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Overview of thyroid disease in pregnancy
Author
Douglas S Ross, MD
Section Editors
David S Cooper, MD
Charles J Lockwood, MD
Deputy Editor
Jean E Mulder, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Aug 2013. | This topic last updated: Oct 03, 2012.

INTRODUCTION — The evaluation and treatment of pregnant women with thyroid disease parallel that of nonpregnant women and men, but present some unique problems. An overview of thyroid physiology and disease during pregnancy is presented here. Some of the disorders reviewed below are discussed separately in individual topic reviews. (See "Hypothyroidism during pregnancy: Clinical manifestations, diagnosis, and treatment" and "Hyperthyroidism during pregnancy: Clinical manifestations, diagnosis, and causes" and "Hyperthyroidism during pregnancy: Treatment".)

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) concentrations and stimulation of the thyrotropin (TSH) receptor by human chorionic gonadotropin (hCG).

Thyroxine binding globulin — During pregnancy, serum TBG concentrations rise almost two-fold 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. Total T4 and T3 concentrations rise 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. Thus, TBG excess leads to an increase in both serum total thyroxine (T4) and triiodothyronine (T3) concentrations. (See "Euthyroid hyperthyroxinemia and hypothyroxinemia".)

hCG and thyroid function — Human chorionic gonadotropin (hCG) is one of a family of glycoprotein hormones, including thyrotropin (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 IU/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 IU/L had a suppressed TSH concentration [8]. (See "Hyperthyroidism during pregnancy: Clinical manifestations, diagnosis, and causes", section on 'hCG-mediated hyperthyroidism'.)

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 Postpartum recommend using trimester-specific reference ranges for TSH and method and trimester-specific reference ranges for serum free T4 [9]. Commercial laboratories should provide these reference ranges, but many commercial laboratories currently do not do this.

In several population studies, the lower limit of the reference range for TSH in healthy pregnant women during the first trimester ranged from 0.03 to 0.1 mU/L [10-14]. In one of the largest population-based studies (over 13,000 pregnant women), the reference range (2.5 to 97.5th percentile) for TSH in the first trimester was 0.08 to 2.99 mU/L [10,13]. Thus, if the laboratory does not provide trimester-specific reference ranges for TSH (mU/L), the following reference ranges can be used:

First trimester 0.1 to 2.5
Second trimester 0.2 to 3.0
Third trimester 0.3 to 3.0

Some studies report a decrease in free T4 during pregnancy, others report no change or even an increase [1,15,16]. Direct free T4 measurements may be unreliable during pregnancy. Measurement of free T4 in the dialysate or ultrafiltrate of serum samples using liquid chromatography/tandem mass spectrometry appears to be the most reliable, and when this method is used, free T4 concentrations were shown to decrease gradually with advancing gestational age, particularly between the first and second trimester [17,18]. This assay is relatively expensive and not universally available. Other free T4 assays (and probably free T3 assays) frequently fail to meet performance standards in pregnant patients, owing to increases in TBG and decreases in albumin concentrations that cause the immunoassay to be unreliable [15]. To compensate, some kits have provided different free T4 normal ranges for pregnant patients, usually lower than those of nonpregnant patients. Method-specific and trimester-specific reference ranges of serum free T4 should be used, if available [9]. (See "Laboratory assessment of thyroid function", section on 'Serum free T4 and free T3'.)

As an alternative, serum total T4 measurements, which are more reliable during pregnancy, can be measured to assess thyroid function [15]. When free T4 measurements appear discordant with TSH measurements, serum total T4 should be measured. Total T4 and T3 levels during pregnancy are 1.5-fold higher than in nonpregnant women due to TBG excess. Thus a normal reference range for pregnancy should be used.

Iodine requirements — Iodine requirements are higher in pregnant than in nonpregnant women due to the increase in maternal T4 production required to maintain maternal euthyroidism and increased renal iodine clearance. Severe maternal iodine deficiency during pregnancy results in a reduction in maternal thyroxine production, inadequate placental transfer of maternal thyroxine, 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 Institute of Medicine recommends daily iodine intake of 220 mcg during pregnancy and 290 mcg during lactation. For women in the US to achieve this level of daily intake, the ATA recommends that women from the US receive a supplement of 150 mcg of iodine daily during pregnancy and lactation, which is the dose included in the majority of prenatal vitamins marketed in the US [19]. (See "Nutrition in pregnancy".) The tolerable upper intake amount for iodine, as established by European and US expert committees, ranges from 600 to 1100 mcg daily for adults and pregnant women >19 years of age.

