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Endocrine disorders in pregnancy provide a unique challenge to the practitioner. The introduction of the fetal-placental unit alters the maternal endocrine metabolism and hormonal feedback mechanisms. Disease manifestations may be altered by the pregnancy environment and may be difficult to distinguish from the normal hypermetabolic state of pregnancy. Therapeutic needs for the mother and the fetus may differ, requiring a fine balance.

PITUITARY DISORDERS IN PREGNANCY

Anterior Pituitary Gland

The pituitary enlarges during pregnancy (1) and may become hyperintense on scan (2). This enlargement is primarily due to estrogen-stimulated hypertrophy and hyperplasia of the lactotrophs (3), while gonadotrophs decline in number, and corticotrophs and thyrotrophs remain constant (4). Somatotrophs are generally suppressed and may function as lactotrophs (5). Placental estrogens stimulate prolactin synthesis (6,7), while progesterone also stimulates prolactin secretion (8). Prolactin levels progressively increase approximately 10-fold throughout gestation,(9) then decline postpartum in non-lactating women. Despite this increase, the normal lactotroph continues to respond to TRH and anti-dopaminergic stimulation.

Growth hormone variant, which differs from pituitary growth hormone by 13 amino acids and is synthesized by the syncytiotrophoblastic epithelium of the placenta, increases to levels of 10-20 ng/ml during pregnancy (10,11). This variant has similar carbohydrate, lipid (12), and somatogenic properties as pituitary GH, with less lactogenic activity (13). With this increase in GH activity, insulin-like growth factor 1 (IGF-1) levels dramatically increase in the second half of pregnancy (14), contributing to the acromegaloid features of some pregnant women. Through negative feedback, pituitary growth hormone levels consequently decline in the second half of gestation (10,11), with blunted response to stimulation testing.

TSH levels fall in the first trimester, in response to the rise of bhCG (15), but increase within the normal range in the third trimester (16). CRH and ACTH levels rise, despite an increase in cortisol (see below). In response to placental sex steroid production, both hypothalamic GnRH and pituitary gonadotropin (FSH/LH) levels decline in the first trimester of pregnancy, with a blunted gonadotropin response to GnRH (17).

Prolactinomas

Hyperprolactinemia causes one third of all female infertility (18,19). It inhibits pulsatile gonadotropin secretion and the positive feedback of estrogen on gonadotropin secretion (19). Hyperprolactinemia has multiple potential etiologies. In patients with prolactinomas, treatment choices are defined by the clinical presentation and the therapeutic goal. Surgical therapy is initially curative in approximately 70% of patients with microadenomas and rarely causes hypopituitarism. The curative rate is much lower (31.8%) in patients with macroadenomas, and the risks of hypopituitarism and subsequent infertility increase dramatically (19). For both microadenomas and macroadenomas there are recurrence rates of about 20%, therby lowering these long-term cure rates (19). Bromocriptine therapy results in ovulatory menses in 80-90% of patients. Approximately 40% of patients with macroadenomas experience a > 50% reduction in size (19). Pergolide demonstrates similar benefits. Cabergoline is another dopamine agonist which is administered only once or twice weekly. It is more effective and better tolerated than bromocriptine therapy (20) and has a similar efficacy in reducing tumor size (21,22).

The hormonal milieu of pregnancy may cause significant tumor enlargement in women with prolactin-secreting macroadenomas (Figure 1). In pregnant patients with microadenomas previously treated with bromocriptine, 5 of 376 women (1.3%) experienced symptomatic enlargement manifested by headaches and visual field disturbances (23). Symptomatic enlargement was noted in 20 of 86 patients (23.2%) patients with macroadenomas previously treated with bromocriptine, while 2 of 71 (2.8%) individuals previously treated with transsphenoidal surgery or irradiation had symptoms (Table 1). Bromocriptine therapy or transsphenoidal surgery was required to treat 25-50% of those with symptomatic enlargement (23).

Figure 1. MRI scans with coronal (A,C) and sagittal (B,D) views demonstrating a prolactin-secreting macroadenoma before pregnancy (A,B) that progressively enlarged during pregnancy. The third trimester is shown here (C,D). The patient had been complaining of increasing headaches.

Bromocriptine crosses the placenta (24) and is therefore not recommended throughout gestation. Used during the first few weeks of gestation, it has not been associated with increased risk for adverse events such as spontaneous abortion, ectopic pregnancies, multiple gestation, or congenital anomalies (23,25). In more than 100 pregnancies where bromocriptine was used throughout gestation, the only neonatal abnormalities noted were a case of undescended testicle and one case of talipes deformity, which is in the expected range (23,25). There are few data on pergolide safety in pregnancy. Cabergoline has been utilized in more than 200 pregnancies. During this limited experience, it has appeared to be safe (26). However, because of the broader range of experience, bromocriptine therapy is preferred in women who are undergoing therapy for the purpose of fertility.

There are few specific data regarding the use of transsphenoidal surgery during pregnancy. It is presumed that the risks would be similar to other forms of surgery, except for the increased risk of hypopituitarism.

For intrasellar tumors, bromocriptine therapy is preferred as it is safe for the fetus if it is discontinued early in gestation. These tumors demonstrate a small risk for tumor enlargement. Patients should be followed on a trimester basis for symptomatic enlargement. Visual field testing should be performed if clinically indicated.

