Maternal thyroid function tests

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

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: 1^st, first trimester (n = 105); 2^nd, second trimester (n = 39); 3^rd, third trimester (n = 64); NP, nonpregnant (n = 62).

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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 first-trimester 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 0.03–2.30 mIU/l.¹⁴ Subsequent studies have also confirmed the lower limit of the first-trimester serum TSH 95% CI to be 0.02–0.03 mIU/l in healthy pregnant women.^{15, 16} It is critical for clinicians to recognize this appropriate decrease 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 0.03–3.10 mIU/l and 0.13–3.40 mIU/l, respectively; Figure 2).¹⁴

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: 1^st, first trimester (n = 55); 2^nd, second trimester (n = 62); 3^rd, third trimester (n = 25); NP, nonpregnant (n = 63).

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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' disease from gestational thyrotoxicosis may be the most common challenge confronting the clinician. The absence of a goiter and anti-TSH-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 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 hCG-mediated 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 Hashimoto's hypothyroidism. The currently available bioassay is the thyroid-stimulating immunoglobulin (TSI) assay, which measures the generation of cyclic adenosine monophosphate when the patient's serum is incubated with cells that express the TSH receptor.

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 10–15 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

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 (7–8 weeks).²⁵ Historically, propylthiouracil was preferred over methimazole, partly because of early experimental data suggesting that propylthiouracil, which is more highly protein-bound 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 long-term, 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.^{28, 29, 30, 31} 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 mother's 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 0.8–1.9 ng/dl (10.3–24.5 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

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

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 (6–40 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

Administration of radioactive iodine for diagnostic or therapeutic purposes is contraindicated in pregnancy and lactation. After 10–12 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, approximately 1 in 3,000 (0.033%).^{44, 45} It has been suggested that propylthiouracil be administered for 7–10 days after exposure to decrease iodide recycling.¹

Surgery

Owing to obstetric and fetal risks, surgery is not regarded as first-line therapy, but might be considered if necessary for the mother's 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

With a reported incidence of 1–2% 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 41°C), 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.

Fetal thyroid function

By 10–12 weeks gestation, with the increased expression of the sodium iodide symporter gene, the fetal thyroid is capable of concentrating 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.^{50, 51, 52} 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

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}

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.

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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, 60, 61, 62} 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 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 26–28 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.^{64, 65, 66} 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 0.5–2.0% risk of fetal bleeding, bradycardia, infection, and death.^{67, 68}

Neonatal thyroid dysfunction

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 >350–500% (normal <125%) before delivery have predicted neonatal hyperthyroidism in several studies.^{24, 70, 71} Maternal TBII levels >40–70% (normal <10–15%) 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 1–7 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 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 hypothalamic–pituitary–thyroid axis might be impaired.⁷² The incidence of central congenital hypothyroidism in these cases has been found to be about 0.9%.⁹