Iodine requirements and the consequences of inadequate and excess intake are reviewed in detail elsewhere. (See "Iodine deficiency disorders", section on 'Iodine requirements' and "Iodine deficiency disorders", section on 'Pregnancy and lactation' and "Iodine deficiency disorders", section on 'Adverse effects' and "Iodine-induced thyroid dysfunction", section on 'Iodine-induced thyroid disease'.)

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 18th to 20th week. Thereafter, fetal thyroid secretion increases gradually [20].

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. In infants with congenital absence of the thyroid, cord serum concentrations range from 20 to 50 percent of the concentrations in normal infants [21]. TSH-receptor antibodies can cross the placenta and cause either fetal hyperthyroidism or hypothyroidism. (See 'Fetal and neonatal Graves' disease' below.) Little TSH crosses the placenta [22]. Thyrotropin-releasing hormone (TRH) can cross the placenta and exogenously administered TRH can stimulate fetal TSH secretion [23].

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 [24]. Although hyperthyroidism from any cause can complicate pregnancy, Graves' and 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 may occur transiently in the first half of gestation and is typically less severe than Graves’ disease. (See "Hyperthyroidism during pregnancy: Clinical manifestations, diagnosis, and causes", section on 'Establishing the cause'.)

Pregnancy complications — Pregnancy complicated by poorly controlled overt hyperthyroidism (most often due to Graves’ disease) is associated with increased rates of the following [25,26]:

Spontaneous abortion
Premature labor
Low birth weight
Stillbirth
Preeclampsia
Heart failure

Very rare cases of thyroid storm precipitated by labor, infection, preeclampsia, or cesarean section have been reported.

In contrast to these findings, subclinical hyperthyroidism (low TSH with normal free T4) has not been associated with adverse pregnancy outcomes [27]. (See "Subclinical hyperthyroidism".)

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) serum TSH value and elevated thyroid hormone levels that exceed the normal range for pregnancy [9]. If a TSH level is <0.1 mU/L, free T4 (or free T4 index) should be obtained. If the free T4 is in the normal range for pregnancy, a free T3 should also be measured. In the event that free thyroid hormone levels are discordant with serum TSH and clinical findings, total T4 should be measured.

TSH in healthy pregnant women during the first trimester may be as low as 0.03 to 0.1 mU/L [10-14]. 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. (See "Hyperthyroidism during pregnancy: Clinical manifestations, diagnosis, and causes" and "Hyperthyroidism during pregnancy: Clinical manifestations, diagnosis, and causes", section on 'Diagnosis'.)

Because radioiodine administration is contraindicated, it may not be possible to ascertain the cause of the hyperthyroidism during pregnancy. Measurement of thyrotropin receptor antibody (TRAb or thyroid stimulating immunoglobulins) using second-generation thyrotropin-binding inhibitory immunoglobulin (TBII) assays are positive in 95 percent of patients with Graves' disease and should be used to make the diagnosis of Graves' disease during pregnancy if the clinical diagnosis is uncertain. (See "Hyperthyroidism during pregnancy: Clinical manifestations, diagnosis, and causes", section on 'Diagnosis'.)

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. The goal of treatment is to reduce and maintain the mother's serum free T4 concentration in the high normal range for nonpregnant women using the lowest drug dose [9]. This requires assessment of free T4 (and/or total T4) frequently (ie, at four-week intervals) with appropriate adjustment of medication. Treatment recommendations are reviewed in detail separately. (See "Hyperthyroidism during pregnancy: Treatment".)

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 [28].

This topic is reviewed in detail separately. (See "Evaluation and management of neonatal Graves' disease" and "Hyperthyroidism during pregnancy: Treatment", section on 'Fetal hyperthyroidism'.)

