Williams Obstetrics, 24th Edition

CHAPTER 58. Endocrine Disorders

THYROID PHYSIOLOGY AND PREGNANCY

HYPERTHYROIDISM

HYPOTHYROIDISM

SUBCLINICAL HYPOTHYROIDISM

IODINE DEFICIENCY

CONGENITAL HYPOTHYROIDISM

POSTPARTUM THYROIDITIS

NODULAR THYROID DISEASE

PARATHYROID DISEASES

ADRENAL GLAND DISORDERS

PITUITARY DISEASES

There are no endocrine disorders that are unique to pregnancy. However, endocrinopathies seem particularly closely related to pregnancy due to their proclivity for hormone secretion. Indeed, some hormones are secreted in prodigious quantities. This is probably best illustrated by placental lactogen in diabetes, the most common endocrinopathy encountered in pregnancy (Chap. 57p. 1125). Pregnancy is also interrelated with some endocrinopathies that are at least partially due to autoimmune dysregulation. Clinical manifestations of this result from complex interplay among genetic, environmental, and endogenous factors that activate the immune system against targeted cells within endocrine organs. An extraordinary example of these interactions comes from studies that implicate maternal organ engraftment by fetal cells that were transferred during pregnancy. These cells later provoke antibody production, tissue destruction, and autoimmune endocrinopathies.

THYROID DISORDERS

Taken in aggregate, these are common in young women and thus frequently managed in pregnancy. There is an intimate relationship between maternal and fetal thyroid function, and drugs that affect the maternal thyroid also affect the fetal gland. Moreover, thyroid autoantibodies have been associated with increased early pregnancy wastage, and uncontrolled thyrotoxicosis and untreated hypothyroidism are both associated with adverse pregnancy outcomes. Finally, there is evidence that autoimmune thyroid disorder severity may be ameliorated during pregnancy, only to be exacerbated postpartum.

image Thyroid Physiology and Pregnancy

Maternal thyroid changes are substantial, and normally altered gland structure and function are sometimes confused with thyroid abnormalities. These alterations are discussed in detail in Chapter 4 (p. 68), and normal hormone level values are found in the Appendix (p. 1290). First, maternal serum concentrations of thyroid-binding globulin are increased concomitantly with total or bound thyroid hormone levels (Fig. 4-17, p. 69). Second, thyrotropin, also called thyroid-stimulating hormone (TSH), currently plays a central role in screening and diagnosis of many thyroid disorders. Serum TSH levels in early pregnancy decline because of weak TSH-receptor stimulation from massive quantities of human chorionic gonadotropin (hCG) secreted by placental trophoblast. Because TSH does not cross the placenta, it has no direct fetal effects. During the first 12 weeks of gestation, when hCG serum levels are maximal, thyroid hormone secretion is stimulated. The resulting increased serum free thyroxine levels act to suppress hypothalamic thyrotropin-releasing hormone (TRH) and in turn limit pituitary TSH secretion (Fig. 58-1). Accordingly, TRH is undetectable in maternal serum. Conversely, beginning at midpregnancy, TRH becomes detectable in fetal serum, but levels are static and do not increase with advancing gestation.

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FIGURE 58-1 Gestational age-specific values for serum thyroid-stimulating hormone (TSH) levels (black lines) and free thyroxine (T4) levels (blue lines). Data were derived from 17,298 women tested during pregnancy. For each color, the dark solid lines represent the 50th percentile, whereas the upper and lower light lines represent the 2.5th and 97.5th percentiles, respectively. (Data from Casey, 2005; Dashe, 2005.)

Throughout pregnancy, maternal thyroxine is transferred to the fetus (Calvo, 2002). Maternal thyroxine is important for normal fetal brain development, especially before development of fetal thyroid gland function (Bernal, 2007). And even though the fetal gland begins concentrating iodine and synthesizing thyroid hormone after 12 weeks’ gestation, maternal thyroxine contribution remains important. In fact, maternal sources account for 30 percent of thyroxine in fetal serum at term (Thorpe-Beeston, 1991; Vulsma, 1989). Developmental risks associated with maternal hypothyroidism after midpregnancy, however, remain poorly understood (Morreale de Escobar, 2004).

image Autoimmunity and Thyroid Disease

Most thyroid disorders are inextricably linked to autoantibodies against various cell components. Several of these antibodies variably stimulate thyroid function, block function, or cause thyroid inflammation that may lead to follicular cell destruction. Often, these effects overlap or even coexist.

Thyroid-stimulating autoantibodies, also called thyroid-stimulating immunoglobulins (TSIs), bind to the TSH receptor and activate it, causing thyroid hyperfunction and growth. Although these antibodies are identified in most patients with classic Graves disease, simultaneous production of thyroid-stimulating blocking antibodies may blunt this effect (Weetman, 2000). Thyroid peroxidase (TPO) is a thyroid gland enzyme that normally functions in the production of thyroid hormones. Thyroid peroxidase antibodies, previously called thyroid microsomal autoantibodies, are directed against TPO and have been identified in 5 to 15 percent of all pregnant women (Fig. 58-2) (Abbassi-Ghanavati, 2010; Kuijpens, 2001). These antibodies have been associated in some studies with early pregnancy loss and preterm birth (Abramson, 2001; Negro, 2006; Thangaratinam, 2011). Conversely, in a study with more than 1000 TPO antibody-positive pregnant women, there was no increased risk for preterm birth, however, there was an increased risk for placental abruption (Abbassi-Ghanavati, 2010). These women are also at high risk for postpartum thyroid dysfunction and at lifelong risk for permanent thyroid failure (Premawardhana, 2000; Stagnaro-Green, 2011b).

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FIGURE 58-2 Incidence in percent of antithyroid peroxidase antibodies in 16,407 women who are normal or euthyroid, in 233 with isolated maternal hypothyroxinemia (IMH), in 598 with subclinical hypothyroidism (SCH), and in 134 with overt hypothyroidism. (Data from Casey, 2007).

Fetal Microchimerism

Autoimmune thyroid disease is much more common in women than in men. One intriguing explanation for this disparity is fetal-to-maternal cell trafficking (Greer, 2011). When fetal lymphocytes enter the maternal circulation, they can live for more than 20 years. Stem cell interchange also occurs with engraftment in several maternal tissues including the thyroid (Bianchi, 2003; Khosrotehrani, 2004). A high prevalence of Y-chromosome-positive cells has been identified using fluorescence in situ hybridization (FISH) in thyroid glands of women with Hashimoto thyroiditis—60 percent, or Graves disease—40 percent (Renné, 2004). In another study of women giving birth to a male fetus, Lepez and colleagues (2011) identified significantly more circulating male mononuclear cells in those with Hashimoto thyroiditis.

image Hyperthyroidism

The incidence of thyrotoxicosis or hyperthyroidism in pregnancy is varied and complicates between 2 and 17 per 1000 births when gestational-age appropriate TSH threshold values are used (Table 58-1). Because normal pregnancy simulates some clinical findings similar to thyroxine (T4) excess, clinically mild thyrotoxicosis may be difficult to diagnose. Suggestive findings include tachycardia that exceeds that usually seen with normal pregnancy, thyromegaly, exophthalmos, and failure to gain weight despite adequate food intake. Laboratory confirmation is by a markedly depressed TSH level along with an elevated serum free T4 (fT4) level. Rarely, hyperthyroidism is caused by abnormally high serum triiodothyronine (T3) levels—so- called T3-toxicosis.

TABLE 58-1. Incidence of Overt Hyperthyroidism in Pregnancy

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Thyrotoxicosis and Pregnancy

The overwhelming cause of thyrotoxicosis in pregnancy is Graves disease, an organ-specific autoimmune process associated with thyroid-stimulating TSH-receptor antibodies as previously discussed. Because these antibodies are specific to Graves hyperthyroidism, such assays have been proposed for diagnosis, management, and prognosis in pregnancies complicated by hyperthyroidism (Barbesino, 2013). At Parkland Hospital, these receptor antibody assays are generally reserved for cases in which fetal thyrotoxicosis is suspected. With Graves disease, during the course of pregnancy, hyperthyroid symptoms may initially worsen because of chorionic gonadotropin stimulation, but then subsequently diminish with decreases in receptor antibody titers in the second half of pregnancy (Mestman, 2012; Stagnaro-Green, 2011a). Amino and coworkers (2003) have found that levels of blocking antibodies are also decreased during pregnancy.

Treatment. Thyrotoxicosis during pregnancy can nearly always be controlled by thionamide drugs. Propylthiouracil (PTU) has been historically preferred because it partially inhibits the conversion of T4 to T3and crosses the placenta less readily than methimazole. The latter has also been associated with a rare methimazole embryopathy characterized by esophageal or choanal atresia as well as aplasia cutis, a congenital skin defect. Yoshihara and associates (2012) analyzed more than 5000 Japanese women with first-trimester hyperthyroidism and found a twofold increased risk of major fetal malformations in pregnancies exposed to methimazole compared with the risk from PTU. Specifically, seven of nine cases with aplasia cutis and the only case of esophageal atresia were in the group of methimazole-exposed infants.

Until recently, PTU has been the preferred thionamide in the United States (Brent, 2008). In 2009, however, the Food and Drug Administration issued a safety alert on PTU-associated hepatotoxicity. This warning prompted the American Thyroid Association and the American Association of Clinical Endocrinologists (2011) to recommend PTU therapy during the first trimester followed by methimazole beginning in the second trimester. The obvious disadvantage is that this might lead to poorly controlled thyroid function. Accordingly, at Parkland Hospital we continue to prescribe PTU treatment throughout pregnancy.

