Overview of thyroid disease in pregnancy

Author: Douglas S Ross, MD

Literature review current through: Jan 2019. | This topic last updated: Feb 23, 2018

THYROID ADAPTATION DURING NORMAL PREGNANCY The diagnosis of

thyroid disease during pregnancy requires an understanding of the changes in thyroid physiology
and thyroid function tests that accompany normal pregnancy.

Thyroid physiology — To meet the increased metabolic needs during a normal pregnancy, there
are changes in thyroid physiology that are reflected in altered thyroid function tests [1]. The major
changes in thyroid function during pregnancy are:
●An increase in serum thyroxine-binding globulin (TBG)
●Stimulation of the thyrotropin (thyroid-stimulating hormone [TSH]) receptor by human
chorionic gonadotropin (hCG)

Thyroxine-binding globulin — During pregnancy, serum TBG concentrations rise almost twofold

because estrogen increases TBG production and TBG sialylation, which results in decreased
clearance of TBG [2]. To maintain adequate free thyroid hormone concentrations during this period,
thyroxine (T4) and triiodothyronine (T3) production by the thyroid gland must increase. The TBG
excess leads to an increase in both serum total, but not free, T4 and T3 concentrations. Levels of
total T4 and T3 rise by approximately 50 percent during the first half of pregnancy, plateauing at
approximately 20 weeks of gestation, at which time a new steady state is reached and the overall
production rate of thyroid hormones returns to prepregnancy rates.

hCG and thyroid function — Human chorionic gonadotropin (hCG) is one of a family of

glycoprotein hormones, including TSH, with a common alpha subunit and a unique beta subunit.
However, there is considerable homology between the beta subunits of hCG and TSH. As a result,
hCG has weak thyroid-stimulating activity [3]. In a human thyroid cell culture assay, as an example,
1 microU of hCG was equivalent to 0.0013 microU of TSH [4].

Serum hCG concentrations increase soon after fertilization and peak at 10 to 12 weeks. During this
peak, total serum T4 and T3 concentrations increase. Serum free T4 and T3 concentrations increase
slightly, usually within the normal range, and serum TSH concentrations are appropriately reduced
[3]. However, in 10 to 20 percent of normal women, serum TSH concentrations are transiently low
or undetectable [5-7]. In a report of 63 women with extremely high hCG concentrations (>200,000
international units per L), TSH was <0.2 microU/mL in 67 percent of samples, and free T4 was
above 1.8 ng/dL in 32 percent of samples. All women whose hCG was greater than 400,000
international units per L had a suppressed TSH concentration [8]. Very high levels of hCG can be
seen in multiple pregnancies (ie, twins, triplets, etc) and in hyperemesis gravidarum.

This transient, usually subclinical, hyperthyroidism should be considered a normal physiologic

finding. It is not known if this action of hCG benefits the mother or fetus. Later in pregnancy, as
hCG secretion declines, serum free T4 and T3 concentrations decline, and serum TSH
concentrations rise slightly to or within the normal range.

Trimester-specific reference ranges — Because of the changes in thyroid physiology during

pregnancy, the Guidelines of the American Thyroid Association (ATA) for the Diagnosis and
Management of Thyroid Disease during Pregnancy and the Postpartum recommend using
population-based, trimester-specific reference ranges for TSH and assay method and trimester-
specific reference ranges for serum free T4 [9]. Unfortunately, many commercial laboratories
currently do not provide these reference ranges. When trimester-specific reference ranges for free
T4 are not available and free T4 levels appear discordant with TSH, measurement of total T4 may
be superior to free T4.

In the absence of population and trimester-specific normal ranges, ATA guidelines suggest the
following for interpretation of thyroid function tests [9]:

●Weeks 7 to 12 – Reduce the lower limit of the reference range of TSH by approximately
0.4 mU/L and the upper limit by 0.5 mU/L (corresponding to a TSH reference range of
approximately 0.1 to 4 mU/L).
●Second and third trimester – There should be a gradual return of TSH towards the
nonpregnant normal range.
●The upper reference range for total T4 increases by approximately 5 percent per week,
beginning at week 7. At approximately 16 weeks, total T4 (and T3) levels during pregnancy
are 1.5-fold higher than in nonpregnant women (due to TBG excess).

Assessment of thyroid function — When evaluating thyroid tests during pregnancy, we typically

measure TSH and free T4 (if there is a trimester-specific reference range), and/or total T4. It is not
uncommon to find free T4 levels to be at or below the reference range for nonpregnant adults in
association with normal serum TSH levels, a finding related to free T4 assay inaccuracy due to
changes in binding proteins. In such settings where free T4 measurements appear discordant with
TSH measurements, total T4 should also be measured.

Iodine requirements — Iodine requirements are higher in pregnant than in nonpregnant women

due both to the increase in maternal T4 production required to maintain maternal euthyroidism and
an increase in renal iodine clearance. Severe maternal iodine deficiency during pregnancy results in
a reduction in maternal T4 production, inadequate placental transfer of maternal T4, and
impairment of fetal neurologic development. However, markedly excessive iodine intake may also
be harmful as it can lead to fetal hypothyroidism and goiter.

Iodine requirements — Iodine requirements are higher in pregnant than in nonpregnant women

due both to the increase in maternal T4 production required to maintain maternal euthyroidism and
an increase in renal iodine clearance. Severe maternal iodine deficiency during pregnancy results in
a reduction in maternal T4 production, inadequate placental transfer of maternal T4, and
impairment of fetal neurologic development. However, markedly excessive iodine intake may also
be harmful as it can lead to fetal hypothyroidism and goiter.

