Adrenal disease in pregnancy

Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 959–973

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Adrenal disease in pregnancy Oksana Lekarev, DO, Clinical Instructor of Pediatrics 1, Maria I. New, MD, Professor of Pediatrics, Genetics and Genomic Sciences * Adrenal Steroid Disorders Group, Division of Pediatric Endocrinology, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1198, New York, NY 10029, USA

Keywords: pregnancy adrenal disease Cushing’s syndrome Cushing’s disease adrenal insufficiency Addison’s disease congenital adrenal hyperplasia (CAH)

Adrenal disorders in pregnancy are relatively rare, yet can lead to significant maternal and fetal morbidity. Making a diagnosis is challenging as pregnancy may alter the manifestation of disease, many signs and symptoms associated with pregnancy are also seen in adrenal disease, and the fetal-placental unit alters the maternal endocrine metabolism and hormonal feedback mechanisms. The most common cause of Cushing’s syndrome in pregnancy is an adrenal adenoma, followed by pituitary etiology, adrenal carcinoma, and other exceedingly rare causes. Medical therapy of Cushing’s syndrome includes metyrapone and ketoconazole, but generally surgical treatment is more effective. Exogenous corticosteroid administration is the most common cause of adrenal insufficiency, followed by the endogenous causes of ACTH or CRH secretion. Primary adrenal insufficiency is least common. A low early morning cortisol <3 mcg/dL (83 mmol/L) in the non-stressed state and in the setting of typical clinical symptoms confirms the diagnosis. In the second and third trimester cortisol rises to levels 2–3 fold above those in the non-pregnant state, therefore a baseline level of <30 mcg/dL (823 mmol/L) warrants further evaluation. ACTH stimulated normal cortisol values have been established for each trimester. Hydrocortisone, which does not cross the placenta, is the glucocorticoid treatment of choice, and fludrocortisone is used as mineralocorticoid replacement in patients with primary disease. Congenital adrenal hyperplasia is an autosomal recessive disorder; 21-hydroxylase deficiency (21OHD) is the most common form of the disease. Non-classical 21OHD is most common, followed by the salt-wasting and simple virilizing forms. The treatment of choice for pregnant women affected with

* Corresponding author. Tel.: þ1 212 241 7847; Fax: þ1 212 241 5405. E-mail addresses: [email protected] (O. Lekarev), [email protected] (M.I. New). 1 Tel.: þ1 212 241 6268; Fax: þ1 212 241 5405. 1521-690X/$ – see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.beem.2011.08.004

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CAH is hydrocortisone, and fludrocortisones is added for those with the salt-wasting form of the disease. If the fetus is at risk for classical CAH, dexamethasone treatment can be used prenatally to prevent masculinization of the genitalia in a female infant. Because dexamethasone crosses the placenta, it should not be used to treat pregnant women with CAH if the fetus is not at risk for the disease. Ó 2011 Elsevier Ltd. All rights reserved.