Therapeutic options for tumors extending outside the sella include prepregnancy surgical debulking, intensive monitoring without bromocriptine therapy, and continuous bromocriptine therapy throughout gestation. The latter is not likely to harm the fetus, based on the small number of cases available to date. Patients require monthly assessments and visual field examinations every trimester. Prolactin levels provide little benefit in the clinical assessment, as they may not rise with tumor enlargement (27). With evidence of tumoral enlargement, immediately reinstitute bromocriptine therapy and rapidly titrate the dose as tolerated. Transsphenoidal surgery or, if gestation length is adequate, delivery should be considered if the response to bromocriptine therapy is inadequate (23).

Breastfeeding stimulates prolactin secretion in normal women in the first few weeks or months postpartum (19). However, there is no evidence that suckling stimulates prolactinoma growth. Therefore, we do not discourage breastfeeding in women with prolactinomas.

Anovulation secondary to hyperprolactinemia in untreated women is associated with hypoestrogenemia and a potential for osteoporosis (19). Although the estrogen in oral contraceptives stimulates lactotrophs and mild increases in prolactin levels in normal women, it does not usually cause growth of microadenomas or precipitate neoplastic development in women with idiopathic hyperprolactinemia (28). Prolactin levels should be evaluated periodically to find the rare estrogen-sensitive tumor. If prolactin levels are found to increase substantially, the estrogen should be stopped to forestall tumor growth. For patients with macroadenomas, dopamine agonists are preferred to estrogens because of their efficacy in reducing tumor size.

Acromegaly

Infertilily is common in women with acromegaly, as approximately 75% of acromegalic women of child-bearing years have menstrual irregularities (29). The ovarian dysfunction is often the result of the hyperprolactinemia found in 30-40% of cases(30) and to possible mass effects of the tumor. An additional factor is the coexisting polycystic ovary syndrome seen in a number of patients (31). Many patients require bromocriptine to ovulate and conceive, as normalization of the hyperprolactinemia frequently restores menstruation. GH and IGF-1 also regulate ovarian function, as GH increases ovarian responsiveness to gonadotropins (32) either directly or through IGF-1 production in the ovarian follicle (33).

Pituitary growth hormone secretion is autonomous in acromegaly, so both pituitary and placental GH variants persist throughout pregnancy (34). Diagnosing acromegaly during gestation may be difficult as conventional radioimmunoassays are unable to distinguish between the 2 forms of GH; such distinction requires special radioimmunoassays with antibodies which recognize specific epitopes on the pituitary and placental GH variants (10). However, pituitary growth hormone secretion in acromegaly demonstrates a pulsatility of 13-19 pulses per 24 hours (35) vs. the tonic secretion seen with the placental variant (11). In addition, paradoxical GH release after TRH occurs with pituitary GH excess (30) and is not seen with the placental variant (34). Postpartum, the placental variant, disappears from the circulation within 24 hours (10). IGF-1 levels are not useful in the diagnosis of acromegaly in pregnancy, as they elevate in the second half of both normal and acromegalic pregnancies (36).

To date, pregnancy has exacerbated the underlying condition in 4 of the 24 (17%) pregnant patients with acromegaly who have been described in the literature (37). Tumor enlargement during pregnancy has been described in 2 patients with acromegaly (38,39). Glucose tolerance, hypertension, and cardiac derangements also require monitoring (30). Glucose intolerance occurs in 50% of patients with acromegaly, with overt diabetes mellitus in 10-20% (30). The risk for gestational diabetes mellitus is consequently increased by the insulin resistance of acromegaly. Sodium retention leads to hypertension in 25-35% of patients, with potential for exacerbation in pregnancy. Because of their underlying cardiomyopathy and increased risk for coronary artery disease, these complications may also be exacerbated during pregnancy (30,40).

GH does not cross the placenta, and maternal acromegaly has little direct impact on the fetus. Fetal somatic growth is largely GH-independent, and macrosomia in such pregnancies is likely secondary to maternal glucose intolerance.

Bromocriptine therapy may provide limited benefit in treating individuals with acromegaly, with no reduction in tumor size and rare normalization of GH levels. Its use in pregnancy has been described above. Somatostatin analogs can cross the placenta. Ten cases of women with acromegaly treated with octreotide during pregnancy have been described (40-42), two cases with acromegaly treated with lanreotide (43,44), one with a TSH-secreting tumor treated with octreotide during pregnancy (45), and one with nesidioblastosis treated with octreotide during pregnancy (46). In most cases the somatostatin analog was stopped before the end of the first trimester, but in two cases octreotide was given throughout the pregnancy (40,46). No malformations were noted in any case, but because of such limited data, the use of somatostatin analogs cannot be recommended for use during pregnancy except under extraordinary circumstances.

Other Pituitary Adenomas

The ACTH-secreting neoplasm will be described in the adrenal disorders section. There are little data regarding nonsecreting, gonadotropin-secreting, or TSH-secreting pituitary adenomas in pregnancy. Although unlikely to enlarge under the influence of estrogen stimulation in pregnancy, there are case reports of enlargement of 1 nonsecreting (38) and 1 TSH-secreting adenoma during pregnancy (45).

