Adrenal Disease and Pregnancy

Adrenal disease—including disorders such as congenital adrenal hyperplasia (CAH), Addison disease, Cushing syndrome, pheochromocytoma, and primary hyperaldosteronism—can reduce female fertility or severely impact maternal and fetal health during pregnancy. Adrenal insufficiency, for example, was associated with a 35-45% maternal mortality rate prior to the introduction of glucocorticoid replacement therapy, while pheochromocytoma was once associated with maternal and fetal mortality rates of 48% and nearly 55%, respectively. ^[1]

However, proper treatment of adrenal dysfunction, including steroid therapy and, in the case of Cushing syndrome and pheochromocytoma, surgical intervention, can result in successful gestation and delivery.

For patient education information, see the Pregnancy Center, as well as Pregnancy.

Human pregnancy involves considerable endocrine changes. The pregnant woman and the fetus adapt to this unique endocrine milieu by various mechanisms. The development of a new endocrine organ, the fetoplacental unit, accounts for a variety of these changes.

Large quantities of estrogen are produced during normal human pregnancy, and, after the first 3-4 weeks of gestation, the placenta produces nearly all of the estrogen. The major precursor for estrogen production is dehydroepiandrosterone sulfate, which is synthesized in the fetal adrenal glands.

The adrenals of the human fetus at term are as large as those of adults, weighing 8-10g or more. The fetal adrenals are principally composed of an inner fetal zone that accounts for 85% of the total volume. The outer zone, the neocortex, develops into the mature adrenal cortex, which is only 15% of the total volume. The capacity of the fetal adrenals for steroidogenesis is enormous, and, near term, the fetal adrenals secrete 100-200mg of the estrogen precursor daily. The total daily steroid production by the adrenals in an unstressed adult is only approximately 35mg daily.

In addition to its role in providing precursors for placental estrogen formation, the fetal adrenal cortex may participate in the events that lead to the initiation of labor and to maturation of the fetal lungs.

Corticotropin levels in human fetal blood decline as gestation progresses, but the adrenals continue to grow in late gestation. The trophic stimulus for the fetal adrenal may not be corticotropin, and the pattern of steroids secreted by the fetal adrenal is also different. Therefore, a trophic role has been proposed for other hormones, including growth hormone, human chorionic gonadotropin, prolactin, and human placental lactogen.

More than 90% of the estradiol and estriol and 85% or more of the progesterone formed in the trophoblast are secreted into the maternal compartment. The net transfer of steroids to maternal blood is approximately 10 times that of the net transfer to fetal blood, secondary to the nature of placentation in human pregnancy.

Only a small amount of the steroids in the maternal circulation reach the fetal compartment in normal pregnancy. The steroids are cleared rapidly from the maternal plasma, and steroids that enter the trophoblast reenter the maternal compartment. For example, a small amount of cortisol in maternal plasma crosses the placenta, both because the reentry pathway dominates and because cortisol within the trophoblast is converted to cortisone by 11beta-hydroxysteroid dehydrogenase.

Circulating C-19 steroids in the maternal compartment, such as dehydroepiandrosterone sulfate, dehydroepiandrosterone, androstenedione, and testosterone, do not reach the fetal compartment because of the presence of aromatase enzymes of the syncytiotrophoblast that are used for the conversion of C-19 steroids to estrogens. This mechanism protects the female fetus from possible virilization in women who develop androgen-secreting tumors of the ovary during pregnancy.

No class of steroid hormones, other than estrogen and progesterone, appears to be formed or secreted by the placenta. No evidence indicates that the placenta synthesizes glucocorticoids or mineralocorticoids.

The levels of cortisol in maternal plasma are markedly increased in association with the rise in estrogen production, partly because of a 3- to 4-fold increase in the level of corticosteroid-binding globulin. The rate of secretion of cortisol by maternal adrenals is not increased in pregnancy, but the rate of clearance is decreased. The corticotropin level is suppressed in women during pregnancy. The lowest level of corticotropin is observed early in pregnancy, rising to a maximum between week 26 and term.

Normal pregnancy is associated with many changes in the renin-angiotensin-aldosterone system. Despite the increase in extracellular fluid volume, a 4-fold increase in plasma renin activity is evident by the eighth week of gestation. Estrogen stimulates the hepatic synthesis of angiotensinogen. Estrogen and progesterone, alone or together, stimulate the secretion of renin, which catalyzes the conversion of angiotensinogen to angiotensin I.

