HYPERTHYROIDISM IN PREGNANCY

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HYPERTHYROIDISM IN PREGNANCY

Jorge H. Mestman, MD

The interpretation of thyroid tests and the diagnosis of thyroid pathology may be a challenge for the physician caring for pregnant women. In the last decade, improvements in the sensitivity of thyroid tests, such as serum thyrotropin (TSH), have clarified some issues related to thyroid physiology in the pregnant state.z2 Although autoimmunity has traditionally been considered to be the most common etiology of disorders of the thyroid gland affecting pregnant women, new studies indicate that hyperthyroidism caused by the inappropriate production of human chorionic gonadotropin (hCG) is the leading cause of abnormalities in thyroid tests during the first half of pregnancy.z’ However, from a clinical point of view, hyperthyroidism owing to Graves’ disease remains the most important cause of maternal and fetal m0rbidity.4~

Hyperthyroidism is second to diabetes mellitus as the most common endocrine disorder seen in pregnancy. Women with active or treated hyperthyroidism need to be advised concerning the potential medical problems that they and their fetuses may encounter during gestation, particularly if thyroid dysfunction is not managed properly. The outcome of pregnancy may be affected not only in women with active hyperthyroidism but in some patients with Graves’ disease who have previously been treated with ablation therapy, involving either surgery or radioactive iodide (RAI). A team approach to management is strongly recommended, with the participation of an endocrinologist, obstetrician, perinatologist, neonatologist, and anesthesiologist. This article reviews the prevalence and etiology of hyperthyjoidism in pregnancy; hyperthyroidism caused by the inappropriate secretion of hCG; potential maternal, fetal, and neonatal morbidity in hyperthyroidism associated with Graves‘ disease; management of hyperthyroidism during gestation; prepregnancy counseling; issues related to breast-feeding in mothers taking antithyroid drugs (ATD); and postpartum thyroid dysfunction in patients with Graves’ disease.

From the Departments of Medicine and Obstetrics and Gynecology, University of Southern California, School of Medicine, Los Angeles, California

ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA

VOLUME 27 * NUMBER 1 * MARCH 1998 127

128 MESTMAN

PREVALENCE

The prevalence of clinical hyperthyroidism in pregnancy has been reported to be approximately 0.2Y0.~~ At the author's institution, the incidence is 0.1Y0.",~ In Japan, Kamijo and co -w~rke r s~~ screened 9453 women in the first trimester of pregnancy; 0.4% had suppressed serum TSH and other chemical markers of autoimmune thyroid disease. In an additional 0.4% of women, the serum TSH was suppressed without other indicators of autoimmunity, which is consistent with the finding of suppressed or undetected serum TSH in the first trimester of some otherwise normal pregnancies.

ETIOLOGY

Transient hyperthyroidism in the first half of pregnancy caused by the inappropriate secretion of hCG is now the most frequent cause of hyperthyroidism in pregnancy. Other causes accounting for less than 10% of all cases of this condition in pregnancy include the following:

Graves' disease Multinodular goiter Toxic adenoma Subacute thyroiditis Iatrogenic thyrotoxicosis Thyrotoxicosis factitia TSH-producing pituitary tumor (an isolated case was recently reported in a

letter to the editor9) Struma ovarii Transient hyperthyroidism of hyperemesis gravidarum Hydatidiform mole

PREPREGNANCY COUNSELING

The natural course of Graves' hyperthyroidism in pregnancy is characterized by aggravation of symptoms in the first half of pregnancy, with amelioration in the second half and recurrence in the postpartum period.2,47 It is advisable for hyperthyroid women desiring to conceive to achieve euthyroidism before conception. The preconception control of hyperthyroidism becomes as important as in diabetic woman; oral contraceptives are not contraindicated in most women with thyroid disease. If ablation therapy using RAI is chosen, it is customary to avoid pregnancy for the first 6 months post-treatment. No evidence suggests that radioactive treatment given to the mother before pregnancy has an adverse effect on the fetus or on offspring later in life.26 Potential fetal complications when ATD therapy is used in pregnancy are a concern. Fetal goiter and neonatal hypothyroidism are caused by an excessive dosage of propylthiouracil (PTU) or methimazole (MMI).7 ATDs are not responsible for the development of congenital malformation^.^^, 68 Only one study reports a small increase in congenital malformations in patients with hyperthyroidism during embryogene~is.~~ Cou- ples with a hyperthyroid woman who wishes to conceive should also be made aware that the dosage of ATDs is frequently adjusted during the course of pregnancy; therefore, thyroid tests must be performed at regular intervals, with the goal of keeping free thyroid hormone levels in the upper one third of the

HYPERTHYROIDISM IN PREGNANCY 129

limits of normal? ATD requirements decrease during gestation; and, in about 30% of women, the dose may be discontinued in the last few weeks of gestation. The risk for postpartum thyroiditis or recurrent hyperthyroidism also should be discussed with patients.’, s, 54 The rare occurrence of fetal and neonatal hyperthy- roidismZ0, 39 should be included during the counseling sessions.

HYPERTHYROIDISM CAUSED BY INAPPROPRIATE PRODUCTION OF HUMAN CHORlONlC GONADOTROPIN

In 1955, Tisne and co-workers” reported the association of hyperthyroidism in women with trophoblastic tumors, findings that were later confirmed.2R The severity of hypermetabolic symptoms ranged from mild to severe (including pulmonary edema), with the symptoms resolving as soon as the tumor was removed.15 There is no correlation between the values of thyroid tests and the severity of symptoms; and, indeed, in many cases, symptomatology is absent despite significant elevations in free thyroid hormones. Enlargement of the thyroid gland is usually not detected, the ratio of serum T, to T, is higher than in Graves’ disease, and serum TSH is suppressed or undetectable. Thyroid antibodies are not present; and, in the few cases in which the uptake of RAI has been measured, the thyroid uptake is greatly increased. The only effective therapy is surgical removal of the mole. Because many of these patients have significant hyperthyroid symptoms, they should be pretreated with iodine with or without beta-adrenergic blocking drugs before evacuation of the mole. It is estimated that 20% of women with complete moles have hyperthyroidism.2s

Hyperthyroidism in women with severe hyperemesis gravidarum was origi- nally described by Bruun and Kristoffersen.6 Their studies included 35 pregnant women with hyperemesis gravidarum, 14 pregnant women with hydatidiform mole, and 57 normal pregnant women. Serum protein-bound iodine (PBI) was measured. In 12 of the 35 women with hyperemesis gravidarum, the serum PBI value was significantly higher than in women with normal pregnancy (P<O.OOl), returning to normal after the resolution of hyperemesis. Bruun and Kristoffersen suggested a common cause of thyroid stimulation in patients with mole and hyperemesis gravidarum.

A few years later, Bouillon and co-workers4 detected an increased free thyroxine index (FTJ) in 24 of 33 (72.7%) consecutive patients with hyperemesis gravidarum. The free triiodothyronine index (FTJ) was elevated in 4 of 11 women (36%). Patients were hospitalized for a mean duration of 4 weeks, and the mean weight loss was 5 kg. Slight disturbances in liver function tests occurred in five patients. The clinical presentation is characterized by severe nausea and vomiting beginning between 6 and 9 weeks’ gestation, weight loss, ketonuria, and hospitalization as the result of significant dehydration. In the most severe cases, abnormalities in serum electrolytes and liver function tests are common. Patients with the most severe symptoms have more abnormal thyroid test indices as well as abnormalities in liver function and serum electrolytes. Goodwin and colleaguesz4 published the findings in a group of 67 patients seen during a period of 10 months at Los Angeles County/University of South- em California Women’s and Children’s Hospital (Fig. 1). Criteria for the diagnosis of hyperemesis gravidarum included persistent vomiting, large ketonuria, and weight loss greater than 5%. Abnormal thyroid tests consistent with hyperthyroidism were detected in 44 of 67 patients (66%). Serum FT41 ranged from 13.2 to as high as 37.6. Undetectable serum TSH was found in 30% of cases; in another 30% of patients, serum TSH was suppressed. Elevations in serum T,

130 MESTMAN

No vomiting (n = 30) Vomiting (n = 27)

Hyperemesis (n= 38) T

vere hvDeremesis

40

30

FreeT4 2o (nmol/L)

10

0

125 I 100

hCG (IU/ml) 75

50

25

0

(n = 19)

Figure 1. Relationship between the severity of vomiting and serum concentrations of TSH, free T, and hCG (mean f SE). Hormone concentrations differed significantly (P > 0.05) between each group of patients except where indicated. (From Goodwin TM, Montoro M, Mestman JH: The role of gonadotropin in transient hyperthyroidism of hyperemesis gravi- darium. J Clin Endocrinol Metab 75:1333-1337, 1992; with permission.)