Hypopituitarism

Hypopituitarism, secondary to neoplastic, vascular, traumatic, or infiltrative disorders, is commonly associated with gonadotropin deficiency and infertility. Fertility is possible with the assistance of the reproductive endocrinologist. Hypopituitarism may also present during pregnancy or postpartum, secondary to adenoma expansion, lymphocytic hypophysitis, and pituitary infarction. Recognition may be difficult because fatigue, nausea, and vomiting are frequent accompaniments of normal pregnancies. Dynamic testing during pregnancy is also difficult to interpret in light of the physiologic changes during normal pregnancy. During gestation, adrenal and thyroid hormones should be replaced as needed (see below). Inadequately treated hypopituitarism may lead to poor pregnancy outcome, including spontaneous abortion, intrauterine fetal demise, maternal hypotension, hypoglycemia, and even maternal death.

Sheehan's Syndrome

Sheehan's syndrome consists of pituitary necrosis secondary to ischemia occurring within hours of delivery (47). It is usually secondary to hypotension and shock from an obstetric hemorrhage. Pituitary enlargement during pregnancy apparently predisposes to the risk for ischemia with occlusive spasm of the arteries to the anterior pituitary and stalk (47). The degree of ischemia and necrosis dictates the subsequent patient course.

Acute necrosis is suspected in the setting of an obstetric hemorrhage where hypotension and tachycardia persist following adequate replacement of blood products (Table 2). In addition, the woman fails to lactate and may have hypoglycemia (47,48). Investigation should include levels of ACTH, cortisol, prolactin, and free T4. The ACTH stimulation test would be normal, as the adrenal cortex would not be atrophied. T4 levels may prove normal initially, as the hormone has a half-life of seven days. Prolactin levels are usually low, although they are generally 5-10 fold elevated in the puerperium,. Treatment with saline and stress doses of corticosteroids should be instituted immediately after drawing the blood tests. Additional pituitary testing with subsequent therapy should be delayed until recovery. DI may also occur secondary to vascular occlusion with atrophy and scarring of the neurohypophysis (49).

When milder forms of infarction occur, the diagnosis of Sheehan's may be delayed for months or years. These women generally have a history of amenorrhea, decreased libido, failure to lactate, breast atrophy, loss of pubic and axillary hair, fatigue, and symptoms of secondary adrenal insufficiency with nausea, vomiting, diarrhea, and abdominal pain (Table 2). Some women experience only partial hypopituitarism and may have normal menses and fertility (48). Although the women may have episodes of transient polydipsia and polyuria, many demonstrate impaired urinary concentrating ability and deficient vasopressin secretion (50). CT or MRI scans generally reveal partial or completely empty sellas (51).

Lymphocytic Hypophysitis

Lymphocytic hypophysitis is thought to be autoimmune in nature and is manifested by massive infiltration and destruction of the parenchyma of the pituitary and infundibulum by lymphocytes and plasma cells. It generally occurs during pregnancy or the postpartum period. It is associated with symptoms of hypopituitarism or an enlarging mass lesion and is suspected based on its timing and lack of association with an obstetric hemorrhage or prior history of menstrual difficulties or infertility. It is generally associated with mild hyperprolactinemia (<150 ng/ml) and diabetes insipidus. Differentiation from a pituitary neoplasm cannot be made based on CT or MRI scans, but only on biopsy results (52,53). Treatment is generally conservative and involves identification and correction of any pituitary deficits, particularly of ACTH secretion (54). There are no data to indicate that high dose corticosteroids may be of benefit in treating the destructive process. Surgery to debulk but not remove the gland is indicated in the presence of uncontrolled headaches, visual field defects, and progressive enlargement on scan. Spontaneous regression and resumption of partial or normal pituitary function may occur, although most patients progress to chronic panhypopituitarism. Other autoimmune disorders may also be associated.

Posterior Pituitary

The osmostat, the setpoint for plasma osmolality at which arginine vasopressin (AVP) is secreted, is reduced approximately 5-10 mOsm/kg in pregnancy. As a result, pregnant women experience thirst and release AVP at lower levels of plasma osmolality than do nonpregnant women (55). This reset osmostat is possibly due to high levels of human chorionic gonadotropin (hCG) (55). The placenta produces an amino-terminal peptidase, vasopressinase, an enzyme that rapidly inactivates AVP and oxytocin. Vasopressinase levels increase 1000-fold between the 4th and 38th weeks of gestation.(56) AVP consequently has a four- to sixfold increased metabolic clearance rate during gestation (57,58).

The lower osmostat and increased clearance of AVP by vasopressinase in pregnancy alter the nomograms of plasma osmolality and AVP used in the nonpregnant patient. Serum sodium levels may also be lower than those normally expected in patients with diabetes insipidus (58). Urinary concentrating ability in the pregnant patient should be determined in the seated position, as the lateral recumbent position inhibits maximal urinary concentration (55,58). Delivery of the placenta generally results in a return to normal AVP metabolism in 2 to 3 weeks.

Plasma oxytocin levels increase progressively during pregnancy, with a dramatic increase at term (59). Hypophysectomy does not alter onset of labor, indicating that oxytocin provides only a facilitatory role (60). Oxytocin levels rise rapidly during suckling (61).

Diabetes Insipidus

Diabetes insipidus usually worsens during gestation (58), likely due to the increased clearance of AVP by the vasopressinase. Patients with asymptomatic DI may develop symptoms during pregnancy (62,63). Patients with mild disease usually treated with chlorpropamide should discontinue this agent, as it readily crosses the placenta and causes hypoglycemia in the fetus. The AVP analog desmopressin (dDAVP) is resistant to vasopressinase and provides satisfactory treatment during gestation, although a higher dose may be required (58). During monitoring of the clinical response, clinicians should remember that normal basal plasma osmolality and sodium concentration are 5 mEq/L lower during pregnancy (64). No adverse events have been described in the offspring of pregnancies where dDAVP was used throughout gestation (65,66). DDAVP transfers minimally into breast milk(58) and is poorly absorbed from the gastrointestinal tract, so its use will not adversely affect an infant's water metabolism.