The net consequence is an enhancement in the synthesis of angiotensin II. The zona glomerulosa of the maternal adrenal remains responsive to the trophic action of angiotensin II as aldosterone secretion increases during pregnancy. However, the maternal vasculature becomes refractory to the pressor effects of angiotensin II. These 2 phenomena are important for the expansion of blood volume during pregnancy. Refractoriness to the pressor effect of angiotensin II develops early in pregnancy and persists throughout gestation in women who do not develop pregnancy-induced hypertension.

Progesterone, levels of which are markedly increased in pregnancy, is a competitive inhibitor of aldosterone in the distal tubule. Therefore, the physiologic effects of increased aldosterone are attenuated in pregnancy.

Congenital adrenal hyperplasia (CAH) refers to a family of genetic disorders caused by a deleterious mutation in the gene encoding adrenal steroidogenic enzyme, which is essential for cortisol biosynthesis. The common feature of these disorders is decreased negative feedback inhibition of cortisol on pituitary corticotropin secretion.

A deficiency in 21-hydroxylase enzyme accounts for more than 90% of all cases of CAH. Approximately 5-8% of cases of CAH are caused by a deficiency in 11beta-hydroxylase. A deficiency in 17alpha-hydroxylase is a rare cause of CAH, and experience with this disorder is limited to case reports. Successful live birth in a woman with 17 alpha-hydroxylase deficiency through IVF frozen- thawed embryo transfer was reported by Bianchi et al. ^[2]

Women with CAH resulting from a 21-hydroxylase deficiency, particularly those with the salt-wasting variant of this syndrome, have decreased fertility rates. Contributing factors include insufficient hormonal control of hyperandrogenism with glucocorticoid replacement therapy, inadequate introitus as a result of poor surgical repair, and an absence of heterosexual activity. Pregnancies are limited in this group of patients.

However, in a British study of pregnancy and birthrates in women with CAH, Casteras et al observed that, compared with the general population, pregnancy rates were relatively normal but the live birthrate was low. In the study, among 23 women with classic CAH who had actively tried to conceive, 21 (91.3%) of them became pregnant, including 88.9% of those who had the salt-wasting form of the disease and 92.9% of the women who did not.

These figures were close to the pregnancy rate for the general population (95%). However, the live birthrate for the women in the study was 0.25, compared with 1.8 in the general population of the United Kingdom. ^[3]

In a retrospective study of pregnancy, delivery, and neonatal outcomes, Badeghiesh et al found that rates of chorioamnionitis, cesarean section, and maternal infection were higher in women with CAH than in controls. In addition, women with CAH were more likely to have infants who had congenital anomalies or were small for gestational age. ^[4]

Glucocorticoid therapy

Lo et al reported successful pregnancy outcomes in 4 women with classic 21-hydroxylase deficiency—3 of whom were female pseudohermaphrodites with the salt-wasting form—following treatment with glucocorticoids. The patients gave birth to 4 females, all healthy and with normal female external genitalia. None of the neonates was affected with 21-hydroxylase deficiency. The placental aromatase activity was sufficient to prevent masculinization of the fetuses' external genitalia in all of these patients. ^[5]

The authors recommended treatment with glucocorticoids that are inactivated by placental 11beta-hydroxysteroid dehydrogenase type II (ie, hydrocortisone, cortisone acetate, prednisone, methylprednisolone) to minimize fetal adrenal suppression.

The glucocorticoid dexamethasone, which provides longer and more effective suppression of adrenal androgen production, is transferred across the placenta without oxidation of the 11-hydroxyl group and can suppress the fetal adrenal gland.

Guidelines for pregnancy and delivery

The following guidelines are for the treatment of women during pregnancy and delivery who have classic CAH resulting from a 21-hydroxylase deficiency. The guidelines are adapted from the 2001 article "Pregnancy outcomes in women with congenital virilizing adrenal hyperplasia" by Lo and Grumbach. ^[6]

Gestational management

Institute adrenal steroid replacement and adrenal androgen suppression using a glucocorticoid that is metabolized by placental 11beta-hydroxysteroid dehydrogenase II (ie, hydrocortisone, cortisone acetate, prednisone, methylprednisolone).