Table 1. BIOCHEMICAL ABNORMALITIES IN HYPEREMESIS GRAVIDARUM

Range of Abnormality Number* Percent Values

Thyroid Increased free T4 index Increased free T, index TSH (mU/mL)

Undectable Suppressed

Elevated free T4 index or TSH suppressed

Sodium <I35 rnEq/L Potassium <3.2 mEq/L Chloride <99 mEq/L Bicarbonate >26 mEq/L

Aspartate arninotransferase or alanine

Total bilirubin >1 .O rng/dL Amylase >150 U/dL

Electrolytes

Liver/gastrointestinal

aminotransferase >40 U/L

39 6

20 40 44

19 10 16 10

28 14 6

59 9

30 60 66

28 15 24 15

42 21 9

13.2-37.6 225-350

c0.04 <0.4

125-1 34 2.3-3.1

27-34 80-98

41 -324 1 .l-5.3 151-391

*n = 67. From Goodwin TM, Hershman JM: Hyperthyroidism due to inappropriate production of human chorionic gonadotropin. Ciin Obstet Gynecol 40:32-44, 1997; with permission.

were present in six cases (9%), consistent with the high serum T, to T, ratio reported in patients with hydatidiform mole. The low elevation in serum T, values is most likely the result of the severity of patients’ nausea and vomiting. Hypokalemia was found in 15% of affected patients and hyperbilirubinemia (with values as high as 5.3 mg/dL) in 21% of cases. The highest alanine aminotransferase value was 324 U/L; serum amylase was slightly elevated in some patients (Table 1). 41 values, with the exception of serum TSH, normalized after vomiting subsided; and, in almost every patient, this was achieved by 16 to 20 weeks’ gestation. Serum TSH remained suppressed for a few more weeks, occasionally, until 30 weeks‘ gestation (Fig. 2). Clinically, most of the patients in the study were slender despite their Latino background; in addition to weight loss and vomiting, complaints of mild tremor, heat intolerance, and palpitations were reported in the most severe cases.

On physical examination, tachycardia and dehydration with postural hypo- tension are common findings. Goiter is usually absent, and there are no extrathy- roidal signs such as exophthalmopathy. Serum thyroid antibodies are not detected. The most severe cases may require total parenteral nutrition. In such patients, anemia and hypoproteinemia are not unusual. Because of the significant elevation in thyroid hormones, the marked tachycardia, and the severity of dehydration, the physician is confronted with a unique situation in which the differential diagnosis between hyperemesis gravidarum and Graves’ disease is challenging. In the presence of a history of autoimmune thyroid disease, goiter, or other signs of thyrotoxicosis, the distinction from Graves‘ disease may be difficult. Vomiting may be a presenting symptom in patients with Graves’ disease.5R The presence of positive antibodies, including thyroid-stimulating immunoglobulin (TSI), may favor the diagnosis of Graves’ disease. Lack of resolution of hyperthyroxinemia by 16 to 20 weeks of gestation is another indication for considering antithyroid medication. However, only patients with severe nausea and vomiting have a significant elevation in serum free thyroxine

132 MESTMAN

WEIGHT KG

60

50

40

I -vomiting 1 r

TSH FT,I FT,I pU/ml )M - ---

10 350 20 \ \

5 210 12

0 3 70 4

0 4 8 12 16 20 24 28 32 36 40

Weeks Gestation

Figure 2. Clinical course of a patient with transient hyperthyroidism of hyperemesis gravidarum (TTHG). (From Mestman JH: Thyroid disorder in pregnancy. Endocrinol Metab Clin N Am 24:41-71, 1995.)

values. They may have had a history of similar symptoms in previous pregnancies. A very important clinical clue is that.they have no hyperthyroid symptoms antendating the pregnancy.

In the author's experience, most women in whom the diagnosis of hyperthyroidism due to Graves' disease is made for the first time in pregnancy have hypermetabolic symptoms for some time before the diagnosis of pregnancy. Chemical hyperthyroidism (suppressed serum TSH) is also seen in women with less severe vomiting,z3, 55 in multiple gestation,2I and even in normal pregnancy.22

Resolution of hyperthyroxinemia closely follows the improvement in nausea and vomiting. ATD therapy has been used by some clinicians, however, it is difficult for patients to tolerate oral medications with such severe nausea and vomiting.

Furthermore, ATDs have been shown to be of no value in reducing vomiting despite the normalization of thyroid tests.% In the study by Bouillon and co- workers: ATD therapy was used in six patients (10 to 30 mg of MMI per day) during several weeks; euthyroidism was achieved in a mean of 17 days as compared with a mean of 19 days in untreated hyperthyroxinemic women. The duration of gestation was similar in both groups, as well as the birth weight of infants. However, birth weight was significantly lower than in infants born to mothers without hyperemesis gravidarum (3420 g versus 3166 g, P<O.Ol). The weight of newborns of euthyroid mothers with hyperemesis gravidarum was similar to that in the control group. Weight gain during pregnancy was significantly lower in the hyperthyroxinemic mothers in comparison with the control


patients and euthyroid patients with hyperemesis gravidarum (12 kg versus 8.7 kg).

The lowest birth weight was observed in the infant born to the mother with the highest FTJ value. It is the author’s practice not to use ATD in the management of this condition. From the previous observations, it seems advisable to observe patients after the resolution of vomiting to ensure a normal weight gain. More studies are needed in the long-term follow-up of infants. The term transient hyperthyroidism of hyperemesis gravidarum (THHG) is preferable for defining this syndr0me,2~ because it describes better the etiology and the transient course of the symptoms.

Other investigators have used the term gestational thyrotoxicusis; however, there are other conditions in pregnancy in which thyroid tests are in the hyperthyroid range without symptoms of hyperemesis. Such conditions of hCG- mediated hyperthyroidism in early pregnancy include the following:

Subclinical hyperthyroidism-normal FT, and suppressed TSH Normal pregnancy (up to 15%) Multiple gestation Mild nausea/vomiting Hyperreactio luteinalis-luteoma of pregnancy (later in pregnancy)

Multiple gestation Transient hyperthyroidism of hyperemesis gravidarum Hydatidiform mole

Clinical hyperthyroidism-high FT, and suppressed TSH

The majority of i-nvestigators in the field believe that an inappropriate level of serum hCG is the cause of THHG.25, 65 hCG, as well as luteinzing hormone (LH), follicle-stimulating hormone (FSH), and TSH, are members of a glycopro- tein hormone family that contains a common alpha-subunit and a hormone- specific beta-subunit (Fig. 3). hCG stimulates the human thyroid; even in early normal pregnancy, hCO can stimulate the thyroid gland and lower serum TSH levels even to undetectable levels. Furthermore, there is an inverse relationship between serum levels of TSH and hCG, best seen in early pregnancy.27 Recent studies have clarified the structural homology not only of TSH and hCG mole- cules but also of their receptors. This homology suggests the basis for the crossreactivity of hCG with the TSH re~eptor.6~ The hCG molecule is heteroge- nous; its immunoreactivity in serum represents a mixture of hCG-related mole- cules, the thyrotropic action of which depends on their molecular structures. Modifications in the oligosaccharide side chain may affect the biologic activity.