The World Health Organization (WHO) recommends 250 mcg of iodine daily during pregnancy
and lactation. The National Academy of Medicine (formerly the Institute of Medicine) recommends
daily iodine intake of 220 mcg during pregnancy and 290 mcg during lactation. For women in the
United States to achieve this level of daily intake, the ATA recommends supplementation with 150
mcg of iodine daily during pregnancy and lactation, which is the dose included in the majority of
prenatal vitamins marketed in the United States, though pregnant women should verify the iodine
content in their own prenatal vitamin. The WHO sets the tolerable upper intake amount for iodine
as 500 mcg daily for pregnant women, while the National Academy of Medicine uses 1100 mcg
daily for adults and pregnant women >19 years of age.
 THYROID FUNCTION IN THE FETUS During the 10th to 12th week of gestation, fetal

TSH appears, and the fetal thyroid is capable of concentrating iodine and synthesizing
iodothyronines. However, little hormone synthesis occurs until the 18 th to 20th week. Thereafter,
fetal thyroid secretion increases gradually [23].

At term, fetal serum T4, T3, and TSH concentrations differ substantially from those in the mothers.
Serum TSH concentrations are higher, serum free T4 concentrations are lower, and serum T3
concentrations are one-half those of the mothers. Soon after birth, serum TSH concentrations
rapidly increase to 50 to 80 mU/L and then fall to 10 to 15 mU/L within 48 hours. Serum T3 and T4
concentrations rapidly increase to values slightly higher than those in normal adults.

The extent to which maternal thyroid hormones cross the placenta is controversial, but maternal
thyroid hormones are critical for growth and development in the first trimester, when the fetus has
no functional thyroid of its own. In infants with congenital absence of the thyroid, cord serum
concentrations range from 20 to 50 percent of the concentrations in normal infants [ 24]. TSH-
receptor antibodies can cross the placenta and cause either fetal hyperthyroidism or hypothyroidism.
Little TSH crosses the placenta.

HYPERTHYROIDISM COMPLICATING PREGNANCY Overt hyperthyroidism

(suppressed TSH, elevated free T4 and/or T3) is relatively uncommon during pregnancy, occurring
in 0.1 to 0.4 percent of all pregnancies [26]. Although hyperthyroidism from any cause can
complicate pregnancy, Graves' disease and human chorionic gonadotropin (hCG)-mediated
hyperthyroidism are the most common causes of hyperthyroidism. Graves' disease usually becomes
less severe during the later stages of pregnancy due to a reduction in TSH-receptor antibody
concentrations or, rarely, mediated by a change in the activity of TSH-receptor antibodies from
stimulatory to blocking. hCG-mediated hyperthyroidism usually occurs transiently in the first half
of gestation and is typically less severe than Graves' disease.

Diagnosis — The diagnosis of hyperthyroidism during pregnancy should be based primarily upon a

finding of a suppressed (<0.1 mU/L) or undetectable (<0.01 mU/L) serum TSH value and elevated
thyroid hormone levels that exceed the reference ranges for pregnancy [9]. If a TSH level is
<0.1 mU/L, free T4 (or free T4 index) and total T3 (or free T3) should be obtained. In the event that
free thyroid hormone levels are discordant with serum TSH and clinical findings, total T4 should be
measured. It should be recalled that 10 to 20 percent of normal women have a subnormal or
suppressed serum TSH in the first trimester, usually in association with normal free T4 levels.

Most pregnant women with significant overt hyperthyroidism in the first trimester will have a serum
TSH below that which is seen in asymptomatic, healthy pregnant women (ie,
<0.01 mU/L), associated with an elevated free T4 and/or free T3 (or total T4 and/or total T3)
measurement. 

Treatment — hCG-mediated hyperthyroidism is usually transient and does not require treatment.

Treatment options for pregnant women with overt hyperthyroidism due to Graves' or nodular
thyroid disease are limited because therapy may be harmful to the fetus. However, a good fetal and
maternal outcome depends upon controlling the mother's hyperthyroidism. Most women are treated
with thionamides. The goal of thionamides is to reduce and maintain the mother's serum free T4
concentration in the high normal range for nonpregnant women using the lowest dose [9]. This
requires assessment of free T4 (and/or total T4) frequently (ie, at four-week intervals) with
appropriate adjustment of medication.

The goal of treatment is to maintain persistent but mild hyperthyroidism in the mother in an attempt
to prevent fetal hypothyroidism since the fetal thyroid is more sensitive to the action of antithyroid
drugs [4]. Overtreatment of maternal hyperthyroidism with thionamide antithyroid drugs (ATDs)
can cause fetal goiter and primary hypothyroidism. On the other hand, transient central
hypothyroidism may be seen in infants whose mothers had poorly controlled hyperthyroidism
during pregnancy, presumably due to suppression of the fetal pituitary-thyroid axis.

To attain the goal of mild hyperthyroidism, the mother's serum free thyroxine (T4) concentration
should be maintained at or just above the trimester-specific normal range for pregnancy or
(especially if the trimester-specific reference range is not available) the total T4 and
triiodothyronine (T3) should be maintained at 1.5 times above the nonpregnant reference range. The
serum thyroid-stimulating hormone (TSH) concentration should be below the reference range for
pregnancy (eg, goal TSH approximately 0.1 to 0.3 mU/L), using the lowest possible dose of
medication.