Introduction Adrenal disorders in pregnancy are not common, but a timely diagnosis is imperative because these disorders can lead to significant maternal and fetal morbidity. Making the diagnosis poses a particular challenge to the clinician because the fetal-placental unit alters the maternal endocrine metabolism and hormonal feedback mechanisms. Pregnancy and its hypermetabolic state may alter the manifestation of disease, making the diagnosis difficult. Pregnancy has a profound effect on adrenal steroidogenesis. Although the maternal adrenal glands do not change morphologically during pregnancy, the adrenal steroid metabolism is modified substantially. In contrast to the hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoid levels provide a positive feedback on the placental corticosteroid axis. Placental Corticotropin Releasing Hormone (CRH) rises several hundred-fold during pregnancy, which modulates both maternal and fetal pituitary-adrenal axes, and may regulate labor.1 Both maternal and placental ACTH and cortisol levels rise dramatically during pregnancy with the initial surge at the 11th week of gestation, a significant rise after 16–20 weeks gestation, and a final surge of these hormones during labor (Fig. 1).2,3 In addition, the fetoplacental unit has a marked capacity for steroidogenesis, causing plasma cortisol levels to rise 2–3 fold over the course of the pregnancy above the levels of non-pregnant controls, reaching values that are in the range seen in Cushing’s syndrome.4,5 Furthermore, increased estrogens from the placenta stimulate hepatic production of Cortisol Binding Globulin (CBG) levels, leading to an increase in total cortisol levels and a decrease in cortisol clearance.6,7 As cortisol is displaced from CBG by progesterone, free cortisol levels also increase.6 Plasma 17-hydroxysteroids rise during pregnancy as well.8 Despite the increase in placental hormones and increased HPA axis function, a normal maternal circadian rhythm of ACTH persists throughout pregnancy. The renin–angiotensin system (RAS) undergoes significant changes as well. Plasma renin activity (PRA) increases early in the first trimester, reaching values 3–7-fold above the normal range by the third trimester.9–11 (Fig. 2) Plasma aldosterone levels increase 5–20-fold during gestation, with a plateau at 38 weeks.9,12–14 Despite the significant increase in aldosterone levels, aldosterone secretion continues to respond normally to physiologic stimuli such as posture and varies inversely with changes in volume and dietary salt.15–17 As glomerular filtration rate (GFR) and progesterone increase during pregnancy, aldosterone increases as well. The increase of aldosterone promotes sodium retention at the distal renal tubules. In addition, progesterone has an anti-kaliuretic effect.17 Other mineralocorticoids such as corticosterone, deoxycortisol and cortisone mirror the 2–3-fold rise of cortisol.12 Deoxycorticosterone (DOC), a potent mineralocorticoid, increases from 2-fold normal in early pregnancy to 60–100 ng/100 mL in the third trimester,18 which may contribute to sodium retention of pregnancy.19,20 Cushing’s syndrome Cushing’s syndrome is rare in pregnancy, likely because hypercortisolism inhibits normal ovulation. In pituitary disease, there is altered gonadotropin secretion, and in adrenal disease there is secretion of adrenal androgens. To date, approximately 140 cases of Cushing’s syndrome in pregnancy have been reported,21–42 with 18 weeks being the mean gestational age.43 The incidence of adrenal and pituitary disease in pregnant women is quite different from non-pregnant women. Of the total number of Cushing’s syndrome cases, adrenal adenomas comprise approximately 40–50% of cases in pregnancy,

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Fig. 1. Serial increases in serum cortisol (B) and ACTH (C) during pregnancy in normal controls throughout pregnancy.

Fig. 2. Sequential changes in PRA (C) and in PRA normalized to the post-partum (PP) substrate values (B) (mean  SE) throughout pregnancy (*, P < 0.05; ***, P < 0.001).

