Endocrine Diseases in Pregnancy
Jorge H. Mestman
Table Of Contents
Jorge H. Mestman, MD
Anterior Pituitary Insufficiency
Anterior pituitary insufficiency is an uncommon disease. The etiology includes destruction of the anterior pituitary gland by tumors, infarction (postpartum necrosis or Sheehan's syndrome), idiopathic disease (Simmonds' disease), surgery, and radiotherapy to the pituitary gland. There have been recent reports of pituitary necrosis in patients with elevated intracerebral pressure.1 Disease of the hypothalamus affecting the secretion of releasing hormones may produce a similar clinical picture. Indeed, some cases of Sheehan's syndrome and idiopathic hypopituitarism are due to hypothalamic diseases.2
The most common cause of panhypopituitarism in women of childbearing age is postpartum necrosis, or Sheehan's syndrome. The pathogenesis is not clear, although Sheehan in his original description did associate it with severe postpartum hemorrhage.3 The classic clinical presentation of Sheehan's syndrome in about 90% of patients is severe bleeding during delivery or immediately postpartum; however, in more than 10% of patients no catastrophic event can be detected. Lack of lactation after delivery, amenorrhea, loss of pubic and axillary hair or failure of pubic hair to grow back, anorexia and nausea, lethargy and weakness, and weight loss are typical presenting signs and symptoms. On physical examination, the findings depend on the severity and duration of the disease. Commonly, the skin has a waxy character with fine wrinkles about the eyes and mouth. There is some periorbital edema, and a decrease in pigmentation is often seen. Axillary and pubic hair becomes increasingly sparse. Atrophy of the breast tissue may be present. Even in those patients losing weight, cachexia is not a feature of the disease. Hypotension may be present. Normocytic anemia is common. However, this constellation of symptoms does not occur in every patient, and it is not unusual for the full-blown picture to take 10 to 20 years to develop. Occasionally, the diagnosis is made when the patient develops acute adrenal insufficiency secondary to a stressful situation (infection, trauma, surgery).
Another cause of pituitary insufficiency in women of childbearing age is the presence of a pituitary tumor with an increased production of prolactin. The most common symptom is secondary amenorrhea with galactorrhea, although cases of primary amenorrhea have been reported. When there is local expansion of the tumor, patients may have neurologic symptoms, such as headache or bilateral temporal hemianopia. In such cases, other pituitary hormones may become affected with growth hormone, adrenocorticotropic hormone (ACTH), and thyrotropin-stimulating hormone (TSH) deficiencies.
The diagnosis is confirmed by the use of appropriate tests to investigate each of the pituitary hormones. Baseline or random determination of serum pituitary hormone concentrations is of no value in the diagnosis of the disease; dynamic tests to evaluate pituitary reserve must be used. The most practical ones are presented in Table 1. However, their use in pregnancy is limited because of the blunted response of many of these tests.
GH, growth hormone; ACTH, adrenocorticotropic hormone; TSH, thyrotropin-stimulating hormone; TRH, thyrotropin-releasing hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; LHRH, luteinizing hormone-releasing hormone; 17-KGS,17-ketogenic steroids; substance S, 11-desoxycortisol
It was recognized by Sheehan that not all patients develop panhypopituitarism, and partial pituitary insufficiency is not uncommon. In a review of anterior pituitary function in patients with pituitary apoplexy due to different causes, growth hormone deficiency was common and appeared to occur in almost 90% of patients. ACTH deficiency occurred in about 66% of patients, hypothyroidism due to TSH deficiency in about 42% of patients, and hypogonadism in 65% of patients.4 The incidence of diabetes insipidus in this group was less than 5%.
A few patients with partial hypopituitarism may present with the classic syndrome of acute panhypopituitarism with deficiency of all pituitary hormones. After treatment with corticosteroids alone, there is a spontaneous normalization in the menstrual cycle, with a return of thyroid test results to normal limits. Such a case is presented in Table 2. This patient had growth hormone and ACTH deficiency, although she presented originally with typical symptoms of Sheehan's syndrome (lack of gonadotropin and estrogen, partial response to luteinizing hormone-releasing hormone [LHRH] stimulation, low serum thyroxine [T4] concentration, and a delayed TSH response to thyrotropin-releasing hormone [TRH] stimulation, as in patients with hypothalamic disorders). Menstrual function returned to normal shortly after initiation of cortisone therapy. Discontinuation of this drug produced signs and symptoms of adrenal insufficiency, and the insulin tolerance test confirmed the diagnosis. It is therefore advisable to start treatment in patients with Sheehan's syndrome with corticosteroid therapy alone and evaluate thyroid and gonadal function. If they do not return to normal, replacement therapy with these hormones should be instituted.
Several cases of successful pregnancies following a diagnosis of Sheehan's syndrome have been reported.5 In a few patients, the diagnosis of partial hypopituitarism was made for the first time during pregnancy. Placental function is not altered in patients with pituitary insufficiency. Although several patients conceived after treatment with gonadotropin, others conceived spontaneously, an indication of partial pituitary failure.
Grimes and Brooks5 reviewed the outcome of pregnancy in women with Sheehan's syndrome. The perinatal outcome was good in those patients with proper replacement therapy, with 87% delivering live births and 13% undergoing spontaneous abortion.
When anterior pituitary insufficiency develops in pregnancy, the clinical manifestations may be local signs such as headaches and visual disturbances, which are the consequence of an acute enlargement of, or bleeding into, the pituitary gland. The initial manifestations also could be related to endocrine deficiency-mainly hypoglycemia, nausea, vomiting, and hypotension, secondary to ACTH deficiency.
Of 43 cases of isolated ACTH deficiency reported in the literature,6 2 were in pregnant women; in a third patient the diagnosis was made 6 months postpartum. Acute enlargement of the pituitary gland is characterized by severe, deep, midline headaches (lasting for 2 to 3 days) and visual field disturbances. Severe hypoglycemia with convulsions and coma, unresponsive to large doses of glucose but rapidly reversed after the administration of hydrocortisone, have been reported.7,8,9,10 Notterman and co-workers9 described the case of a 32-year-old woman with Recklinghausen's disease. By week 32 of gestation she suffered a grand mal seizure with a blood glucose of 26 mg/dL. To maintain the blood glucose level at 90 mg/dL, she required 12 to 14 g/hr of glucose (the normal requirement during pregnancy is 1 to 4 g/hr). The patient's serum cortisol was very low. Cortisol, 10 mg every 6 hours, normalized glycemia. Results of computed tomography (CT) scans of the sella turcica were normal. Thyroid function was depressed. The patient delivered a 2785-g full-term infant. Tests performed after delivery were consistent with total anterior hypopituitarism.
Partial or total hypopituitarism developing in patients with diabetes mellitus has been reported. In a review of 31 cases,11 19 of whom were women, the episode was associated with pregnancy in 11 (during the postpartum period in 7 and during the antepartum period in 4, with 3 maternal deaths). The authors included 3 of their own cases with maternal and fetal survival in this review. The mean age of these patients was 27 years, and the mean duration of their diabetes mellitus was 6 years, which makes vascular complications unlikely as the cause of pituitary insufficiency. Furthermore, no specific vascular changes were found in the examined pituitary glands. Characteristically, the patients developed severe headaches that lasted for a few days with or without visual field disturbances, and a decrease in insulin requirements. Fetal loss was high.
Lymphocytic hypophysitis as the cause of pituitary dysfunction has been recognized increasingly.9,12,13,14,15 Sheehan16 reported lymphocytic infiltration of the pituitary gland in some women with postpartum pituitary insufficiency. It is possible that many of the cases mentioned above were due to lymphocytic hypophysitis. The clinical presentation may be characterized by headaches and visual disturbances17 related to pressure from the expanding lesion mimicking a pituitary tumor, or the patient may present with symptoms and signs of hypopituitarism such as protracted hypoglycemia responding to glucocorticoid therapy, and hypotension. It can also present in the postpartum period as pituitary insufficiency, similar to Sheehan's syndrome without the history of profound bleeding. It can be precipitated by acute infections, and in one case it was brought on by labor.18 Josse in 198514 reviewed 16 cases of lymphocytic hyperplasia reported in the literature, all of whom were women. In over 60%, the diagnosis was made during pregnancy or in the postpartum period. Asa and associates12 reported two patients with severe headache, nausea, vomiting, and impaired vision, one of whom required pituitary surgery at 6 months' gestation because of an enlarging pituitary mass. Light and electron microscopic studies of the pituitary gland were consistent with lymphocytic hypophysitis. The authors found another eight cases of proven lymphocytic hypophysitis reported in the literature, five seen on postmortem examination and three on biopsy; in five of them the diagnosis was made during the postpartum period. In four patients there was evidence of other autoimmune endocrine disease. Involvement of other endocrine glands has been recognized, consistent with the concept of an autoimmune disease.18 Antibodies against the pituitary cells were reported.12 An unusual case of postpartum thyroiditis with reversible ACTH deficiency was described by Bevan and colleagues.19 Hyperprolactinemia and partial pituitary insufficiency, with or without a pituitary mass, have been reported in the postpartum period.20,21,22,23 When available, the pathologic specimen showed significant lymphocytic infiltration. Spontaneous regression of the lesion was seen in several cases.21,24 The differential diagnosis between pituitary tumor and hypophysitis can be made only by histologic examination. In some cases, surgery was performed in pregnancy with the preoperative diagnosis of pituitary tumor.25 It is possible that these cases are typical of the autoimmune polyendocrine deficiency syndrome that may be exacerbated during pregnancy or in the immediate postpartum period.
Patients with partial or total hypopituitarism who become pregnant spontaneously or after treatment with gonadotropin may carry a normal pregnancy with no increase in the dose of corticosteroid replacement therapy. The usual amount of hydrocortisone in patients with pituitary insufficiency is 20 to 30 mg/day, two thirds of the total amount in the morning and one third in the evening. In some instances, the amount of hydrocortisone can be decreased by one third of the total dose because the effect of hydrocortisone is potentiated during pregnancy by estrogen administration.26 This potentiation does not occur when synthetic corticosteroids (prednisone, dexamethasone) are used. The equivalent amounts of prednisone and dexamethasone, respectively, are 5 to 7.5 mg daily and 0.5 to 0.75 mg daily. Because these patients suffer from ACTH deficiency, aldosterone secretion is normal and there is no need for mineralocorticoid replacement therapy. If thyroid deficiency is present, the amount of levothyroxine needed for replacement is 0.1 to 0.2 mg daily.
Pregnancy in cases of isolated growth hormone deficiency has been reported.27 In these patients lactation was unimpaired, placental function studies were normal, and intrauterine growth was also normal.
The most common pituitary tumor diagnosed in women of childbearing age is the prolactinoma. This can be accompanied by amenorrhea, oligohypomenorrhea, and anovulation, with or without galactorrhea. Hyperprolactinemia decreases gonadotropin-releasing hormone (GnRH) secretion, accounting for the infertility seen in these patients. Pituitary tumors are divided, according to size, into microadenomas (less than 10 mm in diameter) and macroadenomas (greater than 10 mm in diameter); the latter are further classified according to suprasellar extension and invasion of adjacent structures.28 Serum prolactin concentrations correlate fairly well with the size of the tumor. Hyperprolactinemia in the absence of pituitary abnormality is a common finding and is known as idiopathic hyperprolactinemia. Once the diagnosis of prolactinoma is made, several types of therapy are available. The choice of therapy depends on tumor size, radiologic classification, local symptoms, and the patient's age and desire for pregnancy.28
Radiation therapy as the initial and only therapy is seldom indicated. Radiation therapy takes a long time to normalize serum prolactin levels and may produce hypopituitarism as a last sequela.29 Its use has been recommended by some in conjunction with bromocriptine therapy with the thought of preventing enlargement of the tumor during gestation.30 However, when it was used it did not prevent further enlargement of the tumor during pregnancy.31 Radiation therapy is indicated after surgery in those patients with a residual lesion so that recurrences can be prevented.28
Surgical treatment, mainly transsphenoidal adenectomy, has been effective in restoring ovulation in those patients with small tumors. The cured rate (i.e., normalization of serum prolactin and pregnancy) is about 60% to 70%.32,33,34 However, there is a high recurrence rate (25% – 40%) that occurs months or years after surgery. Feigenbaum and associates34 followed over 400 patients for a mean of 9.2 years after surgery for prolactinoma. Hyperprolactinoma recurred in 47% of all patients. The best results were obtained in patients with microadenomas and with serum prolactin levels of less than 5 ng/mL 1 day postsurgery.
Medical therapy with bromocriptine, a dopamine-receptor agonist, has been very effective in producing ovulation in 80% to 90% of hyperprolactinemic women.35 Most patients respond to doses of 2.5 to 5 mg/day, although occasionally a dose of 7.5 mg/day or more is needed. Bromocriptine is effective not only in normalizing prolactin levels but also in reducing the size of the tumor.36,37 It is advisable to use mechanical contraception during the first few months of bromocriptine therapy until the rhythm of the menstrual period is established. In those patients who have side effects such as nausea and vomiting, the oral bromocriptine tablet can be administered vaginally with normalization of prolactin levels as when the oral route is employed.38
Once conception takes place, bromocriptine should be discontinued and the patient followed closely. For those women whose initial prolactin levels are over 200 pg/mL, or who have an abnormal magnetic resonance imaging (MRI) scan with suprasellar extension, bromocriptine therapy during pregnancy should be continued.39,40
The incidence of complications during pregnancy in patients with pituitary tumors varies according to tumor size.41,42,43 The incidence of headaches and visual field disturbances in patients with microadenomas after the induction of ovulation with bromocriptine is between 1% and 4%. In patients with macroadenomas, the incidence of headaches and visual field defects is close to 35%. In those patients with macroadenomas who conceived after surgical or radiotherapeutic treatment, the complication rate is around 4%. Complications can occur with equal frequency at any stage of pregnancy. In patients with microadenomas, visual field examinations are indicated only if there are signs and symptoms of tumor enlargement, in which case an MRI is also indicated. If there is any objective evidence of tumor enlargement, bromocriptine is resumed and continued throughout pregnancy (up to 20 mg/day). If after a few days there is no improvement, dexamethasone 4 mg every 6 hours is indicated. Surgery is indicated in those complicated cases not responding to the above therapies.41
Serum prolactin levels in women with prepregnancy hyperprolactinemia, with a few exceptions, remained unchanged during pregnancy. It was shown that prolactin levels did not change significantly in most women with baseline prolactin levels of over 60 pg/dL.40 However, in those patients with prolactin levels of less than 60 pg/dL, the mean level doubled at the end of pregnancy and returned to pretreatment levels at the end of lactation. Therefore, serum prolactin determination during pregnancy is not predictable of tumor growth and is of no value in monitoring tumor growth.
