Cushing’s syndrome is uncommon, with an incidence of 2 in 1,000,000. Just over 100 cases have been reported in pregnancy to date.138-156 Fertility is generally reduced by the altered gonadotropin secretion in pituitary disease, and increased adrenal androgen secretion in adrenal disease. Anovulation may be less prevalent with adrenal Cushing’s syndrome, as the proportion of adrenal and pituitary disease in pregnancy differs from that found in the nonpregnant woman. Approximately 40% of cases are secondary to a pituitary adenoma vs. an 80% rate expected in the nonpregnant woman. Of the remaining, 44% are adrenal adenomas, 11% adrenal carcinomas,138-144 and the remainer a mix of primary pigmented nodular adrenal disease, ACTH-independent hyperplasia, and ectopic ACTH secretion.140 Several cases of pregnancy-dependent Cushing's syndrome have been described, with no interpartum adrenal steroid abnormalities noted.145,146,153 The placental CRH rise apparently caused a pregnancy-induced exacerbation and recognition of the hypercortisolism, with occasional improvement in the symptoms postpartum.139,140 Recurrent Cushing’s syndrome may occur in pregnancy with remission postpartum.141,154

It may be difficult to diagnose Cushing’s syndrome during pregnancy because the typical symptoms of central weight gain, fatigue, emotional lability, glucose intolerance, hypertension, and edema are also common accompaniments of pregnancy. Pigmentation of striae and development of hirsutism or acne may suggest the hyperandrogenemia of Cushing’s syndrome, and proximal myopathy may also help to distinguish Cushing's syndrome from normal pregnancy symptoms. Pathologic fractures may occur.157 The laboratory evaluation is confounded by the normal pregnancy rise in ACTH and cortisol levels. The hypercortisolism of pregnancy continues to exhibit a normal circadian rhythm, though with a higher nighttime nadir; loss of diurnal rhythm is characteristic of all forms of Cushing’s syndrome.147 Salivary cortisol measurements may assist in determining this lack of diurnal response, but normal midnight levels have not been standardized for pregnancy.153,155,156,158 Urinary free cortisol levels greater than 3 times the upper limit of normal may be interpreted as indicating Cushing’s syndrome in the second and third trimester. There are limited or no data using antibody-based assays or mass spectrometry. Normal pregnancy is also associated with “inadequate” suppression of ACTH and cortisolduring the overnight dexamethasone suppression test.141 ACTH levels may not reliably distinguish between pituitary and adrenal etiologies, as the levels may be normal or high in all forms of Cushing’s syndrome, likely from placental ACTH production or from the placental CRH-stimulated pituitary ACTH production.138-144,155,156,159 When plasma ACTH levels are suppressed, preferably as measured using a two-site immunometric assay, no further biochemical testing is needed.

The high-dose dexamethasone suppression test (HDST) will cause > 80% suppression of serum cortisol in normal pregnancy. Patients with adrenal Cushing’s may be identified with this test as they don’t suppress, but the HDST may misclassify those with Cushing’s disease, as three of seven cases failed to suppress in a small series.155,156 Petrosal sinus sampling with CRH stimulation (pregnancy category C) has been used with no ill effects using the direct jugular vein approach to minimize fetal irradiation.148,155 Clear central-to-peripheral ACTH gradients were found. Response to CRH stimulation testing is variable. Ross et al142 described the typical exaggerated ACTH response to CRH in one patient, while Mellor et al152 saw only a doubling of cortisol levels in response to CRH in another patient. Lindsay et al155 found a more than threefold increase in ACTH but a less than twofold elevation in cortisol levels in 2 patients. Pituitary MRI, performed without gadolinium enhancement, is often nondiagnostic in patients with Cushing’ syndrome. Adrenal ultrasound may be used to characterize adrenal lesions in patients with borderline or low plasma ACTH or no suppression on the HDST.

Maternal complications of Cushing's syndrome include hypertension, preeclampsia, diabetes, myopathy, opportunistic infections, and fracture. Postoperative wound infection and dehiscence may occur following cesarean delivery. Premature labor occurs in more than 50% of cases.138-144,150-153,155,156 Fetal effects include intrauterine growth retardation, effects of prematurity, and 25% mortality from spontaneous abortion, stillbirth, and prematurity.138-144,150-153,155,156 The maternal hypercortisolemia may occasionally lead to fetal adrenal suppression,149 and the neonate should be tested for this and treated prophylactically until the results are known.