Transient AVP-resistant forms of DI may occur spontaneously in one pregnancy, but not in a subsequent one (64). Some of these patients may respond to dDAVP therapy. The symptoms resolve within several weeks of delivery (58,64).

Acute fatty liver of pregnancy may be associated with late onset transient DI of pregnancy in some patients (67,68). It is presumed the hepatic dysfunction is associated with reduced degradation of vasopressinase, further increasing vasopressinase levels and the clearance of AVP. The polyuria may develop either prior to delivery or postpartum. Complete resolution of the hepatic abnormalities and DI occurs by the 4th week postpartum.

DI that develops postpartum may be a result of Sheehan's syndrome, particularly in the setting of an obstetric hemorrhage (see above). Transient DI of unknown etiology has been described postpartum, lasting only days to weeks (69).

Congenital nephrogenic DI is a rare disorder which predominantly affects males. Female carriers of this disease may have significant polyuria during pregnancy. Treatment is with thiazide diuretics (58), which should be used with caution in pregnant women.

In patients with idiopathic DI, oxytocin levels are normal and labor may begin spontaneously and proceed normally (70). Patients with DI secondary to trauma, infiltrative disease, or a neoplasm may have adversely affected oxytocinergic pathways, resulting in poor progression of labor and uterine atony.

THYROID DISORDERS IN PREGNANCY

Thyroid disorders are commonly encountered during pregnancy. Three major factors alter maternal thyroid physiology in pregnancy. These include significant alterations in iodide physiology, the stimulation of the thyroid by the increase in hCG, and an increase in thyroxine-binding globulin (TBG).

Iodine Metabolism

Renal iodide clearance dramatically increases early in gestation secondary to the increased glomerular filtration rate (GFR), resulting in a fall in plasma iodine concentrations. The thyroid compensates by increasing thyroidal iodine clearance, elevating iodide entry into the gland (71). This supports the increase in thyroidal activity which occurs early in gestation. Later in gestation, maternal iodine losses increase with transplacental passage of iodine to the fetus to support fetal thyroid function. To sustain these roles, adequate iodine intake for pregnant and lactating women is estimated at 150-200 mg/day (71), which is provided in the U.S. in the form of prenatal vitamins and iodized salt. Nevertheless, the recent NHANES III report indicates that iodine intake has declined 50% in the U.S. since the completion of NHANES I (72). Iodine deficiency has increased 4-fold and is found in 6.7% of pregnant women and 14.9% of women of child-bearing age (72). Iodine deficiency is the leading cause of intellectual deficiency in the world (73) as iodine is critical for the myelination and maturation of the CNS. Furthermore, iodine deficiency increases miscarriage rates, stillbirths, and neonatal mortality and reduces birth weights (73). Iodine supplementation is critical to reduce these risks. Small amounts of iodine supplementation may cause a transient, mild fall in fetal free T4 levels, but both the fetus and mother soon escape this inhibition (74). In areas with mild to moderate iodine deficiency, maternal supplementation of iodine throughout pregnancy apparently improves fetal thyroid function, with normal thyroid volumes seen in the neonates (75,76). If iodine supplementation is gven at term (77), or iodine disinfectants are used at delivery (78,79), higher cord levels of TSH are found, suggesting an inhibitory effect of iodine supplementation on the fetal thyroid. This fetal thyroid inhibition does not occur when iodine is given to iodine-replete mothers (80). Excessive iodine intake should be avoided because of a risk for fetal goiter.

In areas of marginal iodine intake and inadequate supplementation, the demands of pregnancy can result in overt iodine deficiency and thyroid enlargement in an attempt to produce sufficient thyroid hormone (71). Goiter ensues if the plasma iodine concentration falls below 0.08 mg/dl (81). Thyroid enlargement varies proportional to iodine intake (82), with an inverse relationship between iodine intake and thyroid blood flow. Goiter is not found with increased frequency in iodine-replete pregnant women (83,84). In a study of 309 pregnant adolescents, 19 had goiters, 2 with Graves' disease, 3 with Hashimoto's thyroiditis, 4 with subacute thyroiditis, and 9 with simple nontoxic goiters (84). Therefore, the occurrence of a palpable goiter in iodine-replete areas indicates clinical disease in approximately 50% and warrants investigation. In patients with goiters from a variety of thyroid conditions, an increase in size of 17-55% may occur during gestation (85).

Hypothalamic-Pituitary-Thyroid Axis

There is a transient fall in TSH in the first trimester during the 2nd and 3rd months. This is postulated to be secondary to hCG stimulation of the thyroid due to the structural homology between the TSH and hCG molecules and their receptors (86). The role of hCG in increasing thyroid stimulating activity was first postulated with the thyrotoxicosis noted in molar pregnancies and trophoblastic disease (87), with cure after surgical excision of the mole or neoplasm. A negative correlation was later demonstrated between hCG and TSH in women undergoing elective abortion (88). Sequential TSH determinations between 8 and 14 weeks' gestation revealed that the nadir in TSH coincides with the peak in hCG (71) with an inverse correlation found in individual samples. There is also a linear relationship between hCG and free T4 concentrations early in gestation (71). In the majority of patients, this effect is transient and not clinically significant, as the peak of hCG is brief. However, sequential evaluations of TSH in a large cohort of pregnant women revealed that 18% demonstrated transient subnormal TSH in the 1st trimester, with 5% still subnormal in the 2nd trimester, with significantly higher levels of hCG found in these women than in those who maintained a normal TSH (89). Furthermore, in hyperplacentosis(90) and in twin pregnancies where the hCG peak is generally higher and of longer duration, there is more frequent and greater lowering of TSH than in singleton pregnancies (91). In the second half of gestation, TSH levels return to normal prepregnant levels. In iodine deficient regions, TSH increases near term but remains within the normal range (71).