Potential perinatal complications due to the use of bromocriptine have been evaluated.44 Abortion rates (11.1%), multiple pregnancy rates (1.2%), and prematurity rates (10.1%) are similar to those seen in the infertile population. Early reports of cervical incompetence have not been confirmed. The congenital malformation rate of 3.5% (major and minor lesions) is comparable to the rate of 2.7% reported in a control group. Although bromocriptine crosses the placenta, no abnormal mental or physical developments were detected in a small number of infants followed for a short period of time.45
Breastfeeding is not contraindicated in mothers with a diagnosis of prolactinoma. There is no increase in prolactin secretion after suckling in these women, and the mean value of prolactin is not increased compared with that of pregnancy.46 Actually, spontaneous remission of hyperprolactinemia has been reported in a significant number of women after delivery. It is advisable in patients with microadenomas to measure prolactin levels a few months after delivery and to reinstate bromocriptine therapy in the presence of persistent hyperprolactinemia. An MRI should be repeated in cases of macroprolactinoma soon after delivery, because an increase in the size of the tumor has been reported.
The choice of treatment in patients who wish to conceive is summarized in Table 3. Although a serum prolactin level of less than 100 pg/dL and normal results of a radiologic examination of the pituitary gland before pregnancy are predictors of low complication rates, exceptions have been reported.40 It is suggested that treatment with bromocriptine be continued for at least 12 months before conception because it seems to reduce the risk of tumor enlargement during pregnancy.40
*Therapy for 1 year before conception.
Acromegaly is a chronic disease caused by hypersecretion of growth hormone by the adenohypophysis. It is almost always associated with a benign pituitary tumor and is characterized by slow and progressive enlargement of the acral parts. Facial changes are typical, but they develop so gradually that neither the family nor the patient recognizes the changes. As in other endocrine disorders, comparison of the patient's photographs taken over many years may be the only clue to the progression of the disease. Symptoms may be due to local expansion of the tumor, with headaches and visual field disturbances, or they may be due to the somatic effects of chronic excess growth hormone, such as hyperhidrosis, weight gain, arthralgias, and acroparesthesia (carpal tunnel syndrome). Most women with acromegaly have been reported to suffer from oligohypomenorrhea or amenorrhea. In addition to the bony deformities, organomegaly, particularly enlargement of the heart, thyroid, and liver, is not uncommon on physical examination. The skin appears coarse and leathery. Galactorrhea with hyperprolactinemia is a common finding.
The diagnosis is confirmed by an elevation in plasma growth hormone levels and a lack of suppression with the administration of a glucose load. For the test, growth hormone levels are obtained before and 1 and 2 hours after the administration of a solution of 100 g glucose. A normal response is characterized by growth hormone levels lower than 5 ng/dL after glucose administration. Patients with acromegaly have elevated baseline levels and respond to the glucose load with no suppression or with a paradoxical increase in plasma growth hormone concentrations.
The diagnosis of acromegaly during pregnancy is difficult to confirm because the conventional radioimmunoassay for growth hormone does not distinguish normal pituitary growth hormone from the variant produced by the placenta,47 unless special radioimmunoassays are used. Two other tests may be used to separate both hormones-the highly pulsatile secretion of pituitary growth hormone in acromegaly, which is not observed in placenta growth hormone,48 and the response of pituitary growth hormone to an injection of TRH, which is often present in acromegaly; placental growth hormone does not respond to TRH.49
Treatment is mandatory in patients with the disease because the long-term prognosis is poor, as reported in a group of 55 untreated patients with acromegaly. The number of deaths was almost twice that actually expected from the general population.50 The treatment of choice depends on the author's experience. Conventional pituitary irradiation, transsphenoidal hypophysectomy, and drug therapy with octreotide51 are used most often.
Only a few cases of successful pregnancy in women with acromegaly have been described. In 1954, Abelove and co-workers52 reported two normal pregnancies in an acromegalic woman and reviewed 33 reported cases from the world literature of pregnancies occurring in patients with active disease. Since that time, several other cases have been published. In most instances, the infants have been reported as being normal; however, in the case described by Fisch and associates,53 the infant was born with acromegalic features. During the neonatal period, growth was above average, but a normal growth pattern subsequently returned. Unfortunately, no serum growth hormone determinations were obtained on the newborn. The lack of acromegalic features in most cases is in accordance with the demonstration by King and colleagues54 of no placental transfer of growth hormone from mother to fetus.
Few cases of pregnancy in acromegalic women during therapy with bromocriptine have been reported.55,56,57,58 In each case, pregnancy occurred in spite of persistent elevated serum growth hormone levels. Pregnancies occurred when prolactin levels returned to normal after drug therapy. In the case of Bigazzi and co-workers,55 the fetus developed normally, and several interesting observations of hormonal changes in both mother and newborn were observed. Maternal serum growth hormone concentrations were very high in spite of the administration of bromocriptine, and serum maternal prolactin was suppressed. The plasma growth hormone level was normal in the newborns, and plasma prolactin concentration was low at birth but increased in the following days. The authors postulate that bromocriptine crosses the placenta and suppresses the production of prolactin and growth hormone by the fetal pituitary gland. On the other hand, amniotic fluid concentrations of prolactin were elevated and did not correlate with maternal or fetal concentrations.
Two cases have been reported of successful pregnancy in acromegalic women treated with a long-acting analogue of somatostatin (octreotide).59,60 Octreotide has been reported to cross the placenta by passive diffusion without producing adverse effects in the fetus.61 An acromegalic woman developed pituitary apoplexy, and surgery was performed during pregnancy.62
Shortly after conception, plasma osmolality decreases by about 9 to 10 mOsm/kg and remains low throughout pregnancy. Despite this, basal levels of serum arginine vasopressin (antidiuretic hormone) are similar to those seen in nonpregnant women.63 It has been suggested that in pregnancy there is a resetting of the “osmostat” with a decrease in the osmotic threshold for antidiuretic hormone release of 8 to 10 mOsm/kg. The ability to concentrate the urine remains within normal limits.64
Diabetes insipidus is an uncommon disease characterized by polyuria (over 3 L/24 hr) and polydipsia due to a deficiency of antidiuretic hormone (central or neurogenic diabetes insipidus), or due to peripheral resistance to the action of the hormone at the level of the renal tubules (nephrogenic diabetes insipidus). Central diabetes insipidus may be a result of different lesions at the level of the hypothalamus or pituitary gland. It is seen after hypophysectomy, invasion of the neurohypophysis by tumors, metastasis (breast), trauma, granulomas, or infection. In 50% of cases, however, it is considered idiopathic, with some causes probably on an autoimmune basis. Nephrogenic diabetes insipidus is a hereditary disorder affecting males; therefore, symptomatic women carriers are extremely rare. Several cases of transient nephrogenic diabetes insipidus during pregnancy and/or postpartum have been reported. A third type of diabetes insipidus, called psychogenic, which is rarely reported in pregnancy,65 is differentiated from the other two in most cases by the results of the water deprivation test.
The clinical presentation of idiopathic central diabetes insipidus is generally acute, with polyuria and polydipsia developing in a few days. Patients usually remember the day their symptoms began, they prefer cold water to drink, and their urinary output varies from 4 to 15 L in 24 hours.
The diagnosis of diabetes insipidus is confirmed by the results of the water deprivation test (Table 4).66 In emergency situations with acute onset of symptoms, such as cases of acute fatty liver of pregnancy or preeclampsia, treatment cannot be delayed, and diagnostic tests to assess the etiology of diabetes insipidus must be postponed. The water deprivation test is started early in the morning. The patient's weight, pulse, and blood pressure are obtained, along with baseline determinations of serum and urine osmolarity and baseline determinations of plasma vasopressin levels. Thereafter, urine osmolarity is obtained with each voided specimen. The test is terminated when the patient loses 3% of body weight or when urinary osmolarity shows no increment in three successive specimens. At the end of the test, serum osmolarity and vasopressin levels are measured. In patients with diabetes insipidus, regardless of the cause, there is no increment in urinary osmolarity, but plasma osmolarity does increase as a result of dehydration. Plasma vasopressin levels are low in central diabetes insipidus, and they are inappropriately high in the nephrogenic type. Injection of aqueous vasopressin 5 U subcutaneously at the end of the test separates the two types of diabetes insipidus in most cases. L-deamino-8-D-arginine vasopressin (dDAVP, a synthetic analogue of vasopressin resistant to vasopressinase) is preferable in pregnancy. A dose of 10 μg is given intranasally. In central diabetes insipidus there is a decrease in urinary output and an increase in urinary osmolarity. No changes are seen in the nephrogenic type. Patients with primary polydipsia or psychogenic diabetes insipidus respond to the administration of Pitressin with some increase in urine osmolarity, but the increase is not as high as it is in patients who have central diabetes insipidus.
*The test must be carried out under careful supervision in order to avoid either severe dehydration in patients with significant ADH deficiency, or water intoxication in patients with primary polydipsia due to continuous water ingestion after the administration of Pitressin.
In patients with newly diagnosed central diabetes insipidus, a complete evaluation to define the cause of the disease is imperative. Radiologic examination of the hypothalamic - pituitary area and hormonal studies for anterior pituitary function assessment should be performed.
Uterine atony at the time of labor has been described in an earlier report, but since that time most cases have reported normal labor. Plasma oxytocin concentration values have been reported as normal, with normal pulsatile release during labor and lactation.
Diabetes insipidus during pregnancy can occur in different clinical settings.67 These are listed below.
Pregestational diabetes insipidus
Hime and Richardson,68 who reviewed 67 cases of diabetes insipidus in pregnancy up to 1978, reported a low incidence (1 case in 66,000 delivered). Worsening of the symptoms during pregnancy occurred in over 50% of cases, spontaneous improvement of symptoms occurred in 20%, and no changes were reported in the rest. Labor progressed normally in most cases, with few patients requiring induction of labor or cesarean section. In three cases, preeclampsia occurred with improvement in the diabetes insipidus a few weeks after delivery.
Transient vasopressin-resistant diabetes insipidus has been recognized in the last trimester of pregnancy.69 It is associated with preeclampsia, acute fatty liver of pregnancy, or HELLP syndrome. The lack of response to vasopressin is due to the significant increase in the plasma clearance of antidiuretic hormone (ADH) caused by the activity of the enzyme vasopressinase. This also explains the good response to dDAVP, which is not metabolized by vasopressinase.
In the transient recurrent form of diabetes insipidus, patients with a decreased ADH reserve may manifest symptoms of diabetes insipidus in pregnancy for the first time. This occurs because of the inability to increase the secretion of ADH in the presence of an increased metabolic clearance rate of ADH due to the normal increased secretion of vasopressinase in pregnancy, which may underscore mild, asymptomatic diabetes insipidus.70
Desmopressin (dDAVP) is the drug of choice in the treatment of diabetes insipidus. Pitressin tannate in oil or water has been the standard drug of choice for many years and is still used occasionally. Synthetic 8-lysine vasopressin as a nasal spray has been almost replaced by dDAVP. The latter is a synthetic analogue of vasopressin. Its antidiuretic effects last from 8 to 24 hours. It is available in three forms-nasal insufflation, parenteral, and tablet form (no experience in pregnancy). The usual dose of the nasal spray is 10 to 25 μg once or twice daily as needed to control polyuria. In the presence of rhinitis or other conditions that would interfere with absorption, or in the postoperative period, the parenteral form is used. Two to 4 μg are injected subcutaneously or intravenously and repeated every 12 to 24 hours, according to urinary osmolality and output. Plasma electrolytes and water intake and urinary output should be followed closely to avoid water intoxication. The experience of dDAVP in pregnancy is extensive.71 The fetus suffers no side effects, and it is safe to use in lactating mothers. In the rare case of nephrogenic diabetes insipidus, thiazide diuretics72 are the only drug that can be used; nonsteroidal anti-inflammatory drugs are not recommended in pregnancy.
Parathyroid diseases, although uncommon in pregnancy, can produce significant perinatal and maternal morbidity and mortality if not diagnosed and properly managed. After a brief review of calcium homeostasis during pregnancy, primary hyperparathyroidism, hypoparathyroidism, and osteoporosis will be discussed.
Calcium Homeostasis During Pregnancy
Two hormones, parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (1,25-D), are responsible for maintaining calcium homeostasis. About 50% of serum calcium is protein bound (mostly to albumin), 10% is complexed to anions, and 40% circulates free as ionized calcium. During pregnancy, there is an active transfer of maternal calcium to the fetus. A full-term infant requires 25 to 30 g of calcium during the course of pregnancy for new bone mineralization; this accumulation occurs during the last trimester of pregnancy.
Total serum calcium is slightly decreased during gestation because of physiologic hypoalbuminemia. The ionized calcium levels, however, remain unchanged throughout gestation. Normal total serum calcium is 8% below the postpartum level.73 The upper limit of normal for total serum calcium during pregnancy is 9.5 mg/dL. However, as mentioned earlier, ionized serum calcium remains within normal limits.
Maternal serum PTH has been shown to remain unchanged throughout pregnancy when measured by an immunoradiometric assay. Blood levels of 1,25-dihydroxyvitamin D (calcitriol) increase after the 20th week of gestation as a result of stimulation of renal 1α-hydroxylase activity by estrogen, placental lactogen, and PTH, and as a result of synthesis of calcitriol by the placenta.74 Twenty-four-hour urinary calcium excretion also increases with each trimester of gestation and falls in the postpartum period.75 However, in a recent study of 10 women followed in each trimester of pregnancy, fasting urinary calcium - creatinine ratio values fell throughout pregnancy, with the lowest value occurring at 6 weeks postpartum.76 Parathyroid hormone - related protein (PTHrP), a peptide responsible for the hypercalcemia found in many malignant tumors, has been measured during pregnancy and the postpartum period. High values have been reported during lactation, and new evidence indicates that this hormone is involved in the transfer of calcium from the breast into milk.77 It has been shown to have a physiologic role in transporting calcium through the placenta in sheep.78 The situation in human pregnancy is less clear. PTHrP has been measured in pregnancy with a very sensitive assay, and it was shown that there is a slight increase with progression of pregnancy, although the values remain within normal limits.76
Osteocalcin is a bone-specific protein released by osteoblasts into the circulation proportional to the rate of new bone formation. It has been shown to be slightly decreased during the second trimester of pregnancy and increased in the postpartum period.74,76
The first case of primary hyperparathyroidism during pregnancy was reported in 1931.79 Shortly thereafter, the first case of neonatal hypocalcemia causing tetany in a mother with undiagnosed hypercalcemia due to hyperparathyroidism was described by Friderichsen.80 Since then, several review articles on the subject have been published.81,82,83,84 The most common cause of primary hyperparathyroidism in pregnancy is a single parathyroid adenoma in about 80% of cases. Primary hyperplasia of the four parathyroid glands accounts for about 15% of the cases reported; 3% are due to multiple adenomas; and 2% are due to parathyroid carcinoma. In the first review of the literature in 1962, Ludwig85 found an incidence of fetal wasting of 27.5% in 40 pregnancies of 21 women with primary hyperparathyroidism. The incidence of neonatal tetany was 19% and was the first indication of maternal hyperparathyroidism. In 1972, Johnstone and co-workers86 confirmed a perinatal mortality rate of 25% with a high incidence of neonatal hypocalcemia. In most of the cases reported up to that time, patients with hyperparathyroidism had significant complications, particularly bone disease and renal involvement. In 1991, Kelly82 reviewed the literature from 1976 to 1990. Only 2 perinatal deaths (5%) were reported among 37 infants of mothers with primary hyperparathyroidism. Two additional cases of perinatal death were reported in mothers with hypercalcemic crisis.81,87
Almost 70% of nonpregnant patients are asymptomatic, so the diagnosis is made through the routine use of biochemical screening.88 In pregnancy, however, manifestations of the disease are present in nearly 70% of patients. In a review of 70 pregnant women, 36% of patients had gastrointestinal symptoms such as nausea, vomiting, and anorexia; 34% presented with weakness and fatigue; and 26% had mental symptoms such as headache, lethargy, agitation, emotional lability, confusion, and inappropriate behavior. Nephrolithiasis was detected in 36%, bone disease in 19%, pancreatitis in 13%, and hypertension in 10%. Only 24% of this group of 70 pregnant patients were asymptomatic.83
Some clinical features of primary hyperparathyroidism in pregnancy need to be discussed. Acute pancreatitis has been reported in 13% of women with primary hyperparathyroidism. The incidence in nonpregnant hyperparathyroid women is about 1.5%, and it is less than 1% in normal pregnancy.89 This complication is associated with significant neonatal and maternal morbidity. It is more common in the primipara than in women who have had multiple pregnancies and is most likely to occur during the last trimester of pregnancy or the postpartum period. It has also been reported in the first trimester of pregnancy and should be evaluated in any pregnant woman with persistent significant nausea, vomiting, and abdominal pain.84
Hyperparathyroid crisis has been reported during gestation and in the postpartum period. Of the 10 cases reported in the literature, 4 of them occurred in the postpartum period. Patients present with severe nausea, vomiting, generalized weakness, changes in mental status, and an elevation in serum creatinine due to dehydration. Serum calcium levels of over 14 mg/dL are commonly found. Three maternal deaths have been reported.90,91,92 Six cases have been associated with pancreatitis, and four fetal deaths have been reported. Hyperparathyroid crisis might occur in the postpartum period as a result of removal of the placenta with loss of the shunt that transfers calcium from the mother to the fetus, or it could occur because of an increase in placental production of 1,25-dihydroxyvitamin D by the end of gestation.