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compared with approximately 15% of cases in non-pregnant women.22, 32 On the other hand, Cushing’s disease, i.e. disease which is of pituitary etiology, comprises only over 30% of cases in pregnant women compared with 58–70% in non-pregnant women.7,22,32 Of the remaining cases, about 10% are due to adrenal carcinoma, with the rest due to ACTH-independent hyperplasia, ectopic ACTH secretion, and unspecified causes.43 In many cases, Cushing’s syndrome first becomes evident during pregnancy, with improvement or resolution of symptoms after delivery. The theory is that the placental rise in CRH is instrumental in manifestation and exacerbation of symptoms.21,30 Recurrent Cushing’s syndrome with post-partum remission has been reported as well.21 A case of pregnancy-induced Cushing’s syndrome has been reported in which the pathogenesis was due to ectopic LH/hCG-receptors in the adrenal gland. The patient developed Cushing’s syndrome with each pregnancy, leading to multiple miscarriages and with resolution of symptoms post-partum.44 The diagnosis of Cushing’s syndrome during pregnancy may pose a challenge because the typical symptoms of the disorder and pregnancy may overlap. These include central weight gain, edema, fatigue, emotional upset, hypertension and glucose intolerance. The signs and symptoms that can help differentiate Cushing’s syndrome from normal physiologic pregnancy include hyperpigmented violaceous striae as opposed to skin-colored striae, easy bruising, as well as the pathologic findings of acne and hirsutism due to a significant elevation of adrenal androgens. In addition, pathologic fractures have been reported.25 Making a biochemical diagnosis of Cushing’s Syndrome in pregnancy is also not straightforward. As discussed, the diagnosis is complicated by physiologically elevated levels of total serum cortisol, serum and urine free cortisol and ACTH. In addition, during the third trimester these values are not suppressible with low-dose dexamethasone (1-mg), but they are suppressible with high-dose dexamethasone (8-mg).7,43,45 In patients with adrenal adenomas, plasma cortisol is not suppressible even with high-dose dexamethasone.46 The response of ACTH suppression in patients with an ectopic source is highly variable.47 ACTH levels have been reported to be in the normal to elevated range in all pregnant patients with Cushing’s syndrome, irrespective of the etiology. This is likely due to both the placental ACTH production and the placental CRH-stimulated pituitary ACTH production. Therefore, patients with adrenal adenomas have ACTH levels in the “normal” range, while nonpregnant patients with the same condition would have suppressed ACTH levels. Identifying a lack of diurnal variation of free and total cortisol is helpful in establishing the diagnosis of Cushing’s syndrome. Although cortisol levels are elevated in normal pregnancy, normal diurnal variation remains, and identifying persistently elevated morning and evening cortisol levels can aid in establishing a diagnosis. Midnight plasma or salivary cortisol levels would therefore be helpful, but unfortunately no normative data have been established.7,29,43 Limited experience has been reported with CRH stimulation testing to diagnose Cushing’s disease. CRH in late gestation can potentially induce early labor by potentiating oxytocin to stimulate a contractile uterine response.48 CRH use in pregnancy has not been systematically studied, however Lindsay et al43 and other authors reported a substantial rise in plasma cortisol, consistent with surgically confirmed Cushing’s disease. A blunted cortisol response to ACTH would be more consistent with normal pregnancy. No adverse effects were detected in these studies. The approach was via the internal jugular vein and not the femoral vein to minimize irradiating the fetus.33,39,43 Radiographic studies are important when there is biochemical evidence of Cushing’s syndrome or Cushing’s disease. Because the pituitary volume is usually increased during pregnancy, CT or MRI of the pituitary may show more incidentalomas. However, in some cases a focal abnormality can be identified. Although further studies are needed to evaluate the safety of MRI in pregnancy,49 it is safer than CT during pregnancy and is thus the preferred imaging modality for evaluation of the adrenal glands. Gadolinium is contraindicated because it is FDA category C.50 The complications of Cushing’s syndrome to both the mother and the fetus are severe. The mother may experience hypertension, preeclampsia, diabetes, infections, myopathy and muscle wasting, hirsutism and acne, and emotional instability. Premature labor occurs in more than 50% of cases. The fetus may suffer from intrauterine growth restriction, prematurity, mortality from spontaneous abortion, and stillbirth.43,50–52 Fetal adrenal suppression is a reported complication as well.53 Furthermore, female infants have been reported to have masculinization of the genitalia in mothers with adrenocortical carcinoma.54 A literature review of 136 pregnancies demonstrates that the