The increase in estrogens produced by the fetal-placental unit stimulates hepatic production of thyroxine-binding globulin and increases the sialylation of the TBG, thereby prolonging its half-life (92,93). This increase in TBG results in higher levels of total T4 and T3, starting at 4-6 weeks gestation (93)(Figure 2). Free T4 levels may increase transiently in the 1st trimester as a result of the hCG peak. However, both free T4 and free T3 generally remain within the normal range throughout gestation (71,92,93), though they may be 10-15% lower at term in iodine-sufficient women. Placental deiodination increases maternal T4 turnover.

Figure 2. Serum thyroid hormone binding globulin (TBG), percent saturation of TBG, Free T4, and Free T3 levels from 606 normal pregnancies in Brussels, showing the progressive rise in serum TBG during the first part of gestation , accompanied by a a progressive decrease in the free T4 index (saturation level of TBG by T4), and free T4 and T3 concentrations. (From Glioner D. The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocrine Revs 1997;18:404.)

Initial studies indicated that minimal maternal TSH, T4 and T3 crossed the placenta (94). However, early in gestation the fetus is totally dependent on maternal thyroid function. Maternal T4 is present in the coelomic fluid by 6 weeks of gestation (95). Precolloid stage thyroid follicular cells are detected between the 7 and 10 weeks' gestation. The fetal brain contains T3 receptors by 10 weeks' gestation (96), and these receptors increase dramatically in number through 18 weeks. The fetal thyroid begins to concentrate iodine by 11 to 15 weeks, and TSH, thyroglobulin, and T4 are detected in the circulation. The fetal thyroid is fully functional by week 26 (94). Fetal serum TSH, TBG, T4, and T3 rise throughout gestation (97). Maternal thyroid hormone continues to cross the placenta in small amounts and is even present in cord blood (94). T4 crosses the placenta in larger amounts than T3, and its administration to the mother can provide an amelioration of the effects of congenital hypothyroidism in the fetus (98).

Hyperthyroidism

Hyperthyroidism occurs in 0.2% of pregnancies (99). Approximately 95% of these cases are secondary to Graves' disease. Autoimmune hyperthyroidism often ameliorates during pregnancy, likely due to the immune modification of pregnancy which allows the successful allograft of the fetus, a foreign tissue (99,100). This decline in immune surveillance includes a decrease in thyroid stimulating immunoglobulins (100), a decrease in the CD4+/CD8+ ratio (101), and a depression of both humoral and cell-mediated immunity. Soluble factors produced by activated fetal suppressor T cells may also cross the placenta and cause a transient decrease in the intensity of maternal Graves' disease during pregnancy. The postpartum exacerbation of Graves' disease may in part be due to the loss of these fetal suppressor T cells at delivery (102). Other factors which may assist in amelioration of hyperthyroidism in pregnancy include the increased clearance of iodine stores and the increase in TBG, which decreases the fraction of free hormones in the circulation.

Untreated hyperthyroidism has adverse consequences on maternal morbidity and fetal outcome. It increases the risk of maternal congestive heart failure, preeclampsia (RR 4.7), premature labor (RR 16.5), low birthweight infants (RR 9.2), and perinatal mortality (103,104). There may also be a mild increase in congenital anomalies in offspring of untreated or incompletely treated women with hyperthyroidism. These complications are not increased in women whose hyperthyroidism was controlled throughout the pregnancy (103).

Hyperthyroidism may be difficult to distinguish from the hypermetabolic state of pregnancy. Heat intolerance, warm skin, tachycardia and systolic flow murmurs are common to both. Goiter may occur in iodine-deficient pregnant women. Weight loss, hyperdefecation, thyroid eye signs, thyroid bruit and significant tachycardia suggest thyrotoxicosis (99,100). The diagnosis is confirmed by finding a suppressed TSH and elevated free T4 and T3 levels in the blood. Radioactive tracers such as 131I or technecium-99 should not be used in the diagnostic process to avoid fetal exposure.

Medical therapy with one of the thionamide derivatives, PTU or methimazole, is generally the treatment of choice. An early in vivo study showed that methimazole crosses the placenta at a rate 4-times greater than PTU, attributed to differences in protein binding (105). More recent data suggest that there is little difference in the placental transfer of the drugs (106), confirmed by equal concentrations of PTU in simultaneously obtained maternal and cord blood (107). However, there are multiple anecdotal case reports of the localized congenital scalp anomaly aplasia cutis with methimazole use (108). Furthermore, there is a 3-fold increase in this anomaly in regions of Spain where methimazole is used as a fattening agent in animal feed (109). More recently, there are descriptions of a methimazole embryopathy including choanal atresia, tracheo-esophageal fistula, facial anomalies, and psychomotor delay (110,111). PTU is therefore the preferred modality in pregnancy, though methimazole may be used as a second-line agent in the case of patient intolerance or an adverse reaction to PTU. Except in mild cases, initial doses of PTU of 100-150 mg every 8 hours are used, with dose titration based on serial measurements of free T4 and TSH. Doses up to 800 mg/day may be required, though most patients require lower doses as pregnancy progresses and may even be able to discontinue the agent. Maintenance of maternal free T4 concentration in the upper normal range with a mildly suppressed TSH may be optimal to avoid fetal hypothyroidism or goiter (99,112,113). Pregnant women tolerate mild degrees of hyperthyroidism without much difficulty. Children exposed to PTU in utero have demonstrated no intellectual or physical defects in long-term studies (114).