HYPOTHYROIDISM DURING PREGNANCY — When iodine nutrition is adequate (as in the US), 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 of the thyroid or disorders of the pituitary or hypothalamus, can also occur in pregnant women. (See "Disorders that cause hypothyroidism".)

Pregnancy complications — Hypothyroidism can have adverse effects on the mother and child, depending upon the severity of the biochemical abnormalities. This topic is reviewed briefly below and in detail elsewhere. (See "Hypothyroidism during pregnancy: Clinical manifestations, diagnosis, and treatment", section on 'Clinical features'.)

Overt hypothyroidism (elevated TSH, reduced free T4) complicating pregnancy is unusual (0.3 to 0.5 percent of screened women), owing to a reduced fertility rate in hypothyroid women and a high rate of first trimester spontaneous abortion [29-31].

In continuing pregnancies, overt hypothyroidism has been associated with an increased risk of several complications, including [32-38]:

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 [36], but not in a second study where the rate of preeclampsia was negligible) [39]
Increased rate of cesarean section [39]
Perinatal morbidity and mortality
Neuropsychological and cognitive impairment
Postpartum hemorrhage

Subclinical hypothyroidism (elevated TSH, normal free T4) is far more common than overt hypothyroidism, occurring in 2 to 2.5 percent of screened women in the US (iodine sufficient region) [40,41]. The risk of pregnancy complications is lower in women with subclinical rather than overt hypothyroidism. However, in some studies, women with subclinical hypothyroidism were also at increased risk for preterm delivery and/or pregnancy loss. It is uncertain if the children of women with subclinical hypothyroidism are at risk for neuropsychological impairment.

Isolated hypothyroxinemia (low T4) is defined as a maternal free T4 concentration in the lower 5th or 10th percentile of the reference range, in conjunction with a normal TSH. The effect of isolated maternal hypothyroxinemia on perinatal and neonatal outcome is also unclear.

Diagnosis — The diagnosis of primary hypothyroidism during pregnancy is based upon the finding of an elevated serum TSH concentration, defined using trimester-specific TSH reference ranges for pregnant women [9]. For women in the first trimester of pregnancy with a TSH above 2.5 mU/L (above 3 mU/L in the second and third trimester), we also measure a free T4. Overt hypothyroidism is defined as an elevated 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 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. (See "Central hypothyroidism", section on 'Diagnosis'.)

Screening — The universal screening of asymptomatic pregnant women for hypothyroidism during the first trimester of pregnancy is controversial. This topic is reviewed briefly below and in detail elsewhere. (See "Hypothyroidism during pregnancy: Clinical manifestations, diagnosis, and treatment", section on 'Screening'.)

Because of insufficient evidence to support universal TSH screening in the first trimester, most professional societies, including the ATA, the Endocrine Society, and the American College of Obstetricians and Gynecologists (ACOG) recommend targeted case finding rather than universal screening [9,42-44]. The ATA recommends measurement of serum TSH in pregnant women if they are symptomatic, from an area of known moderate to severe iodine insufficiency, or have a family or personal history of thyroid disease, thyroid peroxidase antibodies (TPOAb), type 1 diabetes, history of preterm delivery or miscarriage, history of head or neck radiation, morbid obesity (BMI ≥40 kg/m2), infertility, or age >30 years [9].

However, this approach may miss up to one-third of women with hypothyroidism and preliminary data suggest that universal screening is cost-effective if one assumes that treatment improves the offspring IQ. Therefore, some endocrinologists have argued for universal screening for thyroid dysfunction in pregnant women or those planning to become pregnant in the near future [45].

We suggest a targeted approach to screening. We favor screening pregnant women if they are from an area of moderate to severe iodine insufficiency, have symptoms of hypothyroidism, a family or personal history of thyroid disease, or a personal history of thyroid peroxidase antibodies, type 1 diabetes, head and neck radiation, recurrent miscarriage, morbid obesity, or infertility. In women who meet the screening criteria, we measure serum TSH during the first trimester. If the serum TSH is normal, no further testing is performed. If the TSH is >2.5 mU/L, free T4 should be measured to determine the degree of hypothyroidism.

