A look at Graves’ hyperthyroidism in pregnancy

Introduction

The management of Graves’ hyperthyroidism (GH) in pregnancy remains a challenge for the physician who must recognize the signs and symptoms of thyrotoxicosis; assess any history of thyroid disease along with its course and management; correctly interpret thyroid labs, which are complicated by the changes that occur in thyroid physiology during pregnancy; and choose the best treatment plan for the patient and the fetus. Furthermore, treatment of GH with antithyroid drugs (ATDs) has been associated with teratogenicity.

Maternal, obstetrical, and neonatal complications are increased in women with poorly controlled thyroid disease. In 1975, a study of 26 pregnancies of hyperthyroid women treated with ATDs resulted with four infants born with goiter, three with hyperthyroidism, and five with congenital abnormalities (1). Today, complications due to uncontrolled GH still occur.

The key to the successful management of GH in pregnancy begins with preconception counseling. In addition, early recognition of the symptoms of disease and a multidisciplinary approach involving the endocrinologist, maternal-fetal-medicine specialist, anesthesiologist, neonatologist, and pediatric endocrinologist are essential.

This review will discuss: (I) preconception counseling; (II) alterations in thyroid physiology in pregnancy; (III) thyroid laboratory testing; (IV) etiologies of hyperthyroidism; (V) pregnancy-related complications; (VI) maternal management; (VII) neonatal management; (VIII) ATDs and the associated maternal and fetal complications; and (IX) post-partum management.

Preconception counseling

GH is an autoimmune disease characterized by antibodies that stimulate the thyroid stimulating hormone receptor (TSHR). The likelihood that a pregnant woman age 20–45 years old has had a prior history of GH is 0.5% to 1.3% (2). All women of reproductive age with GH or a past history of GH should receive preconception counseling. These women should be advised to plan their pregnancies and contact their physician before or as soon as pregnancy has been confirmed (3).

Women with a history of GH treated with either radioactive iodine ablation (RAIA) or surgery will need an increase in their levothyroxine dose early in pregnancy due to the 30–50% increase in thyroid hormone demand in the first half of pregnancy (4,5). Some studies have shown that a TSH greater than 2.5 mIU/L in the first trimester of pregnancy increases the incidence of miscarriages, premature labor, and intellectual deficiencies in the offspring later in life (6,7). However, other studies have shown no clinically important association between maternal thyroid dysfunction in early pregnancy and impaired educational achievement (8). Abalovich et al. showed that a TSH of 1.2 mIU/L before conception prevents development of hypothyroidism after conception in almost 85% of hypothyroid women on thyroid replacement therapy (9).

Counseling should take into consideration the woman’s desired timeline to conception and a discussion of the potential risks and benefits of treatment options including ATD, 131-RAIA, and surgery. Women should not become pregnant until hyperthyroidism is controlled. Women with difficult to control GH on high doses of ATD should consider definitive therapy prior to conception. Women should be educated about the frequency of medical and obstetric visits during pregnancy, need for serial thyroid blood tests, the potential for congenital abnormalities of ATDs, the risks of uncontrolled hyperthyroidism in pregnancy, the possibility of recurrence of hyperthyroidism in pregnancy and postpartum, and breastfeeding.

Women who are on ATDs for GH should be on contraception and counseled to pay close attention to their menstrual cycles. If a period is missed, a pregnancy test should be done immediately. The risk of birth defects due to ATDs is greatest during weeks 6–10 during organogenesis (10). Methimazole (MMI) is generally preferred to propylthiouracil (PTU) in the treatment of GH for ease of once daily dosing compared to PTU, which is dosed three times daily. PTU also is associated with an increased risk for hepatotoxicity. However, women are often switched to PTU in the first trimester of pregnancy because the teratogenic effects associated with PTU are considered less severe than those associated with MMI. Patients may be switched from MMI to PTU once pregnant or in anticipation of pregnancy. An argument for the latter is that pregnancy is typically not diagnosed until a missed period and the switch from MMI to PTU often occurs after week 6 when the risk of potential side effects from the medication is highest (11).

In women who will be treated with RAIA, a pregnancy test should be done beforehand and conception should be delayed for 6 months until the woman is euthyroid on levothyroxine therapy. The risks to the fetus of inadvertent treatment with RAIA during pregnancy are dependent on the timing of exposure and the radiation dose (12). Spontaneous miscarriage is more likely when exposure occurs in the first two weeks after fertilization, prior to implantation (13). A surviving embryo exposed at this early stage would be less likely to have a major malformation. Exposure at later stages in pregnancy such as during organogenesis or thyroidogenesis (from week 10) may result in fetal thyroid ablation or birth defects (12).

After RAIA therapy, TSH receptor antibodies (TRAb), which are measurable in 95% of patients with GH (14), may increase and stay elevated for months to years (15-17). Persistently elevated TRAb levels throughout pregnancy are prognostic of fetal thyroid dysfunction (18). Therefore, women with very elevated TRAb levels prior to conception may be better candidates for thyroidectomy as TRAb levels tend to decrease and normalize within months to one year after surgery (15,16). Rarely, TRAb levels may remain elevated years after surgery (19).

Changes in thyroid physiology during pregnancy

The increased demand for thyroid hormone production during pregnancy is attributed to (I) an almost two-fold increase in thyroxine-binding globulin (TBG) due to the stimulatory effects of estrogen on the production of TBG by the liver and possibly the prolonged half-life of sialylated TBG in pregnancy (20) (II) stimulatory effects of human chorionic gonadotropin (hCG), a glycoprotein that has structural similarity to TSH, on the TSHR (21), and high concentrations of Deiodinase Type 3 in the placenta, which deactivates thyroxine and triiodothyronine (22).

The thyroid compensates for this increased demand by increasing T4 synthesis and secretion. Requirements of iodine, essential to thyroid hormone synthesis, consequently increase in pregnancy. The suggested daily iodine ingestion for pregnant women varies between 220–250 µg/day (23). Prenatal vitamins should contain 150 µg of iodine in the form of potassium iodine and are meant to supplement daily dietary iodine intake (24). However, not all prenatal vitamins contain iodine. The physician should alert the patient to obtain prenatal vitamins containing the proper iodine supplementation.

In the setting of adequate iodine intake, the normal thyroid gland is able to compensate for the increased thyroid hormone demands. However, in patients with thyroid abnormalities or in women on thyroid hormone replacement, this demand may not be met and hypothyroidism may result. The fetus relies entirely on the mother for thyroid hormone until 10–12 weeks when the fetal gland begins to secrete thyroid hormone. Significant fetal thyroid hormone production occurs around week 20 (25).

Laboratory tests

TSH is the screening test used for detection and diagnosis of thyroid dysfunction along with levels of thyroxine when TSH values are abnormal. In early pregnancy, hCG rises contributing to TSH concentrations that may be below the non-pregnant reference range in up to 10% of normal pregnant women. The American Thyroid Association Thyroid and Pregnancy Guidelines (ATATPG) recommended an adjusted reference range (decreases of the lower limit of the reference range of TSH by 0.4 mU/L and upper limit by approximately 0.5 mU/L) be used in weeks 7–12 with a gradual return to non-pregnancy reference ranges in the second and third trimester (23). Notably, 0.5–1% of women may have completely suppressed TSH levels in early pregnancy (26). TSH below 0.10 mIU/L in the first trimester is not associated with obstetric complications (27).

The most common commercially available tests in clinical practice for measurement of free thyroxine (FT4) are automated immunoassays by non-equilibrium methods. However, in the latter half of pregnancy, increased thyroid-binding globulin (TBG) and decreased serum albumin concentration lead to inconsistency between available FT4 immunoassays and falsely low FT4 levels (28-30) making trimester-specific pregnancy reference ranges necessary if FT4 is used (30). A comparison of FT4, total T4 (TT4) levels, and FT4 index (FT4I) found that the latter two more accurately demonstrate changes in thyroxine throughout gestation (30,31).

