Management of Thyrotoxicosis

Preconception, Pregnancy, and the Postpartum Period

Elizabeth N. Pearce, MD, MSc, FACE


Endocr Pract. 2019;25(1):62-68. 

In This Article

Abstract and Introduction


Objective: To review the diagnosis and management of thyrotoxicosis in women who are preconception, pregnant, and in the postpartum period.

Methods: Literature review of English-language papers published between 1980 and 2018.

Results: Overt thyrotoxicosis occurs in 0.2% of pregnancies and subclinical thyrotoxicosis in 2.5%. Hyperthyroidism in women of childbearing age most frequently is caused by Graves disease (GD). Gestational thyrotoxicosis, transient human chorionic gonadotropin (hCG)-mediated hyperthyroidism, may develop in the first trimester. In the first year following delivery, postpartum thyroiditis, which frequently includes a thyrotoxic phase, occurs in 5% of women. Hyperthyroidism from nodular autonomy is uncommon in women of childbearing age. It is essential to understand the underlying etiology for thyrotoxicosis in order to recommend appropriate treatment. Gestational thyrotoxicosis requires supportive care, without antithyroid drug therapy. GD may be treated with antithyroid drugs, radioactive iodine, or thyroidectomy. Pregnancy, plans for pregnancy, and lactation have important implications for the choice of GD treatment. When thyrotoxicosis presents following delivery, postpartum thyroiditis must be differentiated from GD.

Conclusion: The diagnosis and management of thyrotoxicosis in the peripregnancy period present specific challenges. In making management decisions, it is essential to weigh the risks and benefits of treatments not just for the mother but also for the fetus and for breastfed infants. A team approach to management is critical, with close collaboration among endocrinologists, maternal-fetal medicine specialists, and neonatologists.


Thyrotoxicosis is relatively common among pregnant women and women of childbearing age. Overt persistent hyperthyroidism in women of childbearing age most frequently is caused by Graves disease (GD), which affects 0.4 to 1.0% of women in the preconception period and about 0.2% of women during pregnancy.[1,2] The incidence of gestational thyrotoxicosis, transient human chorionic gonadotropin (hCG)-mediated hyperthyroidism, in the first trimester of pregnancy has been variably estimated at between 1 and 11%, and may be highest in Asian populations.[3,4] Toxic nodular goiter can occasionally occur, but accounts for fewer than 5% of cases of hyperthyroidism during gestation.[5] In the first year following delivery, postpartum thyroiditis, which frequently includes a thyrotoxic phase, occurs in 5% of women.[6] Other causes of thyrotoxicosis in women of childbearing age are less frequent (Table 1). It is essential to understand the underlying etiology for thyrotoxicosis in order to recommend appropriate treatment. The diagnosis and management of thyrotoxicosis in the peripregnancy period present specific challenges. In making management decisions it is essential to weigh the risks and benefits of treatments not just for the mother but also for the fetus and breastfed infant.

Assessment of Thyroid Function in Pregnancy

Thyroid function tests in pregnant women must be interpreted in light of the gestational stage, and in many cases the nonpregnancy laboratory reference ranges do not apply. One important driver of thyroid function alterations in early pregnancy is hCG, which acts as a weak stimulator of the thyroid-stimulating hormone (TSH) receptor. Under this stimulation, serum free thyroxine (T4) levels rise, with a concomitant fall in serum TSH values.[7] Typically in the first trimester there is a downward shift of about 0.4 mIU/L in the lower reference limit for TSH compared to the nonpregnancy reference range.[8] Between weeks 7 and 11 of gestation, when hCG levels are highest, serum TSH values <0.1 mIU/L occur in about 5% of women, with levels being completely suppressed in 0.5 to 1%.[9] High levels of estrogen in pregnant women cause a rise in thyroxine-binding globulin (TBG) levels and thus an increase in serum total triiodothyronine (T3) and T4 levels. The serum TBG levels rise from week 7 to 16 and then plateau, so that gestational upper limits for both total T4 and T3 can be calculated by increasing the nonpregnancy upper reference limit by 5% per week from weeks 7 to 16.[10] The high circulating TBG levels in pregnancy tend to confound the measurement of free T4 by indirect analogue immunoassays.[11] Where possible trimester-specific, assay-specific reference ranges for free T4, developed in a similar population, should be employed. Alternatives are using the free T4 index, which may be more reliable than indirect free T4 analogue immunoassays in pregnancy,[11] or using the total T4 level as a surrogate.