As a clinical response to thionamides is delayed until the thyroid hormone stored in colloid is used, b-blockers may be useful to control symptoms, including significant tachycardia (> 120 beats/min) or tachyarrhythmias, in severely hyperthyroid women. These agents also cross the placenta. However, earlier reports of neonatal bradycardia and hypoglycemia have not been confirmed (115). These drugs should not be used in isolation, as they do not reduce the basal metabolic rate or protein catabolism of hyperthyroidism, nor protect from thyroid storm at delivery (116).

As noted above, iodides cross the placenta readily and may cause fetal hypothyroidism and large goiters (117). This complication has not been seen in the offspring of pregnant women with milder forms of Graves' disease who were treated with iodine alone during their pregnancies (74). In general, iodides should only be used in a short course to prepare patients for surgery or for rare cases of thyroid storm. Ultrasound should be used to evaluate for fetal goiter, which may complicate delivery (118).

Lithium carbonate should not be used in pregnancy as it is teratogenic in the first trimester, and may cause neonatal lithium intoxication and goiter if given near term (119). Surgery is reserved for patients who develop adverse effects to the medications (rash, hepatitis, vasculitis, or agranulocytosis), or demonstrate an inadequate response. Surgery may pose an increased risk to the fetus (99,100,120). Surgery is delayed until after the first trimester, as the spontaneous abortion rate is highest during that time. The risks of thyroid surgery are lowest in the second trimester, though fetal loss may still occur. After 24 weeks' gestation, surgery may increase the risk of premature labor. Patients are prepared medically with thionamides and ß-blockers to prevent thyroid storm. Surgeons believe that iodine administration will reduce the vascularity of the gland, minimizing intraoperative blood loss (121). Studies have not demonstrated any benefit of adding iodine to hyperthyroid patients prepared with propranolol (122), or to patients rendered euthyroid with thionamides (123).

Radioactive iodine is contraindicated in pregnancy as it can cross the placenta and ablate the fetal thyroid. A pregnancy test is performed prior to the administration of radioactive iodine to women of child-bearing years. If a pregnant woman is mistakenly given a therapeutic dose of radioactive iodine, she may immediately be treated with PTU 300 mg/day for 7 days to attempt to block the organification and the recycling of the radioactive iodine in the fetal gland (148,149). There are no case reports to determine the efficacy of this therapy, but PTU is known to decrease thyroidal uptake and organification of iodide, and several studies have demonstrated diminished effectiveness of 131I therapy in Graves' patients previously treated with PTU (150-152).

Thyroid Storm

Thyroid storm is a medical emergency associated with 25% mortality for mother and fetus. It generally occurs in previously undiagnosed hyperthyroid patients who are subject to a stress, such as an infection, labor, or surgery. The presentation includes fever, marked tachycardia, severe dehydration, and prostration. Treatment involves alleviating the precipitating factor, replacing fluid losses, and using high dose PTU, b-blockers, corticosteroids, and sodium iodide. In this setting, the theoretic risks to the fetus of iodine administration are outweighed by the benefits of acute reduction in maternal thyroid hormone release and control of the hyperthyroidism. Subsequent ultrasound monitoring for fetal goiter is recommended.

Hyperemesis Gravidarum

Hyperemesis gravidarum is defined as severe nausea and vomiting that develops in the first trimester, and can result in nutritional deficiencies, ketosis, dehydration, and electrolyte imbalance. It starts at 6-9 weeks' gestation and usually resolves by 18-20 weeks' gestation. It is generally idiopathic but on occasion may be associated with an underlying pathology such as hyperthyroidism.

Elevated free T4 levels with a suppressed TSH may be found transiently in up to 30-60% of patients with hyperemesis gravidarum (124-127). These elevated thyroid hormone levels require no pharmacologic intervention and are caused by the high rate of hCG secretion (128). The elevation in hCG contributes to an elevation in estradiol levels that may contribute to the nausea and emesis. The degree of biochemical hyperthyroidism and severity of vomiting generally correlate with the level of hCG, although deglycosylated and desialylated modifications of its oligosaccharide side chain have the greatest thyrotropic effect and are more often isolated from women with hydatidiform moles and women with hyperemesis gravidarum (129,130).

Clinical evaluation of the patient is critical to distinguish between autoimmune thyrotoxicosis and transient hyperthyroidism of hyperemesis gravidarum (THHG). Patients with THHG have few manifestations of thyrotoxicosis, have no goiter, and their hyperthyroxinemia is generally transient and resolves by 18 weeks' gestation without antithyroid drug therapy (131)(Figure 3). Symptomatic patients can be treated with beta blockers. Thionamide therapy should be considered for women with a prepregnancy history suggestive of hyperthyroidism, overt manifestations of Graves' disease, or with persistent hyperemesis and hyperthyroxinemia past 20 weeks' gestation.

