REVIEW

www.nature.com/clinicalpractice/endmet

Therapy Insight: management of Graves disease during pregnancy

Grace W Chan and Susan J Mandel* S U M M A RY
The diagnosis of Graves disease in pregnancy can be complex because of normal gravid physiologic changes in thyroid hormone metabolism. Mothers with active Graves disease should be treated with antithyroid drugs, which impact both maternal and fetal thyroid function. Optimally, the lowest possible dose should be used to maintain maternal free thyroxine levels at or just above the upper limit of the normal nonpregnant reference range. Fetal thyroid function depends on the balance between the transplacental passage of thyroid-stimulating maternal antibodies and thyroid-inhibiting antithyroid drugs. Elevated levels of serum maternal anti-TSH-receptor antibodies early in the third trimester are a risk factor for fetal hyperthyroidism and should prompt evaluation of the fetal thyroid by ultrasound, even in women with previously ablated Graves disease. Maternal antithyroid medication can be modulated to treat fetal hyperthyroidism. Serum TSH and either total or free thyroxine levels should be measured in fetal cord blood at delivery in women with active Graves disease, and those with a history of 131I-mediated thyroid ablation or thyroidectomy who have anti-TSH-receptor antibodies. Neonatal thyrotoxicosis can occur in the first few days of life after clearance of maternal antithyroid drug, and can last for several months, until maternal antibodies are also cleared.
KEYWORDS antithyroid drugs, fetal thyroid dysfunction, Graves disease, neonatal thyroid dysfunction, pregnancy Continuing Medical Education online Medscape, LLC is pleased to provide online continuing medical education (CME) for this journal article, allowing clinicians the opportunity to earn CME credit. Medscape, LLC is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide CME for physicians. Medscape, LLC designates this educational activity for a maximum of 1.0 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To receive credit, please go to http://www.medscape.com/cme/ncp and complete the post-test. Learning objectives Upon completion of this activity, participants should be able to: 1 Describe thyroid physiology and hormone levels during pregnancy. 2 Identify clinical features of Graves disease during pregnancy. 3 List differential diagnoses for Graves disease during pregnancy. 4 Describe markers of thyroid status that are most predictive of thyroid function in fetuses of women with Graves disease during pregnancy. 5 List signs of fetal hyperthyroidism.

REVIEW CRITERIA We searched PubMed for articles and abstracts between 1965 and 2006 about Graves disease and pregnancy. The search terms we used were Graves disease, hyperthyroidism, pregnancy, pregnancy complications, antithyroid drug, fetal thyroid dysfunction and neonatal thyroid dysfunction. All papers were English-language full text papers. We also searched the reference lists of identified articles for further papers.

INTRODUCTION

CME

GW Chan is a Fellow, and SJ Mandel is Associate Professor of Medicine and Radiology, in the Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Correspondence
*611 Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104, USA smandel@mail.med.upenn.edu
Received 27 September 2006 Accepted 24 January 2007
www.nature.com/clinicalpractice doi:10.1038/ncpendmet0508

Hyperthyroidism complicates approximately 0.10.4% of pregnancies, with 85% of cases due to Graves disease.1,2 Graves disease, which has a peak incidence in the child-bearing third to fourth decades, is caused by thyroid-stimulating antibodies and can be accompanied by autoimmune ophthalmopathy or dermopathy. Treating Graves disease during gestation can be complex because of the impact of pregnancy both on the autoimmune course of the disease and on normal thyroid hormone metabolism. Although subclinical hyperthyroidism has not been implicated in adverse pregnancy outcomes, overt hyperthyroidism during pregnancy has been associated with stillbirth, prematurity, pre-eclampsia, and maternal congestive heart failure.35 Some data have linked significantly elevated maternal serum T4 levels with miscarriage as well.6 Uncontrolled hyperthyroidism during gestation has been associated with low birth weight and

470 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM

JUNE 2007 VOL 3 NO 6

REVIEW
www.nature.com/clinicalpractice/endmet

Total T4 (nmol/l)

150

149 109

140 138 143 11.5 85 87 86

15.1 15.5 14.2 12.9 13.0 11.2 11.0 10.7 8.3 7.6 11.4 8.8 8.7 8.4 6.5 6.0 11.7

15

100

10

THYROID FUNCTION IN THE MOTHER Maternal thyroid function tests

50

67

During pregnancy, estrogen-induced sialylation of T4-binding globulin (TBG) causes an increase in TBG levels, resulting in an increase in serum total T4 concentrations and a decrease in T3 resin uptake, an indirect measure of TBG capacity that is inversely proportional to available TBG binding sites. If a woman is not TBG deficient, then a T3 resin uptake during pregnancy in the normal nonpregnant reference range is suggestive of hyperthyroidism.10 As a result of these TBG changes, normal serum total T4 and T3 levels throughout pregnancy are predictably about 1.5 times the normal nonpregnant reference range (Figure 1).11 No trimester-specific normal ranges for serum free T4 (FT4) concentrations exist for commonly available commercial assays. This difficulty is compounded by the fact that estimates of FT4 are method-dependent, and that nonpregnant serum FT4 ranges vary widely. All FT4 assays, even equilibrium dialysis, show a decrease in serum FT4 levels as pregnancy progresses compared with their own nonpregnant reference range. By the third trimester, serum FT4 levels are often lower than the normal nonpregnant reference range (Figure 1).12,13 Serum TSH levels also fluctuate during pregnancy. The increase in thyroid hormone synthesis mediated by human chorionic gonadotropin (hCG) and coinciding with the firsttrimester peak in hCG is reflected by a reciprocal fall in serum TSH levels. A 2001 study of Chinese women without pre-existing thyroid disease or hyperemesis gravidarum showed that in the first trimester, the 95% CI for serum TSH levels was 0.032.30 mIU/l.14 Subsequent studies have also confirmed the lower limit of the first-trimester serum TSH 95% CI to be 0.020.03 mIU/l in healthy pregnant women.15,16 It is critical for clinicians to recognize this appropriate decrease