Rates of fetal loss and premature labor decrease, though are still significant, in patients who are treated during pregnancy.138,141 In two published reviews, fetal loss rates of 30% and 38% were seen in 26 and 43 women for whom treatment was delayed, vs. 9% and 24% in 11 and 17 women who were treated during pregnancy.138,141 Similarly, premature labor rates were 48% and 72% in the 26 and 43 women for whom treatment was delayed, vs. 20% and 47% in the 11 and 17 women who were treated.138,141 Medical therapy is generally not effective,140,141,144 though it may be used pending definitive surgical therapy. Metyrapone has proved efficacious in a few patients, with side effects including hypertension and preeclampsia.160-162 Ketoconazole therapy in three patients was associated with intrauterine growth retardation, but no malformations or neonatal adrenal insufficiency.150,151,155 Aminoglutethamide may cause fetal masculinization and mitotane is teratogenic; both should be avoided. Adrenal surgery may be performed using a laparoscopic approach. The live birth rate is approximately 87% after unilateral or bilateral adrenalectomy.155,156 Because of the high rate of adrenal carcinoma, early surgery may improve the poor prognosis. Transsphenoidal surgery has also been used successfully.139,142,148,149,152,153,155,156 The risks of surgery to both mother and fetus are outweighed by the benefits of appropriately treating the Cushing’s syndrome.

The prevalence of primary adrenal insufficiency in pregnancy is unknown, with a series from Norway suggesting an incidence of 1 in 3000 births from 1976 to 1987.163 In developed countries, the most common etiology for primary adrenal insufficiency is autoimmune adrenalitis, which may be associated with autoimmune polyglandular syndrome. Primary adrenal insufficiency from infections (tuberculous or fungal), bilateral metastatic disease, hemorrhage or infarctions is uncommon. Secondary adrenal insufficiency, from pituitary neoplasms or glucocorticoid supression of the hypothalamic-pituitary-adrenal axis, is more common.

Recognition of adrenal insufficiency may be difficult in the first trimester as many of the clinical features are found in normal pregnancies, including weakness, lightheadedness, syncope, nausea, vomiting, hyponatremia, and increased pigmentation. Addisonian hyperpigmentation may be distinguished from chloasma of pregnancy by its presence on the mucous membranes, on extensor surfaces, and on non-exposed areas. Weight loss, hypoglycemia, salt craving, hyponatremia more severe than the normal 5 mmol/L decrease of pregnancy, or seizures, should prompt a clinical evaluation. If unrecognized, adrenal crisis may ensue at times of stress, such as a urinary tract infection or labor.163 Fetal cortisol production may be protective, shielding the mother from severe adrenal insufficiency until postpartum.164

The fetoplacental unit largely controls its own steroid milieu, so maternal adrenal insufficiency generally causes no problems with fetal development. Maternal antiadrenal autoantibodies may cross the placenta, but usually not in sufficient quantities to cause fetal or neonatal adrenal insufficiency.165 Although earlier studies observed intrauterine growth retardation in offspring of women with Addison’s disease,166,167 this observation has not been supported in most subsequent case series. Severe maternal hyponatremia or metabolic acidosis may cause a poor fetal outcome, including death.168 Association with other autoimmune conditions such as anticardiolipin antibodies may lead to additional risks such as miscarriage.169

Adrenal insufficiency is associated with laboratory findings of hyponatremia, hyperkalemia, hypoglycemia, eosinophilia, and lymphocytosis. Hyperkalemia may be absent, because of the pregnancy increase in the renin angiotensin system.168,170 Early morning plasma cortisol levels of < 3.0 mcg/dl (83 nmol/L) confirms adrenal insufficiency,171 while a cortisol >19 mcg/dl (525 nmol/L) in the first or early second trimester excludes the diagnosis in a clinically stable patient.171,172 Plasma cortisol levels may fall in the normal “nonpregnant” range due to the increase in CBG concentrations in the second and third trimesters, but will not be appropriately elevated for the stage of pregnancy. Appropriate pregnancy-specific cutoffs for diagnosis with the standard cosyntropin (1-24 corticotropin) test using a 250 mcg dose have not been established. Plasma cortisol levels were 60% to 80% above nonpregnant responses in normal pregnant women tested in the second and third trimesters in one series.173 McKenna et al171 examined the 1 mcg low dose cosyntropin test for diagnosis of secondary adrenal insufficiency in women at 24-34 weeks gestational age, and found high sensitivity of diagnosis using a cutoff of 30 mcg/dl (828 nmol/L). Accuracy of dosing is more difficult with this than with the standard cosyntropin test. The cosyntropin test is less sensitive to detect early secondary or tertiary forms of adrenal insufficiency. Cortisol and ACTH responses to CRH are blunted in pregnancy,174 making the CRH stimulation test unreliable for differentiating secondary and tertiary adrenal insufficiency in pregnancy. With primary adrenal insufficiency, ACTH levels will be elevated, and a level above 100 pg/ml (22 pmol/L) is consistent with the diagnosis.172 However, ACTH will not be low with secondary forms because of the placental production of this hormone, which is nevertheless insufficient to maintain normal maternal adrenal function. ACTH values fluctuate widely, and a single value is insufficient for diagnosis. Adrenal antibodies may assist in confirming idiopathic adrenal insufficiency, as approximately 90% of patients will have 21-hydroxylase antibodies and 30% will have antibodies to 17-hydroxylase and side-chain cleavage enzymes.175 Aldosterone to renin ratios are low with elevated plasma renin activity in patients with mineralocorticoid deficiency from adrenal atrophy.176