Bone disease in patients with primary hyperparathyroidism is rare. However, in the early series it was a common complication.86 One case involved a 27-year-old woman who had generalized musculoskeletal pain and radiographic evidence of advanced bone disease detected by 34 weeks' gestation. Radiologic evaluation of the bones showed diffuse demineralization, subperiosteal resorption of the phalanges, and, in severe cases, single or multiple cystic lesions and generalized osteoporosis.93
Prematurity due to maternal complications may be seen in hyperparathyroidism. Neonatal hypocalcemia is related to the severity of maternal serum calcium. It develops between the 2nd and 14th day of life and lasts for a few days.80,85
The diagnosis of primary hyperparathyroidism is based on persistent hypercalcemia in the presence of an increase in serum PTH levels. A serum calcium value of over 9.5 mg/dL is suspicious of hypercalcemia. Serum phosphorus is decreased in about 50% of pregnant women with primary hyperparathyroidism. A 24-hour urinary calcium excretion test is indicated, because most women with primary hyperparathyroidism will have an increase in urinary calcium excretion. The urinary calcium excretion is low or low-normal in the syndrome of familial hypocalciuric hypercalcemia (FHH), another cause of hypercalcemia that will be discussed below. The serum alkaline phosphatase level may be increased in primary hyperparathyroidism; however, it is also increased in normal pregnancy.
DIFFERENTIAL DIAGNOSIS OF HYPERCALCEMIA.
Although most young women with hypercalcemia have primary hyperparathyroidism, other unusual causes should be ruled out, namely, endocrine disorders, vitamin D or A overdose, the use of thiazide diuretics, and granulomatous diseases (Table 5). Three uncommon syndromes associated with hypercalcemia during pregnancy are briefly discussed.
Primary hyperparathyroidism (most common)
Familial hypocalciuric hypercalcemia*
Other causes not related to pregnancy
Milk alkali syndrome
Acute and chronic renal failure
Total parenteral nutrition
*Different expression with significant neonatal manifestations.
PTHrP, parathyroid hormone-related protein.
The only effective treatment for primary hyperparathyroidism is removal of the abnormal parathyroid gland(s). The high perinatal morbidity and mortality reported in the early series was related to significant maternal hypercalcemia. If the diagnosis is made during the first two trimesters of pregnancy, surgical treatment is preferred, particularly for those patients with symptoms or those with a persistent serum calcium of over 11 mg/dL. In the series reported by Carella and Gossain,83 38 women underwent parathyroidectomy during pregnancy-7 in the first trimester and 18 in the second trimester. In this group of 25 women, there was only 1 fetal loss due to spontaneous abortion. In the 12 women having surgery during the third trimester of pregnancy, the incidence of perinatal complications was 58%. In another study, the hypercalcemia resolved in 21 of 23 pregnant women who underwent surgical treatment of hyperparathyroidism.102
For women in whom hyperparathyroidism is first diagnosed after 28 weeks of gestation, the optimal treatment strategy is unclear. The decision in such a situation should be based on general patient condition, severity of hypercalcemia, and other complicating circumstances.
Medical therapy is reserved for those patients with significant hypercalcemia that are not surgical candidates. Oral phosphate therapy 1.5 to 2.5 g/d has been shown to be effective in controlling hypercalcemia.103 Side effects of oral phosphate therapy include nausea, vomiting, and hypokalemia. This can be easily avoided by decreasing the dose of the medication.
In those patients in whom surgery is not advisable, it is important to prevent elevations in serum calcium. Good hydration, early treatment of urinary tract infections, and avoidance of medications that may produce an elevation in serum calcium, such as vitamin D, vitamin A, aminophylline, and thiazide diuretics, are mandatory. Serum calcium should be checked on a regular basis.
In patients undergoing surgical treatment, hypocalcemia, albeit transient, may occur postsurgery. Serum calcium should be checked every 6 hours. If the patient develops hypocalcemic symptoms, intravenous calcium in the form of calcium gluconate 10% solution 10 to 20 mL should be given during a period of 5 to 10 minutes. Intermittent infusions can be repeated, or calcium gluconate can be diluted in 5% dextrose or isotonic saline and infused continuously at 1 mg/kg/bw per hour. In patients with bone disease, postsurgical hypocalcemia may be profound, and aggressive treatment is needed. These patients may benefit from vitamin D supplementation in the form of calcitriol 0.25 to 0.5 μg/d for a few days before operative intervention.104
The most common cause of hypoparathyroidism is damage to or removal of the parathyroid glands in the course of an operation on the thyroid gland. Idiopathic hypoparathyroidism is a much less common cause of the disease. The incidence of hypoparathyroidism after thyroid surgery has been estimated to be between 0.2% and 3.5%. In many cases, hypocalcemia in the immediate postoperative period is only transitory.
The diagnosis of hypoparathyroidism is based on previous history (particularly a history of thyroid surgery) and on clinical, radiologic, and laboratory information. Symptoms of hypocalcemia include numbness and tingling of the fingers and toes and around the lips. Patients may complain of carpopedal spasm, laryngeal stridor, and dyspnea. Convulsions may be a manifestation of severe hypoparathyroidism. Symptoms of irritability, emotional lability, impairment of memory, and depression are common. On physical examination, papilledema and cataracts may be seen. In patients with idiopathic hypoparathyroidism, changes in the teeth, skin, nails, and hair are common. Chvostek's sign, which is a twitch of the facial muscles (notably those of the upper lip) when a sharp tap is given over the facial nerve, is seen in many patients with hypocalcemia, although it has been described in 10% of normal adults. Trousseau's sign is another sign of hypocalcemia. This is the induction of carpopedal spasm caused by reducing the circulation in the arm with the blood pressure cuff. The constriction should be maintained above the systolic blood pressure for 2 minutes before the test is considered negative.
The diagnosis is confirmed by the presence of persistent low serum calcium and high serum phosphate levels. The plasma alkaline phosphatase level usually is normal. The differential diagnosis of hypocalcemia includes rickets, osteomalacia, and hypomagnesemia.
One of the first reports of hypoparathyroidism in pregnancy was in 1942, when Anderson and Musselman105 reviewed the literature on pregnancy and tetany and collected 240 cases. Of these, 26 were caused by post-thyroid surgery and 140 were the so-called idiopathic type. It is likely that in some of these cases tetany was not caused by hypoparathyroidism. Before specific therapy was available, fetal and maternal mortality was so high that therapeutic abortion was routinely recommended. With the availability of vitamin D and the use of calcium supplementation, the prognosis is much better and the infants reveal no unusual abnormalities.
Graham and co-workers106 reported several cases of hypoparathyroidism that were well controlled during pregnancy with vitamin D therapy. If the mother is not properly treated, hypoparathyroidism with hypocalcemia can be very serious for the newborn. The infant can develop intrauterine hyperparathyroidism with radiologic bony changes. Loughead and associates107 reported 16 infants who were born with secondary hyperparathyroidism caused by severe chronic hypocalcemia in the mother. This resolved by 1 month of age. Treatment of hypoparathyroidism in pregnancy does not differ from that in the nonpregnant state. Vitamin D requirements do not seem to increase during pregnancy. Treatment includes a normal high-calcium diet and vitamin D supplementation on the order of 50,000 to 150,000 IU/d or calcitriol (1,25[OH]D2) 1 to 3 μg/day.99,108,109 The normal calcium supplementation of pregnancy is about 1.2 g/d. The major problem in the treatment of hypoparathyroidism is the recurrent episodes of hypercalcemia and hypocalcemia. Serum calcium determinations should be performed at regular intervals. The most common symptoms of vitamin D intoxication are nausea, constipation, fatigue, headaches, and, in more severe cases, vomiting and dehydration. It is important to assess serum calcium and phosphorus during pregnancy and particularly in the postpartum period (see “Hyperparathyroidism”). Lactation in mothers taking vitamin D is perhaps not indicated because the metabolite of vitamin D, 25-hydroxyvitamin D, has been detected in breast milk in high content in a mother taking 50,000 U of vitamin D daily.110 Regardless of the form of vitamin D prescribed, serum calcium determination should be done in the postpartum period, particularly in breastfeeding mothers.
Pseudohypoparathyroidism encompasses several different disorders having as a common feature varying degrees of target organ resistance to PTH. Somatic changes, such as short stature, obesity, round face, brachydactyly, and mental retardation, are present in some forms of the syndrome. This variant is known as Albright's syndrome type 1a. Most of these patients suffer from hypocalcemia caused by a derangement of renal 1α-hydroxylase and production of 1,25(OH)D2 (calcitriol). A few cases have been reported during pregnancy. Spontaneous normocalcemia occurred in two patients during during pregnancies; the authors provided evidence of placental synthesis of 1,25(OH)D2 to account for the normocalcemia. In both patients, serum PTH, which was significantly increased before pregnancy, was reduced by 50% during gestation. Serum cord calcium, phosphorus, and 1,25(OH)D2 concentrations were within normal limits.111,112
Osteoporosis is suspected in pregnancy when the patient presents with back or hip pain. Recent studies measuring calciotrophic hormones and biochemical markers of bone resorption in each trimester of pregnancy and in the postpartum period showed a slight decrease in bone mass in the third trimester of pregnancy.76,115 In general, there is a recovery by 6 months postpartum. In a study of a group of white, upper-middle-class, postmenopausal women, there was no association between the number of pregnancies and lactation as predictors of a decrease in bone mineral density.116
Osteoporosis has been diagnosed during pregnancy and in the postpartum period. Whether these are two different syndromes or the same entity is unclear, because the symptoms may begin during pregnancy but the diagnosis may be made for the first time after delivery. Osteoporosis diagnosed during pregnancy may be localized in the hip(s) or lumbar spine, or both. Pain in one hip or back pain is the presenting symptom in most cases. It usually occurs in the second half of gestation, and spontaneous recovery is the usual course a few months postpartum.117 A case has been reported of onset in the first trimester with recovery after abortion.118
Although osteoporosis has been diagnosed during pregnancy, recent evidence appears to indicate that pregnancy unmasks rather than causes low bone mass. As suggested by Rizzoli and Bonjour,119 it is feasible for changes in posture (such as hyperlordosis of pregnancy), when superimposed on a small and transient decrease in bone mass, to impair the resistance of a fragile bone. Furthermore, there is no recorded case of rapid loss of more than a small percentage of bone mass during normal pregnancy. Finally, it is likely that osteoporosis is discovered during pregnancy because of back pain. This pain could be caused by stretching of ligaments in hyperlordosis rather than to osteoporosis. This concept has been supported by studies in which women were followed during and after pregnancy. In one study120 of 24 women, 18 presented with back pain, 5 with hip pain, and 1 with ankle pain in late pregnancy or up to 8 months after delivery. Radiologic examination of the spine showed that 17 of these women had vertebra deformities. These women had symptoms for many years. Bone mass was measured in 21 of them; 7 showed evidence of osteoporosis and 13 were osteopenic. The authors concluded that bone mass was probably low before pregnancy. A transient and slight decrease in bone mass during pregnancy could have weakened the bone further.
Dunne and associates121 examined the prevalence of osteoporosis during pregnancy. The authors identified 35 women who became symptomatic and developed radiologically proven fractures during or shortly after pregnancy. They were matched for age, weight, height, and calcium status with a control population. The authors also investigated, through questionnaires, the incidence of fractures in both parents of the osteoporotic group. In 29 out of 35 women, no underlying cause for osteoporosis (other than pregnancy) was evident. Six women had secondary osteoporosis; two were treated with heparin therapy. Eighty-three percent of the patients complained of severe back pain; 33% suffered unilateral or bilateral hip pain; 27% showed a decrease in height; and 17% had increased difficulty with weightbearing. The symptoms occurred during the first full-term pregnancy in 73% of the women. In half of the women the symptoms occurred in the third trimester, and in the other half of the women the symptoms occurred in the postpartum period. Radiographs revealed osteopenia and vertebra compression fractures in 27 women and hip fractures in 2 women. Bone mineral density showed significant osteoporosis in most of the women. Of interest, the incidence of osteoporosis and fractures in the mothers of these women was significantly increased, and in most of these mothers the fractures occurred before the age of 45 years. The authors suggested that osteoporosis in pregnancy may be more common than reported. Most likely these women had an abnormal skeleton before pregnancy, and the extra stress of pregnancy and delivery triggered the diagnosis of osteoporosis.
Carbone and co-workers122 reported a 10-year follow-up of two patients with osteoporosis diagnosed in pregnancy. Of significance was the fact that both offspring of these patients, when studied at age 11 and 13, showed osteopenia. The authors suggested that this could be a familial disease, and they recommended that the offspring of mothers with osteoporosis be evaluated for the presence of bone loss. Goldman and colleagues123 reviewed 53 cases of idiopathic transient osteoporosis of the hip in pregnancy and added 1 case of their own. The syndrome is characterized by hip joint pain in the third trimester of pregnancy and signs of demineralization of the femoral head. The authors suggested that the course is benign. Recovery occurred after birth, and no specific therapy was required except bed rest.