As TBG increases, TT4 rises from the first trimester until mid-gestation when TT4 stabilizes. After 16 weeks, the non-pregnancy reference range for TT4 may be adjusted by a factor of 1.5 and used to assess thyroid status. For example, the normal reference range of 4.5–12.5 µg/dL multiplied by 1.5 becomes 6.75–18.75 µg/dL (30). Alternatively, the FT4I can be calculated by adjusting the TT4 for alterations in TBG using the T3 resin uptake test (32). Equilibrium dialysis technique and tandem mass spectrometry are more accurate at FT4 measurement, but they are also more expensive and less commonly available (33).

The role of serum FT3 or TT3 is limited in pregnancy. If TSH is suppressed, but FT4/FT4I is normal, an elevated FT4/TT3 would be suggestive of an autonomous functioning nodule or exogenous triiodothyronine (T3) hormone. T3 may be elevated in GH as well, more commonly when being treated with ATDs.

TRAb

TSH receptor antibodies (TRAb) may be stimulating (TSAb), neutral, or blocking antibodies of the TSH receptor. TSAbs are the pathogenetic hallmark of GH with 97% sensitivity and 99% specificity for GH (14). TRAbs cross the placenta, act on the fetal TSHR, and can cause thyroid dysfunction. Consequently, TRAb levels play an important role in assessing the risk of fetal and neonatal hyperthyroidism (34,35).

TRAbs may be measured by two different methods, a “receptor assay” and a “bioassay.” The receptor assay measures TRAbs by TRAbs’ capacity to compete with radiolabeled TSH to bind to a TSHR preparation. The first generation receptor assay was referred to as TSH-binding inhibiting immunoglobulins (TBII). The second and third generation receptor assays are now referred to as TRAb. The sensitivity and specificity of each subsequent generation of the assay has improved. The third-generation TRAb assay is 98% and 99.2% sensitive and specific respectively (36,37).

The major limitation of the TRAb receptor assays is that they do not differentiate between the TSAB, neutral, or blocking antibodies. Furthermore, there has not been an established association between TRAb and the clinical and biochemical severity of the disease. In the bioassays, the functional property of the TRAbs may be measured and the antibodies may be distinguished from one another, providing useful clinical information. The bioassay entails incubating the patient’s serum with cells expressing TSHR and measuring cyclic AMP production by radioimmunoassay or chemiluminescent assay (35).

In patients with active GH, a positive TRAb level via either the receptor or bioassay method is indicative of TSAb. In patients with GH treated by RAIA or surgery, TRAb may be stimulating, neutral, or blocking antibodies. A bioassay can provide clinically relevant information on the function of the TRAb, and in pregnancy its effect on the fetus. A recent study by Diana et al. demonstrated that 4.2% of non-pregnant patients with GH had detectable blocking antibodies (38). However, in another study of 788 neonates who had neonatal screening suggestive of neonatal hypothyroidism, only 9 had blocking antibodies (39).

TRAb levels tend to decrease after week 20 due to the immunosuppressive effects of pregnancy and are often undetectable towards the term of pregnancy coinciding with the subsiding of hyperthyroid symptoms often observed in GH patients. However, if TRAb levels remain elevated over 3 times the upper limit of normal (3× >ULN) in the latter half of pregnancy, there is an increased risk of fetal and neonatal hyperthyroidism (16) with 100% sensitive and 43% specificity (40).

TPO-Ab

Thyroid peroxidase antibody (TPO-Ab) is a nonspecific marker of thyroid autoimmunity. It has been associated with increased risk of miscarriage and premature delivery in euthyroid women. It does not have a role in GH.

Etiology of hyperthyroidism

Gestational transient thyrotoxicosis (GTT)

The etiology of hyperthyroidism in pregnancy is broad (Table 1), but the majority of cases are due to GTT. GTT affects 1–5% of all pregnant women, making it much more common than GH, which affects 0.2% of pregnancies (2,42). Differentiating GH from GTT is important because the latter is a transient, mild hyperthyroidism that does not require treatment with ATD and in most cases is not associated with adverse pregnancy outcomes (43,44).

Negative TRAb along with absence of Graves’ ophthalmopathy, goiter, and prior history of hyperthyroidism is suggestive of GTT. TSH is typically suppressed and FT4 is mildly elevated. The clinical course coincides with hCG levels, which begin to rise week 7 of gestation and decrease between weeks 14 and 20 (45,46). TSH levels may exhibit a “lag phase” and remain suppressed weeks after resolution of the GTT.

The etiologies of GTT are many (Table 2), but the most common cause of thyrotoxicosis in the first trimester of pregnancy is hyperemesis gravidarum (HG) (50). It is characterized by significant nausea, vomiting, and weight loss of up to 5 kg. Patients frequently present to the hospital for IV hydration (51). Symptoms of hyperthyroidism are typically mild, although patients may present with palpitations, tremors, and night sweats.

Twin and multiple pregnancies have increased and prolonged levels of hcG production and may present with GTT. Trophoblastic diseases such as hydatidiform moles, choriocarcinoma, and hyperplacentosis are also associated with increased levels of hcG, but are rare (52). Women with a prior history of GTT have a higher likelihood of having a repeat episode (42).

GH

In pregnancy, GH may present as: a first-time diagnosis, a patient undergoing treatment with ATD, a patient with recurrence of hyperthyroidism after treatment with ATD, radioiodine ablation therapy, and less commonly today, surgery (53). The diagnosis of GH should be suspected in a hyperthyroid pregnant woman who was having symptoms prior to pregnancy, had a prior diagnosis of hyperthyroidism, or gave birth to an infant with a thyroid dysfunction. The signs and symptoms of GH are similar to those seen in non-pregnant patients. Although the clinical diagnosis may be difficult in pregnancy as mild palpitations, HR 90–100 bpm, mild heat intolerance, shortness of breath on exertion, and warm skin can be seen in normal pregnancy. Clinical clues such as ophthalmopathy, goiter, frequent bowel movements, persistent tachycardia, weight loss, or inability to gain weight despite increased appetite are suggestive of GH

Worsening GH symptoms in early pregnancy along with a small increase in GH incidence is thought to be from the increase in hCG and or elevation in TRAb levels during the first trimester (54-57). With the progression of pregnancy, changes in the immunologic response lead to improvement in symptoms. Some women are able to discontinue ATD. In the postpartum period, however, GH may recur as the immune system rebounds (58).

Autonomous functioning thyroid nodule or toxic adenoma

A rare cause of maternal hyperthyroidism, a toxic adenoma typically presents with a palpable thyroid nodule on exam. Clinical signs of GH such as ophthalmopathy are absent. Thyroid function tests may reveal a FT4 or FT4Index mildly to moderately elevated. Thyroxine may be normal and the nodule may be predominantly T3 secreting. This is one occasion when a T3 measurement is useful. Management of these patients is different in that the hyperthyroidism does not improve with progression of pregnancy. Rather ATD requirements stay stable or may increase. These patients are TRAb negative. Consequently, the fetus is at greater risk for hypothyroidism in the setting of overtreatment with ATD.

Management and treatment of GH in pregnancy

Successful management of a pregnant woman with hyperthyroidism consists of controlling the hyperthyroidism and early detection of fetal thyroid dysfunction. Considerations include when to initiate ATD treatment, ATD choice, and titration of ATD throughout pregnancy. The lowest effective dose to maintain TT4 1.5× the upper limit of the non-pregnant reference range or the FT4I in the upper limit of the reference range should be used. If FT4 is used, one should maintain the FT4 towards the upper limit of normal or use trimester-specific reference ranges if available.