0 NP 1st 2nd 3rd NP 1st 2nd 3rd Stage of pregnancy NP 1st 2nd 3rd

Figure 1 Serum total T4 and free T4 levels by trimester. The shaded boxes show interquartile ranges, with the median value also indicated. Serum total T4 levels rise to approximately 1.5-times the normal NP reference range. Although serum free T4 ranges were method-dependent, as shown by the differences in measurement by the Elecsys (Boehringer Mannheim GmbH, Mannheim, Germany) and Tosoh (Tosoh Corporation, Yamaguchi, Japan) methods, both methods show a consistent decrease in free T4 levels as pregnancy progresses. Figure courtesy of Carole Spencer.13 Abbreviations: 1st, first trimester (n = 105); 2nd, second trimester (n = 39); 3rd, third trimester (n = 64); NP, nonpregnant (n = 62).

in the TSH range during normal pregnancy, as up to 18% of women in the first trimester will have serum TSH levels below the nonpregnant reference range.17 Median serum TSH levels then rise during the second and third trimesters (95% CI 0.033.10 mIU/l and 0.133.40 mIU/l, respectively; Figure 2).14
Diagnosis of Graves disease in pregnancy

Maternal hyperthyroidism The clinical diagnosis of mild to moderate hyperthyroidism in pregnancy can be difficult because pregnant women often exhibit hyperdynamic signs similar to hyperthyroidism, such as tachycardia, warm, moist skin, heat intolerance, and wide pulse pressure.2 Almost all patients with Graves disease will, however, have a goiter, although ophthalmopathy and dermopathy are only rarely present.10 In symptomatic patients, serum TSH levels that are suppressed below the lower limits of the trimester-specific ranges, with either elevated serum FT4 levels or total T4 levels higher than the pregnant reference range, confirm the diagnosis of hyperthyroidism. Differentiation of Graves

JUNE 2007 VOL 3 NO 6 CHAN AND MANDEL

NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM 471

Free T4 (pmol/l)

congenital malformations unrelated to antithyroid drug (ATD) ingestion.5,79 Clearly, proper management is essential for the health of both the mother and the fetus. First, we will discuss maternal thyroid physiology during pregnancy, the diagnosis and consequences of maternal Graves disease, and therapeutic options for Graves disease. Then we will detail the ontogeny of the fetal thyroid and discuss the impact of maternal Graves disease and its therapy on fetal and neonatal thyroid function.

250

Total T4

Free T4 (Elecsys) 21.9

Free T4 (Tosoh ) 23.1

25

200

187 187

198 16.8

19.2 18.1

19.4

20

REVIEW
www.nature.com/clinicalpractice/endmet

TSH 4

3.51 3.4 3.1

2.3

1.28 1.17 1.1 0.8

0.39 0.03 0.03 2nd

0.13 3rd

0
NP 1st Stage of pregnancy

Figure 2 Serum TSH concentrations by trimester. The 95% CIs are shown by the shaded boxes, with the median value also indicated. Adapted from Panesar et al.14 Abbreviations: 1st, first trimester (n = 55); 2nd, second trimester (n = 62); 3rd, third trimester (n = 25); NP, nonpregnant (n = 63).

ablation or surgery. Relapse of Graves disease during pregnancy has been associated with short duration of euthyroidism before pregnancy.19 In addition, the course of maternal Graves disease is variable, with remission in up to 30% of women by the middle of the third trimester.1,19 The differential diagnosis also includes toxic adenoma, subacute thyroiditis, excessive thyroid hormone intake (either factitious or therapeutic), gestational thyrotoxicosis, hyperemesis gravidarum, hydatidiform mole, and choriocarcinoma.1,2 Autoimmune thyroiditis, including postpartum thyroiditis (PPT), can start with a hyperthyroid phase. As PPT may occur up to 1 year after delivery or miscarriage, if a woman conceives again during that time, hyperthyroidism during the first trimester might be due to the hyperthyroid phase of PPT.20 A hypothyroid phase can then ensue, so women need to be monitored closely for hypothyroidism and initiation of levothyroxine therapy. Gestational thyrotoxicosis refers to the hCGmediated increased production of thyroid hormone that occurs in the late first and early second trimesters at the time of peak hCG secretion. Through its subunit, which it shares with TSH, hCG has weak thyrotropic activity. In most cases, gestational thyrotoxicosis manifests as a serum TSH level below the nonpregnant reference range; however, in hyperemesis gravidarum, up to 60% of women can have suppressed serum TSH and elevated serum FT4 levels, but these normalize with resolution of the hyperemesis.21 For these conditions, ATDs are generally not required, as they have not been shown to improve clinical outcome. Measurement of antibodies Different assays for maternal TRAbs exist. The most commonly used radioreceptor assay is the TSH-binding inhibitory immunoglobulin (TBII) assay. This method detects maternal antibodies that displace radiolabeled TSH from the TSH receptor. In patients with Graves disease, the assumption is that these antibodies stimulate thyroid hormone production. Such detected antibodies could, however, potentially block endogenous TSH stimulation; this effect occurs (rarely) in women with Hashimotos hypothyroidism. The currently available bioassay is the thyroidstimulating immunoglobulin (TSI) assay, which measures the generation of cyclic adenosine monophosphate when the patients serum is incubated with cells that express the TSH receptor.