Several studies have demonstrated that the deglycosylated and desialylated hCG enhances its thyrotropic potency. These forms have been isolated from hydatidiform and the serum of women with hyperemesis g rav ida r~m.~~ The latest studies explain past discrepancies among several investigators regarding the role of hCG in the etiology of THHG. The correlation among hCG levels, symptoms, and hyperthyroxinemia is not always present.

Removal of sialic acid from the hCG molecule enhances its TSH receptor binding and also sharply reduces its plasma half-life. Therefore, it seems that the in vivo thyrotropic activity of hCG is regulated by both factors: the amount of desialylated hCG produced from trophoblast cells and its plasma half-life.z5, 69

Hyperreactio luteinalis, also known as multiple luteinized follicular cysts, is a rare condition in which hCG levels are higher than in normal pregnancy, with an increased sensitivity of the ovaries to hCG action. The syndrome is characterized clinically by enlargement of the ovaries, numerous luteinized cysts, and maternal ~iri l ization.~~ Recently, the author had the opportunity to


her family. Most of the complications reported in pregnancy in women with a past history or active hyperthyroidism are related to poor understanding of the natural history of the disease, poor patient compliance with drug therapy, or diagnosing the disease late in pregnancy, either because the condition was not previously diagnosed or because of late booking. The prognosis for the mother and conceptus is excellent if the diagnosis and treatment plan are made early in pregnancy, and therapeutic guidelines are properly followed.47

Hyperthyroidism Diagnosed for the First Time in Pregnancy

There are several situations, particularly in the first half of pregnancy, in which the results of thyroid tests are in the hyperthyroid range with or without the clinical manifestations of hyperthyroidism. A clinical history of hypermetabolic symptoms preceding pregnancy, the presence of goiter and exophthalmopathy, and a positive anti-thyroid peroxidase (TPO) titer support the diagnosis of hyperthyroidism caused by autoimmune thyroid disease.

Patient Undergoing ATD Therapy at the Time of Conception

If the serum FT, levels or FTJ are within normal limits, the amount of ATD should be adjusted to the minimum dose to achieve a FT, value in the upper one third of normal. If the serum TSH is also within normal limits, the ATD may be discontinued, keeping in mind that relapses of hyperthyroidism may occur in the first trimester of pregnancy; therefore, thyroid tests should be ordered a few weeks after adjusting or stopping an ATD. The author continues with the same ATD that the patient was taking before conception; however, other clinicians recommend switching from MMI to PTU, owing to the potential occurrence of aplasia cutis in the scalp of newborns from mothers taking MMI.

Hyperthyroidism in Remission Following ATD Therapy

For reasons not yet clearly understood, hyperthyroidism may recur in early pregnancy.’ An increase in the titer of TSI has been suggested as the cause of the aggravation, and a role of hCG has also been proposed.63 If hyperthyroidism recurs, ATD therapy may be needed for a few weeks until normalization of serum FT,. Postpartum recurrences are not uncommon in this situation.

History of Ablation Therapy for Graves’ Disease

Following ablation therapy, thyroid replacement therapy is needed in almost every patient; after conception, the dose of thyroid hormone needs to be increased in a significant number of women.32 Serum TSH should be kept within normal limits and determined at the time of diagnosis of pregnancy, between 20 and 24 weeks’ gestation, and again between 28 and 32 weeks’ gestation. The dose of thyroxine should be reduced to the prepregnancy amount after delivery. In an occasional patient, serum levels of TSI remain elevated despite previous ablation therapy. This IgG immunoglobulin, when present in high titers in maternal serum, may cross the placenta and stimulate the fetal thyroid gland, producing fetal hyperthyroidism?’ Although a rare event, the patient and her

136 MESTMAN

obstetrician should be aware of early signs such as fetal tachycardia and fetal growth retardation or the occasional detection of fetal goiter by ultrasonography. Situations in which the determination of serum TSI is indicated include the following:

Fetal or neonatal hyperthyroidism in previous pregnancies Treated Graves’ disease in the presence of

Fetal tachycardia Intrauterine growth retardation Incidental fetal goiter on ultrasound

Active disease (third trimester) during treatment with ATD to predict neonatal hyperthyroidism

Previous Birth of an Infant with Thyroid Dysfunction

Fetal and neonatal hyperthyroidism are rare occurrences that have been reported in 1% to 2% of pregnancies affected by Graves’ disease.zo Recurrences of fetal and neonatal hyperthyroidism in subsequent pregnancies are not un~sual.’~ Morbidity and mortality are significant, and early detection and prompt treatment are mandatory. As mentioned previously, high maternal values of serum TSI are predictive and should be measured in women at the time of conception.

Recurrence of Hyperthyroidism in the Postpartum Period

Hyperthyroidism often recurs in the postpartum period in women with a previous history of Graves’ disease or may present for the first time within 1 year following delivery.

CLINICAL PRESENTATION

The clinical diagnosis of hyperthyroidism in pregnancy may be difficult. Normal pregnancy may mimic many of the symptoms and signs of hyperthyroidism, such as heat intolerance and palpitations. In hyperthyroid women, the most common initial symptoms are tiredness, palpitations, insomnia, heat intolerance, proximal muscle weaknesses, shortness of breath, and irritability. Two of the most suggestive hyperthyroid signs in pregnancy are the failure to gain weight despite good appetite and persistent tachycardia, with a pulse rate over 90 beats per minute at rest. Both signs are also useful in assessing the response to antithyroid therapy.

In other situations when the patient presents to the physician with pregnancy-induced hypertension (toxemia) or even in congestive heart failure, the etiology does not become apparent until thyroid tests are Congestive heart failure may develop under stressful situations such as operative delivery,’O intercurrent infections, or severe anemia. As mentioned previously, aggravation of the symptoms may be seen in the first half of pregnancy. The author recently treated a patient with Graves’ hyperthyroidism who discontinued ATD therapy at conception and in whom congestive heart failure developed in the first weeks of gestation. In another case, hyperthyroidism, diagnosed 6 months’ postpartum, was in remission. The patient was admitted to the hospital and presented with symptoms related to the cardiovascular system (shortness of breath, severe

PTU

25 FT41


PTU

LNMP TSH mU/L

20

15

10

5

0

RAIU=35'%, Anti-TPO=< 0.3 UlmL

6 8 12 16 20 24 30 7 11 15

Months post-partum Weeks gestation

5

0.4

Figure 4. Onset of hyperthyroidism 6 months postpartum with subsequent remission and recurrence early in the next pregnancy. LNMP = Last menstrual period; FT,I = Free thyroxine index; TSH = Thyroid stimulating hormone; RAlU = 24 hour radioactive iodine; PTU = propylthiouracil.

tachycardia, muscle weakness) (Fig. 4). A complete cardiovascular evaluation including an echocardiogram was normal, a pregnancy test was positive, and pelvic ultrasound was consistent with 7 weeks' gestation. Thyroid tests were in the hyperthyroid range. The patient responded quickly to MMI, 10 mg twice daily, with remission of the symptoms and normalization of thyroid tests after 4 weeks of therapy.