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frequency of live births increased from 76% to 89% when treatment was initiated by 20 weeks of gestation, therefore treatment during pregnancy is recommended.43 Medical therapy of Cushing’s syndrome includes metyrapone and ketoconazole. Metyrapone has been shown to be effective in some patients and has been used most frequently. Its side effects include hypertension and preeclampsia.27,55,56 Ketoconazole has been shown to be effective in some patients as well, but its side effects include intrauterine fetal growth restriction and potential antiandrogenic effects via inhibition of aromatase activity.50 There are, however, case reports of ketoconazole use in pregnancy resulting in a birth of a normal male infant without genital abnormalities.57,58 Generally surgical therapy is the more effective and preferred form of treatment. Transsphenoidal surgery has been conducted successfully to treat Cushing’s disease,7,33,36,43,51,59 and in cases of adrenal adenomas and carcinomas, adrenal surgery has been utilized successfully using a laparoscopic approach.27,29,46 Adrenal insufficiency Adrenal insufficiency is very rare in pregnancy, and the exact prevalence is unknown. In the largest series published to date, which comes from Norway, the incidence of primary adrenal insufficiency was 1:3000 pregnancies. In this series five women with adrenal insufficiency gave birth to six children.60 In the general population, autoimmune adrenalitis is the most common cause of primary adrenal insufficiency in developed countries, and tuberculosis is more common in the developing world. Other causes include fungal infections, hemorrhage, bilateral metastases and infarction. Autoimmune polyglandular syndrome (APS) type 2 (primary autoimmune hypoadrenalism or Addison’s disease, type 1 diabetes, and thyroid autoimmune disease) is more common in women and more common than other forms of APS in the general population. There are several cases of APS type 2 in pregnancy,60–63 with three patients presenting with the diagnosis at the time of pregnancy.64–66 Secondary and tertiary adrenal insufficiency is more common than Addison’s disease. Exogenous corticosteroid administration for such conditions as asthma, rheumatoid arthritis and Crohn’s disease is the most common cause, followed by the endogenous causes of impaired ACTH or CRH secretion. While in primary adrenal insufficiency there is associated mineralocorticoid deficiency, this is not the case in secondary and tertiary disease because the zona glomerulosa continues to be responsive to the action of the renin-angiotensin system.50 The prevalence of adrenal insufficiency due to long-term exogenous corticosteroid administration is unknown, and there are only a few case reports of this complication in pregnancy.67,68 Sheehan’s syndrome (post-partum pituitary necrosis) and lymphocytic hypophysitis are the primary causes of post-partum hypopituitarism. Approximately 20% of cases of Sheehan’s syndrome are due to antepartum hemorrhage, and approximately 90% of cases of lymphocytic hypophysitis present in the last trimester of pregnancy or in the early post-partum period.50 Other causes of hypopituitarism and resulting adrenal insufficiency include intracranial neoplasms and associated surgery to remove such lesions. Most cases of adrenal insufficiency in pregnancy are diagnosed before a woman becomes pregnant. In the first trimester the diagnosis may be difficult to make because many of the signs and symptoms seen in adrenal insufficiency are also seen in routine pregnancy. These include fatigue, dizziness, syncope, nausea and vomiting, weight loss, increased pigmentation and hyponatremia. Excessive dizziness, syncope, nausea, vomiting and weight loss should warrant further evaluation. Hyperpigmentation in Addison’s disease can be differentiated from chloasma of pregnancy by the presence of hyperpigmentation on the non-exposed parts of the skin, creases of the hands, the extensor surfaces and mucous membranes. Severe salt cravings and decrease in Naþ (Sodium) which is greater than the normal 5 mmol/L decrease in pregnancy should also warrant further evaluation.69 Hyponatremia with metabolic acidosis has been reported to cause poor fetal outcome.70 In contrast to the classic presentation of primary adrenal insufficiency, reported pregnant patients with the disorder did not present with hyperkalemia.69,70 Patients have presented in stress-induced adrenal crisis in the third trimester, triggered by illness or labor.60,71 Fetal adrenal production may be protective during pregnancy, hence an adrenal crisis may only present in the post-partum period.64 Careful attention must be given to the positive history of autoimmune disorders in the patient and her family members as this would make the diagnosis of Addison’s disease more likely.