Treatment — A good fetal and maternal outcome depends upon treating maternal hypothyroidism with thyroid hormone (thyroxine, T4). The goal of treatment is to maintain the mother's serum TSH in the trimester-specific reference range (0.1 to 2.5 mU/L, 0.2 to 3 mU/L, and 0.3 to 3 mU/L for the first, second, and third trimesters, respectively). 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. The treatment of newly diagnosed and preexisting hypothyroidism is reviewed in detail elsewhere. (See "Hypothyroidism during pregnancy: Clinical manifestations, diagnosis, and treatment", section on 'Treatment'.)

Congenital hypothyroidism — Most cases of congenital hypothyroidism are due to agenesis or dysgenesis of the fetal thyroid, congenital dyshormonogenesis, or iodine deficiency in endemic areas. This topic is reviewed in detail separately. (See "Clinical features and detection of congenital hypothyroidism" and "Treatment and prognosis of congenital hypothyroidism", section on 'Maternal hypothyroidism'.)

THYROID PEROXIDASE ANTIBODIES — An increased risk of fetal loss, perinatal mortality, and large-for-gestational-age infants has been reported in euthyroid women with high serum antithyroid peroxidase antibody (TPO antibodies) concentrations [46-48]. In meta-analyses of case-control and cohort studies, the presence of thyroid autoantibodies in euthyroid women is associated with an increased risk of spontaneous miscarriage that is two to three times higher than in women without antibodies [49,50]. In addition, the risk of preterm birth is approximately doubled [50].

In some women, treatment with T4 may improve miscarriage rates. As an example, in a prospective study of 115 TPO antibody positive patients, half were randomly assigned to T4 (median dose 50 mcg daily) and half were not treated, and comparison was made with 869 TPO antibody negative patients. Miscarriage rates were 3.5 percent in TPO antibody positive treated patients, 2.4 percent in the TPO antibody negative patients, and 13.8 percent in TPO antibody positive untreated patients. Premature delivery rates were 7 percent, 8.2 percent, and 22.4 percent, respectively [51]. (See "Management of couples with recurrent pregnancy loss", section on 'Thyroid dysfunction and diabetes mellitus'.)

In the same study, some euthyroid women with TPO antibodies developed subclinical hypothyroidism. In early pregnancy, the TPO positive women had significantly higher serum TSH levels than TPO negative women, although the level was in the normal range. Approximately 20 percent of TPO positive women subsequently developed subclinical hypothyroidism by term if left untreated.

Euthyroid women with positive TPO antibodies undergoing in vitro fertilization (IVF) also have higher miscarriage rates. In a meta-analysis of four observational studies (1098 women undergoing IVF), the risk of miscarriage was two-fold higher in euthyroid women with than without positive TPO antibodies (RR 1.99, 95% CI 1.42-2.78) [52]. In a randomized trial of T4 versus placebo in 72 euthyroid subfertile women with positive TPO antibodies undergoing assisted reproductive technologies (ART), however, thyroid hormone therapy did not lower the risk of early pregnancy loss [53]. However, these results are confounded by the presence of additional infertility factors in women undergoing ART.

It is unclear if the presence of TPO antibodies in euthyroid pregnant women affects the cognitive or behavioral development of their children. In a population-based cohort study from the Netherlands, 4770 pregnant women had blood collected at 13.5 weeks of gestation and cord blood was obtained immediately after birth in 2121 of the neonates [54]. All samples were analyzed immediately post delivery for TSH, free T4, and thyroid peroxidase antibodies. TPO antibodies were elevated in 4.7 percent. TSH levels were higher in TPO positive than negative women (3.8 versus 1.5 mU/L), but TSH levels in the cord blood did not differ between positive and negative women. Elevated titers of TPO antibodies during pregnancy did not predict the verbal and nonverbal cognitive function of the children when tested at 2.5 years. However, children of euthyroid mothers with positive TPO antibodies were at higher risk of attention deficit/hyperactivity problems (OR 1.77, 95% CI 1.15-2.72). When the analysis was adjusted for maternal TSH level, the association was attenuated but remained significant (OR 1.56).

The decision to treat euthyroid women with elevated TPO antibodies with levothyroxine (T4) or to monitor for the development of hypothyroidism during pregnancy is controversial. Most pregnant women are unlikely to know their antithyroid antibody status because universal screening is not routinely done. The ATA found there was insufficient evidence to recommend for or against thyroxine therapy in euthyroid antibody positive pregnant women; however, monitoring for the development of hypothyroidism was recommended [9].