Transient leukopenia can be documented in up to 10 percent of women taking antithyroid drugs, but this does not require therapy cessation. In 0.3 to 0.4 percent, however, agranulocytosis develops suddenly and mandates drug discontinuance. It is not dose related, and because of its acute onset, serial leukocyte counts during therapy are not helpful. Thus, if fever or sore throat develops, women are instructed to discontinue medication immediately and report for a complete blood count (Brent, 2008).

As mentioned above, hepatotoxicity is another potentially serious side effect that develops in 0.1 to 0.2 percent. Serial measurement of hepatic enzymes has not been shown to prevent fulminant PTU-related hepatotoxicity. Also, approximately 20 percent of patients treated with PTU develop antineutrophil cytoplasmic antibodies (ANCA). However, only a small percentage of these subsequently develop serious vasculitis (Helfgott, 2002; Kimura, 2013). Finally, although thionamides have the potential to cause fetal complications, these are uncommon. In some cases, thionamides may even be therapeutic, because TSH-receptor antibodies cross the placenta and can stimulate the fetal thyroid gland to cause thyrotoxicosis and goiter.

The initial thionamide dose is empirical. For nonpregnant patients, the American Thyroid Association recommends that methimazole be used at an initial higher daily dose of 10 to 20 mg orally followed by a lower maintenance dose of 5 to 10 mg. If PTU is selected, a dose of 50 to 150 mg orally three times daily may be initiated depending on clinical severity (Bahn, 2011). At Parkland Hospital, we usually initially give 300 or 450 mg of PTU daily in three divided doses for pregnant women. Occasionally, daily doses of 600 mg are necessary. As discussed, we generally do not transition women to methimazole during the second trimester. The goal is treatment with the lowest possible thionamide dose to maintain thyroid hormone levels slightly above or in the high normal range while TSH levels remains suppressed (Bahn, 2011). Serum free T4 concentrations are measured every 4 to 6 weeks (National Academy of Clinical Biochemistry, 2002).

Subtotal thyroidectomy can be performed after thyrotoxicosis is medically controlled. This seldom is done during pregnancy but may be appropriate for the very few women who cannot adhere to medical treatment or in whom drug therapy proves toxic (Davison, 2001; Stagnaro-Green, 2012a). Surgery is best accomplished in the second trimester. Potential drawbacks of thyroidectomy during pregnancy include inadvertent resection of parathyroid glands and injury to the recurrent laryngeal nerve (Fitzpatrick, 2010).

Thyroid ablation with therapeutic radioactive iodine is contraindicated during pregnancy. These doses may also cause fetal thyroid gland destruction. Thus, when given unintentionally, many clinicians recommend abortion. Any exposed fetus must be carefully evaluated, and the incidence of fetal hypothyroidism depends on gestational age and radioiodine dose (Berlin, 2001). Tran and colleagues (2010) describe a case in which a relatively high dose (19.8 mCi) of radioiodine early in the first trimester resulted in a normal euthyroid male infant assessed at 6 months. The authors hypothesized that the exposure occurred well before thyroid embryogenesis. There is no evidence that radioiodine given before pregnancy causes fetal anomalies if enough time has passed to allow radiation effects to dissipate and if the woman is euthyroid (Ayala, 1998). The International Commission on Radiological Protection has recommended that women avoid pregnancy for 6 months after radioablative therapy (Brent, 2008). Moreover, during lactation, the breast also concentrates a substantial amount of iodide. This may pose neonatal risk due to 131I-containing milk ingestion and maternal risk from significant breast irradiation. To limit maternal exposure and her cancer risks, a delay of 3 months between lactation and ablation will more reliably ensure complete breast involution (Sisson, 2011).

Pregnancy Outcome. Women with thyrotoxicosis have pregnancy outcomes that largely depend on whether metabolic control is achieved. For example, as discussed in Chapter 18 (p. 353), excess thyroxine may cause miscarriage (Anselmo, 2004). In untreated women or in those who remain hyperthyroid despite therapy, there is a higher incidence of preeclampsia, heart failure, and adverse perinatal outcomes (Table 58-2). A prospective cohort study from China reported that women with clinical hyperthyroidism had a 12-fold increased risk of delivering an infant with hearing loss (Su, 2011). Perinatal mortality rates varied from 6 to 12 percent in several studies.

TABLE 58-2. Pregnancy Outcomes in 239 Women with Overt Thyrotoxicosis

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Fetal and Neonatal Effects

In most cases, the perinate is euthyroid. In some, however, hyper- or hypothyroidism can develop with or without a goiter (Fig. 58-3). Clinical hyperthyroidism develops in approximately 1 percent of neonates born to women with Graves disease (Barbesino, 2013; Fitzpatrick, 2010; Luton, 2005). If fetal thyroid disease is suspected, nomograms are available for sonographically measured thyroid volume (Gietka-Czernel, 2012; Ranzini, 2001).

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FIGURE 58-3 Term neonate delivered of a woman with a 3-year history of thyrotoxicosis that recurred at 26 weeks’ gestation. The mother was given methimazole 30 mg orally daily and was euthyroid at delivery. Laboratory studies showed that the infant was hypothyroid.

The fetus or neonate who was exposed to excessive maternal thyroxine may have any of several clinical presentations. First, goitrous thyrotoxicosis is caused by placental transfer of thyroid-stimulating immunoglobulins. Nonimmune hydrops and fetal demise have been reported with fetal thyrotoxicosis (Nachum, 2003; Stulberg, 2000). The best predictor of perinatal thyrotoxicosis is presence of thyroid-stimulating TSH-receptor antibodies in women with Graves disease. This is especially true if their levels are more than threefold higher than the upper normal limit (Barbesino, 2013). In a study of 72 pregnant women with Graves disease, Luton and associates (2005) reported that none of the fetuses in 31 low-risk mothers had a goiter, and all were euthyroid at delivery. Low risk was defined by no antithyroid medications during the third trimester or absence of antithyroid antibodies. Conversely, in a group of 41 women who either were taking antithyroid medication at delivery or had thyroid receptor antibodies, 11 fetuses—27 percent—had sonographic evidence of a goiter at 32 weeks’ gestation. Seven of these 11 were determined to be hypothyroid, and the remaining fetuses were hyperthyroid. In response to such results, the American Thyroid Association and American Association of Clinical Endocrinologists (2011) recommend routine evaluation of TSH-receptor antibodies between 22 and 26 weeks’ gestation in women with Graves disease. The American College of Obstetricians and Gynecologists (2013), however, does not recommend such testing because management is rarely changed by the results. If the fetus is thyrotoxic, treatment is by adjustment of maternal thionamide drugs even though maternal thyroid function may be within the targeted range (Duncombe, 2001; Mestman, 2012). Occasionally, neonatal thyrotoxicosis may also require short-course antithyroid drug treatment.

A second presentation is goitrous hypothyroidism caused by fetal exposure to maternally administered thionamides (see Fig. 58-3). Although there are theoretical neurological implications, reports of adverse fetal effects seem to have been exaggerated. Available data indicate that thionamides carry an extremely small risk for causing neonatal hypothyroidism (Momotani, 1997; O’Doherty, 1999). For example, of the 239 treated thyrotoxic women shown in Table 58-1, there was evidence of hypothyroidism in only four infants despite relatively high maternal PTU doses. Furthermore, at least four long-term studies report no abnormal intellectual and physical development of these children (Mestman, 1998). If hypothyroidism is identified, the fetus can be treated by a reduced maternal antithyroid medication dose and injection of intraamnionic thyroxine if necessary.

A third presentation, nongoitrous hypothyroidism, may develop from transplacental passage of maternal TSH-receptor blocking antibodies (Fitzpatrick, 2010; Gallagher, 2001). And finally, fetal thyrotoxicosisafter maternal thyroid gland ablation, usually with 131I radioiodine, may result from transplacental thyroid-stimulating antibodies. In the previously described case of early fetal exposure to radioiodine, neonatal thyroid studies indicated transient hyperthyroidism from maternal transfer of stimulating antibodies (Tran, 2010).

Fetal Diagnosis. Evaluation of fetal thyroid function is somewhat controversial. Although fetal thyroid sonographic assessment has been reported in women taking thionamide drugs or those with thyroid-stimulating antibodies, most investigators do not currently recommend this routinely (Cohen, 2003; Luton, 2005). Kilpatrick (2003) recommends umbilical blood sampling and fetal antibody testing only if the mother has previously undergone radioiodine ablation. Because fetal hyper- or hypothyroidism may cause hydrops, growth restriction, goiter, or tachycardia, fetal blood sampling may be appropriate if these are identified (Brand, 2005). The Endocrine Society Clinical Practice Guidelines recommend umbilical blood sampling only when the diagnosis of fetal thyroid disease cannot be reasonably ascertained based on clinical and sonographic data (Garber, 2012). Diagnosis and treatment are considered further in Chapter 16 (p. 324).

Thyroid Storm and Heart Failure

Both are acute and life-threatening in pregnancy. Thyroid storm is a hypermetabolic state and is rare in pregnancy. In contrast, pulmonary hypertension and heart failure from cardiomyopathy caused by the profound myocardial effects of thyroxine is common in pregnant women (Sheffield, 2004). As shown in Table 58-2, heart failure developed in 8 percent of 90 women with uncontrolled thyrotoxicosis. In these women, cardiomyopathy is characterized by a high-output state, which may lead to a dilated cardiomyopathy (Fadel, 2000; Klein, 1998). The pregnant woman with thyrotoxicosis has minimal cardiac reserve, and decompensation is usually precipitated by preeclampsia, anemia, sepsis, or a combination of these. Fortunately, thyroxine-induced cardiomyopathy and pulmonary hypertension are frequently reversible (Sheffield, 2004; Siu, 2007; Vydt, 2006).