Adverse Obstetric/Fetal Effects of Hyperthyroidism in Pregnancy

Untreated or inadequately treated overt hyperthyroidism in pregnancy can have devastating consequences for both mother and fetus. These adverse effects of moderate to severe hyperthyroidism include pregnancy-induced hypertension, pregnancy loss, low birth weight, intra-uterine growth restriction, premature delivery, stillbirth, maternal congestive heart failure, and thyroid storm.[5,12–15] High TSH receptor antibody (TRAb) titers increase the risk for fetal or neonatal hyperthyroidism, as discussed below. By contrast, a large pregnancy cohort of 25,765 women with singleton pregnancies demonstrated that subclinical hyperthyroidism (defined in this study as a serum TSH below the 2.5th percentile for gestational age with normal free T4 at the first antenatal visit) is not associated with adverse obstetric effects, and thus this entity typically requires monitoring but no treatment.[16] Whether or not either subclinical or overt maternal hyperthyroidism during gestation is associated with alterations in child developmental outcomes has not been well studied. Although a recent cohort suggested that high, as well as low, maternal free T4 levels were associated with adverse effects on child IQ at 6 years of age,[17] and it has also been reported that maternal hyperthyroidism may be associated with higher risks for seizure disorders and attention deficit hyperactivity disorder in children,[18] these reports require confirmation.

Gestational Transient Thyrotoxicosis

Gestational transient thyrotoxicosis is hCG-mediated hyperthyroidism that occurs in the first trimester of pregnancy. This is most frequent in women with highly elevated serum hCG values, as occurs in twin or higher order gestations. Gestational thyrotoxicosis may occur in pregnant women whose hCG levels are not exceptionally high, but whose TSH receptors are particularly sensitive to hCG.[19,20] Severe thyrotoxicosis due to extremely high hCG levels has also been reported in the setting of hydatidiform mole or choriocarcinoma.[20] Levels of hCG correlate with the degree of nausea, and thus gestational thyrotoxicosis may be associated with hyperemesis gravidarum (loss of 5% body weight, dehydration, and ketonuria).[21] This condition is transient, and normalizes, usually by 15 weeks gestation, as serum hCG levels decline.[22] Differentiating between gestational thyrotoxicosis and other forms of hyperthyroidism can be challenging in the first trimester (Table 2). It is unusual for women with gestational thyrotoxicosis to present without nausea. Thyrotoxic symptoms usually are less severe than in GD (with the exception of tachycardia, which may be exacerbated beyond the levels expected in pregnancy by dehydration). In contrast to GD, free T4 levels are usually more elevated than serum T3.[3] Stigmata of GD are absent. TRAb titers are not detected. Because gestational thyrotoxicosis is transient and antithyroid drugs are teratogenic in the first trimester, their use is not recommended.[8] Supportive care with anti-emetics, management of dehydration, and electrolyte replacement is typically all that is required, although some patients with more marked thyrotoxic symptoms may benefit from a short course of beta-blockers.


Hyperthyroidism in GD is caused by TRAbs. The peak incidence of GD is in women of age 30 to 50,[23] and therefore it often presents either preconception, or during pregnancy or the postpartum period. The TRAb titer tends to decline over the course of pregnancy, likely due to the induction of immune tolerance.[24] Antibody titers subsequently increase in the postpartum setting, which can lead to recurrent or new hyperthyroidism in the first 12 months after delivery.[25–27] Two different assay types can be used to assess for the presence of TRAb. TSH-receptor-binding inhibitory immunoglobulins assays are based on the ability of antibodies to bind to the TSH receptor, but do not distinguish between stimulating and blocking immunoglobulins. Thyroid-stimulating immunoglobulin bioassays detect the production of cyclic adenosine monophosphate and specifically measure TSH receptor-stimulating antibodies.[28]

Hyperthyroidism in GD may be either overt or subclinical. Typically when hyperthyroidism is overt, serum T3 levels are relatively more elevated than the serum T4 [29] (Table 2). Clinical findings of a diffuse goiter with bruit or the presence of ophthalmopathy are diagnostic. In cases where these signs are absent, the diagnosis of GD hyperthyroidism can be confirmed using second- or third-generation TRAb assays, which are highly sensitive (97.4%) and specific (99.2%).[30] Radioactive iodine imaging is contra-indicated in pregnancy.[31]

Treatment options for GD hyperthyroidism include antithyroid medications (propylthiouracil [PTU] or methimazole [MMI]), radioactive iodine treatment, and thyroidectomy. Pregnancy, plans for pregnancy, and lactation have important implications for treatment choice. Both MMI and PTU cross the placenta.[32] MMI has long been known to be teratogenic,[33] but it was only recently recognized that PTU is also associated with birth defects. A national Danish registry study demonstrated that maternal exposure to MMI and/or PTU in the first trimester was associated with an increased risk for birth defects, occurring in approximately 1 of every 30 pregnancies with MMI exposure and 1 of every 40 pregnancies with PTU exposure.[34] The defects associated with the 2 drugs differ; those associated with MMI are typically more severe. MMI-associated birth defects include esophageal or choanal atresia, umbilocele and other abdominal wall defects, aplasia cutis, and ventricular septal defects.[34,35] Defects associated with PTU use include cysts of the face and neck and urinary tract defects in males[34] Antithyroid drugs may be teratogenic when used during the period of organogenesis, in the first trimester. Cases of fulminant hepatic failure have been reported in patients taking PTU, including in pregnant women; thus, PTU is not the preferred drug outside the setting of early pregnancy.[36]