The concern is overtreatment and resulting hypothyroidism in the fetus. This is especially true of women with negative or low TRAb. TSH may remain suppressed during treatment and throughout the pregnancy. ATD should be lowered if TSH becomes detectable (3). “Block and replace” approach in which ATD is used in conjunction with levothyroxine therapy is not recommended in pregnancy (59).

In the first trimester, PTU is traditionally the preferred ATD because the side effects associated with PTU as compared to MMI are considered less severe (discussed further below). PTU is dosed 50–150 mg every 8 hours. Thyroid function tests (TSH along with Total T4, FT4 or FT4 index) should be reassessed every 2–4 weeks depending on patient’s symptomatology and biochemical response. If the risk of relapse or worsening hyperthyroidism is considered low, the physician may consider holding ATD treatment with frequent monitoring of thyroid function. The period of maximum sensitivity to teratogenic effects of ATDs is during weeks 6–10, the period of fetal organogenesis. As most pregnancies are not detected until a menstrual period is missed, the window for intervention is narrow (60).

In the second trimester, patients may be switched from PTU to MMI or remain on PTU (23). Reasons to switch to MMI include ease of once daily dosing and risk of maternal hepatotoxicity associated with PTU (61,62). While both drugs have been associated with hepatotoxicity, the effects associated with MMI generally consist of cholestasis rather than fulminant liver failure (63). The ATATPG recommends using a ratio of 1:20 when switching from MMI to PTU (23). For example, 15 mg of MMI would be equivalent to 300 mg of PTU per day, dosed 100 mg every 8 hours. Higher doses are rarely required, but in very symptomatic patients, up to MMI 40 mg per day have been used. Reasons to remain on PTU include a period of potentially worse control of the hyperthyroidism.

Propranolol 10–20 mg every 6–8 hours may be used to control the hyperadrenergic symptoms and tapered as tolerated. Long-term treatment with ß-blockers has been associated with intrauterine growth restriction, fetal bradycardia, and neonatal hypoglycemia (64). In the majority of patients, clinical improvement is generally seen in two to three weeks and biochemical improvement in the first two weeks of therapy, with normalization of the FT4/FT4I/TT4 within three to seven weeks. TSH may remain suppressed throughout the rest of pregnancy (27).

Because of the immunologic changes that occur with the progression of pregnancy, TRAb levels decrease in the majority of women after week 20 and the requirement of ATD decreases in the latter half of pregnancy. In women with mild disease requiring low doses of ATD (MMI 2.5–5 mg daily or PTU 50–100 mg daily) with negative or mildly elevated TRAb, ATDs may be discontinued and the women monitored for evidence of recurrence. ATD may be successfully discontinued in up to 40% of women after 30–34 weeks of gestation (3). Fetal hypothyroidism is an indication to stop treatment and follow maternal thyroid labs every one to two weeks as clinically indicated. Low levels of TRAb may be an indication to use the minimal amount of ATD (65).

Thyroidectomy in pregnancy is reserved for rare cases of large goiters causing compressive symptoms, patients who are intolerant, allergic, or nonresponsive to ATD, or non-consistent with drug therapy. In pregnancy, surgery is best performed between 18–24 weeks gestation. Beta-blockers should be used to control hyperadrenergic effects before, during, and after the surgery. Potassium iodide (50–100 mg/day) may be used 8–14 days prior to surgery to decrease the vascularity of the thyroid gland in preparation for surgery and is considered safe for the fetus (66). TRAb levels should be checked prior to surgery given the increased risk of fetal hyperthyroidism with TRAb levels >3× ULN as mentioned above. Even if the mother becomes euthyroid after surgery, the TRAb levels may remain elevated as discussed above.

TRAb levels should also be tested at time of presentation with pregnancy in all women with a past history of GH treated with RAIA or surgery. If TRAb is elevated, repeat testing should occur at weeks 18–22. If TRAb is undetectable or low, no further TRAb testing is needed. If the TRAb level is elevated >3× ULN at weeks 18–22, close fetal monitoring for fetal thyrotoxicosis (FT) is warranted and the TRAb level should be checked again at weeks 30–34 to evaluate the need for neonatal and postnatal monitoring (23).

Pregnancy outcomes

Early recognition and treatment of hyperthyroidism helps avoid most pregnancy complications. In women with poorly controlled hyperthyroidism in pregnancy, pregnancy-induced hypertension (PIH) is one of the most common complications. Millar et al. described the risk of preeclampsia in uncontrolled patients as five times greater than those with controlled disease and risk of low-birth weight (LBW) was nine times greater (67). In women who became euthyroid after 20 weeks gestation, the risk remained 2.3 times greater compared to those who became euthyroid before or very early in pregnancy. Women with uncontrolled hyperthyroidism were 16.5 times as likely to undergo preterm delivery.

Other complications associated with poor control of hyperthyroidism include placental abruption, intrauterine growth restriction, stillbirth, miscarriage, maternal congestive heart failure, and thyroid storm (TS) (68-71). The rates of untreated maternal Graves’ disease was associated with perinatal mortality rates of 20–45% prior to the introduction of ATDs (68,72). Nowadays, the rate of complications has improved drastically. A cohort study of 180 cases of 180 pregnancies complicated by overt hyperthyroidism in 2011 showed a 1.7% rate of perinatal death (71). Fetal and neonatal outcomes will be discussed below.

TS

In patients with thyrotoxicosis, the stress of infection or operation may precipitate clinical deterioration (73). In extreme cases, this can lead to TS. TS is a rare complication of uncontrolled GH. Davis et al. described one case in 120,000 deliveries over the span of 11 years at a single institution (68). TS occurs when a chronically hyperthyroid patient encounters a precipitating stressor such as pregnancy, infection, preeclampsia, labor, or surgery and decompensates. Altered mental status should raise suspicion of TS in the setting of tachycardia and fevers. Early recognition and appropriate treatment is crucial as mortality is significant, 10–30% (74,75). Patients require ICU level care and treatment entails beta-blockers, ATD, and supportive care (Table 3).

Complications of anti-thyroid drugs for mother and fetus

ATDs remain the treatment of choice of GH during pregnancy. They are relatively well tolerated with 3–5% of women experiencing side effects, the most common being an allergic reaction such as a skin rash (23,79). More serious side effects such as agranulocytosis or liver failure are rare, occurring in 0.15% and <0.1% of patients respectively (80,81). If a patient has a mild reaction such as skin rash, the patient may be switched to the other ATD. However, if the reaction is more severe, the patient may need to undergo surgery, generally performed in the second trimester. As mentioned above, PTU is also associated with an increased risk of maternal hepatotoxicity.

However, the greatest concern regarding the use of ATDs in pregnancy is the risk of teratogenic effects. PTU and MMI both cross the placenta and can affect the fetus. Rate of birth defects is elevated in patients exposed to ATDs in early pregnancy compared to non-exposed euthyroid patients (82). Rates of fetal defects is similar for both PTU and MMI (2–4%) (82-84) with greater risk associated with ATD exposure during weeks 6–10, the teratogenic period of pregnancy (63,85). However, the fetal defects associated with MMI are considered more severe than those associated with PTU (Table 4) (63,83). The fetal defects associated with PTU are limited to face and neck defects or the urinary system (82,86-88). The American Thyroid Association currently recommends treatment with PTU through week 16 (23). Consideration to switch to PTU prior to pregnancy should be had in preconception counseling as there may be a delay in the diagnosis of pregnancy until after the critical week 6–10. Switching after this period has been shown to have no effect in rates of embryopathies (10,82).