Assess clinical status, serum electrolyte levels, and serum androgen levels regularly to determine the need for increased glucocorticoid therapy, mineralocorticoid therapy, or both.

Serum testosterone and free testosterone levels should be measured every 6 weeks in the first trimester and every 8 weeks thereafter. Target free testosterone levels to the high-to-normal range for pregnancy. Avoid inducing a cushingoid effect with a dose of glucocorticoids that is too high.

Fetal sex determination by ultrasonography may be helpful in guiding treatment goals because maternal androgen excess has minimal effects on the male fetus.

Labor and delivery

Stress-dose glucocorticoid therapy with a soluble hydrocortisone ester (≤50-100mg IV q8h) should be administered at the initiation of active labor and continued until after delivery, followed by a rapid taper to previous maintenance doses.

Regarding cesarean versus vaginal delivery, android pelvic characteristics may increase the risk for cephalopelvic disproportion. Elective cesarean delivery should be considered in patients who have had reconstructive genital surgery.

Evaluation of the infant

Examine the infant for ambiguous genitalia. Female pseudohermaphroditism may be either a consequence of maternal hyperandrogenism or, if the father is a carrier, of fetal 21-hydroxylase deficiency. (Male infants may have enlarged external genitalia.)

If the external genitalia are ambiguous, appropriate laboratory studies should be performed on the infant to exclude 21-hydroxylase deficiency.

Fetal diagnosis and treatment of CAH

Diagnosis

CAH caused by a steroid 21-hydroxylase deficiency is a common cause of genital virilization in the female fetus, resulting from inappropriate fetal adrenal androgen secretion. The striking elevation in the level of plasma 17-hydroxyprogesterone is such a distinctive marker of 21-hydroxylase deficiency that prenatal diagnosis has been made possible by determining its concentration in amniotic fluid.

Histocompatibility leukocyte antigen typing of cells obtained from the amniotic fluid of mothers who had a previously affected offspring has also been used to identify fetuses who are homozygous or heterozygous for 21-hydroxylase deficiency. Chorionic villus sampling has provided methods for more accurate identification of female fetuses affected with 21-hydroxylase deficiency.

Treatment

Prenatal diagnosis has encouraged some investigators to attempt prenatal treatment. ^[7] Dexamethasone crosses the placenta and suppresses the fetal adrenal gland if given in sufficient doses. The placenta does not convert the 11beta-hydroxy group of dexamethasone to the inactive 11-keto group. Dexamethasone administration to pregnant women early in gestation, starting at 4-6 weeks, has been shown to decrease the virilization of the external genitalia in affected female infants. The dose is typically 20mcg/kg of maternal body weight per day in divided doses beginning at 4-6 weeks of gestation.

Amniocentesis or chorionic villus sampling is performed at 9-12 weeks of gestation, and if the sex is male or a CYP21 genotype indicates that the fetus is unaffected, dexamethasone should be promptly discontinued. In an affected female, therapy is continued for the duration of pregnancy.

Prenatal treatment with dexamethasone has led to much discussion and debate because only 1 in 8 pregnancies in a family with an index case results in an affected female fetus. If treatment were administered during each pregnancy, 7 of 8 fetuses would have been exposed to supraphysiologic doses of dexamethasone for at least 6 weeks.

Several reports have shown that prenatal treatment with dexamethasone is safe for the mother and the fetus. An increase in morbidity or mortality has not been reported in fetuses treated to term and monitored through infancy and early childhood. However, dexamethasone therapy can result in weight gain, striae, and glucose intolerance in mothers.

Khattab et al describe a method for noninvasive prenatal diagnosis of CAH with utilization of cell-free fetal DNA in mothers carrying at risk fetuses as early as 6 gestational weeks, therefore limiting the use of dexamethasone to mothers carrying affected females. ^[8]

Because prenatal treatment began only within the past 2 decades, long-term follow-up is needed to ensure safety. Successful prenatal treatment with dexamethasone in an affected female with 11beta-hydroxylase deficiency CAH has been reported. ^[9]

Before glucocorticoid replacement therapy became available, pregnancy in patients with adrenal insufficiency was associated with a maternal mortality rate of 35-45%. In patients with treated autoimmune Addison disease, conception, fetal development, and delivery should not be problematic.