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Laboratory screening for adrenal insufficiency must be rapid once there is clinical suspicion. A low early morning cortisol level of <3 mcg/dL (83 mmol/L) in the non-stressed state and in the setting of a typical clinical presentation, confirms the diagnosis.72 In the first trimester and early second trimester a morning cortisol level of 19 mcg/dL (535 nmol/L) in a clinically stable patient excludes the diagnosis.72,73 As normal pregnancy progresses, cortisol levels rise 2–3 fold above non-pregnant levels, therefore a “normal” morning cortisol level is not normal for pregnancy in the late second and third trimesters. Hence, patients with a clinical presentation consistent with adrenal insufficiency and a plasma cortisol level of 3–30 mcg/dL (83–823 nmol/L) should have further evaluation.50 When the plasma cortisol level is low for pregnancy and the plasma ACTH level is elevated, primary adrenal insufficiency is diagnosed, and Cortrosyn (synthetic ACTH) stimulation testing should be performed using a 250 mcg IV dose. Recently, normal basal and ACTH-stimulated values have been established for pregnant women by Suri et al. The basal morning values for the first, second, and third trimester are 9.3  2.2 mcg/dL (mean  SD), 14.5  4.3 mcg/dL, and 16.6  4.2 mcg/dL, respectively. The stimulated values for each trimester are 29.5 þ 16.1 mcg/dL, 37.9 þ 9.0 mcg/dL, and 34.7 þ 7.5. The same study found baseline and stimulated salivary cortisol levels to be a better measure of cortisol secretion.74 Adrenal antibodies may be helpful in confirming Addison’s disease. One study found that approximately 90% of patients will have 21-hydroxylase antibodies and 30% of patients have 17-a-hydroxylase antibodies.75 After cortisone became available in the 1950s, there have been no reported deaths of adrenal insufficiency in pregnant women. Limited data of about 100 pregnancies demonstrates that when patients are treated appropriately, the pregnancy can progress normally and without fetal compromise.50,60,76 The fetoplacental unit has largely autonomous steroidogenesis, therefore generally maternal adrenal insufficiency causes no problems to the fetus. However, there have been reports of fetal growth restriction among infants born to mothers with untreated disease.60,62,71,77 A recent large population-based historical cohort study from Sweden that looked at over 1000 pregnant women demonstrated that women with adrenal insufficiency had reduced parity, and mothers with diagnosed disease had increased risk of preterm labor and Cesarian section delivery. Women with adrenal insufficiency diagnosed three years or less after delivery, and particularly those diagnosed one year or less after delivery had increased risk of preterm labor and of having a low birth infant, indicating they could have had undiagnosed disease during pregnancy. However, the majority of infants born to mothers with undiagnosed or diagnosed adrenal insufficiency were born at term, with normal birth weight and with a normal Apgar score at 5 min.77 Pregnant patients with adrenal insufficiency should be managed in a multi-disciplinary center that includes an endocrinologist, an obstetrician and a pituitary surgeon, if needed. Hydrocortisone is the preferred glucocorticoid replacement treatment as it is more physiologic than other available glucocorticoids and it is degraded by the placental enzyme 11b-HSD 2, therefore it does not cross the placenta and only affects the mother.50 The recommended dose is 12–15 mg/m2 of body surface area.78 The daily dose is divided into a twice daily regimen with two-thirds of the dose given in the morning and one-third of the dose given in the afternoon. Routine replacement therapy can be continued until onset of labor, at which time the oral dose can be doubled. Alternatively, a parenteral dose of 50 mg of hydrocortisone can be given during the second stage of labor, and further dosing can be adjusted based on the course of labor.79 In an event of a Cesarian section, IV or IM hydrocortisone at a dose of 100 mg should be given initially and then every 6–8 h, with tapering of the dose over the next 48 h.78 Hydrocortisone replacement therapy may be continued during breast feeding, as less than 0.5% of the dose is excreted per liter of milk.80 Congenital adrenal hyperplasia Congenital adrenal hyperplasia (CAH) refers to a group of genetic autosomal recessive disorders that arise from defective steroidogenesis. The production of cortisol in the zona fasciculata of the adrenal cortex occurs in five major enzyme-mediated steps. CAH results from deficiency in any one of these enzymes. Impaired cortisol synthesis leads to chronic elevations of ACTH via the negative feedback system, causing overstimulation of the adrenal cortex and resulting in hyperplasia and oversecretion of the precursors to the enzymatic defect. Impaired enzyme function at each step of adrenal cortisol biosynthesis leads to a unique combination of elevated precursors and deficient products.81