Fetal management

Fetal and neonatal thyroid function

The fetal thyroid gland develops between 5 to 6 weeks gestation (89) and begins to secrete thyroxine at ten weeks gestation (90). However, fetal thyroid hormone production is minimal until 18 weeks of gestation when the fetal TSH receptor begins to function and becomes responsive to TSH and TRAb (19,91-93). Prior to this, the fetus is dependent on mother for TH via transplacental passage (94).

FT

Maternal TRAb levels are prognostic of FT (18,34,35). Studies evaluating TRAb levels using different methodologies have resulted in various TRAb level thresholds associated with increased risk of fetal and neonatal thyrotoxicosis (NT). ATATPG recommends a TRAb threshold of 3× the ULN (~5 IU/L with a second generation assay) as an indicator of increased risk of FT (23,40). TRAb levels >3× ULN in early pregnancy warrants close monitoring and repeat testing. TRAb levels >3× ULN in the second and third trimester predicts neonatal hyperthyroidism with 100% sensitivity and 43%specificity (40,95). In a recent systematic review by van Dijk et al., the lowest level of maternal TRAb leading to NT was 4.4 U/L (3.7× ULN) via a second-generation assay (96).

The rate of FT is hard to establish, but NT occurs in 1–5% of children born to mothers with GH (93,97-99). Women who have poorly controlled GH, elevated TRAb titers, a prior fetus or neonate with a thyroid disorder, or who are requiring high doses of ATD in the second half of gestation are at risk for FT. On US, signs of FT include a HR greater than 160 bpm for more than ten minutes, intrauterine growth restriction, oligo/polyhydramnios, goiter, and advanced bone age that can lead to neonatal craniosynostosis (100). Severe FT can result in fetal heart failure, hydrops, and fetal demise (76,100).

The literature reports that the earliest sonographic sign of fetal thyroid dysfunction is a fetal goiter (100). However, this has not been our experience. Patients may present with fetal tachycardia before a goiter is diagnosed. The US is generally performed at 18–22 weeks and then every 4 weeks thereafter to assess for gestational age, fetal heart rate, amniotic fluid volume, fetal growth, the presence of fetal goiter, and fetal anatomy (23,76). Fetal goiter may lead to fetal, obstetric, and neonatal complications. Polyhydramnnios may result from reduced ability of the fetus to swallow or labor dystocia may occur from hyperextension of the fetal neck due to goiter (101). Consequently, cesarean section may be preferred in the presence of a goiter (102).

A fetal goiter may be due to FT or fetal hypothyroidism. If the thyroid status of the fetus remains unclear, cordocentesis may be used. This involves US-guided placement of a needle into the fetal circulation typically via a free loop of umbilical cord or at the cord insertion site. Risk of fetal complications with cordocentesis is low (0.5–1%) when performed at experienced centers (91,101). Alternatively, TH concentrations in amniotic fluid may be measured. This is a less invasive procedure, but remains to be validated (90).

Treatment of FT involves treatment of the mother with ATDs, which cross the placenta. FT can involve a mother that is euthyroid (i.e., status-post thyroidectomy or RAIA) or hypothyroid (103-105). In these scenarios, a euthyroid mother is treated with MMI 10–20 mg daily or larger doses as clinically indicted. Doses are adjusted every few days based on fetal tachycardia and goiter size (3), using the lowest dose necessary to normalize fetal heart rate (110–160 beats per minute). This is one situation in which the mother is treated with ATD in addition to replacement levothyroxine. Assessment of fetal heart tones with hand-held doppler should be performed every 1–2 weeks or as necessary. US should also be utilized to assess growth, size of fetal thyroid gland, and amniotic fluid index.

Fetal hypothyroidism

In the case of overtreatment of the fetus with ATDs, fetal hypothyroidism may develop. Signs on US include goiter, intrauterine growth restriction, delayed bone age, and bradycardia (76). In this situation, ATD dose is reduced or stopped. Most of the time, this is enough to restore normal thyroid function to reduce the size of the fetal goiter. Rarely, intra-amniotic levothyroxine injection is necessary in conjunction with stopping of ATD dose (106). If the diagnosis of fetal hypothyroidism is not clear, cordocentesis may be considered to determine the fetal thyroid status (91,107). Alternatively, measuring thyroid hormone concentration in the amniotic fluid is a less risky procedure (92,108).

Neonatal management

Uncontrolled GH can lead to significant thyroid dysfunction in the neonate. In a study by Papendieck et al., 28 children were born of hyperthyroid mothers and seen in a pediatric clinic prior to one month of age. Nine of these infants were born with neonatal hyperthyroidism, eleven infants were born with primary hypothyroidism, ten from mothers treated with ATD. Lastly, five infants were born with hypothalamic-pituitary hypothyroidism (61).

Neonatal thyroid function

Immediately after birth TSH, T4, and T3 rise. TSH peaks in the first 24 h of life and remains elevated for up to 3 to 5 days. T4 and T3 levels increase by 6-fold within the first few hours of life and peak 24 to 36 h after birth (91,109). By 3 to 4 days of life, thyroid function tests will gradually decrease to normal levels (110).

NT

NT occurs in 1–5% of offspring of mothers with GH (93,98,99). Those with FT should have thyroid tests checked at birth and every few days as clinically indicated. Neonates with NT may present with tachycardia, tachypnea, pulmonary hypertension, systemic hypertension, and heart failure. They may be small for gestational age with accelerated bone maturation and in more severely affected newborns, craniosynostosis, microcephaly, and psychomotor disabilities may occur (3,76,93,111).

Newborns with a TSH level less than 0.9 mIU/L between days 3 to 7 of life predicted neonatal hyperthyroidism with a sensitivity of 78% and a specificity of 99%, a positive predictive value of 90%, and a negative predictive value of 98% (112). All newborns born to mothers with GH on ATD without evidence of FT should be screened for thyroid dysfunction within two to five days after birth. ATD may cross the placenta and remain in the neonate’s system for up to 48–72 hours, delaying the diagnosis of the hyperthyroidism.

Neonatal hyperthyroidism is generally transient. Typically infants are treated for 1–2 months, but TRAb may remain elevated in the infant’s circulation for up to four months after delivery (3,113). Neonates with positive TRAb should be followed weekly with repeat clinical and laboratory studies until TRAb is normal (95). Banigé et al. recently described an equation to estimate the time it would take for TRAb to be eliminated from the newborn’s circulation: TRAb elimination time (day) = [7.28 + 2.88 × log(TRAb) + 11.62 log(TRAb²)] (112). This may assist clinicians in anticipating the frequency of testing and timing of follow-up.

The recommended regimen for neonatal hyperthyroidism is MMZ 0.5–1 mg/day with propranolol 2 mg/kg/day if severe (23). MMZ is preferred over PTU due to frequency of hepatotoxicity, liver failure, and death in children (114).

Neonatal hypothyroidism

Neonates are at risk for hypothyroidism secondary to maternal ATD therapy, central hypothyroidism from untreated women with suppression of fetal TSH, and impaired hypothalamic-pituitary-thyroid maturation (115). In term neonates with non-transient hypothyroidism, the recommended starting dose of levothyroxine is 10–15 mcg/kg/day. For optimal outcomes, therapy should be initiated within two weeks of life. Most infants and children do well with treatment. The shorter time to normalization of thyroid levels contributes to improved neurodevelopmental outcome (110).

Maternal postpartum care

Women with GH and hyperthyroid at time of delivery will need to be monitored closely and treated according to standard treatment practices. Women with GH who are euthyroid at time of delivery should be followed during the first year postpartum. TSH and FT4 should be checked periodically starting at six weeks postpartum. Women with GH, including those in remission during pregnancy, are at risk for recurrence for up to one year after delivery (116). A report from Japan found that 40% of women ages 20–39 years old with GH had developed GH during the postpartum period (117).

