**3. Adrenal insufficiency**

The adrenal insufficiency (AI) is rare, but early diagnosis is very important to improve maternal-fetal treatment. The primary AI or Addison's disease involves adrenal cortex atrophy with response insensitivity to ACTH and angiotensin 2, which causes a deficiency of glucocorticoids and aldosterone. The secondary and tertiary AI due to lack of ACTH or CRH are secondary to hypothalamic-pituitary diseases or chronic administration of exogenous corticosteroids. The secondary and tertiary AI are not associated with mineralocorticoid deficiency (Ambrosi et al., 2003).

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. The most common etiology for primary adrenal insufficiency is autoinmune adrenalitis, which may be associated with autoinmune polyglandular syndrome. Primary adrenal insufficiency from infections, bilateral metastatic disease, hemorraghe or infarction is uncommon. Secondary adrenal insufficiency, from pituitary neoplasm or glucocorticoid suppression of the hypothalamic-pituitary-adrenal axis is more common (Stechova, 2004).

Gestation in patients with AI should be considered high-risk pregnancy (Lindsay & Nieman, 2005). Maternal mortality is rare today, after the introduction of hydrocortisone in 1950, as well as improved diagnosis and early treatment. When AI is not diagnosed during pregnancy, may not have negative effects to mother or fetus, indicating the transplacental passage of maternal fetal glucocorticoids. In these cases, disease appears in the postpartum.When the disease is previously known, it is necessary to adjust the dose of corticosteroids in order to avoid a default adrenal crisis defect or undesirable effects of excess treatment as hypertension and preeclampsia.

The prevalence of fetal mortality is unknown, although cases have been reported about intrauterine death, most undiagnosed in pregnant women. Intrauterine growth retardation and low birth weight are the most frequent effects in untreated mothers.The concomitance between AI and other autoimmune diseases (DM, lupus, anticardiolipin antibodies) increases maternal-fetal morbidity.

#### **3.1 Diagnosis**

Most cases are diagnosed before pregnancy.

Adrenal Disease and Pregnancy 55

It may appear at any time if the AI is not diagnosed, but it is more often during the delivery, when there is infection, preeclampsia or hemorrhage.Treatment should be started with hydrocortisone intravenous (bolus of 100 or 200mg and then 50-100 mg every 6-8 hours). In

After stabilization, return to oral treatment. It is not necessary to administer Mineralocorticoids in the acute phase. During delivery, the dose of glucocorticoids should be doubled at onset of labor or to administer 50 mg of intravenous hydrocortisone. In case of caesarean, it is necessary to start treatment with hydrocortisone, 100 mg IV every 8 hours.

After delivery, all women must maintain treatment with corticosteroids and with dosis of

It is not necessary to follow hypothalamic-pituitary axis in children of mothers with AI if they have been well treated during pregnancy. It can be necessary in mothers who have

The replacement therapy can continue during lactation. It is excreted 0.5% per liter of milk

Primary hyperaldosteronism rarely has been reported in pregnancy and is most often caused by an adrenal adenoma (Okawa et al., 2002). There are reports of glucocorticoid remediable hyperaldosteronism in pregnancy (Wyckoff et al., 2000). The elevated aldosterone levels found in patients are similar to those in normal pregnant women, but the plasma rennin activity is suppressed. Moderate to severe hypertension is seen in 85%, proteinuria in 52% and hypokalemia in 55%, and symptoms may include headache, malaise, and muscle cramps. Placental abruption and preterm delivery are risks. Progesterone has an antimineralocorticoid effect at the renal tubules, and the hypertension and hypokalemia

The physiologic rise in aldosterone during pregnancy overlaps the levels seen in primary aldosteronism, making diagnosis difficult. Suppressed rennin in the setting of hyperaldosteronism, is diagnostic. Salt loading test may be used to diagnose hyperaldosteronism, but there are potential fetal risks and no normative data. If baseline and suppression testing are equivocal, or radiological scanning does not suggest unilateral disease, patients may be treated medically until delivery to allow more definitive investigations. Spironolactone, the usual nonpregnant therapy, is contraindicated in pregnancy as it cross the placenta and is a potent antiandrogenic which can cause ambiguous genitalia in a male fetus. There is no published experienced with the use during pregnancy of eplerenone, the new aldosterone 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. 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

Pheochromocytoma is a rare cause of hypertension during pregnancy, with clinical features similar to those in the general population (Keely, 1998). The prevalence is estimated at 1 in

women with hypoglycemia, it is necessary to administer dextrose.

The oral treatment must be restarted within 48 hours.

mineralocorticoids similar to the prepregnancy period.

may ameliorate during pregnancy (Matsumoto et al., 2000).

removal of the progesterone effect ( Nursan et al., 2009).

**5. Pheochromocytoma** 

of the absorbed dose (Sidhu & Hawkins, 1981).

received supraphysiological doses.

**4. Primary hyperaldosteronism** 

**3.2.3 Adrenal crisis** 

Adrenal insufficiency is associated with laboratory findings of hyponatremia, hyperkalemia, hypoglycemia, eosinophilia and lymphocytosis. Hiperkalemia may be absent, because of the pregnancy increase in the rennin angiotensin system (Gradden et al., 2001). Early morning plasma cortisol levels of <3.0 mcg/dl confirms AI, while a cortisol >19 mcg/dl in the first or early second trimester excludes the diagnosis in a clinically stable patient. Plasma cortisol levels may fall in the normal "nonpregnant" range due to 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 test using 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 (Nolten et al., 1978).