It appears that women who present with unusual back or hip pain during pregnancy, particularly in the third trimester, may suffer from osteoporosis. Because radiographs cannot be performed during pregnancy, symptomatic treatment is indicated. These women should have radiographic determinations and bone density studies after delivery, and they may need therapy with calcitonin or bisphosphonates plus calcium supplementation. In the few studies available, there was an improvement in bone density after delivery.
The effect of lactation on the progression of osteoporosis is controversial. The physician must decide if cessation of lactation is advisable in the management of this condition. As mentioned earlier, the study by Kritz-Silverstein and associates116 does not appear to indicate that lactation by itself is a determinant of bone mineral density. In one study, lactation for more than 8 months was associated with greater bone mineral density at both the femoral neck and shaft.124 However, in another study, nursing for longer than 9 months produced a greater decrease in bone mass than the 6 to 9 months of nursing.125
In patients receiving heparin, attention must be paid to symptoms such as back pain or hip pain. Heparin-associated osteoporosis has been reported in several cases during pregnancy.126 It may be related to the total dose of heparin. Treatment with a calcium supplement or calcitriol, although not proven, may be helpful. Barbour and co-workers127 followed 14 pregnant women requiring heparin therapy and compared them with a control group. Five of the 14 patients had a 10% decrease from the baseline proximal femur measurements to immediate postpartum values, compared with none of the 14 matched control women. The authors concluded that heparin adversely affects bone density in about one third of exposed patients. Several reports are indicative of the self-limited nature of osteoporosis of pregnancy and the improvement after delivery.
Adrenal Gland Physiology
There are a few studies on the size of the adrenal glands during pregnancy, but there is no conclusive evidence of any significant change in weight.128 Histologically, the adrenal gland is divided into three zones: zona glomerulosa, zona fasciculata, and zona reticularis. The glomerular zone produces aldosterone; the middle, or fascicular, zone produces mainly cortisol; and the inner, or reticular, zone produces androgens and a minimum amount of estrogen.
Cortisol is the chief secretory product of human adrenal glands. In addition to having glucocorticoid activity, it has a potent anti-inflammatory effect when used in pharmacologic doses. Cortisol is present in the circulation in at least three forms: bound to a specific binding protein (corticosteroid-binding globulin [CBG] or transcortin), bound to albumin, and in the free form. In the nonpregnant woman, 70% to 80% is bound to CBG, and only 10% to 15% is in the free or unbound fraction. In pregnancy, there is an increase in the plasma levels of CBG, and by the end of the third trimester the serum levels of CBG have doubled. At the same time, there is an increase in the free or unbound cortisol. This is the only biologically active fraction of cortisol, and its elevation is demonstrated by the first trimester of gestation.129,130
Aldosterone is the most potent mineralocorticoid; its daily secretion rate in nonpregnant women is about 50 to 250 μg on a normal sodium intake. Its secretion is controlled by the renin - angiotensin system, by potassium, and, to a lesser degree, by ACTH. Aldosterone secretion rate and plasma concentration increase during pregnancy, with the first changes occurring as early as 2 weeks after conception.131
The adrenal cortex secretes dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS). The DHEA production rate is increased during pregnancy. It is aromatized to estradiol and estrone by the term placenta and may contribute up to 9% of circulating estradiol.132
Cushing's syndrome is defined as a constellation of signs and symptoms due to chronic excessive production of glucocorticoids by the adrenal glands. As in many other endocrine conditions, women between the ages of 20 and 40 years are more affected than men, with a ratio of about 9:1. Cushing's syndrome can be classified as ACTH dependent or ACTH nondependent (Table 6). ACTH-dependent Cushing's syndrome is caused by hyperproduction of glucocorticoids by the adrenal glands secondary to excessive or inappropriate secretion of ACTH or ACTH-releasing hormone by an ectopic tumor. ACTH-nondependent Cushing's syndrome is caused by an intrinsic disorder of the adrenal gland, such as a benign or malignant adrenal tumor. Alternatively, it may be iatrogenic, secondary to pharmacologic doses of glucocorticoids in the treatment of systemic disease. In women of childbearing age, the most common cause of Cushing's syndrome is bilateral adrenal hyperplasia, which accounts for 75% of all cases. Adrenal tumors are unilateral, are usually benign (adenoma), and represent 20% of all cases. In pregnancy, however, adrenal adenomas are as common as bilateral hyperplasia in the etiology of Cushing's syndrome. Adrenal carcinoma is rare, although several cases have been reported during pregnancy. Ectopic ACTH syndrome is unusual in young people, but occasional cases have been reported in pregnancy.133,134,135,136,137,138,139
Chronic administration of ACTH
Chronic administration of synthetic corticosteroids
ACTH, adrenocorticotropic hormone
Cushing's syndrome is characterized clinically by a slow progression of symptoms. These manifest as muscle weakness, personality changes, oligomenorrhea or amenorrhea, hirsutism, weight change, and back pain due to osteoporosis. One of the first common manifestations in women is oligomenorrhea, which progresses to amenorrhea. Hence, pregnancy in women with Cushing's syndrome is unusual. The anovulation is due to the suppression of pituitary gonadotropin by high levels of glucocorticoids. An increased incidence of thromboembolism also has been reported. On physical examination, hypertension, truncal obesity, fat deposition in the supraclavicular areas and upper dorsal spine (buffalo hump), moon face, atrophy of skin that is easily bruised, and purple striae (over abdomen, axillae, and hip areas) are common clinical features. Weakness due to muscular atrophy can be very marked, particularly in the quadriceps muscles; the patient may be unable to rise from a deep knee bend without assistance. Headaches and visual field disturbances due to a large pituitary tumor are rare. Hirsutism, sometimes of the lanugo type, is common. The severity of virilization depends on the amount of androgen produced; in patients with adrenal adenoma the secretion of androgens is low, whereas it is moderately high in patients with bilateral adrenal hyperplasia. Masculinization is rare, and when it occurs it is due to an adrenal carcinoma producing large amounts of androgens. Kidney stones due to hypercalciuria are reported to occur in 15% to 20% of patients.
An increase in the hematocrit, leukocytosis with relative lymphopenia, and eosinopenia are usually seen. An abnormal glucose tolerance test has been reported in over 50% of patients, and frank diabetes has been seen in 20% to 30%. Mild hypokalemia with metabolic alkalosis is not uncommon. Radiologic examination of the chest may show an enlarged mediastinum secondary to fat deposit; osteoporosis is not uncommon.
The clinical diagnosis may be difficult during pregnancy because characteristically similar striae are seen in both pregnancy and Cushing's syndrome. Comparisons of close-up photographs from earlier years are helpful in detecting subtle changes. The diagnosis is confirmed by the proper use and interpretation of tests assessing the hypothalamic - pituitary - adrenal axis. A significant and persistent elevation in urinary free cortisol is the best indication of cortisol overproduction. It should be kept in mind, however, that an elevation does occur in normal pregnancy. Mean urinary free cortisol levels of 127 μg/d (range, 68 – 252 μg/d), as compared with nonpregnant levels of 37 μg/d (range, 11 – 83 μg/d), have been reported.140 Plasma cortisol increases threefold from the first to the third trimester of pregnancy. Random determinations of plasma cortisol are of little help, because values are normal in many patients with Cushing's syndrome. Furthermore, in pregnancy it is normally elevated because of an increase in serum CBG. The overnight dexamethasone suppression test, although an excellent screening test in nonpregnant women, is of limited value in pregnancy. Lack of diurnal variation for cortisol is suggestive of the disease, but to properly assess the results of the test, specimens should be obtained between 7 AM and 9 AM and late in the evening. A random plasma cortisol 4 PM value could be misleading. Hence, in pregnancy the determination of free cortisol in a 24-hour urine specimen is the best screening test to rule out Cushing's syndrome. Concomitant determination of creatinine in the urine is necessary to assure proper urinary collection. Once the diagnosis of Cushing's syndrome is suggested, the cause should be investigated. As mentioned earlier, bilateral adrenal hyperplasia and adrenal adenomas are the most common causes in pregnancy; adrenal carcinoma is rare. Plasma ACTH levels are helpful when interpreted in the light of urinary cortisol values. High-normal or elevated values in the presence of high urinary cortisol is suggestive of ACTH-dependent Cushing's syndrome (Cushing's disease). Low ACTH values are consistent with unilateral adrenal tumor.
Further delineation of the pathologic cause is accomplished by use of the dexamethasone suppression test. For the test, urinary cortisol is measured before and during 2 days each, first with a small dose (0.5 mg every 6 hours) and then with a high dose of oral dexamethasone (2 mg every 6 hours). Patients with Cushing's syndrome, regardless of the cause, fail to suppress urinary free cortisol with the small doses (0.5 mg every 6 hours). Patients with bilateral adrenal hyperplasia show a 50% or greater fall in urinary free cortisol with dexamethasone given in the high-dose regimen, whereas there is no suppression in patients with adrenal tumor. Exceptions to this type of response are occasionally encountered.141 These tests have been useful in pregnancy.
In patients with Cushing's disease, an MRI of the pituitary gland may identify a tumor. However, one must keep in mind the enlargement of the pituitary gland that occurs during normal pregnancy. Selective petrosal sinus sampling, a procedure used in localization of the pituitary lesion, is not indicated in pregnancy because of radiation exposure. For cases in which the laboratory tests are suggestive of adrenal lesion, an MRI may delineate the adrenal pathology.
Cushing's syndrome itself is an uncommon disorder and is seen rarely during pregnancy. No more than 100 cases have been reported.142 Spontaneous exacerbations143,144,145 and amelioration139,146,147 of symptoms during pregnancy or postpartum have been reported. Wallace and colleagues142 reported on a patient with recurrent Cushing's syndrome in three successive pregnancies. In this woman with “pregnancy-induced Cushing's syndrome,” hormonal and clinical features normalized a few weeks postpartum. Serum ACTH was suppressed early in pregnancy, and there was a lack of urinary cortisol suppression with the administration of dexamethasone. Although the authors were unable to detect any direct adrenal stimulation in vitro and in vivo from extracts of placenta or maternal serum, the clinical course is suggestive of a stimulator originating in the fetal placental unit. The clinical course resembles reports of periodic Cushing's syndrome.
Maternal and perinatal morbidity and mortality are significant in Cushing's syndrome. A few maternal deaths in the postpartum period caused by congestive heart failure have been reported,148 and one death was caused by disseminated aspergillosis in a mother with ectopic ACTH syndrome.138 Arterial hypertension occurs in over 69% of cases,136 overt diabetes in 30%, preeclampsia in 7%, congestive heart failure in 7%, and maternal death in 4%. Prematurity has been reported in 52% of infants, and fetal wastage is close to 30% (abortions, stillbirth, and neonatal death).142 Intrauterine growth retardation has been reported in 25% of patients with Cushing's syndrome.137,149
Medical treatment of Cushing's syndrome during pregnancy has been reported; in several cases metyrapone was used as the sole form of treatment.142,149,150,151 Metyrapone acts primarily to inhibit steroid 11β-hydroxylation, therefore decreasing the secretion of cortisol by the adrenal glands. Its main use is as a diagnostic tool for assessing ACTH reserve, and it is also used in the diagnosis of Cushing's syndrome. It has been used as a therapeutic agent in nonpregnant patients with Cushing's syndrome for a short period of time before surgery or after radiation therapy to the pituitary gland. In the case reported by Gormley and co-workers,149 fetal growth and fetal well-being were satisfactory and the newborn showed no signs of adrenal insufficiency. Metyrapone in doses of 250 to 1000 mg daily was given from 29 weeks' gestation until spontaneous onset of labor at 36 weeks' gestation. Hypertension was controlled with α-methyldopa 500 mg every 6 hours. The authors reported clinical improvement with a reduction in back pain, peripheral edema, and facial plethora. In another case caused by adrenal carcinoma,150 the patient developed preeclampsia a few days after metyrapone therapy. The infant was born prematurely and died a few days later. In the case reported by Wallace and colleagues,142 metyrapone was given in the second and third pregnancies; the second terminated at 32 weeks' gestation because of placenta abruptio, and the third terminated at 37 weeks' gestation. In the third pregnancy, dexamethasone was added at 22 weeks of pregnancy to avoid adrenal insufficiency caused by the use of metyrapone. The infant was born with adrenal suppression, coarctation of the aorta, and nephrocalcinosis. Two cases were treated with cyproheptadine, a serotonin antagonist, with delivery of normal infants.152 One case of adrenal carcinoma was treated with ketoconazole.153
In 11 cases, adrenal surgery was performed during pregnancy, most during the first half of pregnancy and a few during the last half.148 Patients who had surgery performed during the last half of pregnancy (bilateral adrenalectomy for hyperplasia or unilateral adrenalectomy for adenoma) had a significantly better pregnancy outcome, with fewer fetal losses (1 of 11 versus 9 of 30 pregnancies) and less prematurity. Pricolo and associates154 reported on transsphenoidal pituitary surgery performed in a woman at 22 weeks' gestation. The pregnancy had to be terminated at 30 weeks' gestation because of severe hypertension.155 In a recent report, transsphenoidal surgery was performed in the second trimester of pregnancy, and a healthy infant was delivered at 38 weeks' gestation.156
A few cases of Nelson's syndrome (pituitary tumor with skin pigmentation after bilateral adrenalectomy for Cushing's disease) have been reported during pregnancy with good infant outcome.157,158 Because ACTH does not cross the placenta, the fetal adrenal gland is not affected. In four cases, melanosis appeared as the first sign of pituitary tumor during pregnancy, suggesting that pregnancy is an additional predisposing factor in the development of Nelson's syndrome.157 These patients, as in patients with prolactinomas, should be followed carefully during pregnancy with visual field examinations to detect any enlargement of the pituitary gland.
Addison's disease, or primary adrenal insufficiency, results from total destruction of the adrenal cortex. In cases of adrenal insufficiency secondary to ACTH deficiency, the zona glomerulosa is preserved; therefore, there is normal secretion of aldosterone. The most common cause of primary adrenal insufficiency is autoimmune disease of the adrenal glands, which occurs in about 70% of cases of Addison's disease. The second most common cause is tuberculosis. Other unusual causes include surgical bilateral adrenalectomy for systemic diseases, bilateral metastatic carcinoma, bilateral adrenal bleeding during anticoagulant therapy, and, rarely, fundal infections. Severe systemic infections by meningococcus (Waterhouse-Friderichsen syndrome) may present as acute adrenal insufficiency characterized by vascular collapse and petechial hemorrhage in the skin and mucosa.