A recurrence of hyperthyroidism in women with Graves’ disease who are euthyroid at delivery may recur as early as six weeks postpartum and needs to be distinguished from postpartum thyroiditis (PPT). PTT occurs in roughly 5% of pregnancies and does not require treatment with ATD (118). It is characterized by a transient hyperthyroid phase that typically resolves within a few weeks, leading to a brief euthyroid phase and then to a transient hypothyroid phase before returning to euthyroidism in the majority of patients (119). High TRAb titers would support a diagnosis of GH (120). Onset of the hyperthyroidism in the first few months postpartum would be more consistent with PPT while onset after four to six months would suggest GH. If a diagnosis is still not clear, 123-I RAIA uptake is an option. If the patient is breastfeeding, the breast milk must be discarded for several days until the radioactive iodine has cleared from the body (23,121).

Breastfeeding

Patients on ATD at delivery should continue ATD after delivery even if breastfeeding as it has been shown to be safe (122-124). Both ATDs appear in the breast milk in very small concentrations (125-127). Experts recommend using the lowest effective dose possible < MMI 20 mg daily and PTU 300 mg total daily (128). The ATD should be taken just after the mother has breastfed (79). 131-Iodine therapy is contraindicated in lactating mothers. If definitive therapy is needed in a lactating mother, surgery is preferred.