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The most common enzyme deficiency that accounts for more than 90% of all CAH cases is 21hydroxylase deficiency. The next most common form of CAH is 11-b hydroxylase deficiency, followed by 3-b hydroxysteroid dehydrogenase deficiency, and then by the exceedingly rare forms 17ahydroxylase/17,20 lyase deficiency, congenital lipoid adrenal hyperplasia (StAR) and Cytochrome 450 oxidoreductase deficiency (POR). Our discussion will focus on the more common forms. Classical 21hydroxylase deficiency can be of the salt-wasting and simple-virilizing type. Data from close to 6.5 million newborn screenings worldwide indicate that classical CAH occurs in 1:13,000 to 1:15,000 live births,82 and about 75% of patients have the salt-wasting phenotype.83 Females with Classical 21-OHD, 11b-hydroxylase deficiency and 3-b hydroxysteroid dehydrogenase deficiency CAH generally present at birth with masculinization of their genitalia. Adrenocortical function begins around the 7th week of gestation84; thus, a female fetus with classical CAH is exposed to adrenal androgens at the critical time of sexual differentiation (approximately 9–15 weeks gestational age). Androgens interact with the receptors on genital skin and induce changes in the developing external female genitalia. This leads to clitoral enlargement, fusion and scrotalization of the labial folds, failure of labial rotation, and placement of the clitorus in the male position. The degree of genital virilization may range from mild clitoral enlargement to a penile urethra.85 In contrast to the masculinization of the external genitalia, internal female genitalia, such as the uterus, fallopian tubes and ovaries, develop normally. Females with CAH do not have testicular tissue and do not produce anti-Müllerian hormone (AMH), which is produced by the testicular Sertoli cells. These internal female structures are Müllerian derivatives and are not androgen responsive. Therefore, the affected female who is born with masculanized external genitalia will have a normal uterus, normal fallopian tubes, and normal ovaries. Females with classical CAH maintain the internal genitalia potential for fertility.81 When the loss of 21-hydroxylase function is severe, adrenal aldosterone secretion is not sufficient for sodium reabsorption by the distal renal tubules, and individuals suffer from salt wasting as well as cortisol deficiency and androgen excess.86,87 Children with both forms of classical CAH have signs of hyperandrogenism such as premature adrenarche and puberty, rapid somatic growth and bone age advancement, leading to short stature in adulthood. Adolescent and adult women may develop hirsutism, acne, male pattern alopecia, irregular menses, and infertility. Non-classical 21-OHD (NC 21-OHD) is much more common than the classical form, with an incidence as high as 1:27 in Ashkenazi Jews.88 Individuals with the non-classical (NC) form of 21-OHD have only mild to moderate enzyme deficiency. Females with NC-CAH do not have virilized genitalia at birth, however may have many signs and symptoms associated with hyperandrogenemia as seen in classical disease, including impaired fertility. The reasons for infertility in females with CAH include anovulation and irregular menses, secondary polycystic ovarian syndrome, non-suppressible serum progesterone levels, or an inadequate introitus which can affect up to one-third of adult females with classical CAH. In a retrospective survey of fertility rates in a large group of females with classical CAH, simple virilizers were shown to be more likely to become pregnant and carry the pregnancy to term than patients with salt-wasting disease. Non-classical CAH is an important and not an uncommon cause of infertility. Adequate glucocorticoid therapy is a key variable with respect to fertility outcome. The development of PCOS in CAH patients is not uncommon and may be related to both prenatal and postnatal excess androgen exposure, which can affect the hypothalamic-pituitary-gonadal axis. Since vaginal dilatation is needed to maintain good patency in women with classical CAH, vaginoplasty is delayed until sexual intercourse is regular or when the patient can assume responsibility for vaginal dilatation.89 Women with classical disease are aware of their diagnosis before conception and pregnancy. Adequate control of adrenal hormones with sufficient glucocorticoid therapy is needed to achieve fertility. In women with non-classical 21-OHD, the condition may only be diagnosed during a work-up for infertility, at times after multiple failed in-vitro fertilization cycles. The goal of therapy in CAH is to both correct the deficiency in cortisol secretion and to suppress ACTH overproduction. The usual requirement of hydrocortisone (or its equivalent) for the treatment of classical 21-OHD form of CAH is about 10–15 mg/m2/day divided into 2 or 3 doses per day, with the higher dose given at bedtime. Hydrocortisone is the preferred treatment of pregnant women affected with CAH. Non-pregnant adults may be treated with the longer-acting dexamethasone or prednisone, alone or in combination with hydrocortisone. Dosage requirements for patients with NC-21OHD CAH are typically less. A small dose