With the wide use of corticosteroids for the treatment of systemic diseases, adrenal atrophy due to ACTH suppression is perhaps the most common cause of adrenal insufficiency. In these cases, adrenal insufficiency is caused by chronic suppression of pituitary ACTH. Patients receiving corticosteroid therapy for various periods of time may develop relative adrenal insufficiency. This may manifest for the first time during periods of stress, at which time, because of chronic ACTH suppression, the adrenal glands are unable to respond with an increase in cortisol secretion. It has been estimated that it takes an average of 8 months for the hypothalamic - ACTH - adrenal axis to recover completely after the discontinuation of corticosteroid therapy.159
The most common symptoms in patients with chronic primary adrenal insufficiency are weakness, fatigue, and weight loss. Characteristically, these patients feel relatively well in the morning and experience increased fatigue and asthenia as the day progresses. Blood pressure is low, and patients may complain of postural hypotension. Gastrointestinal symptoms, such as nausea, anorexia, and sometimes vomiting and diarrhea, are not uncommon and may result in weight loss. Although pigmentation of the skin and mucosa is characteristically described in patients with Addison's disease, it is not seen in all such patients. The pigmentation is usually seen in body creases, such as palms of the hands, knuckles, knees, and elbows; in scars; and in the genital, gingival, and buccal areas. Vitiligo may be found in 10% to 15% of patients with Addison's disease. These lesions have been ascribed to autoimmune destruction of the melanocyte and occur in hyperpigmented areas. Gonadal function is disturbed, and in women, axillary and pubic hair may be reduced because of lack of adrenal androgens. Adrenal crisis is characterized by severe hypotension, gastrointestinal symptoms such as nausea, vomiting, and diarrhea, and severe dehydration. These patients may present with elevated body temperature, although infection is not always demonstrated.
Typical laboratory findings in patients with Addison's disease include mild anemia, hyponatremia, hyperkalemia, and an increase in serum blood urea nitrogen. Serum electrolytes may remain within normal limits in some cases. Hypercalcemia may be seen during the acute phase of adrenal insufficiency. Hypoglycemia may be found in patients in the fasting state and during adrenal crisis.
Chest radiographs may demonstrate a small heart, and the electrocardiogram may show changes related to electrolyte disturbance.
The diagnosis is confirmed by a lack of cortisol response to continuous ACTH administration or elevated serum ACTH levels in the presence of low serum cortisol concentrations, or both.160
ACTH STIMULATION TEST.
Baseline or random serum cortisol levels are low in most patients with Addison's disease. However, in some patients the adrenal glands are still able to respond to the high levels of circulating plasma ACTH, and these patients may have normal cortisol levels on a random specimen. On the other hand, low plasma cortisol levels are not diagnostic of adrenal insufficiency, because they are seen in many other situations in which the adrenal glands are not diseased. Furthermore, in pregnancy or in patients on estrogen therapy, plasma cortisol is elevated because of an increase in plasma CBG concentrations. Therefore, the diagnosis of adrenal insufficiency is confirmed by dynamic tests, namely, serum cortisol response to the administration of ACTH.
Short ACTH Stimulation Test.
This is the simplest test available to rule out the presence of Addison's disease. For the test, synthetic ACTH (cosyntropin) 0.25 mg is given as a rapid intravenous bolus, and plasma cortisol is measured before administration and 30 and 60 minutes after. A peak cortisol response of 18 μg/dL over the baseline values rules out Addison's disease. However, a lack of response does not confirm the diagnosis, and a more prolonged ACTH stimulation test is needed.161
Long ACTH Stimulation Test.
There are several modifications of the original test. The basis for the test is the continuous administration of ACTH for several days along with measurement of plasma or urinary corticosteroids.162 For the test, ACTH in the form of cosyntropin, 0.25 mg in 500 mL 5% dextrose in normal saline, is given every 12 hours for 48 hours, and serum cortisol is measured before administration and every 12 hours thereafter. An increase in serum plasma cortisol of over 30 μg/dL rules out the presence of primary adrenal insufficiency. To prevent an acute adrenal crisis in patients with significant symptoms of adrenal insufficiency, dexamethasone, 0.5 mg, can be added to the continuous ACTH infusion. This small amount of corticosteroid does not interfere with the determination of serum cortisol and provides enough glucocorticoid to correct the patient's symptoms. This 48-hour continuous ACTH infusion can accurately distinguish between primary and secondary adrenal insufficiency.
PLASMA ACTH DETERMINATION.
Patients with cortisol deficiency caused by primary adrenal disorders have elevated concentrations of ACTH; these can be measured through a radioimmunoassay technique.163,164 Normal values early in the morning are between 20 and 150 pg/mL. Baseline cortisol values less than 10 μg/dL and ACTH levels of greater than 250 pg/mL are diagnostic of primary adrenal insufficiency.
Patients with primary adrenal insufficiency require treatment for the remainder of their lives, with occasional exceptions. Cortisone or hydrocortisone is the treatment of choice, in doses of 20 to 30 mg/day, with two thirds of the dose being given in the morning and one third in the evening. In most patients a mineralocorticoid is added in the form of fluorohydrocortisone. The daily amount has to be adjusted for each patient, and the total dose varies from 0.05 to 0.2 mg. Although cortisol is the natural hormone produced by the adrenal gland, and it is the drug of choice, other synthetic glucocorticoids may be used. Prednisone and prednisolone are less expensive and more available than cortisone, and either one can be used in doses of 3 to 5 mg in the morning and 1 to 3 mg in the evening. In cases of moderate stress, such as fever or gastrointestinal disturbances, the dose of corticosteroids should be doubled for a few days.
Adrenal crisis is an emergency requiring immediate treatment. Intravenous fluids in the form of normal saline and glucose should be given, and 100 mg hydrocortisone should be injected as a bolus intravenously. An additional 200 mg should be given during the first 24 hours. A search for the cause of the acute crisis should be made, because in most cases infection is responsible.
Patients with known adrenal insufficiency and patients on corticosteroid therapy undergoing selective surgery should be given cortisol in total doses of 200 to 300 mg during the day of surgery. Many regimens have been proposed for the management of these patients, but the one that I recommend is the use of cortisol, 100 mg intravenously every 8 hours in continuous infusion for the first 24 hours and then decreased by 50 mg/d until the patient is able to take oral medications. The infusion should be started early in the morning on the day of surgery. In most cases the patient is able to return to a routine daily dosage by the fourth or fifth day postsurgery. Because the amount of cortisol given has enough mineralocorticoid action, no mineralocorticoid supplementation is needed during this time. Daily determinations of serum electrolytes and glucose should be obtained, because this amount of cortisol may produce hypokalemia and hyperglycemia. To supply enough corticosteroids, it is suggested that an injection of cortisone acetate, 50 to 100 mg intramuscularly, be given the day before surgery. The same regimen is applied to patients who received corticosteroid therapy in the past and discontinued it within 1 year. An additional regimen involves cortisone acetate, 50 mg intramuscularly, every 6 hours the first day, every 8 hours the second day, and every 12 hours the fourth day after a surgical procedure. During surgery, 100 mg of hydrocortisone is added to the intravenous drip.
Pregnancy in patients with known Addison's disease has resulted in normal infants. Early reports have indicated no increase in miscarriage rate, prematurity, or intrauterine death.165,166 In general, the amount of glucocorticoid needed is the same as in nonpregnant patients, with the requirement increasing during labor. Patients with Addison's disease should be managed during labor in the same way as patients under stressful situations. Fasting serum glucose is lower during pregnancy, and patients with untreated adrenal insufficiency have a tendency to develop hypoglycemia. Severe hypoglycemia has been reported in a few patients with ACTH deficiency during pregnancy9 and may occur in patients with Addison's disease if not enough corticosteroids are given or if the patient omits a dose. Patients with chronic adrenal insufficiency should be instructed to take the medications, particularly in cases of nausea and vomiting. They should have injectable corticosteroids at home for such cases. Dexamethasone phosphate in 4-mg injectable syringes is available. Patients should always carry with them identification stating their diagnosis and medication. It has been reported that patients may need an increased amount of mineralocorticoids during pregnancy because of the high levels of progesterone, which have a sodium-losing effect. Elevated levels of serum aldosterone are characteristic in normal pregnancy and have been attributed to the high levels of progesterone that are also present.
Infants of mothers who receive corticosteroid therapy rarely develop adrenal insufficiency. In a review of 260 pregnancies in which the mother took steroids for variable periods, only one infant was believed to have adrenal insufficiency.167 Mothers on chronic corticosteroid therapy have low urinary or plasma estriol levels. As mentioned before, occasionally an infant is reported to be born with adrenal insufficiency as a result of maternal steroid therapy.168
Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia (CAH)169 is a hereditary disorder involving both adrenal glands. It is produced by a number of defects of corticosteroid biosynthesis that result in a reduced production of cortisol and a secondary increase in ACTH secretion, which is then responsible for adrenal hyperplasia and an accumulation of hormonal precursors. Defects of several enzymes, such as cytochrome P-450 oxidase, may produce different clinical pictures (Fig. 2).
The most common defect is the 21-hydroxylation defect, which is found in more than 90% of patients with congenital adrenal hyperplasia. It is an autosomal recessive disorder involving a gene on the short arm of chromosome 6. It affects about 1 in every 14,000 live births, but in some populations it is more common (1 in 80 births).170 The clinical manifestations depend on the severity of the abnormality in the 21-hydroxylase genes. Women with severe deficiency of the enzyme (the classical form of 21-hydroxylase deficiency) have a low fertility rate because of oligoanovulation. Abnormal genitalia and sodium wasting are recognized at the time of delivery, as are signs of virilization. In the milder form of the disease, virilization is the only manifestation, because aldosterone secretion is not seriously affected. The third form of the disease is mild and is detected in childhood or adulthood.171 Other types of defects include the 11-hydroxylation defect and, rarely, the defect of the 3-β-hydroxysteroid-dehydrogenase enzyme.
The goals of treatment are to prevent adrenal insufficiency, to provide salt-retaining corticosteroids in the salt-losing types of cases, and to suppress androgen secretion to prevent virilization and abnormalities of growth. This is achieved with doses of hydrocortisone of 25 to 75 mg/d or 25 mg/m2/d. Dexamethasone with a longer half-life is preferred by some in doses of 0.25 to 0.75 mg/d.172 Parameters of adequate glucocorticoid dosage include determination of plasma 17-hydroxyprogesterone (17-OHP), androstenedione, and testosterone. Patients with the salt-losing variety also require mineralocorticoid therapy in the form of Florinef (fludrocortisone) 0.05 to 0.3 mg/d; the dose is adjusted to normalize plasma renin activity. No adjustment is needed in pregnancy.173 The hormonal markers for therapy monitoring change during pregnancy, with the exception of the determination of maternal serum free testosterone, which is useful for the assessment of adequate therapy.173
Klingensmith and co-workers174 reported a group of 18 females, 10 years of age or older, with congenital adrenal hyperplasia followed for many years. Initiation of menstruation was delayed in all of these patients when compared with the general population. Eight patients were treated for the first time after age 20 years, and none of them were able to conceive. Of 20 patients in whom treatment was started between ages 6 and 20 years, 64% who were sexually active had at least one pregnancy. In patients first treated before age 6 years, the pregnancy rate was about 60%. The amount of cortisone needed was between 30 and 56 mg/m2 in 24 hours, and the levels of urinary 17-ketosteroids were between 2.5 and 5.3 mg/d. All women were maintained during pregnancy on the prepregnancy dose of steroids. Of the 13 pregnancies in these patients, 9 were viable and only 1 resulted in an infant born with multiple congenital malformations, but the mother had systemic lupus erythematosus and was treated with large doses of salicylate. All of the mothers underwent cesarean section, and there was only one case of a premature infant with mild residual cerebral palsy. No patient in this study had an infant with CAH. However, the fertility rate was low and first-trimester abortions were high.173,174,175,176
Prenatal evaluation of the partner of a woman who has the disease or is a carrier is important in evaluating for possible fetal involvement. The partner has a 1% to 6% chance of being a carrier of the disease. Determination of plasma 17-OHP at baseline and after the administration of ACTH allows, in most cases, detection of the partner's heterozygous state.169 Fetuses are considered “potentially affected” if: (1) both parents are heterozygous, (2) both parents are homozygous, or (3) one parent is homozygous and the other heterozygous.
Prenatal diagnosis of CAH due to 21-hydroxylase deficiency is possible with the detection of elevated amniotic fluid 17-OHP and adrenal androgen concentrations or with linkage analysis and human leukocyte antigen typing of cultured amniotic fluid cells. However, because these tests cannot be completed before 16 to 17 weeks' gestation, any preventive therapy should be given before the results of the tests become available, because masculinization of the fetus has occurred between 10 and 16 weeks' gestation.177,178
Chorionic villus biopsy at 8 to 10 weeks' gestation allows for the most accurate prenatal diagnosis using molecular genetic techniques.179,180 However, the fetal loss rate after chorionic villus sampling (CVS) is 1.3% to 1.6%.173 Early treatment, before 6 weeks' gestation, may prevent the development of masculinization of external genitalia in the female-affected fetus. Dexamethasone is the drug of choice because it readily crosses the placenta (compared with all the other glucocorticoids) and suppresses fetal adrenal androgen synthesis, reducing masculinization. Mothers who are potentially affected should be treated until fetal sex and involvement are known. The treatment is effective in about two thirds of patients.181,182 The dose of dexamethasone is 1 to 1.5 mg/d from early in pregnancy until delivery (20 μg/kg maternal weight). Maternal estriol levels are an accurate index of fetal adrenal function and genital outcome.183
Pang and colleagues184 reported maternal side effects of this therapy in three women. Cushingoid facial features, facial hirsutism, excessive weight gain, permanent scarring of striae, hypertension, and gestational diabetes were the most common complications of therapy. The authors recommended that future patients should be informed about potential side effects, mothers receiving treatment should be closely monitored, medical intervention should be provided when indicated, and the dose of dexamethasone should be reduced during the second half of pregnancy, to reduce side effects.
In the last 10 years, direct molecular analysis of the 21-hydroxylase (CYP21) gene has been performed since CVS became available in 1984. CVS can be performed at 10 weeks' gestation. Mercado and associates185 published their evaluation of 258 cases from 235 families with a sibling, parent, or close relative with 21-hydroxylase deficiency. They followed 229 pregnancies that resulted in live births. Prenatal diagnosis was made by amniocentesis; 17-OHP was measured in amniotic fluid, or human leukocyte antigen genetic linkage marker analysis was used. The accuracy rate of each diagnostic procedure was 95%. In their protocol, treatment was started with dexamethasone 20 μg/kg/d in two or three divided doses before 10 weeks' gestation in those mothers whose babies could potentially be affected. Treatment was discontinued if the fetus was found to be male or an unaffected female. Prenatal treatment was initiated in 101 mothers, and in 22 of them the fetus was confirmed to be affected with classical 21-hydroxylase deficiency. There were 13 female and 9 male infants. Nine females affected were treated throughout pregnancy; four were normal at birth and five were virilized but to a lesser degree than their siblings. Of 75 cases in which the mothers refused treatment, 15 were affected, 8 of them females. Of these 8 females, there were three elective abortions, and all five that went to term had virilized genitalia. The authors concluded that dexamethasone administered at or before 10 weeks' gestation was effective in reducing, and in some cases preventing, virilization. Follow-up of the 84 newborns prenatally treated showed normal birth weight, birth length, and head circumference compared with untreated fetuses. There is an ongoing evaluation of the long-term effects of dexamethasone-exposed fetuses.185
11-Hydroxylase deficiency is common in the Middle East but rare in European populations.186 The production of cortisol is reduced, and there is an excessive production of 11-deoxycortisol, 11-deoxycorticosterone, and adrenal androgens.169 Hypertension, hypokalemia, and virilization are the most common form of presentation, along with infertility. The diagnosis may be made for the first time in adolescence or adulthood, when the patient presents with infertility, or oligomenorrhea, hirsutism, and short stature. Treatment with glucocorticoids normalizes infertility, and successful pregnancies have been reported.187
Primary aldosteronism was described by Conn in 1955188 and is characterized by hypertension and hypokalemia due to excessive production of aldosterone by the adrenal glands. The first cases described were of patients with single adrenal adenomas, but now it is known that about 20% to 30% of patients with primary hyperaldosteronism suffer from bilateral adrenal hyperplasia or multiple microadenomas; rare cases of corticosteroid suppressive hyperaldosteronism, adrenal carcinoma, and congenital primary aldosteronism have been reported.