Management. Treatment for thyroid storm or heart failure is similar and should be carried out in an intensive care area that may include special-care units within labor and delivery (Fitzpatrick, 2010; Zeeman, 2003). Shown in Figure 58-4 is our stepwise approach to medical management of thyroid storm or thyrotoxic heart failure. An hour or two after initial thionamide administration, iodide is given to inhibit thyroidal release of T3 and T4. It can be given intravenously as sodium iodide or orally as either saturated solution of potassium iodide (SSKI) or Lugol solution. With a history of iodine-induced anaphylaxis, lithium carbonate, 300 mg every 6 hours, is given instead. Most authorities recommend dexamethasone, 2 mg intravenously every 6 hours for four doses, to further block peripheral conversion of T4 to T3. If a β-blocker drug is given to control tachycardia, its effect on heart failure must be considered. Propranolol, labetalol, and esmolol have all been used successfully. Coexisting severe preeclampsia, infection, or anemia should be aggressively managed before delivery is considered.

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FIGURE 58-4 One management method for thyroid storm or thyrotoxic heart failure. gtt = drops; NGT = nasogastric tube; PO = orally.

Hyperemesis Gravidarum and Gestational Transient Thyrotoxicosis

Transient biochemical features of hyperthyroidism may be observed in 2 to 15 percent of women in early pregnancy (Fitzpatrick, 2010). Many women with hyperemesis gravidarum have abnormally high serum thyroxine levels and low TSH levels (Chap. 54p. 1070). This results from TSH-receptor stimulation from massive—but normal for pregnancy—concentrations of hCG. This transient condition is also termed gestational transient thyrotoxicosis. Even if associated with hyperemesis, antithyroid drugs are not warranted (American College of Obstetricians and Gynecologists, 2013). Serum thyroxine and TSH values become more normal by midpregnancy (Fitzpatrick, 2010).

Thyrotoxicosis and Gestational Trophoblastic Disease

The prevalence of increased thyroxine levels in women with molar pregnancy has been reported to be between 25 and 65 percent (Hershman, 2004). As discussed, abnormally high hCG levels lead to overstimulation of the TSH receptor. Because these tumors are now usually diagnosed early, clinically apparent hyperthyroidism has become less common. With definitive treatment, serum free-T4 levels usually normalize rapidly in parallel with the decline in hCG concentrations. This is discussed further in Chapter 20 (p. 399).

image Subclinical Hyperthyroidism

Third-generation TSH assays with an analytical sensitivity of 0.002 mU/mL permit identification of subclinical thyroid disorders. These biochemically defined extremes usually represent normal biological variations but may herald the earliest stages of thyroid dysfunction. Subclinical hyperthyroidism is characterized by an abnormally low serum TSH concentration in concert with thyroxine hormone levels within the normal reference range (Surks, 2004). Long-term effects of persistent subclinical thyrotoxicosis include osteoporosis, cardiovascular morbidity, and progression to overt thyrotoxicosis or thyroid failure. Casey and Leveno (2006b) identified subclinical hyperthyroidism in 1.7 percent of pregnant women. Importantly, these investigators showed that subclinical hyperthyroidism was not associated with adverse pregnancy outcomes. In separate retrospective analyses of almost 25,000 women who underwent thyroid screening throughout pregnancy, Wilson and colleagues (2012) and Tudela and coworkers (2012) confirmed no relationship between subclinical hyperthyroidism and preeclampsia or gestational diabetes.

The American Thyroid Association and American Association of Clinical Endocrinologists guidelines recommend consideration for treatment of subclinical hyperthyroidism in individuals 65 years or older and in postmenopausal women to improve cardiovascular health and bone mineral density. There is, however, no convincing evidence that subclinical hyperthyroidism should be treated in younger nonpregnant individuals. Thus, treatment seems especially unwarranted in pregnancy because antithyroid drugs may affect the fetus. Women identified with subclinical hyperthyroidism may benefit from periodic surveillance, and approximately half eventually have normal TSH concentrations.

image Hypothyroidism

Overt or symptomatic hypothyroidism, as shown in Table 58-3, has been reported to complicate between 2 and 10 pregnancies per 1000. It is characterized by insidious nonspecific clinical findings that include fatigue, constipation, cold intolerance, muscle cramps, and weight gain. A pathologically enlarged thyroid gland depends on the etiology of hypothyroidism and is more likely in women in areas of endemic iodine deficiency or those with Hashimoto thyroiditis. Other findings include edema, dry skin, hair loss, and prolonged relaxation phase of deep tendon reflexes. Clinical or overt hypothyroidism is confirmed when an abnormally high serum TSH level is accompanied by an abnormally low thyroxine level. Subclinical hypothyroidism is defined by an elevated serum TSH level and normal serum thyroxine concentration (Surks, 2004). Included in the spectrum of subclinical thyroid disease are asymptomatic individuals with measurable antithyroid peroxidase or antithyroglobulin antibodies. Euthyroid autoimmune thyroid disease represents a new investigative frontier in screening and treatment of thyroid dysfunction during pregnancy.

TABLE 58-3. Frequency of Overt Hypothyroidism in Pregnancy

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Overt Hypothyroidism and Pregnancy

The most common cause of hypothyroidism in pregnancy is Hashimoto thyroiditis, characterized by glandular destruction from autoantibodies, particularly antithyroid peroxidase antibodies. Clinical identification of hypothyroidism is especially difficult during pregnancy because many of the signs or symptoms are also common to pregnancy itself. Thyroid analyte testing should be performed on symptomatic women or those with a history of thyroid disease (American College of Obstetricians and Gynecologists, 2013). As discussed in Chapter 18 (p. 353), severe hypothyroidism during pregnancy is uncommon, probably because it is often associated with infertility and increased spontaneous abortion rates (Abalovich, 2002; De Groot, 2012). Even women with treated hypothyroidism undergoing in vitro fertilization have a significantly decreased chance of achieving pregnancy (Scoccia, 2012).

Treatment. The American Thyroid Association and American Association of Clinical Endocrinologists (2011) recommend replacement therapy for hypothyroidism beginning with levothyroxine in doses of 1 to 2 μg/kg/day or approximately 100 μg daily. Women who are athyreotic after thyroidectomy or radioiodine therapy may require higher doses. Surveillance is with TSH levels measured at 4- to 6-week intervals, and the thyroxine dose is adjusted by 25- to 50-μg increments until TSH values become normal. Pregnancy is associated with an increased thyroxine requirement in approximately a third of supplemented women (Abalovich, 2010; Alexander, 2004). Because a similar increased requirement is seen in women with postmenopausal hypothyroidism after estrogen replacement, the increased demand in pregnancy is believed to be related to increased estrogen production (Arafah, 2001).

Increased thyroxine requirements begin as early as 5 weeks. In a randomized trial that provided an increased levothyroxine dose at pregnancy confirmation in 60 mothers, Yassa and coworkers (2010) found that a 29- to 43-percent increase in the weekly dose maintained serum TSH values < 5.0 mU/L during the first trimester in all women. Importantly, however, this increase caused TSH suppression in more than a third of women. Significant hypothyroidism may develop early in women without thyroid reserve such as those with a previous thyroidectomy, those with prior radioiodine ablation, or those undergoing assisted reproductive techniques (Alexander, 2004; Loh, 2009; Rotondi, 2004). Anticipatory 25-percent increases in thyroxine replacement at pregnancy confirmation will reduce this likelihood. All other women with hypothyroidism should undergo TSH testing at initiation of prenatal care.

Pregnancy Outcome with Overt Hypothyroidism. Observational studies, although limited, indicate that there are excessive adverse perinatal outcomes associated with overt thyroxine deficiency (Table 58-4). With appropriate replacement therapy, however, adverse effects are not increased in most reports (Matalon, 2006; Tan, 2006; Wolfberg, 2005). In one dissenting study, however, there was an increased risk for some pregnancy complications even in women taking replacement therapy (Wikner, 2008). Most experts agree that adequate hormone replacement during pregnancy minimizes the risk of adverse outcomes and most complications (Abalovich, 2002; Fitzpatrick, 2010).

TABLE 58-4. Pregnancy Complications in 440 Women with Hypothyroidism

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Fetal and Neonatal Effects. There is no doubt that maternal and fetal thyroid abnormalities are related. In both, thyroid function is dependent on adequate iodide intake, and its deficiency early in pregnancy can cause both maternal and fetal hypothyroidism. And as discussed, maternal TSH-receptor-blocking antibodies can cross the placenta and cause fetal thyroid dysfunction. Rovelli and colleagues (2010) evaluated 129 neonates born to women with autoimmune thyroiditis. They found that 28 percent had an elevated TSH level on the third or fourth day of life, and 47 percent of these had TPO antibodies on day 15. Still, autoantibodies were undetectable at 6 months of age. It seems paradoxical that despite these transient laboratory findings in the neonate, TPO and antithyroglobulin (TG) antibodies have little or no effect on fetal thyroid function (Fisher, 1997). Indeed, prevalence of fetal hypothyroidism in women with Hashimoto thyroiditis is estimated to be only 1 in 180,000 neonates (Brown, 1996).

image Subclinical Hypothyroidism

This thyroid condition is common in women, but its incidence can be variable depending on age, race, dietary iodine intake, and serum TSH thresholds used to establish the diagnosis (Cooper, 2012). According to Fitzpatrick and Russell (2010), its prevalence in pregnancy has been estimated to be between 2 and 5 percent. In two large studies totaling more than 25,000 pregnant women screened in the first half of pregnancy, subclinical hypothyroidism was identified in 2.3 percent of women (Casey, 2005; Cleary-Goldman, 2008). The rate of progression to overt thyroid failure is affected by TSH level, age, other disorders such as diabetes, and presence and concentration of antithyroid antibodies. Diez and Iglesias (2004) prospectively followed 93 nonpregnant women with subclinical hypothyroidism for 5 years and reported that in a third, TSH values became normal. In the other two thirds, those women whose TSH levels were 10 to 15 mU/L developed overt disease at a rate of 19 per 100 patient-years. Those women whose TSH levels were < 10 mU/L developed overt hypothyroidism at a rate of 2 per 100 patient-years. The U.S. Preventative Services Task Force on screening for subclinical hypothyroidism also reported that nearly all patients who develop overt hypothyroidism within 5 years have an initial TSH level > 10 mU/L (Helfand, 2004; Karmisholt, 2008). In a 20-year follow-up study of 5805 women who were screened in early pregnancy, only 3 percent developed thyroid disease. Of the 224 women identified with subclinical hypothyroidism during pregnancy, 36 (17 percent) developed thyroid disease in the next 20 years, and most of these had either TPO or TG antibodies during pregnancy (Männistö, 2010). Consequently, the likelihood of progression to overt hypothyroidism during pregnancy in otherwise healthy women with subclinical hypothyroidism seems unlikely.