Figure 3. Changes in plasma total thyroxine (TT4) concentration in 20 subjects with hyperemesis on admission to the hospital (A) and during the course of their pregnancy. The interrupted line represents the mean + SD value seen in normal pregnancy. PN, postnatal.  (From Swaminathan R, Chin RK, Lao TH, et al. Thyroid function in hyperemesis gravidarum. Acta Endocrinol (Copenh), 1989;120:155.)

A rare cause of gestational hyperthyroidism has been found in families with a missense mutation in the extracellular domain of the TSH receptor. This receptor was found to be more sensitive to hCG and created gestational hyperthyroidism at normal levels of hCG (132).

Graves' Disease and Neonatal Thyroid Function

As noted above, all of the potential medical therapies for Graves' disease cross the placenta and may affect fetal thyroid function. Fetal hypothyroidism and goiter may result. A goiter may cause hyperextension of the fetal neck, resulting in malpresentation and trauma at vaginal delivery. In addition, the goiter may compress the non-calcified tracheal rings of the neonate, causing airway obstruction and asphyxia. Fetal hypothyroidism may impair intellectual development. Cord blood should be obtained for TSH and T4 levels, with repeat levels drawn at 3 days as transient hypothyroidism may resolve by that time (113).

Thyroid stimulating immunoglobulins and thyrotropin-binding inhibitor immunoglobulins may also cross the placenta and cause fetal hyperthyroidism in less than 1% of infants born to mothers with Graves' disease (99). Higher titers of these immunoglobulins in the maternal serum in the third trimester increases the risk of hyperthyroidism in the fetus. This may still occur in women who were previously treated for Graves' disease with radioactive iodine, who are currently on thyroid hormone replacement. The hyperthyroidism may manifest as fetal tachycardia, intrauterine fetal growth restriction, and fetal goiter. Cordocentesis may help with the diagnosis. Fetal hyperthyroidism may be treated by increasing the maternal thionamide dosage and titrating it to the fetal heart rate (133). Postpartum, the hyperthyroidism may persist for up to 3 months in the neonate, resulting in irritability, failure to thrive, and poor feeding. It is associated with a mortality rate of 16%. Long-term complications include craniosynostosis. The neonate may be transiently treated with thionamide therapy until the maternal immunoglobulins clear.

Hyperthyroidism and Breast Feeding

The thionamides are excreted into breast milk. The amounts are small and have not been shown to affect infant thyroid function or intellectual development (134-6). Nevertheless, thionamides should be given in divided doses and administered after feedings (108,137). Maternal thyroid hormone levels should be monitored frequently to facilitate thionamide dose adjustment. Monitoring of thyroid function in breast-fed infants is not necessary, so long as infant development proceeds normally and maternal doses do not exceed methimazole 20 mg/day or PTU 450 mg/day. Idiosyncratic reactions to these drugs have not been reported in breast-fed neonates (137).

Iodine is concentrated by the breast (138,139) and excreted into breast milk. Radioactive iodine is therefore contraindicated while the mother is breast feeding as therapeutic doses may be detected in the breast milk for several months (140). Even scanning doses may be found in the breast milk. In a description of an infant who breast-fed 4 hours after the mother received a dose of technecium-99, the infant received a total dose of 82.5 mCi, with the thyroid receiving 300 mRad, the upper large intestine 180 mRad, and other organs lower doses (141). If the infant had breast fed 30 minutes after the scanning dose, the estimated exposure would be 728 mCi. Therefore, bottle feeding should be instituted for 48 hours after a scanning dose before breast feeding may resume. Therapeutic doses of 131I dose should not be given for at least 3 months after breastfeeding is discontinued to avoid an excessive exposure to radiation in the lactating breasts that may potentially increase the risk of breast cancer (142).

Hypothyroidism

Hypothyroidism occurs in 2.5% of pregnancies (71,143). The incidence is higher in women with Type 1 diabetes who have microvascular complications (144). Women with hypothyroidism have a 2-fold greater risk of ovulatory infertility (145). They also appear to have higher rates of spontaneous abortion, congenital anomalies, preeclampsia, pregnancy-induced hypertension, placental abruption, premature birth, low birth weight, and stillbirth (146,147). Thyroid hormone replacement improves but does not eliminate the increased risk (147,153). It is not certain whether the poor pregnancy outcome is a result of the hypothyroidism, or is secondary to a more generalized autoimmune disturbance.

The initial development of the fetal brain occurs when the primary supply of thyroid hormone for the developing fetus is of maternal origin (153). Maternal hypothyroidism and low normal free T4 in the first half of gestation have been associated with irreversible neurologic deficits in the offspring (154-6), while later deficits cause less severe and partially reversible neuropsychologic impairment. The severity, timing of onset and duration of maternal hypothyroidism determine the impact on the neurologic development of the fetus. Even mild forms of maternal hypothyroidism appear to have an impact. As a result, some clinicians now recommend that pregnant women should be screened for hypothyroidism with a TSH and free T4 early in gestation. Detailed reviews of this subject have recently been published (94,153).

In order to reduce the duration a fetus is exposed to maternal hypothyroxinemia, pregnant women identified with hypothyroidism are generally started on levothyroxine at 1.9 mg/kg ideal body weight daily, with monitoring every 6 weeks until the TSH is normalized. Patients who are NPO should be given two thirds of the usual dose intravenously, as only 60-80% is available from the oral form.