disease from gestational thyrotoxicosis may be the most common challenge confronting the clinician. The absence of a goiter and antiTSH-receptor antibodies (TRAbs) as well as a normal serum T3 level are, however, suggestive of gestational thyrotoxicosis, whereas the presence of a goiter, TRAbs, and thyroid hormone levels higher than the pregnant reference range are consistent with Graves disease.18 Differential diagnosis Patients with Graves disease during pregnancy can present de novo, with recurrence after an ATD-induced remission, with exacerbation while taking an ATD, or with signs of fetal thyroid dysfunction despite maternal euthyroidism or hypothyroidism after 131I-mediated thyroid

472 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM

TSH (mIU/l)

CHAN AND MANDEL JUNE 2007 VOL 3 NO 6

REVIEW
www.nature.com/clinicalpractice/endmet

Antibody patterns generally fluctuate with pregnancy, reflecting the clinical course of the disease, but can remain stable in patients with low antibody titers.22 TRAbs can be detected in the first trimester, but values often decrease over the second and third trimesters and might become undetectable before increasing again postpartum.23,24 Clinically, patients can experience relapse or exacerbation of Graves disease by 1015 weeks of gestation. Graves disease can, however, remit late in the second and third trimesters.19 This disease pattern is thought to be caused by decreases in stimulating TRAb levels, as described above, rather than increases in inhibitory TRAb levels.23
THERAPEUTIC OPTIONS

In managing hyperthyroidism during pregnancy, it should be remembered that two patients are being treated: the mother and the fetus. A balance must be made in optimizing treatment for one without impinging on the other.
Antithyroid drugs

Methimazole versus propylthiouracil Thionamide drugs are considered first-line therapy. Propylthiouracil and methimazole are equally effective, and the mean time to normalization of thyroid function is similar (78 weeks).25 Historically, propylthiouracil was preferred over methimazole, partly because of early experimental data suggesting that propylthiouracil, which is more highly proteinbound than methimazole, had more limited transplacental passage than methimazole.26 Since then, however, other studies have found that both drugs readily cross the placenta.27,28 In the United States, propylthiouracil is prescribed more frequently than methimazole because of possible teratogenic effects linked to methimazole (see below), but methimazole and its precursor carbimazole are widely used throughout the world. There have been no longterm, prospective trials addressing the efficacy of combination levothyroxine and ATD therapy during pregnancy, and it is currently the standard of care to treat with an ATD alone. Therapeutic goals Several studies have shown no significant correlation between daily maternal ATD dose and fetal thyroid status.2831 Elevation in serum TSH concentration can still be found

in newborns of 23% of mothers taking low-dose propylthiouracil (100 mg daily or less) and 15% of those taking low-dose methimazole (10 mg daily or less).29 Studies show instead a strong correlation between maternal and neonatal levels of FT4, indicating that maternal thyroid status is the most clinically practical index of fetal thyroid status.30,32 Doses of ATD that maintain maternal serum FT4 levels in the normal nonpregnant reference range might not preclude fetal hypothyroidism; appropriate ATD doses for the mother might be excessive for the fetus.22,24,32 Until recently, it was recommended that ATD doses be individualized such that maternal serum FT4 levels were in the upper third of or just above the normal nonpregnant reference range.30 An abstract published in 2006 analyzed fetal cord FT4 and TSH levels at birth in relation to maternal serum FT4 levels in 249 women with Graves disease who continued ATD therapy through delivery. The authors reported that low fetal cord blood FT4 levels were avoided only when the maternal serum FT4 concentration was >1.9 ng/dl (24.5 pmol/l), although one infant whose mothers serum FT4 level was 2.1 ng/dl (27.0 pmol/l) developed central congenital hypothyroidism.32 The normal nonpregnant reference range for FT4 in this study was 0.81.9 ng/dl (10.324.5 pmol/l). ATD doses should therefore be adjusted to maintain maternal FT4 at or slightly higher (<10% higher) than the upper limit of the normal nonpregnant reference range. When detectable, serum TSH concentrations at or just below the trimester-specific 95% CI are acceptable. Teratogenicity Although there have been no prospective population studies to establish causality, multiple case reports have associated methimazole with two types of congenital anomalies: choanal or esophageal atresia, and aplasia cutis. These malformations can occur as part of an embryopathy that also includes developmental delay, hearing loss, and dysmorphic facial features.33 Several cases of isolated choanal and esophageal atresia have been reported with methimazole use in the first trimester.34,35 The reported incidence of aplasia cutis, a congenital absence of skin usually affecting the scalp, in babies born to women taking methimazole approximates the background rate at which this defect spontaneously occurs (0.03% of newborns).36