Attaining these goals requires assessment of thyroid function frequently (ie, at four-week intervals)
with appropriate adjustment of medication.

Indications for treatment — Women with symptomatic, moderate to severe, overt

hyperthyroidism due to Graves' disease, toxic adenoma, toxic multinodular goiter, or gestational
trophoblastic disease require treatment of hyperthyroidism. Such patients will almost always have
TSH values below 0.05 mU/L and elevations in trimester-specific free T4
concentrations and/or total T4 and T3 concentrations that exceed 1.5 times the upper limit of normal
for nonpregnant patients.

Not all patients with biochemical, overt hyperthyroidism require treatment if the hyperthyroidism is
mild, since the goal of treatment is to maintain mild maternal hyperthyroidism.

Treatment of hyperthyroidism is not required in the following settings:

●Transient, subclinical hyperthyroidism (normal serum total or free T4 and T3 concentrations

for pregnancy in the presence of a subnormal TSH) in the first trimester of pregnancy, because
it is considered a normal physiologic finding and therefore does not require therapy.
●hCG-mediated, overt hyperthyroidism (also called gestational transient thyrotoxicosis),
because it is usually transient and mild.
●Hyperemesis gravidarum-associated hyperthyroidism, because it is usually mild and subsides
as hCG production falls (typically by 16 to 18 weeks gestation). Women with severe
hyperemesis, however, require treatment of dehydration with intravenous fluids.
●Subclinical and mild, asymptomatic, overt hyperthyroidism due to Graves' disease, toxic
adenoma, or toxic multinodular goiter.
Subclinical hyperthyroidism (subnormal TSH and free T4 within the trimester-specific
reference range or total T4 and T3 <1.5 times above the upper limit of normal for nonpregnant
patients) never requires treatment during pregnancy. Biochemical, overt hyperthyroidism
(subnormal TSH and free T4 above the trimester-specific reference range or total T4 and T3
>1.5 times above the upper limit of normal for nonpregnant patients) may not require
treatment if mild and asymptomatic (or minimally symptomatic), since the goal of treatment is
to maintain mild maternal hyperthyroidism.
In women who are being monitored without therapy, we measure TSH, free T4 (if there is a
trimester-specific reference range), and/or total T4 or total T3 every four to six weeks.

Control of symptoms — In pregnant women with symptomatic, moderate to severe

hyperthyroidism, beta blockers may be given to ameliorate symptoms. We typically start
with metoprolol 25 to 50 mg daily. Propranolol, 20 mg every six to eight hours, is an alternative
option. The dose can be increased as needed to control symptoms. However, if possible, beta
blockers should be weaned as soon as the hyperthyroidism is controlled by thionamides because
occasional cases of neonatal growth restriction, hypoglycemia, respiratory depression, and
bradycardia have been reported after maternal administration.

In a retrospective analysis, women with chronic hypertension who used atenolol in early (15 weeks
gestation) compared with late (30 weeks gestation) pregnancy had significantly smaller babies [6].
There has been one report suggesting a higher rate of spontaneous abortion for hyperthyroid women
treated with both a thionamide and propranolol compared with a thionamide alone [12]. In most
patients, beta blockers can and should be tapered and discontinued within two to six weeks.

Decrease thyroid hormone synthesis — For pregnant women with moderate to severe

hyperthyroidism, thionamides are our first choice of treatment to decrease thyroid hormone
synthesis. Both methimazole and propylthiouracil (PTU) probably cross the placenta with equal
transfer kinetics [13] and have similar effects on the fetal thyroid [14,15]. In one report of 77
newborns of euthyroid mothers treated with PTU or methimazole, there were no significant
differences in TSH concentrations measured in cord blood at birth [15]. However, compared with
control neonates who were not exposed in utero to thionamides, mean cord TSH levels were higher
in neonates exposed to PTU but not methimazole.

Low thyroid function at birth is found in approximately one-half of neonates whose mothers
received PTU or methimazole during pregnancy and who had serum T4 concentrations within the
normal (nonpregnant) range [4]. In spite of these observations, two studies reported that the
intelligence quotient (IQ) scores of children who were exposed to thionamides in utero (but were
euthyroid at birth) were normal.

Pretreatment evaluation — Prior to initiating thionamides, we obtain baseline blood tests,

including a complete blood count (white count with differential) and a liver profile (bilirubin and
transaminases). We do not use thionamides in patients with a baseline absolute neutrophil count
<1000 cells/microL or elevated liver transaminases (more than fivefold the upper limit of normal)
except in selected patients after careful assessment of alternatives and risks.

Choice of thionamide — The thionamide drugs available in the United States are PTU
and methimazole. Carbimazole is available in other countries. Carbimazole is completely
metabolized to methimazole, although the carbimazole dose required to yield an equivalent dose of
methimazole is approximately 40 percent higher. The choice of thionamide depends upon which
trimester the drug is being initiated. Methimazole is preferred to PTU except during the first
trimester of pregnancy.