Heart failure may occur in patients with no evidence of previous heart abnormalities.lO, 46 Easterling and co-w~rkers '~ studied six pregnant patients with hyperthyroidism. Hemodynamic measurements included cardiac output measured by Doppler technique, with calculation of total peripheral resistance. Four of the six patients were initially studied before the 12th week of gestation; hernodynamic determinations were repeated throughout pregnancy. There was a 65% elevation in cardiac output and a 35% reduction in total peripheral resistance; in contrast, there was a 21% increase in heart rate. Maternal hemodynamics were more abnormal than would be expected from examining heart rate alone. As shown in previous studies in nonpregnant hyperthyroid patients (article by Cooper on p. 225 of this issue), cardiac parameters remained significantly hyperdynamic for some time after the normalization of thyroid tests.

LABORATORY ~ E S T S

The diagnosis of hyperthyroidism is confirmed by an elevation in FT, or the calculated FT,I and an undetectable serum TSH. In an occasional patient, the serum FT4 may be within normal limits or at the upper limit of normal, in which case the determination of FT, or FT,I will confirm the diagnosis. The

138 MESTMAN

differential diagnosis of hyperthyroxinemia in the first trimester of pregnancy has been discussed previously.

Elevated levels of autoantibodies to thyroperoxidase (anti-TPO), although not essential, confirm the presence of autoimmunity and may predict the development of postpartum thyroid dysfunction. Determination of serum TSI is helpful in specific situations. Titers of both antibodies decrease with the progression of pregnancy. For the predication of neonatal thyrotoxicosis, the TSI test is best performed in the last trimester.

PREGNANCYOUTCOME

Prompt diagnosis and treatment of hyperthyroidism are of paramount importance in preventing maternal and fetal morbidity and mortality. Most of the reported complications have occurred in patients in whom the disease was not diagnosed or remained untreated (Table 2) . In those patients in whom the diagnosis is made early in pregnancy and in whom treatment is started promptly, and in those who become pregnant while the thyrotoxicosis is under control, the prognosis for mother and neonate is excellent in the majority of studies reported to date. However, maternal and fetal complications are significantly increased in patients remaining hyperthyroid in the second half of pregnancy.l4, 48, 4y The incidence of pulmonary edema and thyroid crisis is much higher than in nonpregnant hyperthyroid patients of comparable age. Because of their young age, relative good health, and the lack of complicating factors, many pregnant women tolerate the disease well until an intercurrent complication manifests itself. In other cases, there is a long history of noncompliance with medication, or a delayed recognition of symptoms by patients or health care professionals. Davis and colleague^^^ collected 342 cases reported in the literature from 1972 to 1988. Thyroid crisis was reported in 5 of 265 pregnancies that were medically treated and in 7 of 34 (21%) receiving no treatment for hyperthyroidism (Table 3) . The author’s experience has been similar. In a group of 50 hyperthyroid pregnant women, 18 received no medical treatment. Four of these patients had toxemia (22.2%); one pregnancy was complicated by thyroid crisis, and another two by congestive heart failure and atrial fibrillation. In the 32 treated women, the incidence of toxemia was similar to that in the general pop~lation.”~ In another series, thyroid storm was reported in 3 of 32 patients, with one maternal death.35 Perinatal morbidity and mortality are also affected when maternal hyperthyroidism is not controlled in the first two trimesters of ~ r e g n a n c y . ’ ~ , ~ ~ , ~ ~ In one study:* the relative risk of low birth weight infants was

Table 2. POTENTIAL MATERNAL AND FETAL COMPLICATIONS IN UNCONTROLLED HYPERTHYROIDISM

Maternal Fetal

Pregnancy-induced hypertension Hyperthyroidism Preterm delivery Neonatal hyperthyroidism Congestive heart failure Thyroid storm Small-for-gestational-age Miscarriage Prematurity Placenta abruptio Stillbirth Infection

Intrauterine growth retardation


Table 3. HYPERTHYROIDISM AND PREGNANCY: TREATMENT AND OUTCOME IN 342 PATIENTS (1972 to 1989)

Medical Surgical None

Outcome NO. (Yo) No. (%) No. (“70)

Total number of patients 265 43 34 Stillbirths 13 (5) 3 (7) 8 (24) Premature 29 (11) 4 (9) 18 (53) Anomalies 3 (1) 1 (2) Thyroid crisis 5 (2) 1 (2) 7 (21)

Adapted from Davis LE, Lucas MJ, Hankins GDV, et al: Thyrotoxicosis complicating pregnancy. Am J Obstet Gynecol 160:63-70, 1989; with permission.)

0.74 among women who remained euthyroid throughout pregnancy, 2.36 among women who became euthyroid sometime late in pregnancy, and 9.24 in women who remained hyperthyroid until the time of delivery. The incidence of prematurity, small-for-gestational-age (SGA) infants, intrauterine death, and toxemia is also significantly increased when hyperthyroidism is not controlled (Table 2). Mitsuda and colleagues49 studied 230 consecutive pregnancies in 176 women with Graves’ disease during a period of 14 years. A total of 111 women were treated with ATD; 110 were in remission while off of ATD therapy, of whom 36 had mild chemical thyrotoxicosis. The objective of the study was to identify risk factors for disorders of fetal growth and neonatal thyroid function. Four risk factors were identified for SGA neonates: (1) maternal thyrotoxicosis for 30 weeks or more during pregnancy, (2) a history of Graves’ disease for more than 10 years, (3) the onset of Graves’ disease before age 20 years, and (4) a maternal TSH-binding inhibitory immunoglobulin (TBII) level of 30% or more at delivery. The investigators did not observe an increased incidence of pregnancy-induced hypertension (7.3%) or prematurity (5.7%) in the total group of 230 deliveries. These data emphasize the importance of early control of hyperthyroidism to decrease the high incidence of complications.

Determination of maternal serum TSI (TSH receptor antibody [ T u b ] , TBII) in pregnant women with Graves’ disease has been recommended to predict fetal and neonatal thyroid dysfunction.16, 39 TSI in excess of 300% of control values or a level of TBII in excess of 30% is predictive of fetal hyperthyroidism.’” 20, 3y, 4q

There is no association between TSI titers and low birth weight or preeclampsia.48.49

Transient neonatal hypothyroidism or elevations in serum TSH with normal serum FT, (hyperthyrotropinemia) have been related to the amount of antithyroid medication taken by the mother in the last weeks of gestation. The incidence varies from 1 of 1814R to 13 of 230 ~regnancies .~~ Abruption of the placenta also has been reported in patients with uncontrolled hyperthyroidism.

TREATMENT

Treatment of hyperthyroidism in pregnancy is essential for the well-being of both the mother and conceptus. Medical treatment with ATD is the preferred therapy by most investigators in the field. The addition of beta-adrenergic blocking agents and, occasionally, iodide for a very short period of time is

140 MESTMAN

recommended in some situations. Subtotal thyroidectomy is reserved for se- lected cases.

Antithyroid Drug Therapy

Medical treatment of hyperthyroidism in the United States is limited to two ATDs, PTU and MMI (Tapazole). Carbimazole, which is metabolized to MMI, is used in Europe with similar therapeutic results. Both PTU and MMI are effective in controlling the disease in pregnancy, although the majority of textbooks and reviews favor the use of PTU. This preference is based on the assumption that PTU is more bound to plasma proteins in comparison with MMI; therefore, in theory, less drug would be transferred to the fetus. Another reason for PTU preference in pregnancy is the rare occurrence of a scalp lesion (aplasia cutis congenita) in the neonates born to women treated with MML4" This is a localized lesion in the parietal area of the scalp characterized by congenital absence of the skin, a punched-out ulcerlike lesion that usually heals spontaneously. A total of 17 cases have been reported in infants born to hyperthyroid mothers treated with MMI.*" In the first 11 cases reported, the condition occurred in five infants born to three mothemh6 The incidence in the general population is 0.03% of newborns.66 In some large series, this complication has not been reported.43, 4+50

At the time of conception, a question frequently asked by patients as well as physicians whether it is advisable to discontinue MMI and to start the patient on PTU therapy. It is the author's understanding that, with the exception of the rare occurrence of neonatal scalp lesions, there is no indication that one drug is superior to the other in pregnancy. When both drugs were compared in a large group of pregnant women, the maternal, fetal, and neonatal outcomes were similar.68 There are other reasons why the use of MMI in pregnancy may be favored over PTU. Compliance and acceptance by the patient may be better with MMI, because the same therapeutic result is obtained with a lower number of tablets (MMI is dispensed in 5- and 10-mg tablets and PTU in 50-mg tablets). MMI may be taken once or twice a day as compared with the every 8-hour regimen for PTU. The clinical responses to both drugs are similar, and the time to achieve euthyroidism is the same with an equivalent amount of both drugs.@

Resistance to ATDs is exceptionally rare. Cooper" studied nine patients with Graves' disease, including three pregnant women. He measured serum levels of PTU and concluded that noncompliance was the most likely reason for the lack of response to PTU. He suggested substituting MMI because it may be given as a single daily dose encompassing a fewer number of pills.