Primary hyperaldosteronism is a rare disorder accounting for less than 0.5% of all causes of hypertension. Symptoms such as headaches and muscular weakness are present in some patients, the latter being a complication of hypokalemia. Serum potassium is decreased in more than 90% of the cases. Metabolic alkalosis with hypochloremia and an elevation in serum bicarbonate is commonly seen. Urinary potassium excretion is elevated and inappropriate to the low serum potassium levels. Renal function is within normal limits, and the pH of the urine is neutral or alkaline. Patients with marked hypokalemia may complain of polyuria due to a renal tubular defect characterized by being Pitressin resistant.
The diagnosis is suspected in those patients with hypertension and hypokalemia; all other causes of hypokalemia, particularly ingestion of diuretics, must be ruled out. High levels of urinary potassium in the presence of hypokalemia are very suggestive of primary hyperaldosteronism. The diagnosis is confirmed by (1) an elevation in serum or urine aldosterone, (2) suppressed levels of plasma renin, (3) a lack of plasma renin elevation on administration of a potent diuretic such as furosemide, and (4) failure of the aldosterone level to be suppressed by the administration of 200 μg 9-α-fludrocortisone twice a day for 3 days.189
In normal pregnancy there is an increase in aldosterone secretion and plasma aldosterone levels starting in the first trimester; this peaks at 36 weeks' gestation at a level eightfold to tenfold higher than that in nonpregnant women. This elevation in plasma aldosterone is normally suppressed in pregnancy by the administration of 9-α-fludrocortisone.190 Plasma renin levels increase early in pregnancy, reaching a peak at 12 weeks and remaining elevated throughout pregnancy.
In the few cases of primary hyperaldosteronism reported in pregnancy, the aldosterone levels were elevated and the plasma renin was suppressed.190,191,192,193 In the case reported by Gordon and Tunny,191 surgery was performed during pregnancy with good results. In the case reported by Biglieri and Slaton,192 the metabolic and blood pressure abnormalities improved spontaneously during pregnancy. A case of virilization in the fetus has been reported.193
In the reported cases of primary hyperaldosteronism in pregnancy mentioned above, metabolic alkalosis was present instead of respiratory alkalosis, which is characteristically seen in normal gestation. Serum bicarbonate in plasma is normal or elevated, in contrast to the low value seen in normal pregnant women.
Treatment is based on the cause of aldosteronism. An MRI of the abdomen is effective in localizing the adrenal lesion. In most cases reported in pregnancy, a single adrenal tumor is the cause, in which case adrenalectomy is the treatment of choice. In cases of bilateral adrenal hyperplasia, medical treatment with spironolactone is effective.186,194
Pheochromocytoma is a rare syndrome accounting for about 0.5% of all cases of newly diagnosed hypertension. It occurs with equal frequency in both sexes and is more common in the third and fourth decades of life. In Northern Ireland, the annual incidence of pheochromocytoma is 1 case per 750,000 population, half of them women. In a 21-year period, seven cases occurred during pregnancy.195 In most cases the disease is produced by a single adrenal adenoma; about 15% are multiple, and 10% to 12% are malignant. Involvement of both adrenal glands is seen in cases with a strong family history of pheochromocytoma. Furthermore, it may be part of the syndrome of multiple endocrine neoplasia type II (MEN type IIA and IIB) in association with medullary carcinoma of the thyroid and parathyroid adenoma (Sipple's syndrome). Pheochromocytoma may also be associated with neurofibromatosis, and it is estimated that 5% of patients with neurofibromatosis will develop a pheochromocytoma. In fewer than 10% of cases, the chromaffin tumors initiate from outside the adrenal gland in the organ of Zuckerkandl196 and the bladder wall197 and are named paragangliomas.
Hypertension is the most common symptom; it can be persistent or paroxysmal. In addition to hypertension, headaches, sweating, palpitations, nervousness, tremor, weakness, abdominal pain, and warm flashes are not uncommon. Some patients have markedly labile blood pressure. The attacks can be precipitated by induction of anesthesia, examination of the abdomen, or changes in position. The patient with pheochromocytoma may be hypermetabolic, with weight loss, nervousness, and elevation of the basal metabolic rate. Glycosuria and mild intolerance to glucose are not unusual.
Pheochromocytoma associated with pregnancy is life-threatening for mother and fetus. In 1969, Fox and co-workers198 described 1 case and reviewed 89 cases reported in the literature. In 1982, Schenker and Granat199 reviewed 112 pregnancies occurring in 89 patients. They emphasized the poor prognosis for mother and fetus. The maternal mortality rate was 48% and the fetal mortality rate was 54% when the disease remained undiagnosed during pregnancy; high mortality occurred mainly within 72 hours of delivery. The cause of death included cerebrovascular accidents, cardiac arrhythmias, shock, and acute pulmonary edema. Only 1 of 26 patients died when the diagnosis was made before delivery. This stresses the importance of early diagnosis and effective therapy. In 17 cases the symptoms disappeared between pregnancies, and in two thirds of the cases pheochromocytoma occurred in multiparous women.
Hypertension (paroxysmal or sustained) was present in 82% of the patients, headaches in 66%, palpitations in 17%, anxiety in 15%, and convulsions in 10%. In several cases, sudden shock appeared spontaneously or was induced by anesthesia or vaginal delivery in patients without previous symptoms (Table 7). In 22 patients, the diagnosis was made for the first time during pregnancy. Of 67 patients in whom pheochromocytoma remained undiagnosed during pregnancy, acute toxemia was diagnosed in 29 (43%) and essential hypertension was diagnosed in 11 (16.4%).
Fetal wasting is high in patients with pheochromocytoma. Of 162 pregnancies, the fetal loss was 53%; spontaneous abortion occurred in 12%, intrauterine death in 23%, and neonatal or intrapartum death in 18%. Fetal mortality has improved since the introduction of α-adrenergic receptor blocking agents.200
The diagnosis of pheochromocytoma is confirmed by the demonstration of elevated levels of catecholamines or their metabolites (norepinephrine and epinephrine), methylated metabolites (normetanephrine and metanephrine), and the methylated deaminated metabolite vanillylmandelic acid (VMA). An elevation in VMA, catecholamines, or metanephrine in a 24-hour urine specimen is suggestive of the diagnosis. This should be confirmed, however, by a second 24-hour collection. The following recommendations have been suggested for the proper interpretation of urinary catecholamine and its metabolites:
Total urinary free catecholamines are elevated in most patients with pheochromocytoma. Normal total excretion is between 100 and 150 μg/d, which is similar to that of the nonpregnant state. However, it may be slightly elevated in preeclampsia201 and also in stressed, working normal pregnant women.202 Specific quantitation of epinephrine and norepinephrine may assist in the localization of a lesion; increased epinephrine excretion in excess of 50 μg/d suggests an adrenal lesion. Excessive secretion of noradrenaline is suspicious, but not diagnostic, of extra-adrenal tumor. False-positive elevations may occur in patients who are taking methyldopa, are undergoing strenuous exercise, have increased intracranial pressure, have hypoglycemia, are undergoing clonidine withdrawal, or are undergoing aminophylline administration. Plasma levels of catecholamines can be measured, particularly during a paroxysmal episode. It is important to adhere strictly to the technique of blood collection. Value fluctuations are common under routine stressful situations, such as exercise, venipuncture, and anxiety. It is recommended that the patient rest in the supine position in a quiet environment for 30 minutes before blood is drawn. Blood is obtained through an indwelling catheter. The plasma should be centrifuged and the serum stored at temperatures lower than 4°C until assayed.203
As soon as the diagnosis is confirmed, administration of α-adrenergic blocking agents should be started.204,205 The drug most often used is phenoxybenzamine. Starting with 10 mg/d, the dose can be increased by 10 mg every 2 to 3 days until blood pressure and symptoms are controlled. The blocking dose is 1 mg/kg/d. It may need to be adjusted because it has a half-life of about 24 hours and hence is cumulative. The usual dose of phenoxybenzamine is 40 to 80 mg/d.206 Prazosin in doses of 6 to 10 mg has been used as a selective α1 antagonist in pregnancy.207 In addition, α-adrenergic receptor blockade increases the blood volume and may improve congestive heart failure as well as angina pectoris, if present. A 2-week course of an α-adrenergic receptor blockade is the cornerstone of preoperative management,208 although a 3-day course has been used successfully in pregnancy.209 Beta-blockers are added to the regimen when tachycardia develops after the administration of an α-adrenergic blocking agent.204,210 Propranolol 10 mg three to four times a day is useful in maintaining the pulse rate between 80 and 100 beats a minute. Hypertensive crises are treated with intravenous phentolamine in doses of 1 to 5 mg. Intravenous therapy can also be used in cases of unstable hypertension in preparation for surgery.211 Alpha blockage should be completed before surgery is contemplated; it takes 10 to 14 days to achieve an acceptable result. Indicators of adequacy include a blood pressure less than 165/90 mmHg; the presence of orthostatic hypotension, but with standing blood pressure greater than 90/45 mmHg; no changes in the electrocardiogram for the last 2 weeks (no ST-segment or T-wave abnormalities); and less than one premature ventricular contraction every 5 minutes.212
Surgical intervention is the treatment of choice in cases of pheochromocytoma. Tumor localization in 47 pregnant patients showed that 25% were in the right adrenal gland, 17% were in the left, 17% were bilateral, and 32% were intra-abdominal extra-adrenal.201,213 Localization of the tumor is imperative and is achieved in most cases with modern radiologic techniques. In pregnancy, CAT scans, arteriography, and selected venous catheterization are contraindicated for obvious reasons. MRI is useful in localizing and diagnosing adrenal lesions. In pregnancy, this is the method of choice for localization of the tumor. The major advantages are lack of ionizing radiation, lack of contrast dye, and the ability to distinguish pheochromocytomas from other adrenal lesions by the high-intensity signal emitted in T2-weighted images. Ultrasonography is of little value; pressure exerted by the sonogram probe has been reported as the causative agent in a paroxysmal attack.214,215,216
When the diagnosis is made during the first trimester, elective termination of pregnancy followed by tumor excision is recommended by some,206 whereas selective tumor resection is recommended by others.199,209,217 However, the incidence of spontaneous abortion occurring after surgery is high.
During the last two trimesters of pregnancy, medical treatment is the treatment of choice, with removal of the tumor at the time of cesarean section.215,216 Burgess218 reviewed 42 cases from the literature in which the diagnosis was made antepartum; the maternal mortality rate was 12% and the fetal mortality rate was 40%. The best results are obtained when the pregnancy has advanced to viability, the fetus is delivered by cesarean section, and tumor exploration is done immediately after. Cesarean section rather than vaginal delivery is strongly recommended as the safest procedure for both mother and fetus.199 In Burgess' study, the fetal mortality rate was reduced to 17% when the diagnosis was made in the first two trimesters of pregnancy. For patients in whom the diagnosis was made in the third trimester, the fetal mortality rate was 0%, compared with 42% in the group that did not undergo administration of an α-adrenergic blocking agent. No maternal mortality has been reported in patients treated with an α-adrenergic blocking agent. Stenstrom and Swolin209 reviewed 29 cases from the literature and 3 of their own in which the pheochromocytoma was diagnosed antepartum and treated with α-adrenergic receptor blockade. Fourteen patients underwent short treatment of 4 to 21 days, and 6 underwent treatment of 46 to 91 days; in 9 cases the duration was unknown. The investigators recommended the use of elective tumor resection in the first trimester and medical treatment followed by cesarean section and tumor removal when the diagnosis is made after the first trimester. The fetal mortality rate in the treated cases was 19% compared with 50% in those without the benefit of α-adrenergic receptor blockade treatment. An anesthesiologist should be consulted and become closely involved in the management of patients with pheochromocytoma.211,219
Virilization (Table 8) in pregnancy is exceedingly rare. Several cases have been described with normal fetal outcome. The most common cause is luteoma of pregnancy, which is defined as a benign human chorionic gonadotropin (hCG) - dependent ovarian tumor that develops during pregnancy. Virilization occurs in about 25% of such patients. High levels of testosterone and androstenedione are responsible for virilization. These patients develop hirsutism, acne, deepening of the voice, and clitoral enlargement, beginning early in the second trimester. Fetal virilization is seen in 65% of females born to patients whose virilization began during pregnancy. Regression with normalization of the elevated androgen levels occurs in the postpartum period. In the case reported by Thomas and co-workers,220 virilization had occurred in previous pregnancies; chorionic gonadotropin stimulation 8 months postpartum resulted in increased urinary excretion of 17-KS and ovarian enlargement.221,222,223,224
*Lesions and drugs producing fetal virilization
Thyroid disorders in pregnancy present a unique opportunity for health care professionals to use a team approach that has successfully improved the care of diabetic women. Obstetricians, endocrinologists, perinatologists, and anesthesiologists are often called upon to interact in the management of complex thyroid problems. In addition to changes in thyroid function tests, hypermetabolic symptoms often seen in pregnancy present a challenge in the diagnosis of thyroid disease during pregnancy.
Thyroid hormone concentrations, both total thyroxine (TT4) and total triiodothyronine (TT3), increase during pregnancy as the result of both an elevation in thyroxine-binding globulin (TBG) secreted by the liver and a reduced peripheral TBG degradation rate.225 In spite of these changes in total hormone concentration, the serum free fractions of both T4 and T3 remain within normal limits. However, there is a slight decrease in concentration with progression of pregnancy. The serum levels of TSH, produced by the pituitary gland, have a tendency to decrease in the first trimester of pregnancy; they are undetected in 15% of normal pregnancies. With progression of pregnancy, serum TSH levels return to normal values.226 The suppression of serum TSH values in the first part of gestation is secondary to the normal elevation in hCG, which has a weak thyroid stimulator action on the TSH receptor. High levels of hCG, as in cases of hydatidiform mole and hyperemesis gravidarum, may cause elevations in serum T4 concentrations, as seen in thyrotoxicosis.