In the unstable patient, empiric glucocorticoid therapy (hydrocortisone 100 mg IV) should be administered pending the results of diagnostic testing. Thereafter, stress doses of 50-100 mg every 6-8 hours during the crisis mimics the maximal cortisol production rates of 200 to 300 mg/day.177 Despite the normal increase in plasma cortisol during pregnancy, baseline maternal replacement doses of corticosteroids usually are not different from those required in the non-pregnant state. Higher doses are needed at times of stress, such as during the course of “morning sickness” or during labor and delivery. Patients should be educated in the self-administration of intramuscular hydrocortisone. Hydrocortisone 50 mg IV is generally given in the second stage of labor.178 Mineralocorticoid replacement requirements usually do not change during gestation, though some clinicians have reduced doses of fludrocortisone in the third trimester in an attempt to treat Addisonian patients who develop edema, exacerbation of hypertension, and preeclampsia.163,179

Patients who have received glucocorticoids as antiinflammatory therapy are presumed to have adrenal axis suppression for at least one year.180 These patients should be treated with stress doses of glucocorticoids during labor and delivery. They are at risk for postoperative wound infection and dehiscence as are patients with endogenous Cushing’s, and their offspring are at risk for transient adrenal insufficiency. Although prednisone readily crosses the placenta,181 the maternal:fetal gradient is higher than with other available agents.182,183 Corticosteroid therapy during pregnancy is generally safe and suppression of neonatal adrenal function is uncommon.184 Glucocorticoid therapy during lactation is also safe, as less than 0.5% of the dose is passed into breast milk.167,185

Congenital adrenal hyperplasia occurs in a family of monogenic inherited enzymatic defects of adrenal steroid biosynthesis, with manifestations secondary to an accumulation of precursors proximal to the enzymatic deficiency. The most common form of CAH in the population is 21-hydroxylase (CYP21 gene) deficiency, seen in more than 90% of the CAH cases in pregnancy.186-188 Classic, severe 21-hydroxylase deficiency is associated with ambiguous genitalia, an inadequate vaginal introitis, and progressive postnatal virilization including precocious adrenarche, advanced somatic development, central precocious puberty, menstrual irregularity, a reduced fertility rate, and possibly salt wasting.187,189,190 The spontaneous abortion rate is twice that in the normal population,191 and congenital anomalies are more frequent. Cephalopelvic disproportion from an android pelvis may occur, sometimes complicated by the previous reconstructive surgery.192,193 Conception requires adequate glucocorticoid therapy, which then continues at stable rates during gestation, except at labor and delivery. Nonclassic (late-onset) 21-hydroxylase deficiency patients present with pubertal and postpubertal hirsutism and menstrual irregularity, and may have improved fertility with glucocorticoid therapy.191