JUNE 2007 VOL 3 NO 6 CHAN AND MANDEL

NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM 473

REVIEW
www.nature.com/clinicalpractice/endmet

Despite this lack of definitive evidence, propylthiouracil, if available, should be used for initial therapy, given that there are no case reports of aplasia cutis and only rare anecdotal reports of embryopathies associated with propylthiouracil ingestion.31,37 Since the introduction of propylthiouracil in the 1940s, there has only been one case reported of neonatal hepatitis and lymphocyte sensitization attributed to transplacental passage of propylthiouracil.38 Long-term follow-up of children exposed in utero to ATDs has shown no difference in physical or intellectual development compared to controls.39,40
Propranolol

approximately 1 in 3,000 (0.033%).44,45 It has been suggested that propylthiouracil be administered for 710 days after exposure to decrease iodide recycling.1
Surgery

A useful treatment for hyperthyroid symptoms and preparation for thyroidectomy is -adrenergic blockade, specifically with propranolol; however, continued propranolol use in pregnancy has been associated with fetal growth retardation.41
Iodide

Iodide has not been recommended in the treatment of hyperthyroidism during pregnancy because of its association with neonatal goiter and hypothyroidism when given in conjunction with thionamides. One study in which gravidas with mild Graves disease were treated with low-dose iodine alone (640 mg daily) showed that 6% of neonates had elevated serum TSH levels, but none had a goiter.42 With such little evidence, iodide should not be considered as primary therapy, but can be used short-term for the control of thyrotoxicosis before thyroidectomy, or in the management of thyroid storm (see below).
Radioactive iodine

Owing to obstetric and fetal risks, surgery is not regarded as first-line therapy, but might be considered if necessary for the mothers health. Indications for surgery include the requirement for continued large doses of ATDs (propylthiouracil >450 mg, methimazole >30 mg), goiters causing symptoms of dysphagia or airway obstruction, and noncompliance with or severe reaction to medical therapy. Surgery during the first trimester has been associated with an increased rate of spontaneous abortions.46 If possible, therefore, surgery should be postponed until the second trimester. Preoperative preparation includes ATD therapy (if not contraindicated), short-term use of iodides, and -adrenergic blockade. Thyrotoxicosis should be controlled as best as possible to lower the risk of thyroid storm.
Thyroid storm

Administration of radioactive iodine for diagnostic or therapeutic purposes is contraindicated in pregnancy and lactation. After 1012 weeks of gestation, once the fetal thyroid has the ability to concentrate iodine, congenital hypothyroidism can occur. In one study in which 182 fetuses were exposed inadvertently to 131I therapy during the first trimester, pregnancy resulted in 2 (1.1%) spontaneous abortions, 2 (1.1%) intrauterine deaths, 6 (3.3%) hypothyroid children, and 4 (2.2%) mentally retarded children.43 Although the study did not include a control group, the number of children found to be hypothyroid was substantially higher than the usual incidence of congenital hypothyroidism,

With a reported incidence of 12% of all thyrotoxicosis cases, thyroid storm during pregnancy can be triggered by pre-eclampsia, placenta previa, labor, Cesarean section, or infection.1,10 This is a life-threatening condition characterized by severe symptoms of hyperthyroidism, fever (as high as 41C), and alteration in mental status. Early treatment is essential and includes ATDs, iodide, corticosteroids, -adrenergic blockade, cooling measures, and treatment of the precipitating cause.1 As propylthiouracil blocks the peripheral conversion of T4 to T3, it is usually preferred over methimazole. Doses might need to be given through a nasogastric tube, or by rectal suppository, if the patient is unable to take medications by mouth.1 Iodide should be given at least 1 h after the ATD so that it is not used for continued hormone synthesis. Dexamethasone can also be used to block the peripheral conversion of T4 to T3.1,10 Fetal monitoring should be performed continuously if the fetus is viable.
THYROID FUNCTION IN THE OFFSPRING Fetal thyroid function

By 1012 weeks gestation, with the increased expression of the sodium iodide symporter gene, the fetal thyroid is capable of concentrating

474 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM

CHAN AND MANDEL JUNE 2007 VOL 3 NO 6

REVIEW
www.nature.com/clinicalpractice/endmet

iodide, accumulating colloid, and producing thyroglobulin.47,48 At around 20 weeks of gestation, the TSH receptor is capable of responding to TSH (as well as thyroid-stimulating antibodies).47,49 The placenta is not permeable to TSH but is so to iodide.47 Active iodide transport across the placenta can occur as well, as suggested by the expression of the sodium iodide symporter gene in trophoblasts, although the mechanism has not been fully elucidated.5052 Particularly in the second half of pregnancy when the fetal thyroid produces T4, adequate maternal intake of iodine is crucial as a substrate for fetal thyroid hormone synthesis. The placenta also contains the Type 3 deiodinase, which inactivates much of the T4 and T3 from the maternal circulation and provides a secondary source of iodine for the fetus.47 Maternal T4 crosses the placenta throughout gestation. This amount is biologically significant, particularly in the first trimester before fetal thyroid hormone production.2,53,54
Fetal thyroid dysfunction