Conclusions

Women with a history of GH, either previously treated or those with active disease at the time of pregnancy are at a higher risk for maternal and obstetrical complications compared to euthyroid women. The goal in the care of women with GH is the delivery of a healthy euthyroid newborn. The first step to achieving this begins prior to pregnancy during the preconception counseling. All women of reproductive age with thyroid disease should be counseled on the role of thyroid and pregnancy, management considerations of GH in pregnancy, including the potential side effects of ATDs, definitive treatment options, and postpartum care. Close collaboration between a medical team comprising of an endocrinologist, obstetrician, maternal fetal medicine physician, anesthesiologist, neonatologist, and pediatric endocrinologist during pregnancy and in the postpartum period is essential to reducing the risk of maternal, fetal, and newborn complications.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Fereidoun Azizi) for the series “Thyroid and Pregnancy” published in Annals of Thyroid. The article has undergone external peer review.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/aot.2018.10.02). The series “Thyroid and Pregnancy” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the manuscript and ensure that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Mujtaba Q, Burrow GN. Treatment of hyperthyroidism in pregnancy with propylthiouracil and methimazole. Obstet Gynecol 1975;46:282-6. [PubMed]
2. Cooper DS, Laurberg P. Hyperthyroidism in pregnancy. Lancet Diabetes Endocrinol 2013;1:238-49. [Crossref] [PubMed]
3. Patil-Sisodia K, Mestman JH. Graves hyperthyroidism and pregnancy: a clinical update. Endocr Pract 2010;16:118-29. [Crossref] [PubMed]
4. Mandel SJ, Larsen PR, Seely EW, et al. Increased need for thyroxine during pregnancy in women with primary hypothyroidism. N Engl J Med 1990;323:91-6. [Crossref] [PubMed]
5. Yassa L, Marqusee E, Fawcett R, et al. Thyroid hormone early adjustment in pregnancy (the THERAPY) trial. J Clin Endocrinol Metab 2010;95:3234-41. [Crossref] [PubMed]
6. Haddow JE, Palomaki GE, Allan WC, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341:549-55. [Crossref] [PubMed]
7. Henrichs J, Bongers-Schokking JJ, Schenk JJ, et al. Maternal thyroid function during early pregnancy and cognitive functioning in early childhood: the generation R study. J Clin Endocrinol Metab 2010;95:4227-34. [Crossref] [PubMed]
8. Nelson SM, Haig C, McConnachie A, et al. Maternal thyroid function and child educational attainment: prospective cohort study. BMJ 2018;360:k452. [Crossref] [PubMed]
9. Abalovich M, Alcaraz G, Kleiman-Rubinsztein J, et al. The relationship of preconception thyrotropin levels to requirements for increasing the levothyroxine dose during pregnancy in women with primary hypothyroidism. Thyroid 2010;20:1175-8. [Crossref] [PubMed]
10. Laurberg P, Andersen SL. Therapy of endocrine disease: antithyroid drug use in early pregnancy and birth defects: time windows of relative safety and high risk? Eur J Endocrinol 2014;171:R13-20. [Crossref] [PubMed]
11. Seo GH, Kim TH, Chung JH. Antithyroid Drugs and Congenital Malformations: A Nationwide Korean Cohort Study. Ann Intern Med 2018;168:405-13. [Crossref] [PubMed]
12. Hyer S, Pratt B, Newbold K, et al. Outcome of Pregnancy After Exposure to Radioiodine In Utero. Endocr Pract 2011;1-10. [Epub ahead of print]. [Crossref] [PubMed]
13. Sawka AM, Lakra DC, Lea J, et al. A systematic review examining the effects of therapeutic radioactive iodine on ovarian function and future pregnancy in female thyroid cancer survivors. Clin Endocrinol (Oxf) 2008;69:479-90. [Crossref] [PubMed]
14. Tozzoli R, Bagnasco M, Giavarina D, et al. TSH receptor autoantibody immunoassay in patients with Graves' disease: improvement of diagnostic accuracy over different generations of methods. Systematic review and meta-analysis. Autoimmun Rev 2012;12:107-13. [Crossref] [PubMed]
15. Kautbally S, Alexopoulou O, Daumerie C, et al. Greater Efficacy of Total Thyroidectomy versus Radioiodine Therapy on Hyperthyroidism and Thyroid-Stimulating Immunoglobulin Levels in Patients with Graves' Disease Previously Treated with Antithyroid Drugs. Eur Thyroid J 2012;1:122-8. [Crossref] [PubMed]
16. Laurberg P, Wallin G, Tallstedt L, et al. TSH-receptor autoimmunity in Graves' disease after therapy with anti-thyroid drugs, surgery, or radioiodine: a 5-year prospective randomized study. Eur J Endocrinol 2008;158:69-75. [Crossref] [PubMed]
17. Bisschop PH, van Trotsenburg AS. Images in clinical medicine. Neonatal thyrotoxicosis. N Engl J Med 2014;370:1237. [Crossref] [PubMed]
18. Banigé M, Estellat C, Biran V, et al. Study of the Factors Leading to Fetal and Neonatal Dysthyroidism in Children of Patients With Graves Disease. J Endocr Soc 2017;1:751-61. [Crossref] [PubMed]
19. Donnelly MA, Wood C, Casey B, et al. Early severe fetal Graves disease in a mother after thyroid ablation and thyroidectomy. Obstet Gynecol 2015;125:1059-62. [Crossref] [PubMed]
20. Glinoer D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev 1997;18:404-33. [Crossref] [PubMed]
21. Hershman JM. Physiological and pathological aspects of the effect of human chorionic gonadotropin on the thyroid. Best Pract Res Clin Endocrinol Metab 2004;18:249-65. [Crossref] [PubMed]
22. Huang SA, Dorfman DM, Genest DR, et al. Type 3 iodothyronine deiodinase is highly expressed in the human uteroplacental unit and in fetal epithelium. J Clin Endocrinol Metab 2003;88:1384-8. [Crossref] [PubMed]
23. Alexander EK, Pearce EN, Brent GA, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid 2017;27:315-89. [Crossref] [PubMed]
24. Yarrington CD, Pearce EN. Dietary iodine in pregnancy and postpartum. Clin Obstet Gynecol 2011;54:459-70. [Crossref] [PubMed]
25. Glinoer D. Thyroid hyperfunction during pregnancy. Thyroid 1998;8:859-64. [Crossref] [PubMed]
26. Haddow JE, McClain MR, Lambert-Messerlian G, et al. Variability in thyroid-stimulating hormone suppression by human chorionic [corrected] gonadotropin during early pregnancy. J Clin Endocrinol Metab 2008;93:3341-7. [Crossref] [PubMed]
27. Fraenkel M, Shafat T, Cahn A, et al. Low thyroid-stimulating hormone and its persistence beyond the first trimester of pregnancy. Int J Gynaecol Obstet 2018;142:270-6. [Crossref] [PubMed]
28. Roti E, Gardini E, Minelli R, et al. Thyroid function evaluation by different commercially available free thyroid hormone measurement kits in term pregnant women and their newborns. J Endocrinol Invest 1991;14:1-9. [Crossref] [PubMed]
29. Berta E, Samson L, Lenkey A, et al. Evaluation of the thyroid function of healthy pregnant women by five different hormone assays. Pharmazie 2010;65:436-9. [PubMed]
30. Lee RH, Spencer CA, Mestman JH, et al. Free T4 immunoassays are flawed during pregnancy. Am J Obstet Gynecol 2009;200:260.e1-6. [Crossref] [PubMed]
31. Wilke TJ. Diagnostic value of three methods for assessing free thyroxine in pregnancy. Ann Clin Biochem 1983;20:60-1. [Crossref] [PubMed]
32. Azizi F, Mehran L, Amouzegar A, et al. Establishment of the trimester-specific reference range for free thyroxine index. Thyroid 2013;23:354-9. [Crossref] [PubMed]
33. Kahric-Janicic N, Soldin SJ, Soldin OP, et al. Tandem mass spectrometry improves the accuracy of free thyroxine measurements during pregnancy. Thyroid 2007;17:303-11. [Crossref] [PubMed]
34. McLachlan SM, Rapoport B. Thyrotropin-blocking autoantibodies and thyroid-stimulating autoantibodies: potential mechanisms involved in the pendulum swinging from hypothyroidism to hyperthyroidism or vice versa. Thyroid 2013;23:14-24. [Crossref] [PubMed]
35. Barbesino G, Tomer Y. Clinical review: Clinical utility of TSH receptor antibodies. J Clin Endocrinol Metab 2013;98:2247-55. [Crossref] [PubMed]
36. Bucci I, Giuliani C, Napolitano G. Thyroid-Stimulating Hormone Receptor Antibodies in Pregnancy: Clinical Relevance. Front Endocrinol (Lausanne) 2017;8:137. [Crossref] [PubMed]
37. Giuliani C, Saji M, Bucci I, et al. Bioassays for TSH Receptor Autoantibodies, from FRTL-5 Cells to TSH Receptor-LH/CG Receptor Chimeras: The Contribution of Leonard D. Kohn. Front Endocrinol (Lausanne) 2016;7:103. [Crossref] [PubMed]