The goal of therapy is normalization of thyroid tests and symptoms in the shortest period of time, the prevention of maternal and fetal complications, and the delivery of a healthy newborn who will develop normally without somatic or intellectual sequela. The daily dose of ATD during pregnancy should be the minimum necessary to keep serum FT, in the upper one third of the normal range. Overdosage of ATD may produce fetal goiter and hypothyroidi~m.~, 37

Therapy is recommended for almost every woman in whom the diagnosis of hyperthyroidism is made. The exception are patients with minimal or no symptoms, with normal weight gain, and very mild elevations in free serum levels of thyroid hormones. Therapy is started in the presence of worsening symptoms or thyroid tests. In some patients, thyroid tests may normalize spontaneously with the progression of pregnancy as the result of immunologic changes occurring in normal pregnancy. However, hyperthyroidism frequently recurs in the postpartum period.


Patients are seen every 2 weeks at the beginning of therapy, and tests are performed at each subsequent visit between 2 to 4 weeks as clinically indicated. In following the response to ATD, clinical symptoms and signs by themselves may be misleading; adjusting the ATD dose on the basis of clinical grounds only is strongly discouraged. There is no good correlation between symptoms and signs and the results of thyroid tests. The only exceptions are weight gain as well as a reduction in pulse rate, both being reliable signs of a good therapeutic response; however, the assessment of pulse rate is limited in patients receiving beta-adrenergic blocking agents. Hospitalization should be considered for patients with severe symptoms at the first visit, and for those not responding to ATD and in the presence of medical or obstetric complications (toxemia, intrauterine growth retardation, fetal dysrhythmia). Tests for assessing fetal well- being (nonstress test and biophysical profile) are indicated in patients with persistent hyperthyroidism in the last trimester of pregnancy, in women with active or inactive Graves’ disease and high serum titers of TSI, and for obstetric reasons. Ultrasonography is useful for assessing fetal growth and for the detection of fetal goiter, reported in mothers receiving excessive doses of ATD. Fetal tachycardia or bradycardia and intrauterine growth retardation are indicators of fetal compromise.

Either MMI or PTU may be started at the preference of the physician. The initial dosage for the majority of patients is 150 mg of PTU every 8 hours or 10 to 20 mg of MMI twice a day. The dosage may range from 50 to 200 mg of PTU every 8 hours or an equivalent amount of MMI, 10 to 60 mg a day, according to patient symptomatology. The author begins therapy with no more than 150 mg of PTU three times daily or 20 mg of MMI twice daily. Patients with large goiters, a longer duration of the disease, or more symptoms require larger doses. Patients with small goiters, less severity of symptoms, and short duration of the disease respond more rapidly to therapy. After the initial evaluation, the patient is asked to return in 2 weeks, at which time a slight improvement in serum FT, or FTJ concentration is expected. In most cases, thyroid tests normalize between 3 and 8 weeks after the initiation of therapy.68 Serum FT,, or the equivalent FT41, is the best test to follow the response to ATD therapy. Serum FT, or FT,I has been reported to be inadequate for adjustment to ATD therapy.36 Momotani and colleagues51 do not recommend the use of serum FT, levels as a guide to the amount of ATD, because there is no correlation between maternal FT, levels and cord blood concentrations of either FT, or FT,. Because the normalization of maternal serum FT, precedes that of FT, after the initiation of thionamide therapy, and because there is a good correlation between maternal FT, and cord serum FT, levels, normalization of serum maternal FT, levels is associated with the risk of overtreatment with ATD. Maternal serum TSH levels remain suppressed for several weeks or months after the normalization of FT, levels, therefore it is not useful to obtain serum TSH levels during the first 2 months of antithyroid therapy. However, later on, normalization of serum TSH is a good indicator of adequate response to therapy, at which time the amount of ATD can be reduced and even discontinued in the last weeks of pregnancy. As discussed in the previous section, at the first clinical visit in a patient undergoing antithyroid therapy, serum TSH determination is helpful in adjusting the dose of ATD; in the presence of a normal serum TSH, the physician should reduce the amount of ATD.

After a few weeks of ATD therapy, thyroid tests and symptoms improve, at which time the dose of antithyroid medication can be reduced to half of the initial dose (Fig. 5). Further reduction in dose is achieved in subsequent visits with the goal of keeping serum FTJ or FT, levels in the upper one third of the

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FT41 (-FT41 +TSH 1 TSH 20 40

36

32

24 -

20

16

12

8

5

0.04

0 4 8 10 12 14 16 20 24 28 32 36 40

Weeks Gestation

Figure 5. Example of the management of hyperthyroidism in pregnancy with methimazole. In approximately 30% of hyperthyroid pregnant patients, ATD may be discontinued by 32 to 36 weeks gestation or earlier. (From Mestman JH: Hyperthyroidism in pregnancy. Clin Obstet Gynecol 40:45-64, 1997; with permission.)

normal limits. After the patient has remained euthyroid with the smallest dose of ATD, 50 mg of PTU or 5 mg of MMI for a few weeks, antithyroid medication may be discontinued. In approximately 30% of hyperthyroid patients, antithyroid therapy may be discontinued by 32 to 36 weeks' gestation and, in an occasional patient, even before (Fig. 5). It is advisable to continue therapy until at least 32 weeks' gestation to prevent relapse. If hyperthyroidism recurs, ATD therapy is reinstated, in most cases, 10 mg of MMI twice daily or 200 to 300 mg of PTU in divided doses.

Nodular Thyroid Disease

The treatment of hyperthyroidism caused by nodular goiter, either multiple or single, is similar to the treatment recommended for patients with Graves' disease. In a recent report,12 resolution of hyperthyroidism caused by a single toxic adenoma was achieved in the 13th week of pregnancy with ultrasound- guided percutaneous ethanol injection, the patient becoming euthyroid in 2 weeks. The treatment consisted of four injections of 3 mL of sterile ethanol (95%), one every 3 days. The patient spontaneously aborted at the end of the 17th week of gestation; however, it was stated that the outcome of pregnancy was unrelated to the treatment.

Hyperthyroidism Caused by a TSH-producing Pituitary Tumor

A recent case report described a woman with hyperthyroidism caused by a TSH-producing pituitary tumor.' The patient was treated with a continuous subcutaneous infusion of octreotide, a long-acting analogue of somatostatin. The


hyperthyroidism resolved, and the pituitary tumor decreased in size. The patient became pregnant, octreotide was discontinued, but hyperthyroidism recurred at 6 months' gestation. Therapy was reassumed and continued until delivery. The infant was euthyroid at birth and weighed 3300 g with no evidence of congenital malformations.