Subclinical Hypothyroidism and Pregnancy

Observational studies spanning almost 25 years and shown in Table 58-4 suggest that subclinical hypothyroidism is likely associated with some adverse pregnancy outcomes. In 1999, interest was heightened by two studies that suggested that undiagnosed maternal thyroid hypofunction may impair fetal neuropsychological development. In one study, Pop and associates (1999) described 22 women who had free T4levels < 10th percentile in early pregnancy whose offspring were at increased risk for impaired psychomotor development. In the other study, Haddow and coworkers (1999) retrospectively evaluated children born to 48 untreated women whose serum TSH values were > 98th percentile. Some had diminished school performance, reading recognition, and intelligent quotient (IQ) scores. Although described as “subclinically hypothyroid,” these women had an abnormally low mean serum free thyroxine level, and thus, many had overt hypothyroidism.

To further evaluate any adverse effects, Casey and colleagues (2005) identified subclinical hypothyroidism in 2.3 percent of 17,298 women screened before midpregnancy. As shown in Table 58-5, these women had higher incidences of preterm birth, placental abruption, and admission of infants to the intensive care nursery compared with euthyroid women. In the study of 10,990 participants in the First- and Second-Trimester Evaluation of Risk (FASTER) Trial, Cleary-Goldman and associates (2008) did not find such a link with these adverse obstetrical outcomes.

TABLE 58-5. Pregnancy Outcomes in Women with Untreated Subclinical Hypothyroidism and Isolated Maternal Hypothyroxinemia Compared with Euthyroid Pregnant Women

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In a study of 24,883 women screened throughout pregnancy, Wilson and coworkers (2012) found that women identified with subclinical hypothyroidism had an almost twofold increased risk of severe preeclampsia. The authors hypothesized that this was related to endothelial cell dysfunction that has been linked to subclinical hypothyroidism in older patients. In their analysis of the same cohort, Tudela and associates (2012) identified a consistent relationship between increasing TSH level and risk for gestational diabetes. More specifically, 6.3 percent of women with subclinical hypothyroidism were diagnosed with gestational diabetes compared with 4.2 percent in euthyroid women. Nelson and colleagues (2014) evaluated 230 women diagnosed with subclinical hypothyroidism during a prior pregnancy. These women were at increased risk for diabetes and stillbirth in subsequent pregnancies. Although these findings are intriguing, there is currently no evidence that identification and treatment of subclinical hypothyroidism during pregnancy improves these outcomes.

TSH Level Screening in Pregnancy. Because of the findings from the 1999 studies cited above, some professional organizations recommend routine prenatal screening and treatment for subclinical hypothyroidism (Gharib, 2005). The American College of Obstetricians and Gynecologists (2013) has reaffirmed that although observational data were consistent with the possibility that subclinical hypothyroidism was associated with adverse neuropsychological development, there have been no interventional trials to demonstrate improvement. The College thus has consistently recommended against implementation of screening until further studies are done to validate or refute these findings (American College of Obstetricians and Gynecologists, 2012).

Lazarus and colleagues (2012) reported the findings of the international multicenter Controlled Antenatal Thyroid Screening (CATS) study of thyroid screening and treatment of subclinical hypothyroidism and isolated maternal hypothyroxinemia during pregnancy. The primary outcome was offspring IQ scores at 3 years of age. Cognitive function in the children was not improved with screening and treatment. A second comparable study is being conducted by the Maternal-Fetal Medicine Units Network, and the results are anticipated in 2016.

Consequent to the Lazarus study, clinical practice guidelines from the Endocrine Society, The American Thyroid Association, and the American Association of Clinical Endocrinologists now uniformly recommend screening only those at increased risk during pregnancy (De Groot, 2012; Garber, 2012). Furthermore, previous cost-effectiveness analyses that favored a universal screening strategy are no longer valid since they were based on assumptions of improved neurodevelopmental outcomes in offspring (Dosiou, 2008; Thung, 2009).

image Isolated Maternal Hypothyroxinemia

Women with low serum free T4 values but a normal range TSH level are considered to have isolated maternal hypothyroxinemia. This was identified by Casey and colleagues (2007) in 1.3 percent of more than 17,000 pregnant women screened at Parkland Hospital before 20 weeks. Cleary-Goldman and associates (2008) found a 2.1-percent incidence in the FASTER Trial cohort described earlier. As discussed previously, offspring of women with isolated hypothyroxinemia have been reported to have neurodevelopmental difficulties at age 3 weeks, 10 months, and 2 years (Kooistra, 2006; Pop, 1999, 2003). These findings have not stimulated recommendations for prenatal serum thyroxine screening. Importantly, free T4 estimates by currently available immunoassays may not be accurate during pregnancy because of sensitivity to alterations in binding proteins (Lee, 2009).

In a study of 233 women with isolated maternal hypothyroxinemia, Casey and colleagues (2007) reported that there were no increased adverse perinatal outcomes compared with those of euthyroid women (see Table 58-5). And, as shown in Figure 58-2, unlike subclinical hypothyroidism, these women had a low prevalence of antithyroid antibodies. The only other finding was from Cleary-Goldman and coworkers (2008), who reported a twofold incidence of fetal macrosomia. Taken together, these findings indicate that isolated maternal hypothyroxinemia has no apparent serious adverse effects on pregnancy outcome. Finally, the aforementioned CATS study did not find improved neurodevelopmental outcomes in women with isolated hypothyroxinemia who were then treated with thyroxine (Lazarus, 2012). Because of this, routine screening for isolated hypothyroxinemia is not recommended.

image Euthyroid Autoimmune Thyroid Disease

Autoantibodies to TPO and TG have been identified in 6 to 20 percent of reproductive-aged women (Thangaratinam, 2011). Most who test positive for such antibodies, however, are euthyroid. That said, such women are at a two- to fivefold increased risk for early pregnancy loss (Stagnaro-Green, 2004; Thangaratinam, 2011). The presence of thyroid antibodies has also been associated with preterm birth (Stagnaro-Green, 2009). In a randomized treatment trial of 115 euthyroid women with TPO antibodies, Negro and coworkers (2006) reported that treatment with levothyroxine astoundingly reduced the preterm birth rate from 22 to 7 percent. Contrarily, Abbassi-Ghanavati and associates (2010) evaluated pregnancy outcomes in more than 1000 untreated women with TPO antibodies and did not find an increased risk for preterm birth compared with the risk in 16,000 euthyroid women without antibodies. These investigators, however, found a threefold increased risk of placental abruption in these women. As with nonpregnant subjects with TPO antibodies, these women are also at increased risk for progression of thyroid disease and postpartum thyroiditis (Stagnaro-Green, 2012a).

This group of euthyroid women with abnormally high thyroid autoantibody levels represents a new focus of thyroid research. Dosiou and colleagues (2012) performed a cost-effectiveness analysis of universal screening for autoimmune thyroid disease during pregnancy. Their results favored universal screening. There is, however, a paucity of studies that show benefit to identifying and treating euthyroid women with thyroid autoantibodies. Thus, calls for routine antibody screening seem premature. Currently, universal screening for the thyroid autoantibodies is not recommended by any professional organizations (De Groot, 2012; Stagnaro-Green, 2011a, 2012a).

image Iodine Deficiency

Decreasing iodide fortification of table salt and bread products in the United States during the past 25 years has led to occasional iodide deficiency (Caldwell, 2005; Hollowell, 1998). Importantly, the most recent National Health and Nutrition Examination survey indicated that, overall, the United States population remains iodine sufficient (Caldwell, 2011). Even so, experts agree that iodine nutrition in vulnerable populations such as pregnant women requires continued monitoring. In 2011 the Office of Dietary Supplements of the National Institutes of Health sponsored a workshop to prioritize iodine research. Participants emphasized the decline in median urinary iodine to 125 μg/L in pregnant women and the serious potential impact on the developing fetus (Swanson, 2012).