The usual glucocorticoid and mineralocorticoid replacement dosages are continued throughout pregnancy. Some patients may require slightly more glucocorticoid in the third trimester. During labor, adequate saline hydration and 25mg of intravenous (IV) cortisol (ie, hydrocortisone sodium succinate) should be administered every 6 hours. At the time of delivery or if the labor is prolonged, high-dose parenteral hydrocortisone should be administered (100mg q6h or as a continuous infusion). After delivery, the dosage can be quickly tapered to a maintenance dose in 3 days.

Occasionally, patients develop severe nausea and vomiting in the first trimester and may need intramuscular (IM) dexamethasone at a slightly increased dose (1mg daily). If the patient cannot take medicine orally, 1-2mg daily of desoxycorticosterone acetate in sesame oil may be administered intramuscularly as mineralocorticoid replacement.

Patients with previously undiagnosed adrenocortical deficiency may present with an acute addisonian crisis during labor or postpartum.

Fetal growth restriction

Maternal cortisol deficiency has been suggested as a possible cause of fetal intrauterine growth restriction. Clinical suspicion should arise if fetal growth restriction is associated with abnormally low maternal blood pressure and an unusual increase in skin pigmentation due to maternal corticotropin and melanocyte-stimulating hormone overproduction.

The diagnosis can be confirmed based on results from standard endocrine tests, but these may be problematic because of the overlapping of the aforementioned clinical signs with normal pregnancy changes and the lack of established reference values for pregnancy.

Autoimmune adrenal insufficiency

Autoimmune adrenal insufficiency may be a part of the polyglandular autoimmune syndromes when it is associated with other endocrine diseases. Polyglandular autoimmune syndromes may complicate pregnancy and may be confused with hyperemesis gravidarum as a cause of hypoglycemia and electrolyte imbalance in the first trimester of pregnancy.

New-onset disease

New-onset Addison disease is rare in pregnancy, but it may present with prolonged vomiting and weight loss. Therefore, adrenal failure should also be added in the differential diagnosis of hyperemesis gravidarum. ^[10]

Secondary adrenocortical insufficiency also may occur as a result of hypothalamic or pituitary diseases. Primary lymphocytic hypophysitis usually manifests in pregnancy and is associated with pituitary enlargement. Primary lymphocytic hypophysitis is a very rare autoimmune endocrine disorder and should be considered in the differential diagnosis of pregnancy-associated pituitary enlargement.

Adrenoleukodystrophy

Adrenoleukodystrophy (ALD) is an X-linked recessive disorder characterized by progressive neurologic dysfunction and primary adrenal insufficiency. The disorder is caused by defective fatty acid beta oxidation in peroxisomes, which leads to an elevated plasma concentration of very long-chain fatty acids (VLCFAs) and accumulation of their cholesterol esters and gangliosides in the membranes of cells in the brain, adrenal cortex, and other organs.

Prenatal diagnosis of X-linked ALD is possible using chorionic villus fibroblast culture followed by analysis of VLCFAs and immunofluorescence analysis of the ALD protein. Molecular characterization of ALD has revealed mutation in the gene ABCD1; this gene encodes ABCD1/ALDP, a peroxisomal ABC protein that is thought to be involved in the active adenosine triphosphate (ATP) – driven transport of VLCFA-coenzyme A (CoA) from the cytoplasm into the peroxisomes.

Pregnancy in women previously treated for an adrenocortical carcinoma was studied by de Corbiere et al and no severe fetal or maternal complications were documented. ^[11]

 

 

 

Cushing syndrome occurs only rarely in pregnant women because hypercortisolism results in ovulatory disturbances and relative infertility. ^{[12, 13]} So far, only slightly over 100 cases of Cushing syndrome in pregnancy have been reported in the literature. When Cushing syndrome occurs during pregnancy, it may be difficult to detect clinically because of the central weight gain, abdominal striae, increased blood pressure, and glucose intolerance associated with normal pregnancy.

When established Cushing syndrome coexists with pregnancy, the aforementioned physical effects are much worse and the diagnosis may be clearer. In milder cases, the diagnosis is difficult. A high index of clinical suspicion must be maintained in diagnosing Cushing syndrome so that the disease is found early.

Several cases of exacerbation of Cushing syndrome during pregnancy have been reported. In most of these patients, an adrenal adenoma was the cause of the Cushing syndrome.