●Diagnosed prior to pregnancy – Women diagnosed with Graves' disease prior to pregnancy
who are taking methimazole could [2,3]:
•Elect to have definitive therapy with surgery or radioiodine prior to pregnancy. Women
should then postpone pregnancy until they have become euthyroid following definitive
treatment and on replacement therapy. This option is recommended for women who are
requiring high doses of methimazole to maintain a euthyroid state.
 •Switch to PTU before trying to conceive. This option is most reasonable in younger
women with normal periods who are expected to conceive within one to three months.
•Switch to PTU as soon as the pregnancy test is confirmed. This option is more
reasonable for older women and women having difficulty conceiving. It is recommended
that a pregnancy test be obtained weekly.
•Discontinue methimazole with careful monitoring of thyroid function tests (weekly
throughout the first trimester, then monthly). This option is best chosen for women who
have already been treated with methimazole for 12 to 18 months, have a normal TSH
level on low-dose therapy, and are thyrotropin receptor antibody (TRAb) negative. If
hyperthyroidism recurs after discontinuation, the patient should be treated with PTU (if
relapse occurs in the first trimester) or methimazole (if relapse occurs after the first
trimester).
Patients taking PTU during the first trimester may continue it for the remainder of pregnancy
or switch back to methimazole at the start of the second trimester, as described immediately
below.
●Diagnosed during the first trimester – Women diagnosed with symptomatic, moderate to
severe hyperthyroidism during the first trimester of pregnancy should take PTU. Patients may
continue PTU for the remainder of pregnancy or switch back to methimazole at 16 weeks.
Clinical practice varies, and the decision should be made after discussing the options with
patients and considering their values and preferences. Since methimazole is more potent than
PTU, switching may increase the risk of maternal or fetal hypothyroidism. While switching to
methimazole reduces the exposure to PTU, which has more serious hepatotoxicity than
methimazole, most cases of liver failure occur within the first 60 days of treatment.
●Diagnosed after the first trimester – Women diagnosed with symptomatic, moderate to
severe hyperthyroidism after the first trimester should take methimazole.

All three antithyroid drugs (ATDs) have been associated with possible teratogenic effects, but
teratogenic effects are more severe with methimazole and carbimazole compared with PTU. There
are numerous case series of aplasia cutis, a scalp defect, in newborns exposed to methimazole in
utero. More serious congenital malformations, such as tracheoesophageal fistulas, patent
vitellointestinal duct, choanal atresia, omphalocele, and omphalomesenteric duct anomaly, have
also been observed with maternal use of methimazole and carbimazole but not PTU [ 20-30].
However, mild birth defects, including preauricular sinuses and cysts and urinary tract
abnormalities, have been observed after PTU [30]. In two studies, the prevalence of birth defects
was similar after exposure to either PTU or methimazole/carbimazole, but the PTU-associated
abnormalities were less severe [30,31], while in another study, the prevalence was higher with
exposure to methimazole compared with PTU [32].

Gestational weeks 6 to 10 is the period of highest risk for birth defects from exposure to
thionamides. Therefore, PTU is preferred during the first trimester. However, reports of severe
PTU-related liver failure have raised concerns about the routine use of PTU, including the use of
PTU in pregnancy [33]. Methimazole has also been associated with liver disease, but it is typically
due to cholestatic dysfunction in the United States, and methimazole is less likely to cause liver
failure than PTU. Certainly, a woman with even mild elevations in transaminases while taking PTU
during the first trimester should be transitioned to methimazole during the second trimester, but
because of the concern that methimazole (which is more potent than PTU) might result in transient
maternal or fetal hypothyroidism, endocrinologists treating patients who are stable on PTU might
prefer to continue PTU throughout pregnancy [2]

Initial dosing — To minimize the risk of hypothyroidism in the fetus, we give the lowest dose of
thionamide necessary to control thyroid function:
 ●PTU 50 mg two to three times daily
●Methimazole 5 to 10 mg daily, or
●Carbimazole 5 to 15 mg daily

However, in patients with severe hyperthyroidism, full initial doses of PTU (100 mg three times per
day) or methimazole (10 to 30 mg daily) may be required to control hyperthyroidism.

For patients switching between PTU and methimazole, the closest dose approximation should be
made. Although the ratio of potencies of PTU and methimazole is uncertain, clinical experience
suggests that methimazole is 20 to 30 times as potent on a milligram-to-milligram basis. Therefore,
300 mg of PTU would be roughly equivalent to 10 or 15 mg of methimazole.

Monitoring and dose adjustments — Graves' disease frequently ameliorates in the third trimester.
Whenever possible, based on thyroid function tests and assessment of TRAb measurements,
thionamides should be tapered and potentially discontinued during the third trimester.

Toxic adenoma and toxic multinodular goiter are unlikely to remit during pregnancy, and therefore,
women with hyperthyroidism due to these disorders are usually maintained on thionamides
throughout pregnancy.

Thyroid function tests – Thyroid function tests (TSH and free T4 or total T4 if a trimester-
specific reference range is not available for free T4) should be obtained every four weeks
throughout pregnancy. If thionamides are discontinued in early pregnancy, thyroid tests should
be checked weekly throughout the first trimester, then monthly.
Extra caution is necessary after switching thionamides. Thyroid tests should be performed two
weeks after switching to be sure that a euthyroid state has been maintained and to avoid
maternal overtreatment and fetal hypothyroidism.
The thionamide dose should be adjusted based on the results of the thyroid function tests to
maintain serum free T4 concentrations at or just above the upper limit of normal, using a
trimester-specific reference range, or the total T4 and T3 (if trimester-specific normal ranges
for free T4 are not available) should be maintained at approximately 1.5 times the upper limit
of normal for nonpregnant adults. Serum TSH concentrations should be maintained below the
reference range for pregnancy.
Ultimately, low doses of PTU or methimazole (eg, 50 mg twice daily or less for PTU; 2.5 to 5
mg a day for methimazole) may be all that is required [36]. It is possible to discontinue the
thionamide during the third trimester in at least one-third of women [36]. In this setting,
thyroid tests should be obtained two weeks after discontinuation and then monthly. The
amelioration of hyperthyroidism as pregnancy progresses is due to a fall in serum TRAb
concentrations or, rarely, a rise in TSH receptor-blocking antibodies. However, Graves'
hyperthyroidism often worsens postpartum.
Monitoring thyroid function tests throughout pregnancy is important because maternal
hyperthyroidism in the third trimester may increase the risk of low birth weight (independent
of the risk of neonatal Graves' disease).