Dietary iodine requirements are increased during pregnancy due to increased thyroid hormone production, increased renal losses, and fetal iodine requirements. Adequate iodine is requisite for fetal neurological development beginning soon after conception, and abnormalities are dependent on the degree of deficiency. The World Health Organization (WHO) has estimated that at least 50 million people worldwide have varying degrees of preventable brain damage due to iodine deficiency (Brundtland, 2002). Although it is doubtful that mild deficiency causes intellectual impairment, supplementation does prevent fetal goiter (Stagnaro-Green, 2012b). Severe deficiency, on the other hand, is frequently associated with damage typically encountered with endemic cretinism (Delange, 2001). It is presumed that moderate deficiency has intermediate and variable effects. Berbel and associates (2009) began daily supplementation in more than 300 pregnant women with moderate deficiency at three time periods—4 to 6 weeks, 12 to 14 weeks, and after delivery. They found improved neurobehavioral development scores in offspring of women supplemented with 200 μg potassium iodide very early in pregnancy. Similarly, Velasco and coworkers (2009) found improved Bayley Psychomotor Development scores in offspring of women supplemented with 300 μg of iodide in the first trimester. In contrast, Murcia and colleagues (2011) identified lower psychomotor scores in 1-year-old infants whose mothers reported daily supplementation of more than 150 μg. There are two ongoing randomized controlled trials of iodine supplementation in mildly to moderately iodine-deficient pregnant women in India and Thailand. These studies should provide needed answers as to whether iodine supplementation in these women is beneficial (Pearce, 2013).

The Institute of Medicine (2001) recommends daily iodine intake during pregnancy of 220 μg/day, and 290 μg/day for lactating women (Chap. 9p. 180). The Endocrine Society (De Groot, 2012) recommends an average iodine intake of 150 μg per day in childbearing-aged women, and this should be increased to 250 μg during pregnancy and breast feeding. The American Thyroid Association has recommended that 150 μg of iodine be added to prenatal vitamins to achieve this average daily intake (Becker, 2006). According to Leung and coworkers (2011), however, only 51 percent of the prenatal multivitamins in the United States contain iodine. It has even been suggested that because most cases of maternal hypothyroxinemia worldwide are related to relative iodine deficiency, supplementation may obviate the need to consider thyroxine treatment in such women (Gyamfi, 2009).

On the other hand, experts caution against oversupplementation. Teng and associates (2006) contend that excessive iodine intake—defined as > 300 μg/day—may lead to subclinical hypothyroidism and autoimmune thyroiditis. And the Endocrine Society, in accordance with the WHO, advises against exceeding twice the daily recommended intake of iodine, or 500 μg/day (De Groot, 2012; Leung, 2011).

image Congenital Hypothyroidism

Because the clinical diagnosis of hypothyroidism in neonates is usually missed, universal newborn screening was introduced in 1974 and is now required by law in all states. Congenital hypothyroidism develops in approximately 1 in 3000 newborns and is one of the most preventable causes of mental retardation (LaFranchi, 2011). Developmental disorders of the thyroid gland such as agenesis and hypoplasia account for 80 to 90 percent of these cases (LaFranchi, 2011; Topaloglu, 2006). The exact underlying etiology of thyroid dysgenesis remains unknown. The remaining primary congenital hypothyroidism cases are caused by hereditary defects in thyroid hormone production. The list of identified gene mutations that cause hypothyroidism continues to grow rapidly (Moreno, 2008).

Early and aggressive thyroxine replacement is critical for infants with congenital hypothyroidism. Still, some infants identified by screening programs with severe congenital hypothyroidism who were treated promptly will exhibit cognitive deficits into adolescence (Song, 2001). Therefore, in addition to timing of treatment, the severity of congenital hypothyroidism is an important factor in long-term cognitive outcomes (Kempers, 2006). Accordingly, in infants with screening results suggestive of severe hypothyroidism, therapy should be started immediately without waiting for confirmatory results (Abduljabbar, 2012). Olivieri and colleagues (2002) reported that 8 percent of 1420 infants with congenital hypothyroidism also had other major congenital malformations.

image Postpartum Thyroiditis

Transient autoimmune thyroiditis is consistently found in approximately 5 to 10 percent of women during the first year after childbirth (Amino, 2000; Stagnaro-Green, 2011b, 2012a). Postpartum thyroid dysfunction with an onset within 12 months includes hyperthyroidism, hypothyroidism, or both. The propensity for thyroiditis antedates pregnancy and is directly related to increasing serum levels of thyroid autoantibodies. Up to 50 percent of women who are thyroid-antibody positive in the first trimester will develop postpartum thyroiditis (Stagnaro-Green, 2012a). In a Dutch study of 82 women with type 1 diabetes, postpartum thyroiditis developed in 16 percent and was threefold higher than in the general population (Gallas, 2002). Importantly, 46 percent of those identified with overt postpartum thyroiditis had TPO antibodies in the first trimester.

Clinical Manifestations

In clinical practice, postpartum thyroiditis is diagnosed infrequently because it typically develops months after delivery and causes vague and nonspecific symptoms that often are thought to be stresses of motherhood (Stagnaro-Green, 2004). The clinical presentation varies, and classically there are two recognized clinical phases that may develop in succession. The first and earliest is destruction-induced thyrotoxicosis with symptoms from excessive release of hormone from glandular disruption. The onset is abrupt, and a small, painless goiter is commonly found. Although there may be many symptoms, only fatigue and palpitations are more frequent in thyrotoxic women compared with normal controls. This thyrotoxic phase usually lasts only a few months. Thionamides are ineffective, and if symptoms are severe, a β-blocker agent may be given. The second and usually later phase is clinical hypothyroidismfrom thyroiditis between 4 and 8 months postpartum. Thyromegaly and other symptoms are common and more prominent than during the thyrotoxic phase. Thyroxine replacement with 25 to 75 μg/day is typically given for 6 to 12 months.

Stagnaro-Green and associates (2011b) reported postpartum follow-up from 4562 Italian pregnant women who had been screened for thyroid disease in pregnancy. Serum TSH and anti-TPO antibody levels were measured again at 6 and 12 months. Overall, two thirds of 169 women (3.9 percent) with postpartum thyroiditis were identified to have hypothyroidism only. The other third were diagnosed with hyperthyroidism, but only 14 percent of all women demonstrated the “classic” biphasic progression described above. These findings are consistent with data compiled from 20 other studies between 1982 and 2008 (Stagnaro-Green, 2012a).

Importantly, women who experience either type of postpartum thyroiditis have an approximately 30-percent risk of eventually developing permanent hypothyroidism, and the annual progression rate is 3.6 percent (Lucas, 2005; Muller, 2001; Premawardhana, 2000). Women at increased risk for developing hypothyroidism are those with higher titers of thyroid antibodies and higher TSH levels during the initial hypothyroid phase. Others may develop subclinical disease, but half of those with thyroiditis who are positive for TPO antibodies develop permanent hypothyroidism by 6 to 7 years (Stagnaro-Green, 2012a).

An association between postpartum thyroiditis and postpartum depression has been proposed but remains unresolved. Lucas and coworkers (2001) found a 1.7-percent incidence of postpartum depression at 6 months in women with thyroiditis as well as in controls. Pederson and colleagues (2007) found a significant correlation between abnormal scores on the Edinburgh Postnatal Depression Scale and total thyroxine values in the low normal range during pregnancy in 31 women. Similarly unsettled is the link between depression and thyroid antibodies. Kuijpens and associates (2001) reported that TPO antibodies were a marker for postpartum depression in euthyroid women. In a randomized trial, Harris and coworkers (2002) reported no difference in postpartum depression in 342 women with TPO antibodies who were given either levothyroxine or placebo.

image Nodular Thyroid Disease

Thyroid nodules can be found in 1 to 2 percent of reproductive- aged women (Fitzpatrick, 2010). Management of a palpable thyroid nodule during pregnancy depends on gestational age and mass size. Small nodules detected by sensitive sonographic methods are more common during pregnancy in some populations. For example, Kung and associates (2002) used high-resolution sonography and found that 15 percent of Chinese women had nodules larger than 2 mm in diameter. Almost half were multiple, and the nodules usually enlarged modestly across pregnancy and did not regress postpartum. Biopsy of those > 5 mm3 that persisted at 3 months usually showed nodular hyperplasia, and none was malignant. In some studies, however, up to 40 percent of solitary nodules were malignant (Doherty, 1995; Rosen, 1986). Even so, most were low-grade neoplasms.

Evaluation of thyroid nodules during pregnancy should be similar to that for nonpregnant patients. As discussed in Chapter 46 (p. 934), most recommend against radioiodine scanning in pregnancy despite the fact that tracer doses used are associated with minimal fetal irradiation (Popoveniuc, 2012). Sonographic examination reliably detects nodules larger than 0.5 cm, and their solid or cystic structure also is determined. According to the American Association of Clinical Endocrinologists, sonographic characteristics associated with malignancy include hypoechogenic pattern, irregular margins, and microcalcifications (Gharib, 2005). Fine-needle aspiration (FNA) is an excellent assessment method, and histological tumor markers and immunostaining are reliable to evaluate for malignancy (Bartolazzi, 2001; Hegedüs, 2004). If the FNA biopsy shows a follicular lesion, surgery may be deferred until after delivery.

Evaluation of thyroid cancer involves a multidisciplinary approach (American College of Obstetricians and Gynecologists, 2013). Most thyroid carcinomas are well differentiated and pursue an indolent course. When thyroid malignancy is diagnosed during the first or second trimester, thyroidectomy may be performed before the third trimester (Chap. 63p. 1231). In women without evidence of an aggressive thyroid cancer, or in those diagnosed in the third trimester, surgical treatment can be deferred to the immediate postpartum period (Gharib, 2010).

PARATHYROID DISEASES

The function of parathyroid hormone (PTH) is to maintain extracellular fluid calcium concentration. This 115-amino acid hormone acts directly on bone and kidney and indirectly on small intestine through its effects on synthesis of vitamin D (1,25[OH2]-D) to increase serum calcium. Secretion is regulated by serum ionized calcium concentration through a negative feedback system. Calcitonin is a potent parathyroid hormone that acts as a physiological parathyroid hormone antagonist. The interrelationships between these hormones, calcium metabolism, and PTH-related protein produced by fetal tissue are discussed in Chapter 4 (p. 70).