A benign adrenal tumor is more likely to be the cause of Cushing syndrome in women who are pregnant than in women who are not pregnant, in whom pituitary-dependent disease predominates. Malignant adrenal tumors are rarely observed in association with pregnancy.

Laboratory confirmation of the diagnosis in pregnancy is not well established because of the lack of established reference ranges for the usual interpretive tests in women who are pregnant. Results from the simple overnight low-dose dexamethasone suppression test are inaccurate in the presence of excess estrogen and in pregnancy.

Cortisol levels

Random measurement of urinary or plasma cortisol is not helpful. However, the normal circadian rhythm of plasma cortisol is preserved in a healthy pregnant person, and, because this is often lost in patients with Cushing syndrome, it could be used as a useful preliminary test. As a result, determination of a midnight cortisol level can still be very helpful in making the diagnosis.

Keep in mind that the cortisol test must be interpreted with knowledge of the reference pregnancy range for plasma cortisol.

Carr et al found morning levels (mean plus or minus the standard error of mean) of 14.9 ± 4mg/dL at 11 weeks' gestation and 35.2 ± 0mg/dL at 26 weeks' gestation; the levels remained elevated until labor and delivery. ^[14] These levels overlap those found in patients with Cushing syndrome; therefore, demonstrating 50% suppression of the midnight cortisol level compared with the morning cortisol level, rather than just looking at absolute cortisol levels, is important.

The standard protocols for low-dose (2mg) and high-dose (8mg) dexamethasone tests have been used safely, and interpretation of suppression of 24-hour urine cortisol and plasma cortisol levels seems to yield reliable results.

Corticotropin levels

Once hypercortisolemia is established, corticotropin levels should be measured. For all forms of Cushing syndrome in pregnancy, corticotropin levels are normal or they are high secondary to placental corticotropin production or owing to placental corticotropin-releasing hormone–stimulated pituitary corticotropin production. Therefore, corticotropin levels are not useful in distinguishing between pituitary and adrenal etiologies. If the corticotropin level is clearly elevated, a pituitary cause must be considered.

Imaging studies

Imaging studies become necessary because of the problems encountered with laboratory studies. Ultrasonography or magnetic resonance imaging (MRI) may be used to limit radiation exposure to the fetus. The diagnosis is likely to be suggested by ultrasonographic findings, which are commonly used for fetal assessment and may show a maternal adrenal adenoma.

Morbidity and mortality

The risk of maternal morbidity and a poor fetal outcome is significant when Cushing syndrome coexists with pregnancy. Maternal hypertension may antedate the pregnancy but becomes worse in two thirds of patients. Preeclampsia or pregnancy-induced hypertension is noted in approximately 10% of patients. Gestational diabetes mellitus occurs in approximately one third. Congestive heart failure associated with severe hypertension occurs in 10%. Wound breakdown after surgery is possible. Severe proximal myopathy and mental problems ranging from emotional lability to profound psychosis should be added to the list of medical problems that may occur.

Buescher et al reported maternal mortality in 3 of 65 pregnancies complicated by Cushing syndrome. ^[15] Premature delivery is common and occurs in as many as two thirds of cases. The overall perinatal mortality rate is 15% of reported cases; half were stillborn. The mother and the neonate should also be monitored closely for cortisol withdrawal problems. The mother may develop cortisol deficiency after a successful adrenalectomy, and the neonate may have cortisol deficiency soon after birth.

Treatment

The wide spectrum of severity of Cushing syndrome mandates an individualized approach to therapy, with medical and surgical approaches being used to manage hypercortisolism in pregnancy.

Pricolo et al reported a retrospective comparison of the pregnancy outcome in patients with Cushing syndrome based on the timing of surgical intervention in relation to pregnancy and found better outcomes in patients who received treatment during pregnancy.

In the study, a group of 7 patients who received unilateral adrenalectomy during pregnancy was compared with a group of 19 patients in whom the adrenalectomy was deferred until after the baby was delivered. Of the 7 in the first group, 1 fetal death and no neonatal complications occurred, but fetal death and neonatal complications occurred in 12 of the 19 pregnancies in the second group. ^[16]

Bevan et al reported that surgical treatment during pregnancy is safe and significantly reduces fetal losses, premature labor, and maternal morbidity. ^[17] Chang et al reports a case of Cushing syndrome secondary to adrenal adenoma presenting with hypertension and oligohydramnios during pregnancy. ^[18] The tumor was removed at 29 weeks of gestation and the woman delivered a healthy infant at term.