Since carefully monitored thyroid hormone treatment is safe, some experts, including some UpToDate editors and the author of this topic review, suggest levothyroxine treatment (T4, 50 mcg daily) in TPO positive euthyroid women who have had recurrent miscarriage, until additional data become available. However, other experts, including other UpToDate editors, do not routinely treat euthyroid TPO positive women with T4 because of insufficient evidence of benefit. (See "Evaluation of couples with recurrent pregnancy loss".)

In antibody positive euthyroid pregnant women who are not treated with thyroid hormone, TSH should be measured every four weeks during the first half of pregnancy and at least once during the last trimester to monitor for the development of hypothyroidism. Thyroid hormone should be initiated if TSH rises above the trimester-specific reference range (2.5 mU/L for first, and 3.0 mU/L for second and third trimesters).

GOITER — Increased urinary iodine excretion during pregnancy may deplete thyroidal iodine stores by as much as 40 percent [55]. Plasma iodide concentrations may decrease during pregnancy due to increased maternal renal clearance and fetal uptake of iodide [20]. 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. Studies from Europe show that iodine depletion relative to the nonpregnant states leads to mild thyroid enlargement detectable sonographically (mean increase in volume: 18 percent), a change that is clinically detectable in some women [1,56]. In areas of moderate iodine deficiency, thyroid volume in women correlates with the number of previous pregnancies [57]. (See 'Iodine requirements' above.)

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 [58].

THYROID NODULES — In areas of mild to moderate iodine deficiency, the prevalence of thyroid nodules during pregnancy varies between 3 and 21 percent [59-61]. In retrospective studies, the frequency of thyroid cancer in pregnant women with thyroid nodules ranges from 12 to 43 percent [62-65]. In one prospective study, there were no malignancies among the 15 percent of women with newly detected thyroid nodules (detected via ultrasonography) [59]. The wide range of thyroid cancer prevalence is likely due to differences in patient population and study design.

A pregnant woman found to have a thyroid nodule should be evaluated in the same way as if she were not pregnant. Thyroid function tests (TSH and free T4) and ultrasound should be performed. Thyroid radionuclide scanning is contraindicated during pregnancy. The indications for fine needle aspiration biopsy of the nodule are the same as in nonpregnant patients [9,44,62]. FNA is safe to perform during pregnancy. (See "Diagnostic approach to and treatment of thyroid nodules", section on 'Evaluation'.)

Subsequent management varies according to the biopsy results. (See "Diagnostic approach to and treatment of thyroid nodules", section on 'Management' and "Atlas of thyroid cytopathology".)

Rarely, benign nodules require surgery during the second trimester due to rapid growth and/or the development of compressive symptoms. When fine needle aspiration cytology shows follicular neoplasm or follicular lesion of undetermined significance, patients are frequently followed and further evaluation (thyroid scan, surgery) is delayed until after delivery, as 80 to 95 percent of these nodules are benign. Rarely, second trimester surgery is indicated due to rapid growth or the emergence of lymphadenopathy associated with a suspicious indeterminate nodule.

THYROID CANCER

Diagnosed during pregnancy — In most observational studies, thyroid cancer discovered during pregnancy does not significantly impact the prognosis [66-70]. As an example, a California cancer registry identified 129 antepartum and 466 postpartum thyroid cancers and found no difference in overall prognosis compared to women with thyroid cancer not associated with pregnancy [67].

Women with differentiated thyroid cancer require surgery. However, given the typically indolent nature of thyroid cancer, thyroidectomy is usually delayed until the postpartum period to minimize maternal and fetal complications [66,71]. This approach does not appear to have a negative impact on prognosis, as illustrated by the results of a retrospective study of 61 pregnant women with thyroid cancer of whom 77 percent delayed surgery until after delivery [66]. There was no difference in the outcome after 20 years (recurrence or distant metastases) as compared with those women having surgery in the second trimester or nonpregnant women.

