal methimazole exposure. Teratology 2001;
64:262–266.
33. Bahn RS, Burch HS, Cooper DS, et al. The Role of propylth-
iouracil in the management of Graves’ disease in adults: re-
port of a meeting jointly sponsored by the American Thyroid
Association and the Food and Drug Administration. Thyroid
2009;19:673–674.
34. Mestman JH. Hyperthyroidism in pregnancy. Endocrinol
Metab Clin North Am 1998;27:127–149.
35. Mestman JH. Hyperthyroidism in pregnancy. Clin Obstet Gy-
necol 1997;40:45–64.
36. Glinoer D, De Nayer P, Robyn C, et al. Serum levels of intact
human chorionic gonadotropin (HCG) and its free alpha and
beta subunits, in relation to maternal thyroid stimulation dur-
ing normal pregnancy. J Endocrinol Invest 1993;16:881–888.
37. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid
deficiency during pregnancy and subsequent neuropsycho-
logical development of the child. N Engl J Med 1999;341:
549–555.
38. Williams GR. Neurodevelopmental and neurophysiological
actions of thyroid hormone. J Neuroendocrinol 2008;20:
784–794.
39. Lazarus JH. Thyroid disorders associated with pregnancy:
etiology, diagnosis, and management. Treat Endocrinol 2005;
4:31–41.
40. Negro R, Greco G, Mangieri T, et al. The influence of selenium
supplementation on postpartum thyroid status in pregnant
women with thyroid peroxidase autoantibodies. J Clin Endo-
crinol Metab 2007;92:1263–1268.
41. Lucas A, Pizarro E, Granada ML, et al. Postpartum thyroid
dysfunction and postpartum depression: are they two linked
disorders? Clin Endocrinol (Oxf) 2001;55:809–814.
42. Aoki Y, Belin RM, Clickner R, et al. Serum TSH and total T4 in the
United States population and their association with participant
characteristics: National Health and Nutrition Examination Sur-
vey (NHANES 1999–2002). Thyroid 2007;17:1211–1223.
43. Harman SM, Wehmann RE, Blackman MR. Pituitary-thyroid
hormone economy in healthy aging men: basal indices of
thyroid function and thyrotropin responses to constant infu-
sions of thyrotropin releasing hormone. J Clin Endocrinol
Metab 1984;58:320–326.