The ideal timing for adrenalectomy is early in the second trimester. Patients who undergo surgery for Cushing syndrome during pregnancy should be immediately placed on cortisol replacement, which should be continued until the hypothalamic-pituitary-adrenal axis returns to normal. This process could take several months, so weaning from replacement doses should not be attempted until after delivery.

One case has been reported in which a patient underwent transsphenoidal adenomectomy in the 22nd week of gestation. Also, metyrapone, an inhibitor of 11beta hydroxylase, was used with some success in one case of Cushing syndrome caused by an adrenal adenoma, but this therapy provided no clinical or biochemical improvement in another case caused by an adrenal carcinoma.

Reports indicate that retroperitoneal laparoscopic adrenalectomy has been performed on pregnant women with Cushing syndrome.

Ketoconazole has been used successfully in 3 patients during pregnancy. One patient had pituitary-dependent Cushing disease. Pregnancy and vaginal delivery at 37 weeks' gestation passed uneventfully, and the newborn male infant did not show any congenital malformation and had normal sexual development. Another patient was diagnosed with Cushing syndrome in the third trimester, was treated with ketoconazole for the rest of the pregnancy, and underwent adrenalectomy after delivery. The newborn had transient neonatal hypoglycemia without adrenal insufficiency.

Because of poor wound healing, vaginal delivery is preferable to cesarean delivery in patients with Cushing syndrome.

In cases of adrenal carcinomas diagnosed in pregnancy, termination of the pregnancy may be considered so that definitive therapy can be undertaken. Adrenocortical carcinoma is a rare and severe disease, and, in pregnancy, it is associated with poor fetal and maternal outcome. ^[19]

Pheochromocytoma is a rare endocrine tumor. When associated with pregnancy, it can be potentially disastrous for the mother and fetus. The main sign of the disease is hypertension, which is common in pregnancy.

The first case in pregnancy was reported at autopsy in 1911, and early cases were rarely diagnosed before delivery. An unrecognized pheochromocytoma can be lethal because a fatal hypertensive crisis may be precipitated by anesthesia or even normal delivery.

Pheochromocytoma in some cases occurs as part of type 2 multiple endocrine neoplasia (MEN 2) in association with medullary carcinoma of the thyroid gland and parathyroid adenomas. Identification of the RET proto-oncogene mutations that cause MEN 2 can be used to screen family members of MEN 2 kindreds and to monitor those who are at risk. The women at risk should be monitored very closely during pregnancy.

Langerman et al reported a patient who presented with acute cardiovascular collapse due to catecholamine crisis at term pregnancy and in whom further testing revealed pheochromocytoma as part of MEN 2. ^[20] (Maternal or fetal complications are rare when MEN 2 diagnosis is made before pregnancy.)

Mortality

In 1971, Schenker and Chowers reported a review of 112 pregnancies associated with pheochromocytoma, which disclosed very high maternal and fetal mortality rates of 48% and 54.4%, respectively. ^[1] However, a study by Harper et al of 47 cases that occurred from 1980-1987 found that overall maternal and fetal mortality rates had decreased to 17% and 26%, respectively. ^[21]

A 1999 review by Ahlawat et al also showed a significant reduction in maternal and fetal mortality. In this review of 41 patients with pheochromocytoma in pregnancy, the maternal mortality rate was 4% and the fetal mortality rate was 11%. ^[22] Antenatal diagnosis of pheochromocytoma reduced the maternal mortality rate to 2%.

Diagnosis

Possibly the most important aid to early diagnosis is to consider the diagnosis of pheochromocytoma. Hypertension is very common in pregnant women, and patients must be selected for further testing.

Most pregnant patients with pheochromocytoma present with symptomatic hypertension that is often severe and fluctuating, with associated headache, perspiration, palpitation, and tachycardia. However, even though hypertension is the hallmark for pheochromocytoma, it may not be present in all cases. In 2003, Ahn et al reported on a patient who presented with peripartum cardiomyopathy but was diagnosed with an underlying pheochromocytoma in association with MEN 2. ^[23]

Other reported signs and symptoms of pheochromocytoma include arrhythmias, postural hypotension, chest or abdominal pain, visual disturbance, convulsions, or sudden collapse. The coexistence of diabetes mellitus, possible hyperthyroidism, myocardial infarction, or sudden collapse is important.