When surgery for thyroid cancer is deferred, the patient should be monitored during pregnancy with thyroid ultrasound performed during each trimester. If by 24 weeks there is a significant increase in thyroid cancer size (50 percent in volume and 20 percent in diameter in two dimensions), surgery should be performed during the second trimester [9,72]. However, if the size remains stable or if it is diagnosed in the second half of pregnancy, surgery may be performed after delivery. In such cases where thyroid surgery is deferred, we suggest thyroid hormone suppressive therapy with a goal of maintaining the TSH in the range of 0.1 to 1.5 mU/L.

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 [9,62,73]. However, in one retrospective study of 201 pregnant women undergoing thyroid or parathyroid surgery (92 women underwent thyroidectomy for thyroid cancer), pregnant women had significantly higher rates of surgical complications (11 versus 4 percent) and endocrine-specific complications (16 versus 8 percent) than nonpregnant women [74]. Endocrine-specific complications were defined as maternal hypoparathyroidism, hypocalcemia, or recurrent laryngeal nerve injury. In this study, 50 of the 201 procedures were considered to be emergent/urgent [74]. Higher surgeon volume was a predictor of lower complication rates. Thus, when surgery is required during the second trimester, it should be performed only by expert thyroid surgeons. The risks of nonobstetric surgery during pregnancy are discussed in detail separately. (See "Management of pregnant women undergoing nonobstetric surgery".)

Previously treated — In women previously treated with radioiodine for thyroid cancer, pregnancy should be delayed for at least six months to ensure that thyroid hormone levels have normalized and that additional radiation treatment is not required. (See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Future pregnancy'.)

For women without ultrasound or biochemical (thyroglobulin) evidence of persistent disease, pregnancy itself has not been shown to increase the risk of recurrence [75-77]. However, in women with persistent disease (structural or biochemical), disease progression may occur during pregnancy [75,77]. In women who have persistently elevated thyroglobulin levels or evidence of persistent disease on ultrasound prior to pregnancy, periodic ultrasound and thyroglobulin (once each trimester) monitoring is recommended [9].

During pregnancy, thyroid hormone suppression therapy should continue, and preconception TSH goals should remain the same. To maintain the same degree of TSH suppression, most women will require an increase in dose. Thus, TSH should be measured as soon as pregnancy is confirmed and every four weeks until 16 to 20 weeks of gestation, and then at least once between 26 and 32 weeks of gestation [9]. The dose of thyroxine should be increased to maintain TSH in the desired range. (See "Overview of the management of differentiated thyroid cancer", section on 'Thyroid hormone suppression'.)

POSTPARTUM THYROID DYSFUNCTION

Postpartum thyroiditis — The reported prevalence of postpartum thyroiditis varies globally and ranges from 1 to 17 percent [44,78,79]. Higher rates, up to 25 percent, have been reported in women with type 1 diabetes mellitus [78], 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 antibodies who had normal thyroid function during pregnancy (40 to 60 percent compared with 0 to 5 percent of women without antibodies) [78]. It may occur after pregnancy loss (miscarriage, abortion, ectopic pregnancy), as well as after normal delivery. Postpartum thyroid dysfunction can occur in women already taking thyroid hormone replacement for hypothyroidism antedating pregnancy (eg, goitrous Hashimoto's thyroiditis), if they have some remaining thyroid tissue capable of producing thyroid hormone [80].

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 rarely 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 dose thyroxine dose in the postpartum period [81].

The diagnosis and treatment of postpartum thyroiditis are reviewed in detail separately. (See "Postpartum thyroiditis".)

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. (See "Hyperthyroidism during pregnancy: Treatment", section on 'Postpartum issues'.)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

Basics topics (see "Patient information: Hyperthyroidism (overactive thyroid) (The Basics)" and "Patient information: Hypothyroidism (underactive thyroid) (The Basics)" and "Patient information: Thyroiditis after pregnancy (The Basics)" and "Patient information: Hyperthyroidism (overactive thyroid) and pregnancy (The Basics)")
Beyond the Basics topics (see "Patient information: Hyperthyroidism (overactive thyroid) (Beyond the Basics)" and "Patient information: Hypothyroidism (underactive thyroid) (Beyond the Basics)" and "Patient information: Antithyroid drugs (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS — The following recommendations are largely consistent with Guidelines on the Management of Thyroid Disease During Pregnancy and Postpartum from the American Thyroid Association (ATA) and Endocrine Society [9,44].