When women are diagnosed with GD prior to pregnancy, counseling regarding the risks and benefits of all of the treatment options is essential.[8,37] Women should be instructed to avoid conception until hyperthyroidism is controlled. Definitive therapy with thyroidectomy or radioactive iodine treatment may be considered in order to avoid any antithyroid drug exposure during the period of organ-ogenesis. Following either radioactive iodine or surgery, conception should not be attempted until serum TSH has been optimized on levothyroxine therapy. Following thyroidectomy, TRAb titers decline. However, after radioactive iodine treatment there is a transient rise in TRAb titers above baseline that typically peaks at 3 months and persists for about a year; this could potentially increase the risk for fetal or neonatal hyperthyroidism.[38] If women elect to continue medication therapy, it is advisable to change from MMI to PTU preconception, particularly in young women with regular menses, who are likely to become pregnant within 1 to 3 months.[39]

In carefully selected women (those who are euthyroid on low-dose antithyroid drug prior to pregnancy [MMI ≤5–10 mg/day or PTU ≤100–200 mg/day], who have already been treated for at least 6 months, and who do not have large goiters or positive TRAb), antithyroid drug may be stopped as soon as pregnancy is diagnosed, with close monitoring of symptoms and thyroid function tests every 1 to 2 weeks. Women should not be allowed to become severely hyperthyroid in this setting. This strategy is based on the concept that recurrence of hyperthyroidism often does not happen for several weeks,[40] potentially allowing re-initiation of medication to be deferred until after the first trimester, when it is safer. However, although advocated in recent guidelines,[8] this strategy has not been prospectively studied.

If an antithyroid drug is required in the first trimester of pregnancy, PTU is preferred. When antithyroid drugs must be initiated in pregnancy, starting doses should be based on the degree of free T4 elevation and symptom severity, with starting doses most frequently in the range of PTU 200 to 400 mg daily or MMI 10 to 20 mg daily. Because antithyroid drugs cross the placenta and have the potential to cause fetal hypothyroidism, they should always be used in the lowest possible doses, targeting a maternal serum free T4 level at or just above the upper reference limit.[8] Thyroid function monitoring of pregnant women on antithyroid drugs should be performed every 2 to 4 weeks after therapy initiation, and every 4 to 6 weeks once target free T4 levels are achieved, because TRAb titers may wane over the course of gestation and antithyroid drug requirements often decrease.[41] In approximately one-third of women, antithyroid drugs can be safely discontinued by the third trimester; this is more likely in women in whom TRAb are no longer detectable.[42] In women treated with PTU in the first trimester, it is unknown whether it is safer to continue the PTU throughout gestation or to change back to MMI after organogenesis is complete. Small case-control studies suggest that maternal treatment with PTU or MMI in pregnancy does not affect child developmental outcomes.[43–45] In rare cases where antithyroid drugs are not tolerated or are ineffective, thyroidectomy can be performed most safely in the second trimester.[46]

Both maternal TRAb and antithyroid drugs are able to freely cross the placenta and have the potential to affect fetal thyroid function after around week 20 of gestation, when the fetal thyroid starts to work.[47] Depending on the balance of TRAb stimulation and antithyroid drug inhibition, the fetus may develop either hypo- or hyperthyroidism.[48–50] Neonatal hyperthyroidism occurs in 1 to 5% infants of women with a history of GD.[5] Maternal TRAb titers ≥2.5 to 3 times the upper limit of normal in the second or third trimester predict fetal and neonatal hyperthyroidism risk.[51–54] The fetus may be at risk for hyperthyroidism even if the mother has previously undergone thyroidectomy or ablation.[38] TRAb measurements should be performed at the initial prenatal visit in women with GD hyperthyroidism or a history of thyroidectomy or radioactive iodine treatment for GD.[8] If the initial level is <2.5 to 3 times the upper limit of normal, the measurement does not need to be repeated, but if elevated it should be remeasured at 18 to 22 weeks' gestation. Cordocentesis can be used to directly assess fetal thyroid function, but this confers a risk of morbidity and fetal loss [55] and should be employed only in very rare circumstances. Instead, ultrasound should be used to monitor for signs of fetal hyperthyroidism (sustained heart rate >160 bpm, goiter, intra-uterine growth restriction, advanced bone age) or hypothyroidism (goiter, retarded bone age) in women with elevated TRAb titers or uncontrolled hyperthyroidism in late gestation.[56,57]