Neurofibromatosis is an associated marker, with pheochromocytoma occurring in approximately 2% of patients with these nodules. Von Hippel-Lindau syndrome or retinal angiomatosis is also a recognized association.

The diagnosis of pheochromocytoma is confirmed by accurate 24-hour urine collections for catecholamine assay with epinephrine and norepinephrine and their metabolites, preferably obtained during or after a hypertensive episode.

All pregnant women with hypertension associated with any unusual features, particularly those with severe or symptomatic hypertension, especially with headache, palpitation, or excessive sweating or with a family history of pheochromocytoma or associated syndromes, should have routine screening of 24-hour urinary catecholamine levels. No alteration in catecholamine metabolism develops specifically because of the pregnant state; therefore, the biochemical diagnosis is no different from that in a woman who is not pregnant.

Tumor localization should be initiated once biochemical test results confirm the diagnosis of a catecholamine-secreting tumor. Magnetic resonance imaging (MRI) and ultrasonography are the preferred methods for localization of tumors in pregnant patients because they avoid exposing the fetus to ionizing radiation.

Treatment

Preoperative management with alpha-adrenergic blockade (eg, phenoxybenzamine) is safe in pregnancy. Combined alpha and beta blockers (eg, labetalol) have also been used in pregnancy without adverse fetal effects. Beta blockade should not be used without prior alpha blockage, because unopposed alpha-adrenergic activity may lead to vasoconstriction and a hypertensive crisis. Propranolol has been used after adequate alpha blockade in pregnancy, with a successful outcome.

The definitive treatment of pheochromocytoma is surgical removal. Surgical intervention should be performed before 24 weeks' gestation, after adequate alpha blockade has been achieved. After 24 weeks' gestation, uterine size makes abdominal exploration and access to the tumor difficult. Optimum results are obtained if surgery is delayed until fetal maturity is reached. At that time, with adequate alpha blockade, elective cesarean delivery may be performed, followed immediately by adrenal exploration. Schenker and Granat reported higher maternal mortality rates with vaginal delivery (31%) than with cesarean delivery (19%). ^[24]

Some authors have reported pregnancies in which pheochromocytomas were treated with alpha and beta blockade from the beginning of the second trimester to term, with good fetal outcomes.

Miller et al reported a patient in whom an extra-adrenal pheochromocytoma was diagnosed at 14 weeks' gestation and who received conservative management until term, resulting in favorable maternal and fetal outcomes. ^[25] Kapoor et al reported a patient diagnosed in the third trimester with pheochromocytoma and delivered a healthy baby with medical management. ^[26] The patient underwent adrenalectomy at 6 weeks post partum. Dong et al reported three pregnant women who received laparoscopic resection of pheochromocytoma during pregnancy and had good outcome. ^[27]

Unrecognized pheochromocytoma is still a potential disaster and has resulted in high maternal mortality rates in several series of patients. Malignant pheochromocytoma may recur in pregnancy. Lifelong monitoring is necessary in all patients, with extra caution in those who are pregnant.

Sarathi et al reported a patient with MEN 2A who was diagnosed with pheochromocytoma and medullary thyroid carcinoma during pregnancy and who did well after adrenalectomy and thyroid surgery. ^[28] Oliva et al reported 6 cases of pheochromocytoma managed successfully at the University of Chicago Medical Center between 1984 and 2009. ^[29]

Primary hyperaldosteronism is a rare cause of hypertension in pregnancy. ^{[30, 31]} Eighteen cases of pregnancies complicated by hyperaldosteronism have been reported in the literature.

Diagnosis

Patients with classic aldosteronism present with hypertension, hypokalemia, and elevated urine potassium levels. Hypokalemia should be corrected before making a biochemical diagnosis because a low potassium level suppresses aldosterone. All diuretics should be discontinued for at least 2 weeks. High doses of beta blockers should be reduced because they reduce renin production, and calcium channel blockers should be avoided for 2-3 hours before testing.