Approximately 75-80% of patients previously treated with levothyroxine require an increased dose during pregnancy, with a median increment of 30-50% (71,157). Some of this may be due to the increased T4 turnover during pregnancy (99), while some may be due to intestinal complexing of T4 with the divalent cations, iron and calcium, which are components of prenatal vitamins (158,159). Patients should be advised to take their thyroid hormone prior to breakfast, and their prenatal vitamins at least 2 hours later. Serum TSH levels should be monitored every trimester to facilitate dose adjustment. Levothyroxine doses generally return to prepregnancy levels in the early postpartum period.

Myxedema Coma

Myxedema coma is extremely rare in pregnancy as it primarily affects older individuals. Severe hypothyroidism in younger patients is generally associated with hyperprolactinemia, anovulation, and infertility. When it does occur, it is a medical emergency with a 20% mortality. It is treated the same as in nonpregnant patients.

Postpartum Thyroiditis

Postpartum, subacute lymphocytic thyroiditis occurs in approximately 5-7% of women (160-2). This rate increases to 25% in women with Type 1 diabetes mellitus (163) and is associated with other autoimmune diseases. Postpartum thyroiditis is now conceived as an acute phase of autoimmune thyroid destruction in the setting of an ongoing process of thyroid autosensitization. Postpartum, there is a rebound reaction to the immune tolerance enjoyed during pregnancy. It is closely associated with the presence of thyroid antiperoxidase antibodies. A woman who tests positive for these antibodies early in gestation has a 30-52% risk of developing postpartum thyroiditis (164). An extensive review of the pathogenesis has been published recently (165).

Postpartum thyroiditis classically has a biphasic course of hyperthyroidism followed by hypothyroidism. Transient hyperthyroidism and hypothyroidism may occur in isolation. The onset is variable, with hyperthyroidism occuring 1-6 months' postpartum and lasting 1-2 months, followed by transient hypothyroidism 4-8 months' postpartum which resolves spontaneously in 4-6 months (162). The hyperthyroid phase is seen in two thirds of patients and may be asymptomatic. Many patients complain of fatigue, irritability, increased appetite, rapid weight loss, and palpitations (160-2). It is associated with a low radioactive iodine uptake.

Two thirds of all patients experience hypothyroidism. Some may develop hypothyroidism without preceding hyperthyroidism. They frequently have a painless, firm goiter. The hypothyroid phase may be asymptomatic or associated with complaints of fatigue, myalgias, arthralgias, loss of concentration, constipation, weight gain, and depression (162) and may be mistaken for "postpartum depression." The hypothyroidism resolves spontaneously in approximately 80% of cases but persists in 20% (162). High titers of antiperoxidase antibodies and the severity of the hypothyroidism predict persistent hypothyroidism (160).

As symptoms are generally nonspecific, a high index of suspicion is required for diagnosis. Patients with prior history of hypothyroidism may also develop postpartum thyroiditis (166), leading to a further decline in thyroid function. Because of the changing course of the condition, TSH and free T4 should be elevated at 4-8 week intervals. Patients with severe hyperthyroidism should have an 131I thyroid uptake (if not breast feeding) to distinguish postpartum thyroiditis from Graves' disease which may present in the first year postpartum with the altered immune status. Treatment is instituted for symptomatic cases. Thionamide drugs are not effective in postpartum thyroiditis, and b-blockers are used for symptomatic relief. The hypothyroid phase should be treated with levothyroxine if symptomatic, with withdrawal or halving of the dose of thyroxine after 6 months to determine whether the condition was transient. Repeat TSH testing is done 6 weeks later. A number of patients continue to have positive antiperoxidase antibody titers and organification defects (167). Exposure to excess iodine in the form of radiocontrast media may precipitate hypothyroidism (167). These individuals are at high risk for future permanent hypothyroidism, with a rate of 48% within 7-9 years (168). Regular screening of thyroid status should be instituted so that intervention can occur early. Subclinical hypothyroidism has been associated with accelerated atherosclerosis (169) and deserves intervention. Postpartum thyroiditis recurs in future pregnancies in approximately 70%.

Thyroid Nodules and Thyroid Cancer

The incidence of thyroid nodularity does not increase with parity except in areas of marginal iodine intake (170). The risk of malignancy in a solitary thyroid nodule is approximately 10%. This risk dramatically increases with a history of prior head and neck irradiation (171). The effect of pregnancy on the natural history of thyroid carcinoma is controversial (172). Some have found no apparent effect (173-5), while other studies suggest there is an increased risk of malignancy in nodules which develop during pregnancy (176-8) and that the cancer may be more aggressive (179). The intrinsic TSH-like activity of hCG has been postulated to play a role in the progression of cancers found early in gestation (179).

In women of child-bearing years, approximately 65% of thyroid malignancies are papillary, 30% are follicular, 3% are medullary, 1% are anaplastic, and 1% are lymphoma or metastases to the thyroid (171). Diagnosis is made by fine needle aspiration. A diagnosis of medullary or anaplastic carcinoma or lymphoma warrants immediate surgery. Patients with well-differentiated thyroid malignancies could undergo a near total thyroidectomy in the second trimester or following delivery. Induction of hypothyroidism for adjuvant radioiodine therapy or scanning would then be delayed until the postpartum period to avoid the fetal risks associated with maternal hypothyroidism. Waiting until postpartum does not appear to alter the prognosis of thyroid carcinoma (171,180). If surgery is postponed until postpartum then thyroid hormone suppression therapy should be instituted until the surgery.