Fetal calcium needs—300 mg/day in late pregnancy and a total of 30 g—as well as increased renal calcium loss from augmented glomerular filtration, substantively increase maternal calcium demands. Pregnancy is associated with a twofold rise in serum concentrations of 1,25-dihydroxyvitamin D, which increases gastrointestinal calcium absorption. The effectuating hormone is probably of placental and decidual origin because maternal PTH levels are low normal or decreased during pregnancy (Cooper, 2011; Molitch, 2000). Total serum calcium levels decline with serum albumin concentrations, but ionized calcium levels remain unchanged. Vargas Zapata (2004), and others, have suggested a role for insulin-like growth factor-1 (IGF-1) in maternal calcium homeostasis and bone turnover, especially in mothers with low calcium intake.

image Hyperparathyroidism

Hypercalcemia is caused by hyperparathyroidism or cancer in 90 percent of cases. Primary hyperparathyroidism is reported most often in women older than 50 (Miller, 2008). Because many automated laboratory systems include serum calcium measurement, hyperparathyroidism has changed from being a condition defined by symptoms to one that is discovered on routine screening (Pallan, 2012). It has a reported prevalence of 2 to 3 per 1000 women, but some have estimated the rate to be as high as 14 per 1000 when asymptomatic cases are included (Farford, 2007; Schnatz, 2005). Almost 80 percent are caused by a solitary adenoma, and another 15 percent by hyperfunction of all four glands. In the remainder, a malignancy and the cause of increased serum calcium levels are obvious. Of note, PTH produced by tumors is not identical to the natural hormone and may not be detected by routine assays.

In most patients, the serum calcium level is only elevated to within 1 to 1.5 mg/dL above the upper normal limit. This may help to explain why only 20 percent of those who have abnormally elevated levels are symptomatic (Bilezikian, 2004). In a fourth, however, symptoms become apparent when the serum calcium level continues to rise. Hypercalcemic crisis manifests as stupor, nausea, vomiting, weakness, fatigue, and dehydration.

All women with symptomatic hyperparathyroidism should be surgically treated. Guidelines for management in nonpregnant patients were revised after the Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism (Bilezikian, 2009). Indications for parathyroidectomy include a serum calcium level 1.0 mg/dL above the upper normal range, a calculated creatinine clearance less than 60 mL/min, reduced bone density, or age < 50 years. Those not meeting these criteria should undergo annual calcium and creatinine level measurement and bone density assessment every 1 to 2 years (Pallan, 2012).

Hyperparathyroidism in Pregnancy

In their review, Schnatz and Thaxton (2005) found fewer than 200 reported cases complicating pregnancy. As in nonpregnant patients, hyperparathyroidism is usually caused by a parathyroid adenoma. Gravidas with ectopic parathyroid hormone production and rare cases of parathyroid carcinoma have been reported (Montoro, 2000). Symptoms include hyperemesis, generalized weakness, renal calculi, and psychiatric disorders. Occasionally, pancreatitis is the presenting finding (Cooper, 2011; Dahan, 2001).

Pregnancy theoretically improves hyperparathyroidism because of significant calcium shunting to the fetus and augmented renal excretion (Power, 1999). When the “protective effects” of pregnancy are withdrawn, however, there is significant danger of postpartum hypercalcemic crisis. This life-threatening complication can be seen with serum calcium levels greater than 14 mg/dL and is characterized by nausea, vomiting, tremors, dehydration, and mental status changes (Malekar-Raikar, 2011). Early reports described excessive stillbirths and preterm deliveries in pregnancies complicated by hyperparathyroidism (Shangold, 1982). More recent reports, however, described lower rates of stillbirth, neonatal death, and neonatal tetany (Kovacs, 2011). Other fetal complications include miscarriage, fetal-growth restriction, and low birthweight (Chamarthi, 2011). Schnatz (2005) reported a 25-percent incidence of preeclampsia.

Management in Pregnancy. Surgical removal of a symptomatic parathyroid adenoma is preferable. This should prevent fetal and neonatal morbidities, as well as postpartum parathyroid crises (Kovacs, 2011). Elective neck exploration during pregnancy is usually well tolerated, even in the third trimester (Graham, 1998; Kort, 1999; Schnatz, 2005). In one woman, a mediastinal adenoma was removed at 23 weeks (Rooney, 1998).

None of the three International Workshop Conferences on Asymptomatic Hyperparathyroidism have addressed its management during pregnancy (Bilezikian, 2009). Medical management may be appropriate in asymptomatic pregnant women with mild hypercalcemia. If so, patients are carefully monitored in the postpartum period for hypercalcemic crisis (Kovacs, 2011). Initial medical management might include calcitonin to decrease skeletal calcium release, or oral phosphate, 1 to 1.5 g daily in divided doses to bind excess calcium. For women with dangerously elevated serum calcium levels or those who are mentally obtunded with hypercalcemic crisis, emergency treatment is instituted. Diuresis with intravenous normal saline is begun so that urine flow exceeds 150 mL/hr. Furosemide is given in conventional doses to block tubular calcium reabsorption. Importantly, hypokalemia and hypomagnesemia should be prevented. Adjunctive therapy includes mithramycin, which inhibits bone resorption.

Neonatal Effects. Normally, cord blood calcium levels are higher than maternal levels (Chap. 7p. 135). With maternal hyperparathyroidism, abnormally elevated maternal and thence fetal levels further suppress fetal parathyroid function. Because of this, after birth, there is a rapidly decreasing newborn calcium level, and 15 to 25 percent of these infants develop severe hypocalcemia with or without tetany (Molitch, 2000). Neonatal hypoparathyroidism caused by maternal hyperparathyroidism is usually transient and should be treated with calcium and calcitriol. Calcitriol will not be effective in preterm infants, however, because the intestinal vitamin D receptor is not sufficiently expressed (Kovacs, 2011). Neonatal tetany or seizures should stimulate an evaluation for maternal hyperparathyroidism (Beattie, 2000; Ip, 2003; Jaafar, 2004).

image Hypoparathyroidism

The most common cause of hypocalcemia is hypoparathyroidism that usually follows parathyroid or thyroid surgery. Hypoparathyroidism is estimated to follow up to 7 percent of total thyroidectomies (Shoback, 2008). It is rare and characterized by facial muscle spasms, muscle cramps, and paresthesias of the lips, tongue, fingers, and feet. This can progress to tetany and seizures. Chronically, hypocalcemic pregnant women may also have a fetus with skeletal demineralization resulting in multiple bone fractures in the neonatal period (Alikasifoglu, 2005).

Maternal treatment includes 1,25-dihydroxyvitamin D3 (calcitriol), dihydrotachysterol, or large vitamin D doses of 50,000 to 150,000 U/day; calcium gluconate or calcium lactate in doses of 3 to 5 g/day; and a low-phosphate diet. The therapeutic challenge in women with known hypoparathyroidism is management of blood calcium levels. The goal during pregnancy is maintenance of the corrected calcium level in the low normal range. It is possible that the increased calcium absorption typical of pregnancy will result in lower calcium requirements or that the fetal demand for calcium will result in increased need. Since both scenarios are possible, it is best to carefully monitor the corrected serum calcium on a frequent, perhaps monthly, basis throughout pregnancy (Cooper, 2011; Kovacs, 2011). The fetal risks from large doses of vitamin D have not been established.

image Pregnancy-Associated Osteoporosis

Even with remarkably increased calcium requirements, it is uncertain whether pregnancy causes osteopenia in most women (Kaur, 2003; To, 2003). In one study of 200 pregnant women in which bone mass was measured using quantitative ultrasonometry of the calcaneus, Kraemer and colleagues (2011) demonstrated a decline in bone density during pregnancy. Women who breast fed, carried twin pregnancies, or had a low body mass index (BMI) were at higher risk of bone loss. From their review, Thomas and Weisman (2006) cite a 3- to 4-percent average reduction in bone-mineral density during pregnancy. Lactation also represents a period of negative calcium balance that is corrected through maternal skeletal resorption. Feigenberg and coworkers (2008) found cortical bone mass reductions using ultrasound in young primiparas in the puerperium compared with nulligravid controls. Rarely, some women develop idiopathic osteoporosis while pregnant or lactating. Its incidence is estimated to be 4 per million women (Hellmeyer, 2007).

The most common symptom of osteoporosis is back pain in late pregnancy or postpartum. Other symptoms are hip pain, either unilateral or bilateral, and difficulty in weight bearing until nearly immobilized (Maliha, 2012). In more than half of women, no apparent reason for osteopenia is found. Some known causes include heparin, prolonged bed rest, and corticosteroid therapy (Cunningham, 2005; von Mandach, 2003). In a few cases, overt hyperparathyroidism or thyrotoxicosis eventually develops.

Treatment is problematical and includes calcium and vitamin D supplementation as well as standard pain management. Shown in Figure 58-5 is a hip radiograph from a woman treated at Parkland Hospital during the third trimester for transient osteoporosis of pregnancy.

image

FIGURE 58-5 Anteroposterior plain radiograph with abdominal shielding of a 25-year-old patient’s hips at 26-weeks’ gestation. She complained of left hip and knee pain and progressive weakness. Her transient osteoporosis of the left femur responded over 3 months to physical therapy combined with vitamin D and calcium supplementation.

For women with pregnancy-associated osteopenia, long-term surveillance indicates that although bone density improves, these women and their offspring may have chronic osteopenia (Carbone, 1995). There is an ongoing randomized, placebo-controlled trial of vitamin D supplementation in pregnant women to determine its effect on neonatal bone mineral content as assessed by dual-energy x-ray absorptiometry (DEXA) (Harvey, 2012).