Thyroid Plus Antithyroid Therapy

Because the transfer of levothyroxine from mother to fetus is minimal, there is no clinical indication for combined therapy. In one study, the amount of ATD needed to achieve similar thyroid tests values was greater in the combined treatment group.44 It has been suggested that the addition of levothyroxine in pregnancy reduces the incidence of postpartum thyroiditis.60 These results need to be confirmed.

Long-term Follow-up of Children Exposed In Utero to Antithyroid Drugs

Despite concern regarding the cognitive and somatic development of infants whose mothers are treated with ATD therapy during pregnancy, the few studies available show no intellectual or somatic growth defects in children exposed in utero to ATD in comparison with siblings unexposed to the drug and with an age-matched control group.8, ly, 38, 43

Beta-adrenergic Blockers

Beta-adrenergic blockers are very effective in controlling hypermetabolic symptoms in persons with hyperthyroidism. They should be used only for a few weeks with ATDs until symptoms abate. The usual dosage is 20 to 40 mg of propranolol every 6 to 8 hours, or atenelol, 25 to 50 mg twice a day. Symptoms improve after a few days of therapy. The dose is adjusted to keep the resting pulse rate between 70 and 90 beats per minute. Long-term treatment with propranolol is not recommended because of potential neonatal morbidity.57 In one study in which beta-blockers were used in conjunction with carbimazole in a group of 33 pregnan~ies:~ an increased incidence of spontaneous abortion was reported. The mean dose of propranolol was 91 mg daily in three divided doses for a period of 6 to 12 weeks. The incidence of spontaneous abortion was 24.4% as compared with 5.5% in a group of 72 women receiving ATD alone. The reason for this high incidence of spontaneous abortion is not clear, because the results of thyroid tests were similar in both groups of patients. Propranolol, however, was prescribed to patients with more severe subjective symptoms and for longer periods of time than are usually recommended (6 to 12 weeks). To the author's knowledge, this is the first report showing an increased incidence of miscarriages in propranolol-treated patients.

iodides

The use of iodides during pregnancy is contraindicated because of their association with neonatal goiter and hypothyroidism.'* In the original reports,

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the amount of iodide given to the mother was not quantitated, nor was the time of exposure. Iodides given for a short period of time in preparation for surgery or in the management of thyroid crisis seem to be of no danger to the fetus. Momotani and colleagues53 administered iodide, 6 to 40 mg per day, to a group of mildly hyperthyroid women during pregnancy, mostly in the third trimester. The results of thyroid tests were maintained in the upper limit of normal or in a mildly hyperthyroid range. Fetal outcome was reported as normal, with no evidence of neonatal goiter; a transient elevation in cord blood TSH was found in 2 of the 32 infants. More studies are needed before a definite conclusion can be drawn as to the benefit of this form of therapy in pregnancy.

Surgery

Although subtotal thyroidectomy is an effective therapy for controlling hyperthyroidism, surgery is now rarely performed in pregnancy. It is reserved for patients not responding to antithyroid therapy, either because of noncompliance or an allergy to both drugs, a rare event by itself, or in the unusual case of a large goiter requiring large amounts of ATD. It is preferable to perform surgery in the second trimester of pregnancy, although there is no compelling evidence that surgery in the first trimester increases the risk of spontaneous abortion. Following surgery, achieving euthyroidism is essential. A determination of TSI titer is recommended at the time of subtotal thyroidectomy; a high titer is suggestive and predictive for the development of fetal hyperthyroidism.

Breast-feeding

Traditionally, mothers taking antithyroid medications have been advised not to breast feed their infants. Studies in humans have shown that the amount of PTU present in breast milk is very low; if the mother takes 200 mg three times a day, the infant receives a mean dose of 99 p,g per day. Only 0.077% of an ingested dose is excreted in the milk.31 MMI, however, is excreted in milk in higher concentrations, because it is not bound to plasma protein as much as is PTU. Mothers wishing to breast feed their infants are cautioned to take no more than 150 to 200 mg of PTU a day in divided doses, taking each dose after feeding. Infants should be closely monitored with frequent tests of thyroid function. In one study, a group of hyperthyroid mothers gave birth to infants with a slight elevation of serum TSH.5Z Despite continued treatment with PTU while breast-feeding, the infants’ serum TSH normalized in the first postnatal weeks.

l3’I Therapy

The use of RAI is contraindicated in pregnancy, particularly after the 12th week of gestation when the fetal thyroid is able to concentrate iodine. However, inadvertent l3]I administration in the first trimester of pregnancy may occur. It is important to perform a pregnancy test before therapy; furthermore, it is advisable to treat patients only in the first 2 weeks after a menstrual period. A questionnaire was sent to a group of endocrinologists regarding their attitude toward patients inadvertently receiving l3II therapy in the first trimester of pregnancy.61 A total of 237 such pregnancies were reported, with therapeutic


abortion in 55; in the remaining 182 pregnancies, there were two spontaneous abortions, two intrauterine deaths, and one neonatal death as the result of biliary atresia. Six infants were hypothyroid at birth, and four were mentally retarded; in three of the six mothers, therapy was given beyond 13 weeks of pregnancy. If a pregnant woman receives 13’1 during the first trimester of pregnancy, the two main concerns are the possibility of congenital malformations and of congenital hypothyroidism. Hypothyroidism would be most likely to occur if treatment is administered after the 12th week of gestation. If the pregnancy is not terminated, it has been suggested to administer PTU for 7 to 10 days after the exposure in an effort to decrease iodide recycling, which should reduce fetal radiation exposure.29

POSTPARTUM HYPERTHYROIDISM

Postpartum thyroid dysfunction is known to occur in women with autoimmune thyroid disease. The clinical presentation is characterized by a hyperthyroid phase occurring in the first 3 months postpartum, followed by a hypothyroid phase between 3 and 6 months after delivery, with spontaneous recovery in the majority of patients. The hypothyroid phase is characterized by a low RAI uptake consistent with destructive thyroiditis (see the article by Ross on p. 169 of this issue). Hyperthyroidism owing to Graves’ disease in the postpartum period accounts for 10% to 15% of all cases of postpartum hyperthyr~idism.~ It may present as the initial manifestation of Graves’ disease (not an unusual event), as an episode of destructive thyroiditis, or as recurrent hyperthyroidism following an episode of remission. From a clinical point of view, it is difficult to distinguish hyperthyroidism caused by Graves’ disease from an episode of destructive or postpartum thyroiditis. In the majority of cases, hyperthyroidism owing to Graves’ disease occurs later in the postpartum period (between 3 and 6 months) as compared with the transient hyperthyroidism of destructive thyr~iditis.~, 5, 54, 62

Momotani and co-workersS4 have studied the largest group of women with Graves’ disease in the postpartum period. Among 623 postpartum women with a history of Graves’ disease, hyperthyroidism developed in 96 (11%) following delivery. The women were euthyroid at delivery. Thionamides were discontinued during pregnancy in 78 of the women and before conception in the other 18. Thyroid tests were performed every 2 months for 1 year, and urinary iodine excretion as well as RAI uptake were obtained at the time of hyperthyroidism. The 96 patients were divided in three groups according to the RAI uptake: (1) 37 (38%) with high uptake (>40%); (2) 33 (34.3%) with normal uptake (10% to 40%); and (3) 26 (27%) with low uptake (<lo%).

In the first group (high RAI uptake), treatment with ATD was initiated because of the severity of symptoms. Urinary iodine uptake was in the low normal range. In the second group of 33 patients (normal RAI uptake), eight were treated with ATD because they were symptomatic. In the remaining group of 25 patients, nine had persistent hyperthyroidism, and, in 16, the hyperthyroidism resolved spontaneously. However, in nine of these patients, it recurred a few months later, at which time a repeated RAI uptake was elevated. Therefore, among the total of 33 patients with normal RAI uptake, hyperthyroidism persisted or recurred at the end of the study in 26 (78.7%). In only seven patients did the hyperthyroidism resolve by the end of 1 year.