Fetal goiter

Fetal hypothyroidism: risk factors

Fetal hyperthyroidism: risk factors

1 ATD-treated maternal Graves disease with maternal serum free T4 in normal laboratory reference range 2 3 Normal or low TRAb Delayed fetal bone age

1 Poorly controlled maternal hyperthyroidism 2 Levothyroxine-replaced maternal hypothyroidism after 131 I-mediated ablation or thyroidectomy, with elevated TRAb 3 4 Fetal tachycardia Advanced fetal bone age

Figure 3 Differentiation between fetal hypothyroidism and hyperthyroidism in the presence of a fetal goiter. Abbreviations: ATD, antithyroid drug; TRAb, maternal anti-TSH-receptor antibody.

Diagnosis of fetal thyroid dysfunction is challenging. Although transplacental passage of maternal antibodies (IgG class) to the fetus does occur early in gestation, the fetal concentration is quite low until the end of the second trimester. Placental permeability to these immunoglobulins then increases such that in the last trimester, fetal levels are equivalent to maternal.55 This change in permeability, coupled with the ability of the fetal thyroid to respond to TSH and TRAbs, explains why fetal hyperthyroidism occurs in the second half of pregnancy. In women with Graves disease receiving ATD therapy, fetal thyroid hormone synthesis therefore represents the balance between the transplacental passage of the inhibitory maternal ATD and concentrations of maternal thyroid-stimulating TRAbs. Fetal thyroid ultrasound at 32 weeks to screen for clinically relevant fetal thyroid dysfunction has a reported sensitivity of 92% and a specificity of 100%;22 however, if a fetal goiter is detected, fetal hyperthyroidism and hypothyroidism must be differentiated (Figure 3). Signs suggestive of fetal hyperthyroidism include intrauterine growth retardation, arrhythmias, congestive heart failure, advanced bone age, craniosynostosis, and hydrops.49,56 Another suspicious feature is a diffuse Doppler ultrasound signal throughout the thyroid gland.57 Tachycardia

(>160 beats per minute) can indicate, but is not always present in, fetal thyrotoxicosis.22,58,59 Fetal hypothyroidism can be difficult to diagnose. Studies have suggested criteria including a Doppler ultrasound signal in the periphery of the fetal thyroid gland and retarded bone maturation.22,57,59 As the maternal thyroid is influenced by the same factors (the inhibitory ATD and stimulating TRAbs) as the fetal thyroid, maternal thyroid hormone levels might be indicative of fetal thyroid function.30,32 Extremely high TRAb concentrations associated with poor control of maternal hyperthyroidism usually, therefore, indicate fetal hyperthyroidism, but high maternal ATD doses coupled with low TRAb levels have been associated with fetal hypothyroidism.22 If a fetal goiter indicating hypothyroidism is caused by maternal ATD ingestion, a dosage reduction or discontinuation leads to improvement in, and sometimes resolution of, the goiter that can be documented by serial ultrasounds.57,6062 There have also been case reports of weekly intra-amniotic levothyroxine therapy resulting in improved thyroid function on cordocentesis and prevention of goiter at delivery, but this treatment has been accompanied by simultaneous reduction in maternal ATD therapy.61 In addition, fetuses of levothyroxine-replaced women with a history of 131I-mediated thyroid ablation or surgery for Graves disease are also at

JUNE 2007 VOL 3 NO 6 CHAN AND MANDEL

NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM 475

REVIEW
www.nature.com/clinicalpractice/endmet

risk for hyperthyroidism. Unknown to clinician and patient, the continued maternal production of high levels of TRAbs could stimulate the fetal thyroid without the presence of the tempering effect of ATDs. These women should therefore have TRAb levels measured at 2628 weeks gestation and, if levels are elevated, a fetal thyroid ultrasound should be performed.63 There have been multiple reports of pregnancies in which fetal hyperthyroidism was treated with ATDs.6466 Maternal daily ATD doses have ranged between 50 and 300 mg for propylthiouracil, and 15 and 40 mg for methimazole or carbimazole. For levothyroxine-replaced hypothyroid women, the maternal levothyroxine dose might need to be increased as well. Although the optimal timing for ATD administration is uncertain, the cases reported initiation of ATDs between 20 and 34 weeks. Doses can be modulated clinically and decreased when the fetal heart rate normalizes.65,66 Umbilical cord blood sampling, also called cordocentesis or funipuncture, can be reserved for cases in which definitive diagnosis of fetal thyroid dysfunction is still in doubt after ultrasound. The procedure should, however, only be performed in centers with experience. It has been associated with a 0.52.0% risk of fetal bleeding, bradycardia, infection, and death.67,68
Neonatal thyroid dysfunction

ablation or thyroidectomy, cord blood should be reserved at delivery for measurement of neonatal serum TSH and either total T4 or FT4 levels.63 In addition, infants should be closely observed for signs of thyrotoxicosis in the first few days of life after maternal ATD has been cleared from their system. It has also been suggested that a hyperthyroid fetal environment might cause central congenital hypothyroidism. If a fetus is constantly exposed to high levels of maternal thyroid hormone, the development of the fetal hypothalamicpituitarythyroid axis might be impaired.72 The incidence of central congenital hypothyroidism in these cases has been found to be about 0.9%.9
CONCLUSIONS