Fetal risk depends on the carrier status of the father. Unfortunately, ACTH stimulation testing to measure 17-OH progesterone demonstrates overlap between heterozygotes for CAH and the normal population.194 Ideally, CYP21 genotyping should be performed.188 Virilization is not seen in the female fetus with nonclassic 21-hydroxylase deficiency,195 but occurs in a fetus with classic 21-hydroxylase deficiency unless fetal adrenal androgen production is adequately suppressed. Dexamethasone most readily crosses the placenta as it is not bound to CBG and is not metabolized by placental 11 hydroxysteroid dehydrogenase. It is commonly used at doses of 20 μg/kg maternal body weight per day to a maximum of 1.5 mg daily in 3 divided doses beginning at recognition of pregnancy before the 9th week of gestation,187,189 though lower doses are recommended by some.196 Treatment by the 9th week of gestation is very effective in reducing the risk of virilization in the affected female fetus.189 Maternal plasma and/or urinary estriol levels reflect fetal adrenal synthesis and are monitored to assess efficacy. Maternal cortisol and DHEA-S levels will represent maternal adrenal suppression. There is little effect on maternal 17-OH progesterone with therapy. As only 25% of female fetuses are affected in a family with CAH, it is important to discontinue therapy as soon as possible in the male fetus and unaffected female fetus. Chorionic villus sampling at 9-11 weeks gestation may be used for gender determination and direct DNA analysis for the 21-hydroxylase gene CYP21.186,189,197 This test is associated with a 1-4% risk of miscarriage and 2% risk of limb defects. An alternative is karyotyping and DNA analysis or measuring androstenedione and 17-OH progesterone levels in amniotic fluid at 16-18 weeks of gestation after dexamethasone has been withheld for 5 days.197 Side effects of dexamethasone therapy are potentially significant, including excessive weight gain, severe striae with scarring, edema, irritability, gestational diabetes mellitus, hypertension, and gastrointestinal intolerance.189,198 In affected pregnancies, dexamethasone may be lowered to 0.75 to 1.0 mg/day in the second half of pregnancy to decrease maternal side effects while avoiding fetal virilization.198

Primary hyperaldosteronism rarely has been reported in pregnancy,199-203 and is most often caused by an adrenal adenoma. There are rare reports of glucocorticoid-remediable hyperaldosteronism in pregnancy.204 The elevated aldosterone levels found in patients are similar to those in normal pregnant women, but the plasma renin activity is suppressed.199-202 Moderate to severe hypertension is seen in 85%, proteinuria in 52%, and hypokalemia in 55%,203 and symptoms may include headache, malaise, and muscle cramps.205 Placental abruption and preterm delivery are risks.206 Progesterone has an antimineralocorticoid effect at the renal tubules, and the hypertension and hypokalemia may ameliorate during pregnancy.207

The physiologic rise in aldosterone during pregnancy overlaps the levels seen in primary aldosteronism, making diagnosis difficult.133,203 Suppressed renin in the setting of hyperaldosteronism is diagnostic. Salt loading tests may be used to diagnose hyperaldosteronism, but there are potential fetal risks and no normative data.200 If baseline and suppression testing are equivocal, or radiologic scanning does not suggest unilateral disease, patients may be treated medically until delivery to allow more definitive investigations.201 Spironolactone, the usual nonpregnant therapy, is contraindicated in pregnancy as it crosses the placenta and is a potent antiandrogen which can cause ambiguous genitalia in a male fetus.202 There is no published experienced with the use during pregnancy of dplerenone, the new aldostgerone receptor antagonist. Surgical therapy may be delayed until postpartum if hypertension can be controlled with agents safe in pregnancy, such as amiloride, methyldopa, labetolol, and calcium channel blockers.201,207,208 Potassium supplementation may be required, but as noted above, the hypokalemia may ameliorate in pregnancy because of the antikaliuretic effect of progesterone. Both hypertension and hypokalemia may exacerbate postpartum due to removal of the progesterone effect.209,210

Exacerbation of hypertension is a typical presentation of pheochromocytoma in nonpregnant patients, but during pregnancy is frequently mistaken for pregnancy-induced hypertension or preeclampsia.211 The prevalence is estimated at 1 in 54,000 pregnancies.212 As the uterus enlarges and an actively moving fetus compresses the neoplasm, maternal complications such as severe hypertension, hemorrhage into the neoplasm, hemodynamic collapse, myocardial infarction, cardiac arrhythmias, congestive heart failure, and cerebral hemorrhage may occur. Extra-adrenal tumors which occur in 10%, such as in the organ of Zuckerkandl at the aortic bifucation, are particularly prone to hypertensive episodes with changes in position, uterine contractions, fetal movement, and Valsalva maneuvers.213 Unrecognized pheochromocytoma is associated with a maternal mortality rate of 50% at induction of anesthesia or during labor.214,215

There is minimal placental transfer of catecholamines,216,217 likely due to high placental concentrations of catechol-O-methyltransferase and monoamine oxidase.216,218 Adverse fetal effects such as hypoxia are a result of catecholamine-induced uteroplacental vasoconstriction and placental insufficiency,219-221 and of maternal hypertension, hypotension, or vascular collapse.