Fetal and neonatal Graves' disease — One to 5 percent of neonates born to women with Graves'
disease have hyperthyroidism due to transplacental transfer of TSH-receptor-stimulating antibodies.
The incidence is higher in women with high titers of these antibodies.

High fetal heart rate (>160 beats/minute), fetal goiter, advanced bone age, poor growth, and
craniosynostosis are manifestations of fetal hyperthyroidism. Cardiac failure and hydrops may
occur with severe disease. All fetuses of women with Graves' disease should be monitored for signs
of fetal thyrotoxicosis by determination of fetal heart rate and assessment of fetal growth.
 HYPOTHYROIDISM DURING PREGNANCY When iodine nutrition is adequate (as in

the United States), the most common cause of hypothyroidism during pregnancy is chronic
autoimmune (Hashimoto's) thyroiditis. In iodine-deficient areas, iodine deficiency itself is
associated with hypothyroidism and goiter. Other causes of hypothyroidism, such as prior
radioiodine ablation, prior surgical removal of the thyroid, or disorders of the pituitary or
hypothalamus, can also occur in pregnant women.

Pregnancy complications — Hypothyroidism can have adverse effects on pregnancy outcomes,

depending upon the severity of the biochemical abnormalities:

●Overt hypothyroidism
●Subclinical hypothyroidism
●Maternal hypothyroxinemia (isolated low maternal free T4):  Isolated maternal
hypothyroxinemia (low T4) is defined as a maternal free T4 concentration in the lower 2.5 th to
5th percentile of the reference range, in conjunction with a normal TSH. The effect of isolated
maternal hypothyroxinemia on perinatal and neonatal outcome is unclear.

Overt hypothyroidism — Overt hypothyroidism (elevated TSH, reduced free T4) complicating

pregnancy is unusual (0.3 to 0.5 percent of screened women). Two factors contribute to this finding;
some hypothyroid women are anovulatory [5], and hypothyroidism (new or inadequately treated)
complicating pregnancy is associated with an increased rate of first trimester spontaneous abortion
[6-8].

In continuing pregnancies, hypothyroidism has been associated with an increased risk of several
complications, including [9-18]:

●Preeclampsia and gestational hypertension

●Placental abruption
●Nonreassuring fetal heart rate tracing
●Preterm delivery, including very preterm delivery (before 32 weeks)
●Low birth weight (which was likely due to preterm delivery for preeclampsia in one study
[13] but not in a second study where the rate of preeclampsia was negligible [17])
●Increased rate of cesarean section
●Postpartum hemorrhage
●Perinatal morbidity and mortality
●Neuropsychological and cognitive impairment in the child

The risk of complications during pregnancy is lower in women with subclinical, rather than overt,
hypothyroidism. However, in some, but not all [26], studies, women with subclinical
hypothyroidism were also reported to be at increased risk for severe preeclampsia, preterm delivery,
placental abruption, and/or pregnancy loss compared with euthyroid women.

Diagnosis — The diagnosis of primary hypothyroidism during pregnancy is based upon the finding
of an elevated serum TSH concentration, defined using population and trimester-specific TSH
reference ranges for pregnant women [9]. For women with a TSH above the population and
trimester-specific upper limit of normal, or above 4.0 mU/L when local reference ranges are not
available, we also measure a free T4.
Overt hypothyroidism is defined as an elevated population and trimester-specific TSH
concentration in conjunction with a decreased free T4 concentration (below assay normal using
reference range for pregnant women). Subclinical hypothyroidism is defined as an elevated
population and trimester-specific serum TSH concentration and a normal free T4 concentration.
Women with central hypothyroidism from pituitary or hypothalamic disease will not have elevated
TSH concentrations during pregnancy.

Screening — Because overt and subclinical hypothyroidism are associated with pregnancy

complications, including pregnancy loss, and thyroid tests are widely available and easy to perform,
there is interest in screening for thyroid dysfunction in asymptomatic pregnant women. The
universal screening of asymptomatic pregnant women for thyroid dysfunction during the first
trimester of pregnancy is controversial, however, because of insufficient data showing a benefit of
thyroid hormone replacement. Thus, there is wide variation in screening practices.

Whom to screen — Because of insufficient evidence to support universal TSH screening in the

first trimester, we and others prefer a targeted approach to screening (ie, "case finding"). Pregnant
women with any of the following are candidates for screening:
●Living in an area of moderate to severe iodine insufficiency
●Symptoms of hypothyroidism
●Family or personal history of thyroid disease
●Personal history of:
•Thyroid peroxidase (TPO) antibodies
•Goiter
•Age >30 years
•Type 1 diabetes
•Head and neck irradiation
•Recurrent miscarriage or preterm delivery
•Multiple prior pregnancies (two or more)
•Morbid obesity (body mass index [BMI] ≥40 kg/m2)
•Infertility
•Prior thyroid surgery
•Use of amiodarone, lithium, or recent administration of iodinated radiologic contrast
agents