Neonatal thyrotoxicosis due to persistence of maternal TRAbs occurs in about 1% of babies born to mothers with either active or previously treated Graves disease and lasts for up to 3 months.69 Multiple studies have attempted to predict neonatal thyroid status using maternal antibody levels. Strong correlation has been found between maternal and fetal TSI and TBII levels.24,70 Maternal TSIs >350500% (normal <125%) before delivery have predicted neonatal hyperthyroidism in several studies.24,70,71 Maternal TBII levels >4070% (normal <1015%) before delivery have also predicted neonatal thyrotoxicosis.9,70 Although there is no definitive threshold at which fetal TRAb levels predict neonatal hyperthyroidism, one study found that if TRAb levels on days 17 of life were three times the upper limit of normal, infants developed neonatal hyperthyroidism.22,69 When mothers have active Graves disease or are TRAb-positive after 131I-mediated thyroid

Graves disease during pregnancy should be treated with an ATD (propylthiouracil, if available) in the lowest possible dose to maintain maternal serum FT4 levels at or just above the upper limit of the normal nonpregnant reference range, or serum total T4 levels at 1.5-times the normal nonpregnant reference range. Maternal serum FT4 or total T4 should be measured every 24 weeks for close titration of the ATD. Second-trimester thyroidectomy after preoperative preparation with -adrenergic blockade and iodide can be considered in selected cases. TRAb levels should be measured between 26 and 28 weeks of gestation, including in those women with a prior history of 131I-mediated thyroid ablation or thyroidectomy, to assess the risk of hyperthyroidism to the fetus. If antibody levels are elevated, or if the mother is taking an ATD, fetal ultrasound from 2832 weeks should be performed to evaluate for fetal goiter. At delivery in women with active Graves disease or who have elevated TRAb levels after 131Imediated thyroid ablation or thyroidectomy, cord blood should be checked for serum TSH, and T4 or FT4; if neonatal hyperthyroidism is suspected, cord TRAb levels should be measured as well. Three areas of future research that would be beneficial include: determination of assayspecific and trimester-specific normative FT4 ranges to aid in the diagnosis of thyroid dysfunction, confirmation of maternal serum FT4 targets for optimal titration of ATD, and exploration of noninvasive detection methods for fetal thyroid dysfunction.

476 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM

CHAN AND MANDEL JUNE 2007 VOL 3 NO 6

REVIEW
www.nature.com/clinicalpractice/endmet

KEY POINTS
First-line therapy for Graves disease during pregnancy includes antithyroid drugs (preferably propylthiouracil) Prescribed doses should be as low as possible to maintain maternal serum free T4 levels at or just above the upper limit of the normal nonpregnant range, or total T4 levels at 1.5times the normal nonpregnant reference range If continued administration of antithyroid medication is not possible, second-trimester thyroidectomy can be considered; patients should receive -adrenergic blockade and iodide therapy preoperatively All women with active Graves disease, and levothyroxine-replaced patients with a history of 131I-mediated ablation or thyroidectomy, should have their anti-TSH-receptor antibody (TRAb) levels measured at 2628 weeks gestation to evaluate the risk for fetal hyperthyroidism To assess fetal thyroid function, fetal ultrasound at 2832 weeks should be performed if there is evidence of active maternal Graves disease (elevated maternal TRAb levels, or maternal requirement for antithyroid medication) Serum TSH and total T4 or free T4 concentrations should be measured in fetal cord blood at delivery in women with active Graves disease or positive TRAb screen after 131I-mediated ablation or thyroidectomy

References 1 Mestman JH (1997) Hyperthyroidism in pregnancy. Clin Obstet Gynecol 40: 4564 2 Burrow GN (1993) Thyroid function and hyperfunction during gestation. Endocr Rev 14: 194202 3 Casey BM et al. (2006) Subclinical hyperthyroidism and pregnancy outcomes. Obstet Gynecol 107: 337341 4 Davis LE et al. (1989) Thyrotoxicosis complicating pregnancy. Am J Obstet Gynecol 160: 6370 5 Millar LK et al. (1994) Low birth weight and preeclampsia in pregnancies complicated by hyperthyroidism. Obstet Gynecol 84: 946949 6 Anselmo J et al. (2004) Fetal loss associated with excess thyroid hormone exposure. JAMA 292: 691695 7 Momotani N et al. (1984) Maternal hyperthyroidism and congenital malformation in the offspring. Clin Endocrinol (Oxf) 20: 695700 8 Phoojaroenchanachai M et al. (2001) Effect of maternal hyperthyroidism during late pregnancy on the risk of neonatal low birth weight. Clin Endocrinol (Oxf) 54: 365370 9 Mitsuda N et al. (1992) Risk factors for developmental disorders in infants born to women with Graves disease. Obstet Gynecol 80: 359364 10 Burrow GN (1985) The management of thyrotoxicosis in pregnancy. N Engl J Med 313: 562565