Despite the limitations in the interpretation of serum TSH in the first trimester, a second- or third-generation serum TSH test is the most practical test to screen for thyroid dysfunction. High TSH values are consistent with the diagnosis of primary hypothyroidism, whereas suppressed values are suggestive of hyperthyroidism, with few exceptions (Fig. 3). In the presence of an abnormal serum TSH value, the determination of FT4 or its equivalent, free thyroxine index (FT4I), will help in the assessment of thyroid function. A low TSH value and high concentrations of FT4 or FT4I are diagnostic of hyperthyroidism; if the FT4 or FT4I is normal, a serum FT3 or FT3I determination is obtained. High values are diagnostic of hyperthyroidism, the so-called T3-toxicosis syndrome, which is sometimes seen in patients with an autonomous or “hot” thyroid nodule. Therefore, a few thyroid tests, if properly ordered and interpreted, allow the physician to assess thyroid function in pregnancy.
In areas of iodine deficiency, goiter is commonly seen in pregnancy. However, in the United States and other areas of the world with sufficient iodine intake, the thyroid gland does not clinically increase in size during pregnancy. Therefore, the detection of a goiter in pregnancy is an abnormal finding that requires careful evaluation. One of the most common causes of diffuse goiter is chronic autoimmune thyroiditis or Hashimoto's thyroiditis. Most patients are euthyroid, and the diagnosis is made by the determination of thyroid antibodies (antimicrosomal or anti - thyroid peroxidase [anti-TPO]). Antibody concentration decreases during pregnancy and increases in the postpartum period. High values in the first trimester of pregnancy are predictors of the syndrome of postpartum thyroid dysfunction.
In some patients with a history of autoimmune thyroid disease, active or inactive, the determination of TSH receptor antibodies is indicated to assess the possibility of fetal or neonatal hyperthyroidism. These antibodies, mainly of the immunoglobulin G (IgG) class, have different functional activities-mainly stimulating or blocking antibodies on the TSH receptor of the thyroid gland. When high titers are present in the serum of pregnant women, they cross the placenta and may affect fetal thyroid function. Thyroid-stimulating immunoglobulin (TSI), formerly known as long-acting thyroid-stimulating antibody, may cause fetal or neonatal hyperthyroidism.227,228 Thyroid-blocking antibodies present in women with chronic thyroiditis, particularly those with atrophic thyroiditis, may produce neonatal hypothyroidism, a condition that is transient because of the short half-life of these antibodies.229
Titers of these antibodies decrease with progression of the pregnancy. This could explain, in the case of Graves' disease, the decrease in antithyroid drug requirement in many cases of hyperthyroidism in the second half of pregnancy. A TSH receptor antibody value five times greater than normal is considered predictive of neonatal or fetal hyperthyroidism. The test is relatively expensive and should be ordered only in very special circumstances (Table 9). The ideal time to order the test is between 32 and 34 weeks' gestation because of the gradual decrease in titer concentration with progression of pregnancy.
Fetal or neonatal hyperthyroidism in previous pregnancies
Chronic thyroiditis without goiter
Incidental fetal goiter on ultrasound
Infant born with congenital hypothyroidism
Maternal - Placental - Fetal Interactions
In general it has been accepted that thyroid hormones do not cross the placenta. However, recent studies in animals and some in humans have shown some placental passage of thyroid hormones from mother to fetus in the first few weeks of pregnancy, suggesting an important role of thyroid hormones in embryogenesis.230 Some transplacental transfer from mother to fetus at the end of pregnancy has been shown in cases of congenital hypothyroidism, although the amount of hormone was not sufficient to normalize serum TSH in the neonate.231
Maternal TSH does not cross the placenta. TRH does cross the placental barrier, but the physiologic significance is unknown. TRH has been injected in mothers to accelerate fetal lung maturation in premature infants.232
Methimazole and propylthiouracil (PTU) (drugs used for the treatment of hyperthyroidism) cross the placenta. If given in large doses, they may produce fetal goiter and hypothyroidism.233 Iodine therapy is contraindicated in pregnancy because iodine is accumulated by the fetal thyroid and induces goiter and hypothyroidism.234
Hyperthyroidism is diagnosed in pregnancy in about 0.1% to 0.4% of patients.235,236 In most cases the etiology is Graves' disease; other causes are uncommon (Table 10). In the authors' experience, single toxic adenoma and multinodular toxic goiter are seen in less than 10% of cases, and subacute thyroiditis is rarely seen during gestation. Increased secretion of hCG may cause chemical hyperthyroidism, as in cases of hydatidiform mole and hyperemesis gravidarum.237,238
*Accounts for 85% to 90% of all cases
Transient Hyperthyroidism of Hyperemesis Gravidarum
In cases of severe hyperemesis gravidarum, thyroid tests in the hyperthyroid range are not uncommon. The degree of thyroid abnormalities is directly related to the severity of vomiting and weight loss. In the study by Goodwin and associates,237 67 patients were evaluated. In those with severe vomiting, weight loss of at least 5 kg, and significant dehydration, liver and electrolyte function abnormalities were often found. These patients had significant elevations in FT4 levels with suppression of serum TSH values. Those with lesser degrees of hyperemesis had less severe thyroid function abnormalities. The presentation of transient hyperthyroidism of hyperemesis gravidarum (THHG) is characterized by severe nausea and vomiting requiring hospitalization (sometimes repeated hospitalizations) for intravenous hydration. Weight loss of at least 5 kg, ketonuria, and hypokalemia are common findings. FT4 levels are elevated, sometimes two to three times the normal values. FT3 is also elevated, but not as much as FT4. Serum TSH measured by a sensitive assay is consistently suppressed. In spite of the significant biochemical hyperthyroidism, signs and symptoms of hypermetabolism are mild or absent. Patients may complain of mild palpitations, but heat intolerance, perspiration, and proximal muscle weakness are extremely rare. On physical examination, ophthalmopathy and goiter are absent, a mild tremor of the outstretched fingers is occasionally seen, and tachycardia may be present, mainly a result of dehydration. Significant in the medical history is the lack of hyperthyroid symptoms before conception, which is relevant because patients with Graves' disease diagnosed for the first time during gestation give symptoms antedating the pregnancy. Normalization of hyperthyroxinemia parallels the improvement in vomiting and weight gain, with most cases resolving spontaneously in 2 to 10 weeks. However, suppressed serum TSH may last for a few more weeks (Fig. 4). No antithyroid medication is needed; furthermore, because of the severity of the vomiting, drug therapy is poorly tolerated. In one study in which antithyroid medication was used, the outcome did not differ from that of a similar group of patients receiving no antithyroid medication.239 In most cases, total resolution occurred by midgestation, although in some series persistence of hyperthyroidism beyond 20 weeks' gestation was reported in 15% to 25% of cases.240,241 Occasionally, severe vomiting and hyperthyroidism require parenteral nutrition.
The diagnosis of THHG is suspected when there is a sudden onset of nausea and vomiting in the first part of pregnancy in a patient without hypermetabolic symptoms antedating pregnancy, when there is absence of goiter, when there are no other symptoms or signs of tissue thyrotoxicosis, and when there are negative thyroid antibodies, which are markers of autoimmune thyroid disease.242 Sometimes the differential diagnosis is difficult to make because vomiting may be a presenting symptom of hyperthyroidism due to Graves' disease.243
The cause of hyperthyroidism in patients with hyperemesis gravidarum is still controversial. The most likely explanation is high levels of hCG, a known stimulator of the TSH receptor. There is a significant, albeit weak, correlation between the degree of thyroid stimulation and total hCG levels in normal and hyperemetic women.244 It seems likely, however, that certain hCG fractions may be more important than the total hCG as thyroid stimulators. The thyroid-stimulating activity of early pregnancy and of molar gestations correlates best with the percentage of basic, partially desialylated hCG in serum.245
Although the true incidence of this entity is unknown, a higher prevalence in Asian women has been reported.246 The diagnosis should be considered in pregnant women with severe vomiting, no clinical manifestations of Graves' disease, and biochemical evidence of hyperthyroidism in early pregnancy. The vomiting has to be persistent and severe with significant weight loss, because most women with morning sickness of pregnancy have normal thyroid function tests.247
Graves' disease is the most common cause of hyperthyroidism in pregnancy, accounting for over 85% of all cases. The natural course of the disease is characterized by an exacerbation of symptoms in the first trimester and during the postpartum period and an amelioration of symptoms in the second half of pregnancy. When Graves' disease is properly treated, the outcome for mother and fetus is good; however, untreated or poorly controlled disease may be catastrophic for both the woman and the neonate.248,249,250,251,252
In most patients whose diagnosis is made for the first time during pregnancy, symptoms antedate conception. The clinical diagnosis of thyrotoxicosis may be difficult during gestation because many hypermetabolic symptoms are commonly seen in normal pregnancy, such as mild palpitations and a heart rate of 90 to 100 beats per minute, mild heat intolerance, and warm skin. There are a few important clues to guide the physician toward the diagnosis of hyperthyroidism: presence of goiter, ophthalmopathy, proximal muscle weakness, tachycardia with a pulse rate of over 100 beats per minute, and weight loss or an inability to gain weight in spite of a good appetite. Occasionally the patient is seen for the first time in congestive heart failure. In patients with toxemia, the physician should suspect hyperthyroidism when there is systolic hypertension and an inappropriately low diastolic blood pressure, a wide pulse pressure.
Classical symptoms of hyperthyroidism include nervousness, increased sweating, increased appetite, heat intolerance, insomnia, proximal muscle weakness, irritability, changes in personality, frequent bowel movements, a decreased tolerance to exercise (sometimes manifested as shortness of breath), pruritus, and weight loss. Not all symptoms are present in a given patient; the physician should be aware of subtle complaints, particularly in the presence of weight loss or the inability to gain weight. As mentioned above, differentiating Graves' disease from THHG in the first trimester of pregnancy may present a real challenge to the physician.
On physical examination, the thyroid gland is enlarged in almost every patient with Graves' disease. Indeed, the absence of a goiter makes the diagnosis very unlikely. The gland is diffusely enlarged (between two and six times its normal size) and varies from soft to firm; sometimes it is irregular to palpation, with one lobe more prominent than the other one. A thrill may be felt or a bruit may be heard; these are indications of hyperdynamic circulation. Examination of the eyes may reveal obvious ophthalmopathy, but in most cases exophthalmos is absent or mild, with one eye slightly more prominent than the other one. Stare is common, as well as injection or edema of the conjunctiva. Pretibial myxedema is rare; it is seen in less than 10% of women. A hyperdynamic heart and a loud systolic murmur are common findings. Proximal muscle weakness, fine tremor, and hyperkinetic symptoms are seen often. The skin is warm and moist, and palmar erythema is accentuated.
Cardiovascular manifestations include left ventricular dysfunction. Although these changes are reversible, they may persist for several weeks after euthyroidism is achieved. In one study,253 a reduction in peripheral vascular resistance and a high cardiac output were still present despite normalization of thyroxine levels. This is an important finding with significant clinical implications. Left ventricular decompensation in hyperthyroid pregnant women occurs in the presence of superimposed preeclampsia, at the time of delivery, or with intercurrent complications such as anemia or infection. Careful monitoring of fluid administration is imperative in these situations. Thyroid crisis or storm is rarely reported in pregnancy or the postpartum period.254
The chemical diagnosis of hyperthyroidism presents no difficulties in most cases. FT4 determination or calculation of the FT4I (using TT4 levels and a test for assessment of thyroxine-binding globulin, such as resin T3 uptake [RT3U]) are standard tests in most clinical laboratories and give results in 24 to 48 hours. Almost every patient with Graves' disease has an elevated FT4 concentration. Serum TSH should be measured with a sensitive assay; this should be ordered at the time of the free T4 determination. A suppressed TSH value in the presence of a high free T4 or FT4 index confirms the diagnosis of hyperthyroidism.255 It must be kept in mind, however, that a suppressed serum TSH level is present in about 15% of normal pregnant women in the first trimester of pregnancy.226 In some unusual situations, the serum FT4 is in the upper limit of normal or is slightly elevated, in which case the determination of free T3 and the free T3 index will confirm the diagnosis of hyperthyroidism. Thyroid peroxidase antibodies (antithyroid peroxidase) or thyroid antimicrosomal antibodies, markers of thyroid autoimmune disease, are elevated in most patients with Graves' disease. Determination of these antibodies is indicated for patients in whom the etiology of the hyperthyroidism is in doubt.
Treatment of hyperthyroidism is essential to prevent maternal, fetal, and neonatal complications. The goal of treatment is to normalize the thyroid tests with the minimum amount of antithyroid medication. Antithyroid medications crossing the placenta may affect fetal thyroid function; patients should be monitored at regular intervals, and the amount of medication should be adjusted to keep the FT4 in the upper limits of normal (9.5 to 12). For this purpose, thyroid tests should be performed every 2 weeks at the beginning of treatment and every 2 to 4 weeks when euthyroid is achieved. In patients with small goiters and a short duration of symptoms who are kept euthyroid on minimal amounts of antithyroid medication, the drug can be discontinued during the last few weeks of pregnancy. It is not recommended to discontinue antithyroid therapy before 32 weeks' gestation because relapses can occur. In the United States, the two antithyroid drugs available are PTU and methimazole (Tapazole). Both drugs are effective in controlling the disease; to my knowledge, there are no reports that show PTU to be superior to Tapazole. Furthermore, in a recent report comparing both drugs in a group of pregnant hyperthyroid women, euthyroidism was achieved in both groups with equivalent amounts of drugs and in the same period of time.236 Neonatal events did not differ between groups. Aplasia cutis, an unusual scalp lesion reported in a small group of patients taking methimazole,256,257,258 is not a contraindication for use of this drug in pregnancy. The initial recommended dose of PTU is 200 to 400 mg/d and the dose of methimazole is 20 to 40 mg/d divided into two daily doses.259 This regimen is preferable for outpatient treatment to avoid poor compliance. At initiation of therapy, however, PTU 50 to 150 mg should be given every 8 hours. Very seldom are high doses needed, and indeed there is no evidence that higher doses are therapeutically more effective. In most patients, clinical improvement is seen in 2 to 6 weeks, and an improvement in thyroid tests is seen in 2 to 4 weeks, with normalization into chemical euthyroidism in 3 to 7 weeks.236 Resistance to drug therapy is very unusual; when it occurs it is most likely due to poor compliance.260 Once clinical improvement occurs (mainly weight gain and a reduction in tachycardia), the dose of antithyroid medication can be reduced by half of the initial dose. The amount of medication is adjusted every few weeks according to the clinical response and the results of the thyroid tests. The goal is to keep the FT4 in the upper limit of normal (between 9.5 and 12) with the minimum amount of medication. If there is exacerbation of symptoms or worsening of the thyroid tests, the amount of antithyroid medication is doubled. The main concern of maternal drug therapy is the potential side effects on the fetus, mainly goiter and hypothyroidism. In most studies this is prevented by using doses of PTU no greater than 200 mg and doses of methimazole no greater than 20 mg in the last few weeks of gestation.261 However, small elevations in serum TSH in the neonate have been reported, even with smaller doses of antithyroid drugs.262 Furthermore, in one study, cord blood FT4 was not related to the antithyroid dose.263 There is no evidence in the literature that transient elevations in serum TSH in the neonate affect the long-term mental development of the child.264
Side effects of antithyroid drugs occur in 3% to 5% of treated patients.265 Patients should be advised to discontinue medication and contact their physician in case of pruritus or skin rash. This is the most common complication and resolves by switching to the other antithyroid drug; in general, this occurs 2 to 6 weeks after initiation of therapy. Other side effects much less common are migratory polyarthritis, lupuslike syndrome, and cholestatic jaundice. Agranulocytosis, a serious but unusual complication, has been reported in 1 of 300 patients receiving an antithyroid drug.266 It is manifested by fever, malaise, gingivitis, and sore throat. It occurs in the first 12 weeks of therapy and appears to be related to the amount of medication.267 Patients should be made aware of the symptoms and advised to obtain a leukocyte count. Although some recommend a routine blood count in patients on antithyroid therapy, it does not appear to be indicated because granulocytopenia or agranulocytosis may appear without warning.