Approach to screening — In women who meet the case-finding criteria, we suggest measurement
of serum TSH during the first trimester as the screening test for hypothyroidism:
●If the serum TSH is between the trimester-specific lower limit of normal and 2.5 mU/L, most
women require no further testing.
However, in women at particularly high risk for developing hypothyroidism during pregnancy
(TPO antibody positive, post-radioiodine treatment, post-hemithyroidectomy, history of
childhood exposure to high-dose irradiation of the head or neck region), we reassess TSH
during pregnancy (eg, approximately every four weeks during the first trimester, and then
once during each of the second and third trimesters).
●If the serum TSH is >2.5 mU/L, we measure TPO antibodies.
The presence of TPO antibodies may be useful for making treatment decisions in women with
borderline thyroid function tests (eg, TSH 2.5 to 4.0 mU/L) and in predicting the development
of hypothyroidism and the risk of miscarriage and postpartum thyroid dysfunction.
●If the TSH is >4 mU/L, we suggest measurement of free T4 to determine the degree of
hypothyroidism.
Treatment — A good fetal and maternal outcome depends upon treating maternal hypothyroidism
with thyroid hormone (T4). The goal of treatment is to maintain the mother's serum TSH in the
population and trimester-specific reference range (approximately 0.1 to 4.0 mU/L if local reference
ranges are not available). Women with preexisting hypothyroidism who become pregnant need
more T4 during pregnancy. Dose requirements may increase by as much as 50 percent during
pregnancy, and the increase occurs as early as the fifth week of gestation.
 TSH >4 mU/L – All pregnant women with newly diagnosed, overt hypothyroidism (TSH
above trimester-specific normal reference range [or above 4.0 mU/L if trimester-specific
range unavailable] with low free T4) should be treated with thyroid hormone
(levothyroxine, T4).
Because maternal euthyroidism is potentially important for normal fetal cognitive
development, we and others [51] suggest treatment of pregnant women with subclinical
hypothyroidism (TSH above trimester-specific normal reference range [or above 4.0 mU/L if
trimester-specific range unavailable], with normal free T4), regardless of thyroid peroxidase
(TPO) antibody status (algorithm 1) (see 'Subclinical hypothyroidism' above). This approach
differs slightly from the ATA guidelines (reviewed at the end of this section), in which
treatment recommendations are based on TPO antibody status [4].
●TSH 2.6 to 4 mU/L – For pregnant women with a TSH between 2.6 and 4 mU/L, positive
TPO antibodies, and history of recurrent miscarriage, we suggest treatment with T4.
For pregnant women with TSH in this range and no prior history of miscarriage, we
individualize the decision to treat based upon the presence of TPO antibodies and patient
values and preferences. The data assessing treatment with T4 in this subgroup of women are
conflicting and limited by variability in the TSH criteria used to define hypothyroidism and
the late initiation of thyroid hormone treatment (often late in the first trimester).
Some UpToDate editors and the author of this topic review offer T4 treatment (50 mcg daily)
in TPO-positive women with TSH >2.5 mU/L. Others treat pregnant women with TPO
antibodies, regardless of the TSH level, while others do not routinely treat euthyroid, TPO-
positive women with T4, because of insufficient evidence of benefit.
In pregnant women with TSH between 2.6 and 4 mU/L who are not treated with thyroid
hormone, TSH should be reassessed during pregnancy (eg, approximately every four weeks
during the first trimester and once during each of the second and third trimesters for TPO-
positive women, and at least once more during the first trimester and again mid-pregnancy for
TPO-negative women). If TSH rises above the population and trimester-specific upper limit of
normal (approximately 4 mU/L), we begin treatment with T4.
●TSH between the trimester-specific lower limit of normal and 2.5 mU/L – These women
are euthyroid and do not require T4 treatment. However, if there is a prior history of recurrent
miscarriage, TPO antibodies have typically already been assessed, and thyroid hormone
treatment (T4, 50 mcg daily) offered to TPO antibody-positive patients (algorithm 1). The
management of women with TPO antibodies and normal thyroid function is reviewed
elsewhere.
●Low free T4, normal TSH (maternal hypothyroxinemia) – We do not typically treat
pregnant women with isolated hypothyroxinemia (low free T4, normal TSH).
The ATA guidelines base their treatment recommendations on TPO antibody status [4]. They
recommend measurement of TPO antibodies in pregnant women with TSH >2.5 mU/L and
treatment as follows:
●Positive TPO antibodies: Thyroid hormone should be considered if TSH is above
2.5 mU/L and should be initiated if TSH is above the population and trimester-specific upper
limit of normal (approximately 4.0 mU/L).
●Negative TPO antibodies: Thyroid hormone should be considered if the TSH is above
population and trimester-specific upper limit of normal but <10 mU/L and should be initiated
if the TSH is >10 mU/L.
 ●Maternal hypothyroxinemia: The ATA does not suggest treatment of pregnant women with
isolated hypothyroxinemia (low free T4, normal TSH).

Newly diagnosed hypothyroidism

Levothyroxine initial dosing — The treatment of choice for correction of hypothyroidism in

pregnancy is the same as in nonpregnant patients: synthetic levothyroxine (T4). Several
formulations of T4 are available. Because there may be subtle differences in bioavailability between
T4 formulations, some endocrinologists feel that it is preferable to stay with the same formulation
whenever possible. When using generic preparations, the manufacturer can be identified from the
prescription label, and the patient may request refills from the same generic pharmaceutical
company.