Measuring plasma aldosterone levels may not be useful in the diagnosis of pregnant women, because the normal elevation in pregnancy is often in the primary hyperaldosteronism range. Urinary potassium wasting can be less than that in patients with primary hyperaldosteronism because of the antagonizing effects of progesterone.

Plasma renin levels should be decreased in patients with primary hyperaldosteronism. In a healthy pregnancy, plasma renin activity is usually increased, but it decreases in the setting of primary hyperaldosteronism.

Salt-loading studies may be performed to confirm the autonomous secretion of aldosterone, but in pregnant women, the concern for volume overload and worsening hypokalemia and the lack of reference ranges makes this test less desirable.

Another dynamic test that may be used is stimulation of renin production by positioning the patient in an upright posture. In pregnant patients, prolonged upright posture results in a modest increase in plasma renin activity. If the renin activity remains suppressed, this is suggestive of primary hyperaldosteronism.

Imaging studies are necessary to localize adrenal adenomas. Ultrasonography and MRI are the preferred imaging methods in pregnant women.

Treatment

If an adrenal adenoma is detected, unilateral adrenalectomy is the treatment of choice. Cases of successful adrenalectomy in the second trimester have been reported.

The goals of medical therapy should be adequate control of blood pressure and replacement of potassium. The pharmacologic agents that are helpful in patients who are not pregnant, such as spironolactone and angiotensin-converting enzyme (ACE) inhibitors, are contraindicated in patients who are pregnant. Methyldopa, beta blockers, and calcium channel blockers have been used with variable outcomes.

Nezu et al reported 2 patients who developed primary hyperaldosteronism in the postpartum period; aldosteronomas were then diagnosed and resected. These women were virtually normotensive before and during pregnancy, although severe, progressive hypertension developed within 1 month postpartum. ^[32]

Glucocorticoid-remediable aldosteronism

Glucocorticoid-remediable aldosteronism (GRA) is a hereditary form of primary hyperaldosteronism that manifests with hypokalemia and hypertension from childhood onwards. GRA is characterized by the ectopic production of aldosterone in the cortisol-producing zona fasciculata under the regulation of corticotropin.

In a retrospective review by Wyckoff et al, women with GRA showed a significantly increased risk for an exacerbation of their hypertension during pregnancy and had a primary cesarean delivery rate of 32%, double that observed in other general or hypertensive obstetric populations. The study, which examined 35 pregnancies in 16 women with GRA, also determined that 6% of the pregnancies were complicated by preeclampsia. ^[33] This was no worse than the published rates of preeclampsia in the general obstetric population, which vary from 2.5-10%.

Respiratory distress syndrome is the most common complication associated with preterm delivery, and antenatal corticosteroid treatment is used widely to reduce the morbidity and mortality of premature birth. Betamethasone or dexamethasone is used for threatened premature delivery to hasten the maturation of fetal organ systems.

A meta-analysis of 15 randomized, controlled trials undertaken by a US National Institutes of Health (NIH) expert panel showed that these drugs significantly reduce the prevalence of respiratory distress syndrome and infant mortality, with no clinically important adrenal suppression and a rapid return of adrenal function when corticosteroids are discontinued.

Possible adverse maternal effects of corticosteroids include pulmonary edema in association with tocolytic agents, worsening blood glucose control in patients with diabetes, and increased risk of maternal infection in patients who have preterm rupture of membranes. No long-term adverse effects were reported in mothers or children who were monitored for 12 years.

Corticosteroids have been used safely in patients with asthma and various autoimmune disorders who also were pregnant. High-dose corticosteroids are important in the management of severe asthma, and reviews of this therapy have not shown teratogenic or other adverse effects on human pregnancy. In patients with systemic lupus erythematosus, prednisone or hydrocortisone has been preferred because of placental oxidation. Screening for glucose intolerance and hypertension is important, and stress doses of steroids must be given at the time of delivery in patients who have been receiving long-term steroid therapy with associated adrenal suppression. Myasthenia gravis in pregnancy is another autoimmune disease that may require corticosteroid treatment, usually with high-dose prednisone.

Although glucocorticoid therapy is generally safe in pregnant women, it warrants close follow-up to monitor the disease process and the possible complications of therapy. Glucocorticoid therapy during breastfeeding is also safe, because only minimal amounts of these medications are passed into breast milk.