ADRENAL GLAND DISORDERS

Pregnancy has profound effects on adrenal cortical secretion and its control or stimulation. These interrelationships were reviewed by Lekarev and New (2011) and are discussed in detail in Chapter 4 (p. 70).

image Pheochromocytoma

These tumors are clinically uncommon and complicate approximately 1 per 10,000 pregnancies. Notably, they are found in 0.1 percent of hypertensive patients (Abdelmannan, 2011). However, they are more commonly found at autopsy with infrequent clinical recognition. Pheochromocytomas are chromaffin tumors that secrete catecholamines and usually are located in the adrenal medulla, although 10 percent are located in sympathetic ganglia. They are called the 10-percent tumor because approximately 10 percent are bilateral, 10 percent are extraadrenal, and 10 percent are malignant. These tumors can be associated with medullary thyroid carcinoma and hyperparathyroidism in some of the autosomally dominant or recessive multiple endocrine neoplasia syndromes, as well as in neurofibromatosis and von Hippel-Lindau disease.

Symptoms are usually paroxysmal and manifest as hypertensive crisis, seizure disorders, or anxiety attacks. Hypertension is sustained in 60 percent of patients, but half of these also have paroxysmal crises. Other symptoms during paroxysmal attacks are headaches, profuse sweating, palpitations, chest pain, nausea and vomiting, and pallor or flushing.

The standard screening test is quantification of catecholamine metabolites in a 24-hour urine specimen (Abdelmannan, 2011). Diagnosis is established by measurement of a 24-hour urine collection with at least two of three assays for free catecholamines, metanephrines, or vanillylmandelic acid (VMA). Determination of plasma catecholamine levels may be accurate but is associated with technical difficulties (Conlin, 2001; Lenders, 2002). Boyle and colleagues (2007) determined that measurement of urinary free metanephrine was superior to assessment of a VMA or urinary or plasma catecholamine level. In nonpregnant patients, adrenal localization is usually successful with either computed tomography (CT) or magnetic resonance (MR) imaging. For most cases, preferred treatment is laparoscopic adrenalectomy (Lal, 2003).

Pheochromocytoma Complicating Pregnancy

These tumors are rare but result in dangerous pregnancy complications. Geelhoed (1983) provided an earlier review of 89 cases in which 43 mothers died. Maternal death was much more common if the tumor was not diagnosed antepartum—58 versus 18 percent. As seen in Table 58-6, maternal mortality rates are now lower but still formidable. In their review of 60 cases, Sarathi and associates (2010) confirmed that antepartum diagnosis is the most important determinant of maternal mortality risk. Maternal death was rare if the diagnosis is made antepartum.

TABLE 58-6. Outcomes of Pregnancies Complicated by Pheochromocytoma and Reported in Three Contiguous Epochs

image

Diagnosis of pheochromocytoma in pregnancy is similar to that for nonpregnant patients. MR imaging is the preferred imaging technique because it almost always locates adrenal and extraadrenal pheochromocytomas (Fig. 58-6) (Manger, 2005). In many cases, the principal challenge is to differentiate preeclampsia from the hypertensive crisis caused by pheochromocytoma. Desai and coworkers (2009) describe a woman who was initially treated for severe preeclampsia, suffered an intrapartum fetal death, and was then treated for presumed peripartum cardiomyopathy. When she returned 1 week later with paroxysmal hypertension, pheochromocytoma was diagnosed and her blood pressure and ventricular function returned to normal after tumor resection. Grimbert and colleagues (1999) diagnosed two pheochromocytomas during 56 pregnancies in 30 women with von Hippel-Lindau disease.

image

FIGURE 58-6 Coronal magnetic resonance image taken in a 32-week pregnant woman shows a right-sided pheochromocytoma (arrow) and its position relative to the liver above it.

Management

Immediate control of hypertension and symptoms with an α-adrenergic blocker such as phenoxybenzamine is imperative. The dose is 10 to 30 mg, two to four times daily. After α-blockade is achieved, β-blockers may be given for tachycardia. In many cases, surgical exploration and tumor removal are performed during pregnancy, preferably during the second trimester (Dong, 2014; Miller, 2005). Successful laparoscopic removal of adrenal tumors has become the norm (Junglee, 2007; Kim, 2006; Miller, 2012; Zuluaga-Gómez, 2012). If diagnosed later in pregnancy, either planned cesarean delivery with tumor excision or postpartum resection is appropriate.

Recurrent tumors are troublesome, and even with good blood pressure control, dangerous peripartum hypertension may develop. We have cared for three women in whom recurrent pheochromocytoma was identified during pregnancy. Hypertension was managed with phenoxybenzamine in all three. Two infants were healthy, but a third was stillborn in a mother with a massive tumor burden who was receiving phenoxybenzamine, 100 mg daily. In all three women, tumor was resected postpartum.

image Cushing Syndrome

This syndrome is rare and has an annual incidence of 2 to 3 per million. The female:male ratio is 3:1 (Steffenson, 2010). Most cases are iatrogenic from long-term corticosteroid treatment. However, endogenous Cushing syndrome is typically due to Cushing disease, which is bilateral adrenal hyperplasia stimulated by corticotropin-producing pituitary adenomas. Most are small microadenomas < 1 cm, and half measure ≤ 5 mm. Rarely, abnormal secretion of hypothalamic corticotropin-releasing factor may cause corticotropic hyperplasia. Such hyperplasia may also be caused by nonendocrine tumors that produce polypeptides similar to either corticotropin-releasing factor or corticotropin. Less than a fourth of cases of Cushing syndrome are corticotropin independent, and most of these are caused by an adrenal adenoma. Tumors are usually bilateral, and half are malignant. Occasionally, associated androgen excess may lead to severe virilization (Danilowicz, 2002).

The typical cushingoid body habitus is caused by adipose tissue deposition that characteristically results in moon facies, a buffalo hump, and truncal obesity. Fatigability and weakness, hypertension, hirsutism, and amenorrhea are each encountered in 75 to 85 percent of nonpregnant patients (Hatipoglu, 2012; Williams, 2001). Personality changes, easy bruisability, and cutaneous striae are common. Up to 60 percent may have impaired glucose tolerance. Diagnosis is verified by elevated plasma cortisol levels that cannot be suppressed by dexamethasone or by elevated 24-hour urine free cortisol excretion (Boscaro, 2001). Neither test is totally accurate, and both are more difficult to interpret in obese patients. CT and MR imaging are used to localize pituitary and adrenal tumors or hyperplasia.

Cushing Syndrome and Pregnancy

Because most women have corticotropin-dependent Cushing syndrome, associated androgen excess may cause anovulation, and pregnancy is rare. In their review, Lekarev and New (2011) identified fewer than 140 reported cases of Cushing syndrome in pregnancy. These differ compared with nonpregnant women in that half are caused by corticotropin-independent adrenal adenomas (Abdelmannan, 2011; Klibanski, 2006). Approximately 30 percent of cases are from a pituitary adenoma, and 10 percent from adrenal carcinomas (Lekarev, 2011; Lindsay, 2005). All reports stress difficulties in diagnosis because of pregnancy-induced increases in plasma cortisol, corticotropin, and corticotropin- releasing factor levels. Measurement of 24-hour urinary free cortisol excretion is recommended, with consideration for normal elevation in pregnancy.

Pregnancy outcomes in women with Cushing syndrome are listed in Table 58-7. Heart failure is common during pregnancy and is a major cause of maternal mortality (Buescher, 1992). Hypercortisolism in pregnancy may also cause poor wound healing, osteoporotic fracture, and psychiatric complications (Kamoun, 2014).

TABLE 58-7. Maternal and Perinatal Complications in Pregnancies Complicated by Cushing Syndrome

image

Long-term medical therapy for Cushing syndrome usually is ineffective, and definitive therapy is resection of the pituitary or adrenal adenoma or bilateral adrenalectomy for hyperplasia (Lekarev, 2011; Motivala, 2011). During pregnancy, management of hypertension in mild cases may suffice until delivery. In their review, Lindsay and associates (2005) described primary medical therapy in 20 women with Cushing syndrome. Most were successfully treated with metyrapone as an interim treatment until definitive surgery after delivery. A few cases were treated with oral ketoconazole. However, because this drug also blocks testicular steroidogenesis, treatment during pregnancy with a male fetus is worrisome. Mifepristone, the norethindrone derivative used for abortion and labor induction, has shown promise for treating Cushing disease but should not be used in pregnancy for obvious reasons. If necessary, pituitary adenomas can be treated by transsphenoidal resection (Boscaro, 2001; Lindsay, 2005). Unilateral adrenalectomy has been safely performed in the early third trimester and can also be curative (Abdelmannan, 2011).

image Adrenal Insufficiency—Addison Disease

Primary adrenocortical insufficiency is rare because more than 90 percent of total gland volume must be destroyed for symptoms to develop. Autoimmune adrenalitis is the most common cause in the developed world, but tuberculosis is a more frequent etiology in resource-poor countries (Kamoun, 2014). There is an increased incidence of concurrent Hashimoto thyroiditis, premature ovarian failure, type 1 diabetes, and Graves disease. These polyglandular autoimmune syndromes also include pernicious anemia, vitiligo, alopecia, nontropical sprue, and myasthenia gravis.

Untreated adrenal hypofunction frequently causes infertility, but with replacement therapy, ovulation is restored. The incidence of primary adrenal insufficiency has been cited as being as high as 1 in 3000 births in Norway (Lekarev, 2011). If untreated, symptoms often include weakness, fatigue, nausea and vomiting, and weight loss (Mestman, 2002). Because serum cortisol levels are increased during pregnancy, the finding of a low value should prompt an adrenocorticotropic hormone (ACTH) stimulation test to document the lack of response to infused corticotropin (Salvatori, 2005).