11 Demers LM and Spencer CA (2003) Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Clin Endocrinol (Oxf) 58: 138140 12 Sapin R et al. (2004) Free thyroxine measured with equilibrium dialysis and nine immunoassays decreases in late pregnancy. Clin Lab 50: 581584 13 Spencer CA et al. (2005) Thyroid reference ranges in pregnancy: studies of an iodine-sufficient pregnant cohort [abstract #O 43]. Thyroid 15 (Suppl 1): S-16 14 Panesar NS et al. (2001) Reference intervals for thyroid hormones in pregnant Chinese women. Ann Clin Biochem 38: 329332 15 Casey BM et al. (2005) Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 105: 239245 16 Haddow JE et al. (2004) The reference range and within-person variability of thyroid stimulating hormone during the first and second trimesters of pregnancy. J Med Screen 11: 170174 17 Glinoer D et al. (1993) Serum levels of intact human chorionic gonadotropin (HCG) and its free and subunits, in relation to maternal thyroid stimulation during normal pregnancy. J Endocrinol Invest 16: 881888 18 Goodwin TM et al. (1992) Transient hyperthyroidism and hyperemesis gravidarum: clinical aspects. Am J Obstet Gynecol 167: 648652 19 Amino N et al. (1982) Aggravation of thyrotoxicosis in early pregnancy and after delivery in Graves disease. J Clin Endocrinol Metab 55: 108112 20 Marqusee E et al. (1997) Thyroiditis after pregnancy loss. J Clin Endocrinol Metab 82: 24552457 21 Tan JY et al. (2002) Transient hyperthyroidism of hyperemesis gravidarum. BJOG 109: 683688 22 Luton D et al. (2005) Management of Graves disease during pregnancy: the key role of fetal thyroid gland monitoring. J Clin Endocrinol Metab 90: 60936098 23 Amino N et al. (2003) No increase of blocking type antithyrotropin receptor antibodies during pregnancy in patients with Graves disease. J Clin Endocrinol Metab 88: 58715874 24 Zakarija M and McKenzie JM (1983) Pregnancyassociated changes in the thyroid-stimulating antibody of Graves disease and the relationship to neonatal hyperthyroidism. J Clin Endocrinol Metab 57: 10361040 25 Wing DA et al. (1994) A comparison of propylthiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy. Am J Obstet Gynecol 170: 9095 26 Marchant B et al. (1977) The placental transfer of propylthiouracil, methimazole and carbimazole. J Clin Endocrinol Metab 45: 11871193 27 Mortimer RH et al. (1997) Methimazole and propylthiouracil equally cross the perfused human term placental lobule. J Clin Endocrinol Metab 82: 30993102 28 Gardner DF et al. (1986) Pharmacology of propylthiouracil (PTU) in pregnant hyperthyroid women: correlation of maternal PTU concentrations with cord serum thyroid function tests. J Clin Endocrinol Metab 62: 217220 29 Momotani N et al. (1997) Effects of propylthiouracil and methimazole on fetal thyroid status in mothers with Graves hyperthyroidism. J Clin Endocrinol Metab 82: 36333636 30 Momotani N et al. (1986) Antithyroid drug therapy for Graves disease during pregnancy. Optimal regimen for fetal thyroid status. N Engl J Med 315: 2428 31 Cheron RG et al. (1981) Neonatal thyroid function after propylthiouracil therapy for maternal Graves disease. N Engl J Med 304: 525528

JUNE 2007 VOL 3 NO 6 CHAN AND MANDEL

NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM 477

REVIEW
www.nature.com/clinicalpractice/endmet

Acknowledgments
GW Chan is supported by NIH grant 2-T32DK007314-26. We thank C Spencer for supplying the data used for Figure 1. Dsire Lie, University of California, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscapeaccredited continuing medical education activity associated with this article.

Competing interests
The authors declared they have no competing interests.