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. The major changes in thyroid function during pregnancy are an increase in serum thyroxine-binding globulin (TBG) concentrations and stimulation of the thyrotropin (TSH) receptor by 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. Serum free T4 and T3 concentrations initially increase slightly, usually within the normal range. With advancing gestational age, particularly between the first and second trimester, free T4 concentrations decrease gradually. (See 'Thyroid adaptation during normal pregnancy' above.)
Because of the changes in thyroid physiology during normal pregnancy, thyroid function tests should be interpreted using trimester-specific TSH and T4 reference ranges for pregnant women. If the laboratory does not provide trimester-specific reference ranges for TSH (mU/L), the following reference ranges can be used for the first, second, and third trimester, respectively: 0.1 to 2.5, 0.2 to 3.0, and 0.3 to 3.0 mU/L. Total T4 and total T3 levels during pregnancy are 1.5-fold higher than in nonpregnant women. Reference ranges for free T4 are method-specific, and trimester-specific reference ranges should be provided with the assay kits. (See 'Trimester-specific reference ranges' above.)

Hyperthyroidism

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. (See 'Hyperthyroidism complicating pregnancy' above and "Hyperthyroidism during pregnancy: Clinical manifestations, diagnosis, and causes", section on 'Establishing the cause'.)
The diagnosis of hyperthyroidism during pregnancy should be based primarily upon a suppressed (<0.1 mU/L) or undetectable (<0.01) 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. (See 'Diagnosis' above.)
Treatment options for pregnant women with hyperthyroidism are reviewed in detail separately. (See "Hyperthyroidism during pregnancy: Treatment".)

Hypothyroidism

When iodine nutrition is adequate (as in the US), 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. (See 'Hypothyroidism during pregnancy' above and "Hypothyroidism during pregnancy: Clinical manifestations, diagnosis, and treatment".)
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 trimester-specific serum TSH. Subclinical hypothyroidism is defined as an elevated trimester-specific serum TSH concentration with a normal free T4 concentration. (See 'Diagnosis' above and "Hypothyroidism during pregnancy: Clinical manifestations, diagnosis, and treatment", section on 'Diagnosis'.)
The universal screening of asymptomatic pregnant women for hypothyroidism during the first trimester of pregnancy is controversial. We suggest a targeted approach rather than universal screening (Grade 2C). We favor screening pregnant women if they are from an area of moderate to severe iodine insufficiency, have symptoms of hypothyroidism, a family or personal history of thyroid disease, or a personal history of thyroid peroxidase antibodies, type 1 diabetes, morbid obesity, head and neck radiation, recurrent miscarriage, or infertility. In women who meet the screening criteria, we measure serum TSH during the first trimester. (See 'Screening' above and "Hypothyroidism during pregnancy: Clinical manifestations, diagnosis, and treatment", section on 'Screening'.)
The treatment of newly diagnosed and preexisting hypothyroidism is reviewed in detail elsewhere. (See "Hypothyroidism during pregnancy: Clinical manifestations, diagnosis, and treatment", section on 'Treatment'.)

Thyroid peroxidase antibodies

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 treatment of TPO antibody positive pregnant patients may lower these risks. Since carefully monitored thyroid hormone treatment is safe, until additional data become available, we suggest thyroid hormone treatment (T4, 50 mcg daily) in euthyroid TPO positive women who have had recurrent miscarriage (Grade 2C). However, other experts, including other UpToDate editors, do not routinely treat euthyroid TPO positive women with T4 because of insufficient evidence of benefit. (See 'Thyroid peroxidase antibodies' above.)
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 half of pregnancy and at least once during the last trimester. Thyroid hormone should be initiated if TSH rises above the trimester-specific reference range (2.5 mU/L for first, and 3.0 mU/L for second and third trimesters). (See 'Thyroid peroxidase antibodies' above.)

Goiter and thyroid nodules

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. (See 'Goiter' above.)
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. (See 'Thyroid nodules' above and 'Thyroid cancer' above.)

Thyroiditis

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. (See "Postpartum thyroiditis".)

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