In a large Swedish cohort study, 1188 women with Addison disease were compared with more than 11,000 age-matched controls who delivered between 1973 and 2006. Women diagnosed with adrenal insufficiency within 3 years of delivery were twice as likely to deliver preterm, were three times more likely to deliver a low-birthweight infant, and were more likely to undergo cesarean delivery (Björnsdottir, 2010). Most pregnant women with Addison disease are already taking cortisone-like drugs. These should be continued and women observed for evidence of either inadequate or excessive corticosteroid replacement. During labor, delivery, and postpartum, or after a surgical procedure, corticosteroid replacement must be increased appreciably to approximate the normal adrenal response—so-called stress doses. Hydrocortisone, 100 mg, is usually given intravenously every 8 hours. It is important that shock from causes other than adrenocortical insufficiency—for example, hemorrhage or sepsis—be recognized and treated promptly.

image Primary Aldosteronism

Hyperaldosteronism is caused by an adrenal aldosteronoma in approximately 75 percent of cases. Idiopathic bilateral adrenal hyperplasia comprise the remainder, except for rare cases of adrenal carcinoma (Abdelmannan, 2011; Ganguly, 1998). Findings include hypertension, hypokalemia, and muscle weakness. High serum or urine levels of aldosterone confirm the diagnosis.

In normal pregnancy, as discussed in Chapter 4 (p. 61), progesterone blocks aldosterone action, and thus there are very high levels of aldosterone (Appendixp. 1290). Accordingly, the diagnosis of hyperaldosteronism during pregnancy can be difficult. Since renin levels are suppressed in pregnant women with hyperaldosteronism, a plasma aldosterone-to-renin activity ratio may be helpful for diagnosis (Kamoun, 2014). Medical management includes potassium supplementation and antihypertensive therapy. In many cases, hypertension responds to spironolactone, but β-blockers or calcium-channel blockers may be preferred because of the potential fetal antiandrogenic effects of spironolactone. Mascetti and coworkers (2011) reported successful use of amiloride in a pregnant woman. Use of eplerenone, a mineralocorticoid receptor antagonist, has also been reported (Cabassi, 2012). Tumor resection is curative, and laparoscopic adrenalectomy has been shown to be safe (Kamoun, 2014; Kosaka, 2006; Miller, 2012).

PITUITARY DISORDERS

There is impressive pituitary enlargement during pregnancy, predominately from lactotrophic cellular hyperplasia induced by estrogen stimulation (Chap. 4p. 67).

image Prolactinomas

These adenomas are found often in nonpregnant women since the advent of widely available serum prolactin assays. Serum levels less than 25 pg/mL are considered normal in nonpregnant women (Motivala, 2011). Adenoma symptoms and findings include amenorrhea, galactorrhea, and hyperprolactinemia. Tumors are classified arbitrarily by their size measured by CT or MR imaging. A microadenoma is ≤ 10 mm, and a macroadenoma is > 10 mm. Treatment for microadenomas is usually with bromocriptine, a dopamine agonist and powerful prolactin inhibitor, which frequently restores ovulation. For suprasellar macroadenomas, most recommend surgical resection before pregnancy is attempted (Schlechte, 2007).

In a pooled analysis of more than 500 pregnant women with prolactinomas, only 1.4 percent with microadenomas developed symptomatic enlargement during pregnancy (Molitch, 2003). Symptomatic enlargement of macroadenomas, however, is more frequent and was found in 26 percent of 84 pregnant women included in this analysis. Schlechte (2007) also reported that 15 to 35 percent of suprasellar macroadenomas have tumor enlargement that causes visual disturbances, headaches, and diabetes insipidus.

Gillam and colleagues (2006) recommend that pregnant women with microadenomas be queried regularly for headaches and visual symptoms. Those with macroadenomas should be followed more closely and have visual field testing during each trimester. CT or MR imaging is recommended only if symptoms develop. Serial serum prolactin levels are of little use because of normal increases during pregnancy (Appendixp. 1291). Symptomatic tumor enlargement should be treated immediately with a dopamine antagonist such as bromocriptine or cabergoline. The safety of bromocriptine in pregnancy is well established. It is less well known for cabergoline, which is increasingly used in nonpregnant women because it is better tolerated and more effective. It is generally considered safe for use in pregnancy (Briggs, 2011). Lebbe and colleagues (2010) described 100 pregnancies exposed to cabergoline and found no adverse effects. Similar findings were reported in 85 exposed Japanese pregnant women (Ono, 2010). Surgery is recommended for women with no response, and Gondim and associates (2003) have described transnasal transseptal endoscopic resection.

image Acromegaly

This is caused by excessive growth hormone, usually from an acidophilic or a chromophobic pituitary adenoma. In normal pregnancy, pituitary growth hormone levels decrease as placental epitopes are secreted. Diagnosis is confirmed by the failure of an oral glucose tolerance test to suppress pituitary growth hormone (Melmed, 2006). There have been fewer than 100 cases of acromegaly reported during pregnancy (Motivala, 2011). Pregnancy is probably rare in women with acromegaly, because half are hyperprolactinemic and anovulatory. In a recent report describing 46 pregnant women with acromegaly, Caron and coworkers (2010) concluded that such women were at marginally increased risk for gestational diabetes and hypertension.

Management is similar to that for prolactinomas, with close monitoring for symptoms of tumor enlargement. Dopamine agonist therapy is not as effective as it is for prolactinomas. And transsphenoidal resection, generally considered first-line treatment outside of pregnancy, may be necessary for symptomatic tumor enlargement during pregnancy (Motivala, 2011). Guven and associates (2006) reported a case of pituitary apoplexy necessitating emergent transsphenoidal adenoma resection and cesarean delivery at 34 weeks. Successful treatment of pregnant women with the somatostatin-receptor ligand octreotideand with the GH analogue pegvisomant has also been reported (Brian, 2007; Herman-Bonert, 1998; Neal, 2000).

image Diabetes Insipidus

The vasopressin deficiency evident in diabetes insipidus is usually due to a hypothalamic or pituitary stalk disorder rather than to a pituitary lesion (Lamberts, 1998). True diabetes insipidus is a rare complication of pregnancy.

Therapy for diabetes insipidus is intranasal administration of a synthetic analogue of vasopressin, desmopressin, which is 1-deamino-8-d-arginine vasopressin (DDAVP). Ray (1998) reviewed 53 cases in which DDAVP was used during pregnancy with no adverse sequelae. Most women require increased doses during pregnancy because of an increased metabolic clearance rate stimulated by placental vasopressinase (Lindheimer, 1994). By this same mechanism, subclinical diabetes insipidus may become symptomatic or cases of transient diabetes insipidus may be encountered during pregnancy (Brewster, 2005; Wallia, 2013). The prevalence of vasopressinase-induced diabetes insipidus is estimated at 2 to 4 per 100,000 pregnancies (Wallia, 2013).

In our experiences, as described in Chapter 55 (p. 1086), transient secondary diabetes insipidus is more likely encountered with acute fatty liver of pregnancy (Nelson, 2013). This probably is due to altered vasopressinase clearance because of hepatic dysfunction.

image Sheehan Syndrome

Sheehan (1937) reported that pituitary ischemia and necrosis associated with obstetrical blood loss could result in hypopituitarism. With modern methods of hemorrhagic shock treatment, Sheehan syndrome is now seldom encountered (Feinberg, 2005; Tessnow, 2010). An example is shown in Figure 58-7. Affected women may have persistent hypotension, tachycardia, hypoglycemia, and lactation failure. Because deficiencies of some or all pituitary responsive hormones may develop after the initial insult, Sheehan syndrome can be heterogenous and may not be identified for years (Tessnow, 2010). In one cohort study of 60 women from Costa Rica with Sheehan syndrome, the average time to diagnosis was 13 years (Gei-Guardia, 2011). Because adrenal insufficiency is the most life-threatening complication, adrenal function should be immediately assessed in any woman suspected of having Sheehan syndrome. After glucocorticoid replacement, subsequent analyses and replacement of thyroid, gonadal, and growth hormones should be considered (Gei-Guardia, 2011; Tessnow, 2010).

image

FIGURE 58-7 Sheehan syndrome in a 23-year-old primipara who had major postpartum hemorrhage and hypotension intraoperatively during cesarean delivery. Magnetic resonance imaging was obtained because she failed to lactate, and her serum prolactin level was 18 ng/mL. This sagittal magnetic resonance image shows a large pituitary gland mass (arrows) consistent with hemorrhage. Subsequent imaging showed complete hematoma involution, and replacement therapy was not required.

image Lymphocytic Hypophysitis

This autoimmune pituitary disorder is characterized by massive infiltration by lymphocytes and plasma cells with parenchymal destruction of the gland. Most cases are temporally linked to pregnancy (Caturegli, 2005; Foyouzi, 2011; Madsen, 2000). There are varying degrees of hypopituitarism or symptoms of mass effect, including headaches and visual field defects. A sellar mass is seen with CT or MR imaging. A mass accompanied by a modestly elevated serum prolactin level—usually < 100 pg/mL—suggests lymphocytic hypophysitis. In contrast, levels > 200 pg/mL are encountered with a prolactinoma. The etiology is unknown, but nearly 30 percent have a history of coexisting autoimmune diseases including Hashimoto thyroiditis, Addison disease, type 1 diabetes, and pernicious anemia. Treatment is with hormone replacement and because the disease may be self-limited, a careful withdrawal of hormone replacement should be attempted after inflammation resolution (Foyouzi, 2011; Gagneja, 1999). Surgery during pregnancy is warranted only in cases of severe chiasmal compression unresponsive to corticosteroid therapy (Lee, 2003).

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