In the third group (low RAI uptake), 3 of 26 patients remained hyperthyroid; when the determination of RAI uptake was repeated, it was elevated (54%

146 MESTMAN

to 64%). In the other 23 patients, hyperthyroidism was transient. It did not recur in 14 patients; however, the other nine had a recurrence of hyperthyroidism with elevated RAI uptake. Urinary iodine excretion was the highest of all of the groups at the time of the low RAI uptake. In the 26 patients with a low RAI uptake, hyperthyroidism persisted or recurred in 12 (46.1%) and resolved in 14.

Of the 96 patients with Graves’ disease who were euthyroid at the time of delivery while off of ATD therapy, 75 (78.2%) were hyperthyroid 1 year postpartum. It was concluded that the recurrence of hyperthyroidism in the postpartum period may be the result of Graves’ disease (high RAI uptake) or of an episode of postpartum thyroiditis (low RAI uptake). In the patients with normal RAI uptake, both silent thyroiditis and Graves’ disease contributed to the findings of normal RAI uptake.

Therefore, in the patient with hyperthyroidism in the postpartum period, clinical clues may help the physician to elucidate the etiologic factor. The only helpful test in the majority of cases is the determination of RAI uptake. The use of Iz3I is recommended over I3lI, because thyroid scan is not necessary, and because breast-feeding must be stopped for only 48 hours postpartum.s Titers of serum antibodies, both anti-TPO and TSHRAb, although present in almost all patients, are of little value in discriminating among etiologiesP Urinary iodine excretion is not a routine test in the author’s practice.

In the daily clinical setting, it is inconvenient for the mother to stop breast- feeding, even for 48 hours; furthermore, mothers do not want to be separated from their neonates and are concerned about the potential risks of radioactivity. The author and his colleagues treat each patient in an individual way, respecting her decision. In most cases, the final diagnosis may be postponed for a few months and treatment based on the physician’s clinical opinion.

SUMMARY

Hyperthyroidism is second to diabetes mellitus as the most common endo- crinopathy in pregnancy. Inappropriate secretion of hCG is the most common cause of hyperthyroidism in the first part of gestation. In addition to hydatidiform mole and hyperemesis gravidarum, nonpathologic-conditions including multiple gestation, mild nausea and vomiting, and even normal pregnancies may present with transient undetectable or suppressed serum TSH values. The syndrome of transient hyperthyroidism of hyperemesis gravidarum is defined as severe nausea and vomiting, dehydration, ketonuria, and weight loss of more than 5% by 6 to 9 weeks of pregnancy. Thyroid tests are in the hyperthyroid range, and the abnormalities are related to the severity of symptoms. Tests normalize with resolution of the vomiting, and ATD therapy i s not indicated. The natural history of Graves’ disease in pregnancy is characterized by aggravation in the first trimester, amelioration in the second half, and recurrence in the year following delivery. ATD treatment is the therapy of choice in pregnancy. Either PTU or MMI may be used; the goal is to keep the FTJ in the upper limits of normal with the minimum dose of ATD. In approximately 30% of patients, ATDs may be discontinued in the last few weeks of gestation. Maternal, fetal, and neonatal complications are frequent when hyperthyroidism is not under control. Postpartum hyperthyroidism may be caused by an episode of silent thyroiditis or Graves’ disease.


ACKNOWLEDGMENT

The author thanks Elsa C. Ahumada for secretarial assistance.

References

1. Amino N, Miyai K, Yamamoto T, et al: Transient recurrence of hyperthyroidism after

2. Amino N, Tanizawa 0, Mori H, et al: Aggravation of thyrotoxicosis in early pregnancy

3. Amino N, Tada H, Hidaka Y: The spectrum of postpartum thyroid dysfunction:

4. Bouillon R, Naesens M, Van Assche FA, et al: Thyroid function in patients with

5. Browne-Martin K, Emerson C H Postpartum thyroid dysfunction. Clin Obstet Gynecol

6. Bruun T, Kristoffersen K Thyroid function during pregnancy with special reference to hydatidiform mole and hyperemesis. Acta Endocrinol 88:383, 1978

7. Burrow GN: Neonatal goiter after maternal propylthiouracil therapy. J Clin Endocrinol Metab 25:403, 1965

8. Burrow GN, Bartsocas C, Klatsjin EH, et al: Children exposed in utero to propylthiouracil. Am J Dis Child 116:161, 1968

9. Caron P, Gerbeau C, Pradayrol L Maternal-fetal transfer of octreotide [letter]. N Engl J Med 333:6010, 1995

10. Clark SL, Phelan JP, Montoro M, et a1 Transient ventricular dysfunction associated with cesarean section in a patient with hyperthyroidism. Am J Obstet Gynecol 151:383- 386, 1985

11. Cooper DS Propylthiouracil levels in hyperthyroid patients unresponsive to large doses. Ann Intern Med 102:328-331, 1985

12. Cortelazzi D, Castagnone D, Tassis B, et al: Resolution of hyperthyroidism in a pregnant woman with toxic thyroid nodule by percutaneous ethanol injection. Thyroid 5:473, 1995

13. Cove DH, Johnston P: Fetal hyperthyroidism: Experience of treatment in four siblings. Lancet 1:430, 1985

14. Davis LE, Lucas MJ, Hankins GDV, et al: Thyrotoxicosis complicating pregnancy. Am J Obstet Gynecol 160:63-70, 1989

15. Desai RK, Norman RJ, Jialal I, et al: Spectrum of thyroid function abnormalities in gestational trophoblastic neoplasia. Clin Endocrinol 29:583-592, 1988

16. Dirmikis S, Munro DS: Placental transmission of thyroid stimulating immunoglobulins. BMJ 2:665-666, 1975

17. Easterling TR, Schnocker BC, Carlson KL, et al: Maternal hemodynamics in pregnancy complicated by hyperthyroidism. Obstet Gynecol 78:348-352, 1991

18. Editorial: Dangers of iodides in pregnancy. Lancet 1:1273-1274, 1970 19. Eisenstein Z , Weiss M, Katz Y, et al: Intellectual capacity of subjects exposed to

methimazole or propylthiouracil in utero. Eur J Pediatr 151:558-559, 1992 20. Fisher DA: Fetal thyroid function: Diagnosis and management of fetal thyroid disor-

ders. Clin Obstet Gynecol 40:16-31, 1997 21. Grun JP, Meuris S, DeNayer P, et al: Excessive thyroidal stimulation in gemellar

pregnancy. Abstract presented at the 11th International Thyroid Congress, Toronto, Canada, September 10-15, 1995

22. Glinoer D: The regulation of thyroid function in pregnancy: Pathways of endocrine adaptation from physiology to pathology. Endocr Rev 18:404, 1997

23. Goodwin TM, Montoro MN, Mestman JH, et al: The role of chorionic gonadotropin in transient hyperthyroidism of hyperemesis gravidarum. J Clin Endocrinol Metab

24. Goodwin TM, Montoro MN, Mestman JH: Transient hyperthyroidism and hyperemesis

delivery in Graves’ disease. J Clin Endocrinol Metab 44:130, 1977

and after delivery in Graves’ disease. J Clin Endocrinol Metab 55:108-112, 1982

Diagnosis, management and long-term prognosis. Endocr Pract 2406, 1996

hyperemesis gravidarum. Am J Obstet Gynecol 143:922-926, 1982

4090-101, 1997

75:1333-1337, 1992

gravidarum: Clinical aspects. Obstet Gynecol 167848-852, 1992

148 MESTMAN

25. Goodwin TM, Hershman JM: Hyperthyroidism due to inappropiate production of human chorionic gonadotropin. Clin Obstet Gynecol40:3244, 1997