At the time of the diagnosis and in very symptomatic patients, β-adrenergic blocking agents are very effective in controlling hyperdynamic symptoms after a few days of therapy. Propranolol 20 to 40 mg every 6 hours or atenolol 25 to 50 mg daily is used until antithyroid drugs control the hyperthyroidism, which may take between 4 and 8 weeks.236
Subtotal thyroidectomy in pregnancy is effective in controlling the disease, but the indications for surgical treatment are few: allergy to both antithyroid drugs,268 some cases of very large goiters, and the exceptional case of resistance to drug therapy. Noncompliance could be another indication, although it does not solve the problem of noncompliance. Therapy with 131I is contraindicated in pregnancy because it produces fetal hypothyroidism when given after 10 weeks' gestation.269 A pregnancy test is mandatory in any woman of childbearing age before a therapeutic dose of 131I is administered.
Iodine crosses the placenta and may produce fetal goiter and hypothyroidism234; therefore, its use is contraindicated in pregnancy. However, it has been used in small amounts (6 to 40 mg/d) in a group of pregnant Japanese women with mild hyperthyroidism.270 An elevation in serum TSH was observed in 2 of 35 newborns; however, the mothers were slightly hyperthyroid at the time of delivery. In spite of this observation, iodine therapy is not indicated for the treatment of hyperthyroidism in pregnancy.
Excessive amounts of antithyroid drug have induced fetal hypothyroidism and goiter. The diagnosis of goiter has been made by ultrasonography, which shows hyperextension of the neck and goiter. A few cases of hypothyroidism have been confirmed by measuring thyroxine and TSH in fetal blood obtained by cordocentesis.271,272,273 Treatment with intra-amniotic injection of levothyroxine resulted in resolution of the fetal goiter.272
Breastfeeding should be permitted if the daily dose of PTU is less than 150 to 200 mg/d or the dose of methimazole is less than 10 mg/d. It is prudent to give the total dose in divided doses after each feeding; the infant should be followed with thyroid tests.274 In one study, PTU was given to mothers whose infants had elevated TSH; serum TSH normalized even with continuation of PTU therapy by the mothers.275
Significant maternal and perinatal morbidity and mortality were reported in early studies of pregnancies complicated by hyperthyroidism.276,277 In recent publications, however, there has been a significant decrease in the incidence of maternal and fetal complications directly related to maternal control of hyperthyroidism.278,279,280 Maternal complications include preterm delivery, placenta abruptio, pregnancy-induced hypertension (PIH), and miscarriage. PIH or operative delivery can trigger congestive heart failure in untreated women or women treated for a short period of time.281 Thyroid storm has rarely been reported in pregnancy.254 Fetal and neonatal complications are also related to maternal control of hyperthyroidism: intrauterine growth retardation, prematurity, stillbirth, and neonatal morbidity are the most common complications. Mitsuda and colleagues251 correlate the risk of delivering a small-for-gestational-age infant with maternal thyrotoxicosis lasting for more than 30 weeks of pregnancy, Graves' disease lasting for 10 years or more, and onset of Graves' disease before age 20. Momotani and Ito282 reported a 25.7% rate of spontaneous abortions and a 14.9% rate of premature delivery in mothers hyperthyroid at the time of conception; these rates were 12.8% and 9.5%, respectively, in euthyroid mothers. This is an important and practical aspect in the management of hyperthyroid women of childbearing age; they should be advised about potential complications and birth control during the hyperthyroid period of the disease. In this regard, hormonal contraception is not contraindicated. Congenital malformations are not increased in infants of hyperthyroid mothers.283 However, in one such study, a 6% incidence of congenital malformations was reported in mothers who were hyperthyroid at the time of conception.284 These findings need confirmation.
Fetal well-being assessment with ultrasonography, a nonstress test, and a biophysical profile is indicated for women in poor metabolic control or when fetal tachycardia and/or intrauterine growth retardation is noted.
Neonatal hyperthyroidism is rare; it occurs in less than 1% of infants born to mothers with Graves' disease. Thyroid-stimulating antibodies to the TSH receptor (when present in high concentrations in maternal serum) cross the placental barrier, stimulate the fetal thyroid gland, and may produce fetal hyperthyroidism.285 If the mother is being treated with antithyroid medication, the fetus is also being treated during gestation and therefore will present no symptoms of hyperthyroidism. However, the protective effect of the antithyroid drug is lost after delivery, and the neonate develops clinical hyperthyroidism a few days after birth. A high titer of this TSH receptor antibody (fivefold increase over baseline) in the third trimester of pregnancy is a predictor of neonatal hyperthyroidism. If neonatal hyperthyroidism is not recognized and treated properly, neonatal mortality could be as high as 30%. Because the half-life of the receptor is only a few weeks, complete resolution of neonatal hyperthyroidism is the rule.
In mothers with a history of Graves' disease who were previously treated with ablation therapy, concentrations of thyroid-stimulating antibodies may remain elevated in spite of maternal euthyroidism. As mentioned earlier, when these antibodies are present in high concentrations and cross the placenta, they may induce fetal hyperthyroidism; this is characterized by fetal tachycardia and intrauterine growth retardation.286,287 The diagnosis can be confirmed by measuring thyroid hormone levels in cord blood obtained by cordocentesis. Treatment consists of antithyroid medication given to the mother. Fetal tachycardia resolution and normal fetal growth are indications of a good therapeutic response.
Overt hypothyroidism in pregnancy is rare; only a few series of patients have been reported.288,289,290 Subclinical hypothyroidism is more often encountered because hypothyroid women on thyroid therapy often need an increase in the dose of levothyroxine after conception.291,292 In two screening studies performed in the first half of pregnancy, the incidence of serum TSH above normal was 2.5% in one study293 and 0.19% in another study from Japan.294 The two most common causes of primary hypothyroidism are post-thyroid ablation therapy, surgical or 131I treatment, and autoimmune thyroiditis (Hashimoto's thyroiditis). Original studies reported a high incidence of congenital malformations, perinatal mortality, and impaired mental and somatic development in infants of hypothyroid women.295 However, recent reports showed no increased incidence of congenital malformations, and perinatal mortality was only slightly increased.288,289,290 The incidence of PIH was 21% in 60 patients with overt hypothyroidism (Table 11). Low birth weight was reported in 16.6% of infants. In one series289 there was an increase in postpartum hemorrhage, placenta abruptio, and anemia. In the series from the Los Angeles County/USC Medical Center there was only one case of postpartum hemorrhage in 34 women with overt hypothyroidism.288,290
Data from References 288,289,290.
*LBW < 2000 g.
†LBW < 2500 g.
‡ Congenital syphilis.
§ Class F diabetes.
HCT, hematocrit; LBW, low birth weight.
In patients with subclinical hypothyroidism, the incidence of PIH was 15%290; in the report by Davis and associates,289 2 out of 12 women with subclinical hypothyroidism developed postpartum hemorrhage. Psychologic evaluation of children born to mothers with overt hypothyroidism showed no impairment.288,296 Lui and co-workers296 examined a group of eight children at ages 4 and 10; their mothers were hypothyroid in the first trimester of pregnancy. The children's IQs were not different from those of their siblings, who were born when the mothers were euthyroid.
The spectrum of women with hypothyroidism in pregnancy includes the following:
Women with overt hypothyroidism diagnosed for the first time during pregnancy
Most patients with subclinical hypothyroidism are asymptomatic. Patients with overt hypothyroidism may complain of tiredness, cold intolerance, fatigue, muscle cramps, constipation, and deepening of the voice. On physical examination the skin is dry and cold, deep tendon reflexes are delayed, bradycardia may be detected, and there may be periorbital edema.
The diagnosis of hypothyroidism is confirmed by the determination of serum TSH and FT4 or FT4I. In patients with overt hypothyroidism, the FT4 is low and the serum TSH is elevated. The degree of chemical thyroid abnormalities varies with the severity of the clinical symptoms; however, there is not always a good correlation between clinical and chemical parameters. In the author's series,290 the mean TSH value was 89.7 + 86.2 mU/L, with a mean FT4I of 2.1 + 1.5. Subclinical hypothyroidism is characterized by a normal FT4 or FT4I and an elevation of serum TSH. Serum thyroid antibodies (thyroid peroxidase antibodies) are elevated in patients with autoimmune thyroiditis.
Levothyroxine is the drug of choice in the treatment of hypothyroidism. In view of the complications mentioned above, it is important to normalize the thyroid test as soon as possible. An initial dose of 0.150 mg of levothyroxine is well tolerated by most patients. In patients with severe hypothyroidism, there is a delay in the normalization of serum TSH, but normal serum FT4 values are achieved in the first 2 weeks of therapy. The maintaining dose required for most patients is 0.125 to 0.250 mg of levothyroxine per day. Higher doses may be required in patients who have had total thyroidectomy for thyroid carcinoma, because the goal in these cases is suppression of serum TSH.
Patients on thyroid therapy before conception should have their TSH checked on the first visit and the amount of levothyroxine adjusted accordingly. The serum TSH should be repeated between 20 and 24 weeks and between 28 and 32 weeks. Immediately after delivery, they should return to their prepregnancy dosage. Ferrous sulfate, when given simultaneously with thyroxine, may reduce the efficacy of thyroid hormone. The interaction of these drugs is caused most likely by the binding of iron to thyroxine. These drugs should be ingested 2 hours apart.297
Single Nodule of the Thyroid Gland
The chances for a single or solitary thyroid nodule to be malignant are between 5% and 30%.298 This risk is dependent on known risk factors, previous radiation therapy to the upper body, rapid growth of a painless nodule, patient age, and family history of thyroid cancer. There is a paucity of information in the literature regarding management and timing of the workup in the presence of thyroid nodularity.299 In general, it is recommended that elective surgery be avoided after 24 weeks' gestation because of the potential risk of premature delivery. In a select group of patients operated on during or in the few months after delivery, the incidence of thyroid cancer was reported to be near 40%.300,301 In both studies, fine-needle aspiration biopsy (FNAB) of the thyroid nodule was performed before surgery; the findings were consistent with papillary carcinoma or highly suspicious lesions.
Careful examination of the neck enables the physician to define and characterize the lesion. In addition to the size of the nodule, consistency, tenderness, fixation to the skin, and presence of metastasis should be noted. A hard, painless nodule measuring more than 2 cm in diameter is suspicious of malignancy. The following approach is recommended at the LA-USC Medical Center (Los Angeles)301:
Postpartum Thyroid Dysfunction
Thyroid dysfunction, both hyperthyroidism and hypothyroidism, is recognized with increasing frequency in the postpartum period, within 12 months of delivery. It occurs in 5% to 10% of all women in the postpartum period.303,304 Most of the cases are due to intrinsic thyroid disease, and a few cases are due to hypothalamic or pituitary lesions (Table 12). Patients with autoimmune thyroid disease, chronic thyroiditis, and Graves' disease are most often affected.
Transient hyperthyroidism (low RAIU)
Exacerbation of hyperthyroidism (high RAIU)
RAIU, radioactive iodine uptake.
The clinical diagnosis is not always obvious, and the clinician should be concerned about nonspecific symptoms such as fatigue, depression, palpitations, and irritability in women after the birth of their child. Of these, fatigue is the most common complaint.305
In about half of the cases, mild symptoms develop between 1 and 4 months postpartum. On physical examination, a goiter is felt in most cases; it is firm and nontender to palpation, and tachycardia may be detected. The goiter may be discovered for the first time, or the patient may notice an increase in the size of a previously diagnosed goiter. Thyroid tests are in the hyperthyroid range, and thyroid antibody (antiperoxidase thyroid antibody or antimicrosomal antibody) titers are elevated. This is followed in a few months by hypothyroidism with spontaneous recovery a few months later. The antibody titer has a tendency to increase during this process and in most cases the size of the goiter increases. In a few patients, permanent hypothyroidism may develop. About 50% of patients, however, develop permanent hypothyroidism within 5 years of the diagnosis of postpartum thyroiditis.306,307 In some cases the clinical symptoms resemble the syndrome of postpartum depression. Indeed, thyroid antibodies have been reported to be found more often in women with postpartum depression, but this is still a controversial issue.308,309
Other patients have a different cause of postpartum thyroiditis, characterized by an initial episode of hypothyroidism between 3 and 7 months postpartum without the initial hyperthyroid phase. In others the initial episode of hyperthyroidism is followed by a return to normal thyroid function.
Postpartum thyroid dysfunction can also occur in patients with a known history of Graves' disease. It is common for women with Graves' disease to have exacerbations of their symptoms in the few months postpartum.310 On the other hand, recurrence of hyperthyroidism may be secondary to a concomitant episode of postpartum thyroiditis.311 The differential diagnosis in this situation is important because the treatment is different. If not contraindicated, because of breastfeeding, a 4- or 24-hour thyroid radioactive iodine uptake is helpful. It will be very low in patients with postpartum thyroiditis, and it will be elevated in patients with recurrent hyperthyroidism due to Graves' disease. When it is due to recurrent Graves' disease, treatment with antithyroid medications is indicated, or the physician may advise ablation therapy.
Hypothyroidism may be secondary to hypothalamic or pituitary lesions, such as those seen in Sheehan's disease or lymphocytic hypophysitis (see “Pituitary Diseases”). In such cases there are clinical symptoms related to the deficiencies of other pituitary hormones.
Because most cases of postpartum thyroid dysfunction recover spontaneously, treatment is indicated for symptomatic patients. In the presence of hyperthyroid symptoms, β-adrenergic blocking drugs (propranolol 20 to 40 mg every 6 hours or atenolol 25 to 50 mg every 24 hours) are effective in controlling the symptoms. For hypothyroid symptoms, small amounts of levothyroxine (0.050 mg/d) will control symptoms, allowing for a spontaneous recovery of thyroid function after discontinuation of the drug. Postpartum thyroid dysfunction may recur in future pregnancies.
There are some features that may predict the development of postpartum thyroiditis: the presence of goiter, high titers of thyroid antibodies in the first half of pregnancy, episodes of postpartum thyroiditis in previous pregnancies, and a strong family history of autoimmune thyroid disease.312 Women with insulin-dependent diabetes mellitus are at high risk of developing postpartum thyroiditis.
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