The goal of T4 replacement in pregnancy is to restore euthyroidism as soon as possible. General

dosing guidance is as follows:

●TSH >4 mU/L (or above population and trimester-specific upper limit of normal), with low
free T4 (using assay method and trimester-specific reference range): Close to full replacement
dose (approximately 1.6 mcg/kg body weight per day)
●TSH >4 mU/L, with normal free T4: Intermediate dose (approximately 1 mcg/kg per day)
●TSH 2.6 to 4 mU/L: If a decision has been made to treat, low dose (typically 50 mcg daily)

T4 should be taken on an empty stomach, ideally an hour before breakfast, but few patients are able
to wait a full hour.

Monitoring and dose adjustments — After initiation of T4 therapy, the patient should be

reevaluated and serum TSH measured in four weeks.

The goal is to maintain TSH in the lower half of the trimester-specific reference range. If not
available, a goal TSH of <2.5 mU/L is reasonable.

If the TSH remains above the normal trimester-specific reference range, the dose of T4 can be
increased by 12 to 25 mcg/day. TSH should be measured every four weeks during the first half of
pregnancy because dose adjustments are often required. TSH can be monitored less often (at least
once each trimester) in the latter half of pregnancy, as long as the dose is unchanged.

Postpregnancy adjustments — Since the criteria for treating pregnant women differ from the
criteria from treating nonpregnant women, it is not always necessary to continue levothyroxine after
delivery. In one study, 75 percent of women with subclinical hypothyroidism during pregnancy had
normal thyroid function five years postpartum [56]. Because overt hypothyroidism may interfere
with milk production, it may be prudent to delay assessment until the completion of breastfeeding.
Unless another pregnancy is imminent, however, the majority of women who were started on
levothyroxine for TSH between 2.5 and 4.0 mU/L do not need to continue levothyroxine treatment.

Preexisting hypothyroidism

Goal preconception TSH — Women with preexisting hypothyroidism who are planning to become
pregnant should optimize their thyroid hormone dose preconception. The goal preconception serum
TSH level is between the lower reference limit and 2.5 mU/L [4,51]. However, some experts prefer
a lower preconception TSH level (<1.2 mU/L).

Early dose adjustments — Given that T4 dose requirements may increase during pregnancy in
women with preexisting hypothyroidism, hypothyroid women who are newly pregnant
should preemptively increase their levothyroxine dose by approximately 30 percent and notify their
clinician promptly. We typically accomplish this by increasing the dose from once-daily dosing to a
total of nine doses per week (double the daily dose two days each week). Further dose changes are
made based upon serum TSH concentrations measured every four weeks until the TSH becomes
normal. 

Another approach is to measure serum TSH as soon as pregnancy is confirmed, then again four
weeks later, four weeks after any change in the dose of T4, and at least once each trimester [57].
The dose should be adjusted as needed every four weeks to achieve a normal TSH level.

Monitoring — The T4 dose should be reduced to prepregnancy levels after delivery, but serum
TSH should be measured four to six weeks later to confirm that the reduction was appropriate.

GOITER Goiter during pregnancy is common in regions where iodine intake is low,

occurring in 16 to 70 percent of women in iodine-deficient regions of Western Europe. Increased

urinary iodine excretion during pregnancy may further deplete thyroidal iodine stores by as much as
40 percent [42]. Plasma iodide concentrations may decrease during pregnancy due to increased
maternal renal clearance and fetal utilization of iodide [23]. Studies from Europe show that iodine
deficiency relative to the nonpregnant state leads to mild thyroid enlargement detectable
sonographically (mean increase in volume 18 percent), a change that is clinically detectable in some
women [1,43]. In areas of moderate iodine deficiency, thyroid volume in women correlates with the
number of previous pregnancies.

Goiter during pregnancy is rare in the United States (an iodine-sufficient region). In the United
States, any thyroid growth during pregnancy should be considered potentially abnormal, requiring
further investigation with thyroid function testing and possibly thyroid sonography.

POSTPARTUM THYROID DYSFUNCTION The prevalence of both painless thyroiditis

(postpartum thyroiditis) and Graves' disease is increased postpartum. In one Japanese study, 86
percent of patients developing thyrotoxicosis in the first three months had postpartum thyroiditis,
while after 6.5 months, all the patients had Graves' disease [68].

Postpartum thyroiditis — The reported prevalence of postpartum thyroiditis varies globally and

ranges from 1 to 17 percent [46,69,70]. Higher rates, up to 25 percent, have been reported in women
with type 1 diabetes mellitus [69], and the highest rates occur among women with a prior history of
postpartum thyroiditis (pooled prevalence 42 percent) and in women with positive antithyroid
peroxidase (TPO) antibodies who had normal thyroid function during pregnancy (40 to 60 percent
compared with 0 to 5 percent of women without antibodies).

Two patterns of postpartum dysfunction can be defined: postpartum thyroiditis and a postpartum
exacerbation of chronic lymphocytic (Hashimoto's) thyroiditis. Postpartum thyroiditis is
characterized by transient hyperthyroidism or transient hyperthyroidism followed by transient or,
not infrequently, permanent hypothyroidism. Postpartum exacerbation of Hashimoto's thyroiditis is
characterized by postpartum progression of autoimmune destruction. It may cause a transient or
permanent increase in thyroid hormone requirements. In one study, for example, more than 50
percent of women with Hashimoto's thyroiditis required an increase in their pregestational T4 dose
in the postpartum period [71].

The diagnosis and treatment of postpartum thyroiditis are reviewed in detail separately.