26. Hamburger JI: Management of hyperthyroidism in children and adolescents. J Clin Endocrinol Metab 60:1019, 1985

27. Harada A, Hershman JM, Reed AW, et al: Comparison of thyroid stimulators and thyroid hormone concentrations in the sera of pregnant women. J Clin Endocrinol Metab 48:793, 1979

28. Hershman JM, Higgings HP: Hydatidiform mole-a cause of clinical hyperthyroidism. N Engl J Med 284:573-577, 1971

29. Inzucchi SE, Comite F, Burrow GN: Graves’ disease and pregnancy. Endocr Pract 1:186-192, 1995

30. Kamijo K, Saito T, Sat0 M, et al: Transient subclinical hypothyroidism in early pregnancy. Endocrinol Japan 37397403, 1990

31. Kampmann JP, Hansen JM, Johansen K, et al: Propylthiouracil in human milk. Lancet 1:736, 1980

32. Kaplan MM: Management of thyroxine therapy during pregnancy. Endocr Pract 2:281- 286, 1996

33. Khoury JM, Becerra JE, d’Almada PJ: Maternal thyroid disease and risk of birth defects in offspring: A population based case controlled study. Paediatr Perinat Epidemiol 3:402, 1989

34. Krentz AJ, Redman H, Taylor KG: Hyperthyroidism associated with hyperemesis gravidarum. Br J Clin Pract 4875, 1994

35. Kriplani A, Buckshee K, Bhargava VL, et al: Maternal and perinatal outcome in thyrotoxicosis. Eur J Obstet Gynecol Reprod Biol54:159, 1994

36. Lambert GA, Ikonem E, Teramo K, et al: Treatment of maternal hyperthyroidism with antithyroid agents and changes in thyrotropin and thyroxine in the newborn. Acta Endocrinol 97:186-195, 1981

37

38

39

40

41.

42.

43.

44.

45.

46.

47. 48.

49.

50.

51.

Low LCK, Ratcliffe WA, Alexander W D Intrauterine hypothyroidism due to antithyroid drug therapy for thyrotoxicosis during pregnancy. Lancet 1:370, 1978 McCarroll GN, Hutchinson M, McAuley R, et al: Long term assessment of children exposed in utero to carbimazole. Arch Dis Child 51:532, 1976 McKenzie JM, Zakarjia M: Fetal and neonatal hyperthyroidism and hypothyroidism due to maternal TSH receptor antibodies. Thyroid 2:155-160, 1992 Mandel SJ, Brent GA, Larsen PR Review of antithyroid drug use during pregnancy and report of a case of aplasia cutis. Thyroid 4:129-133, 1994 Manganiello PD, Adams LV, Harris RD, et al: Virilization during pregnancy with spontaneous resolution postpartum: A case report and review of the English literature. Obstet Gynecol Surg 50:404410, 1995 Mayer DC, Thorp J, Baucom D, et al: Hyperthyroidism and seizures during pregnancy. Am J Perinatol 12:192, 1995 Messer MP, Hauffa BP, Olbricht T, et al: Antithyroid drug and Graves’ disease in pregnancy: Long term effects on somatic growth, intellectual development and thyroid function of the offspring. Acta Endocrinol 123:311, 1990 Mestman JH, Manning PR, Hodgman J: Hyperthyroidism and pregnancy. Arch Intern Med 134434,1974 Mestman JH: Diagnosis and management of hyperthyroidism in pregnancy. Curr Probl Obstet Gynecol 4:10, 1981 Mestman JH: Severe hyperthyroidism in pregnancy. In Clark SL, Cotton DB, Hankins GDV, Phelan JP (eds): Critical Care Obstetrics, ed 2. Boston, Blackwell Scientific, 1991,

Mestman JH: Hyperthyroidism in pregnancy. Clin Obstet Gynecol 39:45-64, 1997 Millar LK, Wing DA, Leung AS, et al: Low birth weight and preeclampsia in pregnancies complicated by hyperthyroidism. Am J Obstet Gynecol 84:946-949, 1994 Mitsuda N, Tamaki H, Amino N, et al: Risk factors for developmental disorders in infants born to women with Graves’ disease. Obstet Gynecol 80:359-364, 1992 Momotani N, Ito K, Hamada N, et al: Maternal hyperthyroidism and congenital malformation in the offspring. Clin Endocrinol 20:695, 1984 Momotani N, Noh J, Oyanagi H, et al: Antithyroid drug therapy for Graves’ disease

pp 307-328


during pregnancy: Optimal regimen for fetal thyroid status. N Engl J Med 315:2428, 1986

52. Momotani N, Yamashita R, Yoshimoto M, et al: Recovery from foetal hypothyroidism: Evidence for the safety of breastfeeding while taking propylthiouracil. Clin Endocrinol 31:591, 1989

53. 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 75:738-744, 1992

54. Momotani N, Noh J, Ishikawa N, et al: Relationship between silent thyroiditis and recurrent Graves’ disease in the postpartum period. J Clin Endocrinol Metab 79:285, 1994

55. Mori M, Amino M, Tamaki 0: Morning sickness and thyroid function in normal pregnancy. Obstet Gynecol 129:155-160, 1988

56. Pekary AE, Jackson IMD, Goodwin TM, et al: Increased in vitro thyrotropic activity in partially sialated human chorionic gonadotropin extracted from hydatidiform moles of patients with hyperthyroidism. J Clin Endocrinol Metab 76:70-74, 1993

57. Pruyn SC, Phelan JP, Buchanan GC: Long term propranolol therapy in pregnancy: Maternal and fetal outcome. Am J Obstet Gynecol 135:485489, 1979

58. Rosenthal FD, Jones C, Lewis SI: Thyrotoxic vomiting. BMJ 2:209-211, 1976 59. Sherif IH, Oyan WT, Bosairi S, et al: Treatment of hyperthyroidism in pregnancy. Acta

Obstet Gynecol Scand 70:461463, 1991 60. Singer PA: Will postpartum recurrence of Graves’ hyperthyroidism become a thing of

the past [editorial]? J Clin Endocrinol Metab 75:5A, 1992 61. Stoffer SS, Hamburger JI: Inadvertent I3’I therapy for hyperthyroidism in the first

trimester of pregnancy. J Nucl Med 17:146, 1976 62. Tamaki H, Amino N, Aozasa M, et al: Serial changes in thyroid-stimulating antibody

and thyrotropiri binding inhibitor immunoglobulin at the time of postpartum occurrence of thyrotoxicosis in Graves‘ disease. J Clin Endocrinol Metab 65:324-330, 1987

63. 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

64. Tisne L, Barzelano J, Stevenson S: Study of thyroid function during pregnancy and the postpartum period with radioactive iodine. Bol SOC Chile Obstet Gynecol 20:246- 251, 1955

65. Tsuruta E, Tada H, Tamaki H, et a1 Pathogenic role of asialo human chorionic gonadotropin in gestational thyrotoxicosis. J Clin Endocrinol Metab 80:350-355, 1995

66. Van Dijke CP, Heydendael RJ, De Kleine MJ: Methimazole, carbimazole, and congenital skin defects. Ann Intern Med 10660, 1987

67. Wallace C, Couch R, Ginsberg J: Fetal thyrotoxicosis: A case report and recommenda- tions for prediction, diagnosis and treatment. Thyroid 5:125, 1995

68. Wing DA, Millar LK, Koonings PP, et al: A comparison of propylthiouracil versus methimazole in the treatment of hyperthyroidism in pregnancy. Am J Obstet Gynecol 17090-95, 1994

69. Yoshimura M, Hershman JM: Thyrotropic action of human chorionic gonatropin. Thyroid 5:425, 1995

3:189-193, 1993

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