38. Diana T, Krause J, Olivo PD, et al. Prevalence and clinical relevance of thyroid stimulating hormone receptor-blocking antibodies in autoimmune thyroid disease. Clin Exp Immunol 2017;189:304-9. [Crossref] [PubMed]
39. Brown RS, Bellisario RL, Botero D, et al. Incidence of transient congenital hypothyroidism due to maternal thyrotropin receptor-blocking antibodies in over one million babies. J Clin Endocrinol Metab 1996;81:1147-51. [PubMed]
40. Abeillon-du Payrat J, Chikh K, Bossard N, et al. Predictive value of maternal second-generation thyroid-binding inhibitory immunoglobulin assay for neonatal autoimmune hyperthyroidism. Eur J Endocrinol 2014;171:451-60. [Crossref] [PubMed]
41. Mestman JH. Hyperthyroidism in pregnancy. Curr Opin Endocrinol Diabetes Obes 2012;19:394-401. [Crossref] [PubMed]
42. Goldman AM, Mestman JH. Transient non-autoimmune hyperthyroidism of early pregnancy. J Thyroid Res 2011;2011:142413. [Crossref] [PubMed]
43. Casey BM, Dashe JS, Wells CE, et al. Subclinical hyperthyroidism and pregnancy outcomes. Obstet Gynecol 2006;107:337-41. [Crossref] [PubMed]
44. Kinomoto-Kondo S, Umehara N, Sato S, et al. The effects of gestational transient thyrotoxicosis on the perinatal outcomes: a case-control study. Arch Gynecol Obstet 2017;295:87-93. [Crossref] [PubMed]
45. Niebyl JR. Clinical practice. Nausea and vomiting in pregnancy. N Engl J Med 2010;363:1544-50. [Crossref] [PubMed]
46. Goodwin TM, Hershman JM. Hyperthyroidism due to inappropriate production of human chorionic gonadotropin. Clin Obstet Gynecol 1997;40:32-44. [Crossref] [PubMed]
47. Rodien P, Bremont C, Sanson ML, et al. Familial gestational hyperthyroidism caused by a mutant thyrotropin receptor hypersensitive to human chorionic gonadotropin. N Engl J Med 1998;339:1823-6. [Crossref] [PubMed]
48. Ginsberg J, Lewanczuk RZ, Honore LH. Hyperplacentosis: a novel cause of hyperthyroidism. Thyroid 2001;11:393-6. [Crossref] [PubMed]
49. Gherman RB, Mestman JH, Satin AJ, et al. Intractable hyperemesis gravidarum, transient hyperthyroidism and intrauterine growth restriction associated with hyperreactio luteinalis. A case report. J Reprod Med 2003;48:553-6. [PubMed]
50. Goodwin TM, Montoro M, Mestman JH. Transient hyperthyroidism and hyperemesis gravidarum: clinical aspects. Am J Obstet Gynecol 1992;167:648-52. [Crossref] [PubMed]
51. Fiaschi L, Nelson-Piercy C, Tata LJ. Hospital admission for hyperemesis gravidarum: a nationwide study of occurrence, reoccurrence and risk factors among 8.2 million pregnancies. Hum Reprod 2016;31:1675-84. [Crossref] [PubMed]
52. Grün JP, Meuris S, De Nayer P, et al. The thyrotrophic role of human chorionic gonadotrophin (hCG) in the early stages of twin (versus single) pregnancies. Clin Endocrinol (Oxf) 1997;46:719-25. [Crossref] [PubMed]
53. Dierickx I, Decallonne B, Billen J, et al. Severe fetal and neonatal hyperthyroidism years after surgical treatment of maternal Graves' disease. J Obstet Gynaecol 2014;34:117-22. [Crossref] [PubMed]
54. Andersen SL, Olsen J, Carle A, et al. Hyperthyroidism incidence fluctuates widely in and around pregnancy and is at variance with some other autoimmune diseases: a Danish population-based study. J Clin Endocrinol Metab 2015;100:1164-71. [Crossref] [PubMed]
55. Amino N, Tanizawa O, Mori H, et al. Aggravation of thyrotoxicosis in early pregnancy and after delivery in Graves' disease. J Clin Endocrinol Metab 1982;55:108-12. [Crossref] [PubMed]
56. Weetman AP. Immunity, thyroid function and pregnancy: molecular mechanisms. Nat Rev Endocrinol 2010;6:311-8. [Crossref] [PubMed]
57. Tamaki H, Itoh E, Kaneda T, et al. Crucial role of serum human chorionic gonadotropin for the aggravation of thyrotoxicosis in early pregnancy in Graves' disease. Thyroid 1993;3:189-93. [Crossref] [PubMed]
58. Tagami T, Hagiwara H, Kimura T, et al. The incidence of gestational hyperthyroidism and postpartum thyroiditis in treated patients with Graves' disease. Thyroid 2007;17:767-72. [Crossref] [PubMed]
59. Laurberg P, Bournaud C, Karmisholt J, et al. Management of Graves' hyperthyroidism in pregnancy: focus on both maternal and foetal thyroid function, and caution against surgical thyroidectomy in pregnancy. Eur J Endocrinol 2009;160:1-8. [Crossref] [PubMed]
60. Andersen SL. Risk of embryopathies with use of antithyroidal medications. Curr Opin Endocrinol Diabetes Obes 2017;24:364-71. [Crossref] [PubMed]
61. Papendieck P, Chiesa A, Prieto L, et al. Thyroid disorders of neonates born to mothers with Graves' disease. J Pediatr Endocrinol Metab 2009;22:547-53. [Crossref] [PubMed]
62. Taylor PN, Vaidya B. Side effects of anti-thyroid drugs and their impact on the choice of treatment for thyrotoxicosis in pregnancy. Eur Thyroid J 2012;1:176-85. [Crossref] [PubMed]
63. Andersen SL, Olsen J, Laurberg P. Antithyroid Drug Side Effects in the Population and in Pregnancy. J Clin Endocrinol Metab 2016;101:1606-14. [Crossref] [PubMed]
64. Rubin PC. Current concepts: beta-blockers in pregnancy. N Engl J Med 1981;305:1323-6. [Crossref] [PubMed]
65. Mortimer RH, Tyack SA, Galligan JP, et al. Graves' disease in pregnancy: TSH receptor binding inhibiting immunoglobulins and maternal and neonatal thyroid function. Clin Endocrinol (Oxf) 1990;32:141-52. [Crossref] [PubMed]
66. Momotani N, Hisaoka T, Noh J, et al. Effects of iodine on thyroid status of fetus versus mother in treatment of Graves' disease complicated by pregnancy. J Clin Endocrinol Metab 1992;75:738-44. [PubMed]
67. Millar LK, Wing DA, Leung AS, et al. Low birth weight and preeclampsia in pregnancies complicated by hyperthyroidism. Obstet Gynecol 1994;84:946-9. [PubMed]
68. Davis LE, Lucas MJ, Hankins GD, et al. Thyrotoxicosis complicating pregnancy. Am J Obstet Gynecol 1989;160:63-70. [Crossref] [PubMed]
69. Männistö T, Mendola P, Grewal J, et al. Thyroid diseases and adverse pregnancy outcomes in a contemporary US cohort. J Clin Endocrinol Metab 2013;98:2725-33. [Crossref] [PubMed]
70. Aggarawal N, Suri V, Singla R, et al. Pregnancy outcome in hyperthyroidism: a case control study. Gynecol Obstet Invest 2014;77:94-9. [Crossref] [PubMed]
71. Luewan S, Chakkabut P, Tongsong T. Outcomes of pregnancy complicated with hyperthyroidism: a cohort study. Arch Gynecol Obstet 2011;283:243-7. [Crossref] [PubMed]
72. Chopra IJ. Fetal and neonatal hyperthyroidism. Thyroid 1992;2:161-3. [Crossref] [PubMed]
73. Clark SL, Phelan JP, Montoro M, et al. Transient ventricular dysfunction associated with cesarean section in a patient with hyperthyroidism. Am J Obstet Gynecol 1985;151:384-6. [Crossref] [PubMed]
74. Burch HB, Wartofsky L. Life-threatening thyrotoxicosis. Thyroid storm. Endocrinol Metab Clin North Am 1993;22:263-77. [Crossref] [PubMed]
75. Akamizu T. Thyroid Storm: A Japanese Perspective. Thyroid 2018;28:32-40. [Crossref] [PubMed]
76. King JR, Lachica R, Lee RH, et al. Diagnosis and Management of Hyperthyroidism in Pregnancy: A Review. Obstet Gynecol Surv 2016;71:675-85. [Crossref] [PubMed]
77. Nguyen CT, Sasso EB, Barton L, et al. Graves' hyperthyroidism in pregnancy: a clinical review. Clin Diabetes Endocrinol 2018;4:4. [Crossref] [PubMed]
78. Benvenga S, Amato A, Calvani M, et al. Effects of carnitine on thyroid hormone action. Ann N Y Acad Sci 2004;1033:158-67. [Crossref] [PubMed]
79. Mandel SJ, Cooper DS. The use of antithyroid drugs in pregnancy and lactation. J Clin Endocrinol Metab 2001;86:2354-9. [Crossref] [PubMed]
80. Nakamura H, Miyauchi A, Miyawaki N, et al. Analysis of 754 cases of antithyroid drug-induced agranulocytosis over 30 years in Japan. J Clin Endocrinol Metab 2013;98:4776-83. [Crossref] [PubMed]
81. Watanabe N, Narimatsu H, Noh JY, et al. Antithyroid drug-induced hematopoietic damage: a retrospective cohort study of agranulocytosis and pancytopenia involving 50,385 patients with Graves' disease. J Clin Endocrinol Metab 2012;97:E49-53. [Crossref] [PubMed]
82. Andersen SL, Olsen J, Wu CS, et al. Birth defects after early pregnancy use of antithyroid drugs: a Danish nationwide study. J Clin Endocrinol Metab 2013;98:4373-81. [Crossref] [PubMed]