McKenna et al (McKenna et al., 2000) 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. 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, making the CRH stimulation test unreliable for differentiating secondary and tertiary adrenal insufficiency in pregnancy. With primary AI, ACTH levels will be elevated and a level above 100 pg/ml is consistent with the diagnosis. 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. Aldosterone to renin ratios are low with elevated plasma rennin activity in patient with mineralocorticoid deficiency from adrenal atrophy (Symonds & Craven, 1978).

#### **3.2 Treatment**

Patients with AI should be managed during pregnancy and childbirth by a multidisciplinary team that includes endocrinologist, obstetrician and an expert neurosurgeon.

#### **3.2.1 Glucocorticoids**

The aim is to achieve a physiological replacement dose for optimal maternal and fetal monitoring.

The most important period is the first trimester, because the symptoms may go unnoticed by the emesis of pregnancy and childbirth stress. Hydrocortisone is the glucocorticoid of choice at doses of 12-15 mg/m2 in 2 divided doses at breakfast and 1 / 3 at lunch. It is rare to increase the dose during pregnancy.

Women must be educated on the need for treatment with parenteral hydrocortisone in cases of nausea, vomiting or intercurrent systemic disease. Prednisone or prednisolone should be avoided because Hydrocortisone is more physiological.

#### **3.2.2 Mineralocorticoids**

They are only required in primary AI. The most widely used on the single dose is fluorocortisona 9α ( 0.05 to 0.2 mg/day). The dose is stable during pregnancy, and it can be reduced in the third trimester if there are edemas or hypertension.

#### **3.2.3 Adrenal crisis**

54 Basic and Clinical Endocrinology Up-to-Date

Adrenal insufficiency is associated with laboratory findings of hyponatremia, hyperkalemia, hypoglycemia, eosinophilia and lymphocytosis. Hiperkalemia may be absent, because of the pregnancy increase in the rennin angiotensin system (Gradden et al., 2001). Early morning plasma cortisol levels of <3.0 mcg/dl confirms AI, while a cortisol >19 mcg/dl in the first or early second trimester excludes the diagnosis in a clinically stable patient. Plasma cortisol levels may fall in the normal "nonpregnant" range due to 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 test using 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

McKenna et al (McKenna et al., 2000) 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. 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, making the CRH stimulation test unreliable for differentiating secondary and tertiary adrenal insufficiency in pregnancy. With primary AI, ACTH levels will be elevated and a level above 100 pg/ml is consistent with the diagnosis. 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. Aldosterone to renin ratios are low with elevated plasma rennin activity in patient with mineralocorticoid deficiency

Patients with AI should be managed during pregnancy and childbirth by a multidisciplinary team that includes endocrinologist, obstetrician and an expert

The aim is to achieve a physiological replacement dose for optimal maternal and fetal

The most important period is the first trimester, because the symptoms may go unnoticed by the emesis of pregnancy and childbirth stress. Hydrocortisone is the glucocorticoid of choice at doses of 12-15 mg/m2 in 2 divided doses at breakfast and 1 / 3 at lunch. It is rare

Women must be educated on the need for treatment with parenteral hydrocortisone in cases of nausea, vomiting or intercurrent systemic disease. Prednisone or prednisolone should be

They are only required in primary AI. The most widely used on the single dose is fluorocortisona 9α ( 0.05 to 0.2 mg/day). The dose is stable during pregnancy, and it can be

and third trimesters in one series (Nolten et al., 1978).

from adrenal atrophy (Symonds & Craven, 1978).

**3.2 Treatment** 

neurosurgeon.

monitoring.

**3.2.1 Glucocorticoids** 

**3.2.2 Mineralocorticoids** 

to increase the dose during pregnancy.

avoided because Hydrocortisone is more physiological.

reduced in the third trimester if there are edemas or hypertension.

It may appear at any time if the AI is not diagnosed, but it is more often during the delivery, when there is infection, preeclampsia or hemorrhage.Treatment should be started with hydrocortisone intravenous (bolus of 100 or 200mg and then 50-100 mg every 6-8 hours). In women with hypoglycemia, it is necessary to administer dextrose.

After stabilization, return to oral treatment. It is not necessary to administer Mineralocorticoids in the acute phase. During delivery, the dose of glucocorticoids should be doubled at onset of labor or to administer 50 mg of intravenous hydrocortisone. In case of caesarean, it is necessary to start treatment with hydrocortisone, 100 mg IV every 8 hours. The oral treatment must be restarted within 48 hours.

After delivery, all women must maintain treatment with corticosteroids and with dosis of mineralocorticoids similar to the prepregnancy period.

It is not necessary to follow hypothalamic-pituitary axis in children of mothers with AI if they have been well treated during pregnancy. It can be necessary in mothers who have received supraphysiological doses.

The replacement therapy can continue during lactation. It is excreted 0.5% per liter of milk of the absorbed dose (Sidhu & Hawkins, 1981).