As always, diagnosis of pheochromocytoma requires a high index of suspicion. Preconception screening of families known to have MEN 2 with RET proto-oncogene is essential. Patients with MEN 2A are more likely to have paroxysmal hypertension and have higher rates of bilateral neoplasms than those with sporadic pheochromocytoma.222 Examination for associated evidence for MEN2 may be difficult in pregnancy, with the expected pregnancy alterations in calcium, PTH, and calcitonin. Clinical thyroid examination should be done, with fine needle aspiration of any nodules so that overt medullary carcinoma can be treated immediately. Individuals with neurofibromatosis,223 von Hipple-Lindau disease,224 or retinal angiomatosis should also be screened for pheochromocytomas prior to pregnancy.

The diagnosis should be considered in pregnant women with severe or paroxysmal hypertension, particularly in the first half of pregnancy or in association with orthostatic hypotension or episodic symptoms of pallor, anxiety, headaches, palpitations, chest pain, or diaphoresis. Symptoms may occur or worsen during pregnancy because of the increased vascularity of the tumor and mechanical factors such as pressure from the expanding uterus or fetal movement.220

Laboratory diagnosis of pheochromocytoma is unchanged from the nonpregnant state as calecholamine metabolism is not altered by pregnancy per se.225 If possible, methyldopa and labetolol should be discontinued prior to the investigation as these agents may interfere with the quantification of the catecholamines and VMA.226 Provocative testing should be avoided because of the increased risk of maternal and fetal mortality. Tumor localization with MRI, with high intensity signals noted on T2-weighted images, provides the best sensitivity without fetal exposure to ionizing radiation. Metaiodobenzylguanidine and [18F]-dopamine-labeled positron emission tomography scans are contraindicated in pregnancy, but may be used postpartum to assess extra-adrenal disease.

Differentiation from preeclampsia is generally simple. The edema, proteinuria, and hyperuricemia found in preeclampsia is absent in pheochromocytoma. Plasma and urinary catecholamines may be modestly elevated in preeclampsia and other serious pregnancy complications requiring hospitalization, though they remain normal in mild preeclampsia or pregnancy-induced hypertension.227 Catecholamine levels are 2- to 4-times normal after an eclamptic seizure.228

Initial medical management involves α-blockade with phenoxybenzamine, phentolamine, prazosin, or labetolol. All of these agents are well-tolerated by the fetus, but phenoxybenzamine is considered the preferred agent as it provides long-acting, stable, non-competitive blockade.220 Phenoxybenzamine is started at a dose of 10 mg twice daily, with titration until the hypertension is controlled. Placental transfer of phenoxybenzamine occurs,229 but is generally safe.230,231 If hypertension remains inadequately controlled, metyrosine has also been used successfully to reduce catecholamine synthesis in a pregnancy complicated by malignant pheochromocytoma,232 but may potentially adversely affect the fetus. Beta blockade is reserved for treating maternal tachycardia or arrhythmias which persist after full α-blockade and volume repletion. Beta blockers may be associated with fetal bradycardia and with intrauterine growth retardation, when used early in pregnancy.225,233 All of these potential fetal risks are small compared to the risk of fetal wastage from unblocked high maternal levels of catecholamines. Hypertensive emergencies should be treated with phentolamine (1-5 mg) or nitroprusside, although the latter should be limited because of fetal cyanide toxicity.

The timing of surgical excision of the neoplasm is controversial and may depend on the success of the medical management and the location of the tumor. As noted above, pressure from the uterus, motion of the fetus, and labor contractions are all stimuli that may cause an acute crisis, particularly in patients with a tumor at the organ of Zuckerkandl. In the first half of pregnancy, surgical excision may proceed once adequate α-blockade is established, although there is a higher risk of miscarriage with first trimester surgery. In the early 2nd trimester, abortion is less likely and the size of the uterus will not make excision difficult. If the pheochromocytoma is not recognized until the second half of gestation, increasing uterine size makes surgical exploration difficult. Successful laparoscopic excision of a pheochromocytoma in the 2nd trimester of pregnancy has been described.234 Other options include combined cesarean delivery and tumor resection or delivery followed by tumor resection at a later date. Delivery is generally delayed until the fetus reaches sufficient maturity to reduce postpartum morbidity, providing successful medical management exists.

Although successful vaginal delivery has been reported,235 it has been associated with higher rates of maternal mortality than cesarean section. Labor may result in uncontrolled release of catecholamines secondary to pain and uterine contractions.236 Severe maternal hypertension may lead to placental ischemia and fetal hypoxia. However in the well-blocked patient, vaginal delivery may be possible using intensive pain management with epidural anesthesia and avoidance of mechanical compression, employing techniques of passive descent and instrumental delivery.

There is no available information regarding the impact of maternal use of phenoxybenzamine on the nursing neonate.