83. Yoshihara A, Noh J, Yamaguchi T, et al. Treatment of graves' disease with antithyroid drugs in the first trimester of pregnancy and the prevalence of congenital malformation. J Clin Endocrinol Metab 2012;97:2396-403. [Crossref] [PubMed]
84. Cooper DS, Rivkees SA. Putting propylthiouracil in perspective. J Clin Endocrinol Metab 2009;94:1881-2. [Crossref] [PubMed]
85. Clementi M, Di Gianantonio E, Cassina M, et al. Treatment of hyperthyroidism in pregnancy and birth defects. J Clin Endocrinol Metab 2010;95:E337-41. [Crossref] [PubMed]
86. Andersen SL, Olsen J, Wu CS, et al. Severity of birth defects after propylthiouracil exposure in early pregnancy. Thyroid 2014;24:1533-40. [Crossref] [PubMed]
87. Bahn RS, Burch HS, Cooper DS, et al. The Role of Propylthiouracil in the Management of Graves' Disease in Adults: report of a meeting jointly sponsored by the American Thyroid Association and the Food and Drug Administration. Thyroid 2009;19:673-4. [Crossref] [PubMed]
88. Andersen SL, Laurberg P. Antithyroid drugs and congenital heart defects: ventricular septal defect is part of the methimazole/carbimazole embryopathy. Eur J Endocrinol 2014;171:C1-3. [Crossref] [PubMed]
89. Patel J, Landers K, Li H, et al. Delivery of maternal thyroid hormones to the fetus. Trends Endocrinol Metab 2011;22:164-70. [Crossref] [PubMed]
90. Polak M, Van Vliet G. Therapeutic approach of fetal thyroid disorders. Horm Res Paediatr 2010;74:1-5. [Crossref] [PubMed]
91. Fisher DA. Fetal thyroid function: diagnosis and management of fetal thyroid disorders. Clin Obstet Gynecol 1997;40:16-31. [Crossref] [PubMed]
92. Munoz JL, Kessler AA, Felig P, et al. Sequential Amniotic Fluid Thyroid Hormone Changes Correlate with Goiter Shrinkage following in utero Thyroxine Therapy. Fetal Diagn Ther 2016;39:222-7. [Crossref] [PubMed]
93. Polak M, Le Gac I, Vuillard E, et al. Fetal and neonatal thyroid function in relation to maternal Graves' disease. Best Pract Res Clin Endocrinol Metab 2004;18:289-302. [Crossref] [PubMed]
94. Andersen SL, Olsen J, Laurberg P. Foetal programming by maternal thyroid disease. Clin Endocrinol (Oxf) 2015;83:751-8. [Crossref] [PubMed]
95. Besançon A, Beltrand J, Le Gac I, et al. Management of neonates born to women with Graves' disease: a cohort study. Eur J Endocrinol 2014;170:855-62. [Crossref] [PubMed]
96. van Dijk MM, Smits IH, et al. Maternal Thyrotropin Receptor Antibody Concentration and the Risk of Fetal and Neonatal Thyrotoxicosis: A Systematic Review. Thyroid 2018;28:257-64. [Crossref] [PubMed]
97. McKenzie JM, Zakarija M. Fetal and neonatal hyperthyroidism and hypothyroidism due to maternal TSH receptor antibodies. Thyroid 1992;2:155-9. [Crossref] [PubMed]
98. Mitsuda N, Tamaki H, Amino N, et al. Risk factors for developmental disorders in infants born to women with Graves disease. Obstet Gynecol 1992;80:359-64. [PubMed]
99. Zakarija M, McKenzie JM, Hoffman WH. Prediction and therapy of intrauterine and late-onset neonatal hyperthyroidism. J Clin Endocrinol Metab 1986;62:368-71. [Crossref] [PubMed]
100. Luton D, Le Gac I, Vuillard E, et al. Management of Graves' disease during pregnancy: the key role of fetal thyroid gland monitoring. J Clin Endocrinol Metab 2005;90:6093-8. [Crossref] [PubMed]
101. Nachum Z, Rakover Y, Weiner E, et al. Graves' disease in pregnancy: prospective evaluation of a selective invasive treatment protocol. Am J Obstet Gynecol 2003;189:159-65. [Crossref] [PubMed]
102. Aubry G, Pontvianne M, Chesnais M, et al. Prenatal Diagnosis of Fetal Goitrous Hypothyroidism in a Euthyroid Mother: A Management Challenge. J Ultrasound Med 2017;36:2387-92. [Crossref] [PubMed]
103. Joshi K, Zacharin M. Hyperthyroidism in an infant of a mother with autoimmune hypothyroidism with positive TSH receptor antibodies. J Pediatr Endocrinol Metab 2018;31:577-80. [Crossref] [PubMed]
104. Kiefer FW, Klebermass-Schrehof K, Steiner M, et al. Fetal/Neonatal Thyrotoxicosis in a Newborn From a Hypothyroid Woman With Hashimoto Thyroiditis. J Clin Endocrinol Metab 2017;102:6-9. [PubMed]
105. Hamada N, Momotani N, Ishikawa N, et al. Persistent high TRAb values during pregnancy predict increased risk of neonatal hyperthyroidism following radioiodine therapy for refractory hyperthyroidism. Endocr J 2011;58:55-8. [Crossref] [PubMed]
106. Bliddal S, Rasmussen AK, Sundberg K, et al. Antithyroid drug-induced fetal goitrous hypothyroidism. Nat Rev Endocrinol 2011;7:396-406. [Crossref] [PubMed]
107. Grüner C, Kollert A, Wildt L, et al. Intrauterine treatment of fetal goitrous hypothyroidism controlled by determination of thyroid-stimulating hormone in fetal serum. A case report and review of the literature. Fetal Diagn Ther 2001;16:47-51. [Crossref] [PubMed]
108. American College of Obstetricians and Gynecologists. Practice Bulletin No 148: Thyroid disease in pregnancy. Obstet Gynecol 2015;125:996-1005. [Crossref] [PubMed]
109. Polak M. Human fetal thyroid function. Endocr Dev 2014;26:17-25. [Crossref] [PubMed]
110. Simpser T, Rapaport R. Update on some aspects of neonatal thyroid disease. J Clin Res Pediatr Endocrinol 2010;2:95-9. [Crossref] [PubMed]
111. Léger J. Management of Fetal and Neonatal Graves' Disease. Horm Res Paediatr 2017;87:1-6. [Crossref] [PubMed]
112. Banigé M, Polak M, Luton D, et al. Prediction of Neonatal Hyperthyroidism. J Pediatr 2018;197:249-254.e1. [Crossref] [PubMed]
113. van der Kaay DC, Wasserman JD, et al. Management of Neonates Born to Mothers With Graves' Disease. Pediatrics 2016;137: [Crossref] [PubMed]
114. Rivkees SA, Mattison DR. Propylthiouracil (PTU) Hepatoxicity in Children and Recommendations for Discontinuation of Use. Int J Pediatr Endocrinol 2009;2009:132041. [Crossref] [PubMed]
115. Kempers MJ, van Tijn DA, van Trotsenburg AS, et al. Central congenital hypothyroidism due to gestational hyperthyroidism: detection where prevention failed. J Clin Endocrinol Metab 2003;88:5851-7. [Crossref] [PubMed]
116. Rotondi M, Cappelli C, Pirali B, et al. The effect of pregnancy on subsequent relapse from Graves' disease after a successful course of antithyroid drug therapy. J Clin Endocrinol Metab 2008;93:3985-8. [Crossref] [PubMed]
117. Tada H, Hidaka Y, Tsuruta E, et al. Prevalence of postpartum onset of disease within patients with Graves' disease of child-bearing age. Endocr J 1994;41:325-7. [Crossref] [PubMed]
118. Stagnaro-Green A. Approach to the patient with postpartum thyroiditis. J Clin Endocrinol Metab 2012;97:334-42. [Crossref] [PubMed]
119. Amino N, Tada H, Hidaka Y. Postpartum autoimmune thyroid syndrome: a model of aggravation of autoimmune disease. Thyroid 1999;9:705-13. [Crossref] [PubMed]
120. Ide A, Amino N, Kang S, et al. Differentiation of postpartum Graves' thyrotoxicosis from postpartum destructive thyrotoxicosis using antithyrotropin receptor antibodies and thyroid blood flow. Thyroid 2014;24:1027-31. [Crossref] [PubMed]
121. Gorman CA. Radioiodine and pregnancy. Thyroid 1999;9:721-6. [Crossref] [PubMed]
122. Cooper DS. Antithyroid drugs. N Engl J Med 2005;352:905-17. [Crossref] [PubMed]
123. Eisenstein Z, Weiss M, Katz Y, et al. Intellectual capacity of subjects exposed to methimazole or propylthiouracil in utero. Eur J Pediatr 1992;151:558-9. [Crossref] [PubMed]
124. Azizi F, Khoshniat M, Bahrainian M, et al. Thyroid function and intellectual development of infants nursed by mothers taking methimazole. J Clin Endocrinol Metab 2000;85:3233-8. [Crossref] [PubMed]
125. Kampmann JP, Johansen K, Hansen JM, et al. Propylthiouracil in human milk. Revision of a dogma. Lancet 1980;1:736-7. [Crossref] [PubMed]
126. Johansen K, Andersen AN, Kampmann JP, et al. Excretion of methimazole in human milk. Eur J Clin Pharmacol 1982;23:339-41. [Crossref] [PubMed]
127. Cooper DS, Bode HH, Nath B, et al. Methimazole pharmacology in man: studies using a newly developed radioimmunoassay for methimazole. J Clin Endocrinol Metab 1984;58:473-9. [Crossref] [PubMed]
128. Karras S, Tzotzas T, Kaltsas T, et al. Pharmacological treatment of hyperthyroidism during lactation: review of the literature and novel data. Pediatr Endocrinol Rev 2010;8:25-33. [PubMed]