When GD presents in the postpartum setting, it must be differentiated from the thyrotoxic phase of postpartum thyroiditis, as described below. Both PTU and MMI are secreted in breast milk, but in minute quantities,[58,59] and multiple studies have demonstrated normal thyroid function in the breastfed infants of women taking antithyroid medications.[60,61] Doses of MMI up to 20 mg daily or PTU 450 mg daily are thought to be safe in women who are breastfeeding, and monitoring of infant thyroid function is not required.[8] Because radioactive iodine is concentrated in breast milk, treatment with 131 I is contra-indicated in women who are lactating. Breastfeeding should ideally be stopped at least 3 months before any radioactive iodine treatment, both to avoid transmission of radioactive iodine to the breastfed infant and to avoid excessive radiation exposure to breast tissue.[62]

Autonomously Functioning Nodules

Toxic nodular goiter usually occurs late in life, and, even in historically iodine-deficient regions, is rare in women of childbearing age.[63] The onset of hyperthyroidism in patients with autonomously functioning nodules is typically gradual, and hyperthyroidism is less severe than in GD. If overt hyperthyroidism from autonomously functioning nodules is detected prepregnancy, definitive therapy with thyroidectomy or radioactive iodine should be strongly considered, since the natural history is progressively worsening hyperthyroidism without remission and because antithyroid drug use in pregnancy confers a higher risk for fetal hypothyroidism than in GD (since unlike in GD the fetus is not exposed to maternal thyroid-stimulating antibodies that can counteract the effects of antithyroid drugs on the fetal thyroid). If antithyroid drugs are required in pregnancy, the lowest possible dose should be employed to keep the maternal serum free T4 at or just above the upper limit of normal.[8] Definitive diagnosis of nodular autonomy requires radioactive iodine scanning, which is contra-indicated in pregnancy. Because 123I has a half-life of 13 hours, 123I scanning can be carried out in women who are lactating as long as breast milk is pumped and discarded for 3 to 4 days after the test.[8,6]

Postpartum Thyroiditis

Postpartum thyroiditis (PPT) is the onset of new autoimmune thyroid dysfunction in the first 12 months after delivery in women who do not have GD. It is more frequent in women with a personal or family history of autoimmunity, and in those who are TPO antibody positive in the first trimester of pregnancy.[6,64] The classic sequence is a transient thyrotoxicosis, most frequently beginning in the first 6 months after delivery, followed by transient hypothyroidism (Figure 1).[65] However, half of affected women experience only transient hypothyroidism, and about a quarter experience only the thyrotoxic phase.[6] Thyrotoxicosis, caused by leakage of preformed thyroid hormone from the inflamed thyroid gland, typically starts 2 to 6 months after delivery but may occur at up to a year postpartum, and persists for 1 to 2 months.[66] The hypothyroid phase starts 3 to 12 months postpartum and lasts for 4 to 6 months before euthyroidism is restored. While 80% of women will recover normal thyroid function within a year, up to 50% will subsequently develop chronic hypothyroidism.[67,68] After the first episode of PPT, there is a 70% likelihood of recurrence with subsequent pregnancies.[69]

Figure 1.

Classic clinical course of postpartum thyroiditis, with transient thyrotoxicosis followed by hypothyroidism. 123 I = radioactive iodine; T4 = thyroxine; TSH = thyroid-stimulating hormone. Reproduced from (65) with permission.

The thyrotoxic phase of PPT must be differentiated from GD (Table 2). In the postpartum setting the incidence of PPT is about 20 times higher than that of GD hyperthyroidism.[5] In contrast to GD, TRAbs are not detected in PPT.[70] The TPO antibody is positive in the vast majority of women with PPT.[71] The serum T3:T4 ratio is usually <20 in PPT, reflecting the ratio of stored hormone in the thyroid gland, and differs from GD in which T3 is often preferentially elevated.[72] Likely for this reason, thyrotoxic symptoms are usually mild. Stigmata of GD are absent. The 24-hour radioactive iodine uptake will be low or undetectable in PPT (<5%) rather than elevated as in GD, although this test is rarely needed.

Thyrotoxicosis in PPT is transient and usually does not require therapy. Severe thyrotoxic symptoms, if present, can be managed with beta-blockers such as propranolol or metoprolol, which are safe in lactation[8] Antithyroid drug therapy will be ineffective and should not be employed, since excess thyroid hormone synthesis does not occur. In the hypothyroid phase of PPT, women with symptoms or those who are trying to conceive should be treated with levothyroxine. Doses can be tapered after 12 months of therapy, as long as a woman is not pregnant or attempting pregnancy, to determine whether the underling thyroid function has recovered.