Diagnosis of Cs during pregnancy is difficult because of the physiologic hypercortisolism normally present during pregnancy. Moreover, symptoms and signs of Cs present similarities with those of normal pregnancy. Weight gain, striae, mood changes, hypertension, and diabetes mellitus are commonly present during normal pregnancy and have low discriminative value. However, the report of fetal loss, hypertension, or type 2 diabetes before pregnancy and deep purple striae (especially outside the abdomen), muscular weakness, proximal myopathy, or osteoporosis during pregnancy may imply Cs [ ]. Given the challenging diagnosis, laboratory and imaging tests are necessary.

Laboratory tests in the general population include: 1) measurement of 24 hours urinary free cortisol (Ufc) levels 2) low dose dexamethasone suppression test and 3) midnight serum cortisol or late night salivary cortisol. However, the normal hormonal changes during pregnancy alter the aforementioned, complicating the laboratory diagnosis.

Ufc measurement reflects the circulating free cortisol. In nonpregnant women, a 4-fold increment in Ufc levels is diagnostic for Cs. However, Ufc excretion during pregnancy is normal in the first trimester and rises to 3 times the upper normal value during the second and third trimesters. Thus, only Ufc values greater than 3-fold the upper limit of normal are considered indicative of Cs [ ].

Low dose dexamethasone suppression test is not recommended in pregnancy because of the blunted suppression of cortisol, which can lead to false positive rates [ ].

Late night salivary cortisol is normally elevated 2-fold in pregnancy [ ]. Pregnant women preserve the circadian rhythm, presenting a diurnal cortisol variation, whereas pregnant women with Cs lose this ability. This is a distinguishing difference, indicating Cs.

The next step is determining the etiology of Cs by measuring Acth levels, performing dynamic tests (Crh or desmopressin test, high dose dexamethasone suppression test), bilateral and inferior petrosal sinus sampling, or imaging studies [ ].

High levels of cortisol inhibit Acth secretion by the pituitary. In nonpregnant women with autonomous adrenal pathology Acth is reduced (<10 pg/mL), whereas Acth levels are normal or increased in Cd or ectopic Acth secretion [ ]. However, in pregnant women with adrenal adenomas, Acth may not be suppressed because of placental Acth secretion or pituitary Acth stimulation by placental Crh [ ]. Thus, Acth levels are not diagnostic for adrenal Cs during pregnancy, but they are for Cd when they are in the upper of normal reference or even higher [ , , ].

Concerning dynamic tests, the dosage of 100 μg intravenous Crh administration has not largely been used in pregnancy because ovine Crh is a category C drug, used only when is clinically indicated [ ]. The principle of this test is that adrenal tumors or ectopic Acth secretion do not respond to Crh, but pituitary tumors do [ ]. Studies have shown that Crh did not manage to sufficiently increase Acth in pregnancy [ , ]. An alternative to the Crh test is the administration of 10 μg intravenous desmopressin, which is cheaper and more available than Crh but with poorer rates of sensitivity and specificity (84% vs. 77%, 83% vs. 73%) [ ]. Two case reports during pregnancy demonstrated an increment of 70% in Acth 15 minutes after desmopressin administration and a higher response compared with Crh, respectively [ , ].

The basis of the high dose dexamethasone test is the fact that pituitary tumors have a relative responsiveness to glucocorticoid feedback whereas adrenal tumors and ectopic Acth do not. Reports showed that cortisol has decreased by more than 80%, distinguishing Cd from adrenal sources during pregnancy [ , ].

Bilateral inferior petrosal sinus sampling is not recommended during pregnancy, due to the risk of thromboembolic events and radiation [ ].

In cases of hypercortisolism and normal or low Acth levels, an adrenal Mri without contrast or ultrasound could be performed in pregnancy [ ]. A pituitary Mri without contrast should be performed if surgery is planned before birth. It can be diagnostic when pituitary tumor >6 mm are identified [ ]. However, the fact that the pituitary gland is normally enlarged 2-fold by the third trimester can conceal small tumors [ ]. For ectopic Acth cases, a chest or abdominal Mri can be performed.

Conservative treatment during pregnancy is preferable for cases of mild hypercortisolism without complications or cases diagnosed late in pregnancy. It includes close monitoring of glucose and blood pressure, use of low molecular weight heparin and supportive care when comorbidities are present [ ].

First line treatment during pregnancy is surgery. Transsphenoidal pituitary surgery and bilateral adrenalectomy are performed according to etiology. Pituitary surgery is performed in the second trimester and seems to be safe with a remission rate of 77% [ , , ]. Complications include diabetes insipidus, cerebrospinal fluid leak, and inappropriate diuretic hormone secretion. Adrenalectomy has been performed in the second trimester with favorable outcomes [ ].

Medical treatment, most commonly used in second and third trimesters as second line therapy, includes metyrapone, ketoconazole, cabergoline, mitotane, aminoglutethimide, and cyproheptadine.

Metyrapone, an 11β hydroxylase inhibitor, is the most common medicine used in pregnancy, with a quick onset of action and UFC normalization in a few weeks [ ]. Adverse effects include hypokalemia, secondary to 11β deoxycorticosterone hypertension, preeclampsia, and edema [ ]. It seems that it crosses the placenta in animal studies and recently in a human, thus it may influence fetal adrenal steroidogenesis [ ]. However, no fetal abnormalities have been reported [ , ].

Ketoconazole is a steroidogenesis inhibitor, rarely used in pregnancy [ ]. It crosses the placental membrane with an increased risk of teratogenicity and abortion in rats [ ]. Although ketoconazole has been used in the first trimester, due to its potential antiandrogenic effect it is preferable to be used in the second and third trimesters [ ]. However, recent case reports treated with ketoconazole have reported good outcomes [ , ].

Treatment with cabergoline in pregnancy is not well established. It has been used only in four cases alone or in combination with other medical treatments with good results [ , ]. One drawback is that lactation is disrupted due to its direct effect on the pituitary. Other treatments such as mitotane or aminoglutethimide are not recommended during pregnancy because they can induce teratogenicity and fetal masculinization, respectively [ ]. Cyproheptadine is not recommended due to lack of efficacy [ ].