Graves' disease — Women may develop Graves' disease postpartum or experience an

exacerbation. In addition, women in remission after antithyroid drug therapy have a higher
incidence of relapse during the postpartum period than at times unrelated to pregnancy. 

SUMMARY AND RECOMMENDATIONS

 To meet the increased metabolic needs during a normal pregnancy, there are changes in
thyroid physiology that are reflected in altered thyroid function tests. The major changes in
thyroid function during pregnancy are an increase in serum thyroxine-binding globulin
(TBG) concentrations and stimulation of the thyrotropin (thyroid-stimulating hormone
[TSH]) receptor by human chorionic gonadotropin (hCG). Together, these changes lead to
an increase in both serum total thyroxine (T4) and triiodothyronine (T3) concentrations and
a reduction in serum TSH.
●Because of the changes in thyroid physiology during normal pregnancy, thyroid function
tests should, whenever possible, be interpreted using population and trimester-specific TSH
and T4 reference ranges for pregnant women. If the laboratory does not provide trimester-
specific reference ranges for TSH (mU/L), a TSH reference range of approximately 0.1 to
4 mU/L can be used. Total T4 and total T3 levels during pregnancy are 1.5-fold higher than in
nonpregnant women. Reference ranges for free T4 are assay method-specific, and trimester-
specific reference ranges should be provided with the assay kits.
●When evaluating thyroid tests during pregnancy, we typically measure TSH and free T4 (if
there is a trimester-specific reference range), and/or total T4. In such settings where free T4
measurements appear discordant with TSH measurements, total T4 should also be measured.
●Hyperthyroidism from any cause can complicate pregnancy, but Graves' hyperthyroidism is
the most common cause of overt hyperthyroidism. hCG-mediated hyperthyroidism is a
common cause of subclinical hyperthyroidism. It may occur transiently in the first half of
gestation and is typically less severe than Graves' disease.
●The diagnosis of hyperthyroidism during pregnancy should be based primarily upon a
suppressed (<0.1 mU/L) or undetectable (<0.01 mU/L) serum TSH value and also a serum
free T4 and/or free T3 (or total T4 and/or total T3) measurement that exceeds the normal
range during pregnancy.
●Treatment options for pregnant women with hyperthyroidism are reviewed in detail
separately.
●When iodine nutrition is adequate (as in the United States), the most common cause of
hypothyroidism during pregnancy is chronic autoimmune (Hashimoto's) thyroiditis. In iodine-
deficient areas, iodine deficiency itself is associated with hypothyroidism and goiter.
●The diagnosis of overt primary hypothyroidism during pregnancy is based upon the finding
of a decreased free T4 concentration (below assay normal using reference range for pregnant
women) and an elevated population and trimester-specific serum TSH. Subclinical
hypothyroidism is defined as an elevated population and trimester-specific serum TSH
concentration with a normal free T4 concentration.
●The treatment of newly diagnosed and preexisting hypothyroidism is reviewed in detail
elsewhere.
●An increased rate of fetal loss and premature delivery has been reported in euthyroid women
with high serum antithyroid peroxidase (TPO) antibody concentrations. Although data are
conflicting, levothyroxine (T4) treatment of TPO antibody-positive pregnant patients may
lower these risks. We suggest thyroid hormone treatment (T4, 50 mcg daily) in euthyroid,
TPO-positive women who have had recurrent miscarriage (Grade 2C). We do not routinely
suggest T4 treatment for TPO-positive, euthyroid women without a prior history of
miscarriage whose TSH is in the normal population-based and trimester-specific range.
However, since carefully monitored thyroid hormone treatment is safe, some UpToDate
editors and the author of this topic review will offer T4 treatment (50 mcg daily) to those
patients who prefer this intervention, especially if their TSH is >2.5 mU/L. However, other
experts, including other UpToDate editors, do not routinely treat euthyroid, TPO-positive
women with T4, because of insufficient evidence of benefit.
●Euthyroid women with high serum TPO antibody concentrations are at risk for developing
hypothyroidism. In antibody-positive, euthyroid pregnant women who are not treated with
thyroid hormone, TSH should be measured every four weeks during the first trimester and, if
stable, once during the second and third trimesters to monitor for the development of
hypothyroidism.
●Goiter during pregnancy is rare in the United States. However, goiter during pregnancy is
common in regions where iodine intake is low, occurring in 16 to 70 percent of women in
iodine-deficient regions of Western Europe.
●A pregnant woman found to have a thyroid nodule should be evaluated in the same way as if
she were not pregnant, except that thyroid radionuclide scanning is contraindicated.
●Given the typically indolent nature of differentiated thyroid cancer, most women with newly
diagnosed differentiated thyroid cancer can delay thyroidectomy until the postpartum period to
minimize maternal and fetal complications. Surgery during pregnancy is sometimes indicated
for rare patients with larger, more aggressive or rapidly growing cancers or in the presence of
extensive nodal or distant metastasis. The safest time for any type of surgery during pregnancy
is the second trimester.
●When surgery for thyroid cancer is deferred, the patient should be monitored during
pregnancy with thyroid ultrasound performed during each trimester. In such cases where
thyroid surgery is deferred, we suggest thyroid hormone suppressive therapy (Grade 2C). The
goal is to maintain the TSH in the range of 0.3 to 2.0 mU/L.
●Postpartum thyroiditis occurs in 5 to 10 percent of women in the United States. It may occur
after pregnancy loss (miscarriage, abortion, ectopic pregnancy), as well as after normal
delivery.