32 Momotani N et al. (2006) Anti-thyroid drug therapy for Graves disease during pregnancy: mildest thyrotoxic maternal free thyroxine concentrations to avoid fetal hypothyroidism [abstract #87]. Presented at the 77th Annual Meeting of the American Thyroid Association: 2006 October 1115, Phoenix, AZ 33 Wolf D et al. (2006) Antenatal carbimazole and choanal atresia: a new embryopathy. Arch Otolaryngol Head Neck Surg 132: 10091011 34 Di Gianantonio E et al. (2001) Adverse effects of prenatal methimazole exposure. Teratology 64: 262266 35 Clementi M et al. (1999) Methimazole embryopathy: delineation of the phenotype. Am J Med Genet 83: 4346 36 Van Dijke CP et al. (1987) Methimazole, carbimazole, and congenital skin defects. Ann Intern Med 106: 6061 37 Mujtaba Q and Burrow GN (1975) Treatment of hyperthyroidism in pregnancy with propylthiouracil and methimazole. Obstet Gynecol 46: 282286 38 Hayashida CY et al. (1990) Neonatal hepatitis and lymphocyte sensitization by placental transfer of propylthiouracil. J Endocrinol Invest 13: 937941 39 Eisenstein Z et al. (1992) Intellectual capacity of subjects exposed to methimazole or propylthiouracil in utero. Eur J Pediatr 151: 558559 40 Messer PM et al. (1990) Antithyroid drug treatment of Graves disease in pregnancy: long-term effects on somatic growth, intellectual development and thyroid function of the offspring. Acta Endocrinol (Copenh) 123: 311316 41 Redmond GP (1982) Propranolol and fetal growth retardation. Semin Perinatol 6: 142147 42 Momotani N et al. (1992) Effects of iodine on thyroid status of fetus versus mother in treatment of Graves disease complicated by pregnancy. J Clin Endocrinol Metab 75: 738744 43 Stoffer SS and Hamburger JI (1976) Inadvertent 131I therapy for hyperthyroidism in the first trimester of pregnancy. J Nucl Med 17: 146149 44 Brosco JP et al. (2006) Impact of specific medical interventions on reducing the prevalence of mental retardation. Arch Pediatr Adolesc Med 160: 302309 45 Rose SR et al. (2006) Update of newborn screening and therapy for congenital hypothyroidism. Pediatrics 117: 22902303 46 Brodsky JB et al. (1980) Surgery during pregnancy and fetal outcome. Am J Obstet Gynecol 138: 11651167 47 Fisher DA (1997) Fetal thyroid function: diagnosis and management of fetal thyroid disorders. Clin Obstet Gynecol 40: 1631 48 Szinnai G et al. (2007) Sodium/iodide symporter (NIS) gene expression is the limiting step for the onset of thyroid function in the human fetus. J Clin Endocrinol Metab 92: 7076 49 Chopra IJ (1992) Fetal and neonatal hyperthyroidism. Thyroid 2: 161163 50 Di Cosmo C et al. (2006) The sodium-iodide symporter expression in placental tissue at different gestational age: an immunohistochemical study. Clin Endocrinol (Oxf) 65: 544548 51 Bidart JM et al. (2000) Expression of Na+/I symporter and Pendred syndrome genes in trophoblast cells. J Clin Endocrinol Metab 85: 43674372 52 Mitchell AM et al. (2001) Sodium iodide symporter (NIS) gene expression in human placenta. Placenta 22: 256258

53 Vulsma T et al. (1989) Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med 321: 1316 54 de Escobar GM et al. (2004) Maternal thyroid hormones early in pregnancy and fetal brain development. Best Pract Res Clin Endocrinol Metab 18: 225248 55 Gitlin D (1971) Development and metabolism of the immune globulins. In Immunologic Incompetence 316, (Eds Kagan BM and Stiehm ER) Chicago: Year Book Medical Publishers, Inc. 56 Nachum Z et al. (2003) Graves disease in pregnancy: prospective evaluation of a selective invasive treatment protocol. Am J Obstet Gynecol 189: 159165 57 Polak M et al. (2004) Fetal and neonatal thyroid function in relation to maternal Graves disease. Best Pract Res Clin Endocrinol Metab 18: 289302 58 Wallace C et al. (1995) Fetal thyrotoxicosis: a case report and recommendations for prediction, diagnosis, and treatment. Thyroid 5: 125128 59 Polak M et al. (2006) Congenital hyperthyroidism: the fetus as a patient. Horm Res 65: 235242 60 Cohen O et al. (2003) Serial in utero ultrasonographic measurements of the fetal thyroid: a new complementary tool in the management of maternal hyperthyroidism in pregnancy. Prenat Diagn 23: 740742 61 Van Loon AJ et al. (1995) In utero diagnosis and treatment of fetal goitrous hypothyroidism, caused by maternal use of propylthiouracil. Prenat Diagn 15: 599604 62 Ochoa-Maya MR et al. (1999) Resolution of fetal goiter after discontinuation of propylthiouracil in a pregnant woman with Graves hyperthyroidism. Thyroid 9: 11111114 63 LeBeau SO and Mandel SJ (2006) Thyroid disorders during pregnancy. Endocrinol Metab Clin North Am 35: 117136 64 McNab T and Ginsberg J (2005) Use of anti-thyroid drugs in euthyroid pregnant women with previous Graves disease. Clin Invest Med 28: 127131 65 Bruinse HW et al. (1988) Fetal treatment for thyrotoxicosis in non-thyrotoxic pregnant women. Fetal Ther 3: 152157 66 Serup J and Petersen S (1977) Hyperthyroidism during pregnancy treated with propylthiouracil. The significance of maternal and foetal parameters. Acta Obstet Gynecol Scand 56: 463466 67 Davidson KM et al. (1991) Successful in utero treatment of fetal goiter and hypothyroidism. N Engl J Med 324: 543546 68 Kilpatrick S (2003) Umbilical blood sampling in women with thyroid disease in pregnancy: is it necessary? Am J Obstet Gynecol 189: 12 69 Skuza KA et al. (1996) Prediction of neonatal hyperthyroidism in infants born to mothers with Graves disease. J Pediatr 128: 264268 70 Matsuura N et al. (1988) TSH-receptor antibodies in mothers with Graves disease and outcome in their offspring. Lancet 1: 1417 71 Peleg D et al. (2002) The relationship between maternal serum thyroid-stimulating immunoglobulin and fetal and neonatal thyrotoxicosis. Obstet Gynecol 99: 10401043 72 Kempers MJ et al. (2003) Central congenital hypothyroidism due to gestational hyperthyroidism: detection where prevention failed. J Clin Endocrinol Metab 88: 58515857

478 NATURE CLINICAL PRACTICE ENDOCRINOLOGY & METABOLISM

CHAN AND MANDEL JUNE 2007 VOL 3 NO 6