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of dexamethasone at bedtime (0.25–0.5 mg) is usually adequate for androgen suppression in nonclassical patients who are not pregnant; dexamethasone should be avoided in pregnancy because it crosses the placenta. Prednisone is less favored treatment in non-pregnant patients with CAH, and there is evidence that both prednisone and prednisolone cross the placenta, although in smaller concentration than dexamethasone.90,91 Adequate biochemical control is assessed by measuring serum levels 17-OHP, androstenedione and testosterone. We recommend that hormone levels are measured at a consistent time in relation to medication dosing, usually 2 h after the morning corticosteroid. Titration of the dose should be aimed at maintaining androgen levels within the normal range for adult women and 17-OHP levels of <1000 ng/dL. Over-treatment should be avoided because it can lead to Cushing’s syndrome. During pregnancy, when treating the mother with CAH and not the fetus, hydrocortisone treatment is recommended because, unlike dexamethasone, it is metabolized by the placental enzyme 11b-HSD 2 and does not affect the fetus. We recommend checking 17-OHP and androgens at least every trimester. It is well-known that androgens and 17-OHP rise during pregnancy, but unfortunately pregnancy normal values have not been established. For labor and delivery, stress doses of hydrocortisone should be administered, as discussed above in the Adrenal Insufficiency section. Advances in genotyping of the CYP21A2 gene have made molecular genetic studies of extracted fetal DNA the ideal method to diagnose 21-OHD CAH in the fetus. In family at risk, genotyping both parents before conception is recommended, when possible. Approximately 95%–98% of the mutations causing 21OHD have been identified through a combination of molecular genetic techniques to study large gene rearrangement and arrays of point mutations.92,93 In pregnancies at risk for CAH, the timing of prenatal diagnosis is particularly important when deciding to treat the fetus with dexamethasone prenatally to prevent masculinization of the genitalia (see Prenatal Treatment below). We only wish to treat affected females until term, and as CAH is an autosomal recessive disorder, only ¼ of the fetuses will be affected and ½ will be males; hence, 7 out of 8 fetuses do not require treatment. Amniocentesis, which is usually performed in the second trimester, results in treatment of unaffected fetuses for a longer period of time than chorionic villous sampling (CVS), which can be performed at the 9th to 11th week of gestation. However, amniocentesis can be used as a reliable alternative method of prenatal diagnosis when CVS is unavailable. In such instances, the cells are cultured to obtain a genotype through DNA analysis. In a small percentage of patients undergoing prenatal genetic diagnosis, pitfalls can occur, including undetectable mutations,94 allele drop outs,95 or maternal DNA contamination. Determination of satellite markers may increase the accuracy of molecular genetic analysis.96 Preimplantation genetic diagnosis (PGD) has been utilized in many monogenic recessive disorders and other genetic diseases.97 There is only one report of PGD utilized in a family whose offspring was at risk for CAH,98 however we know from experience that families are seeking PGD with greater frequency. In 21-OHD, prenatal treatment with dexamethasone was introduced in France in 197899 and in the United States in 1986.100 When started before the 9th week of gestation, prior to the onset of adrenal androgen secretion, prenatal treatment of 21-OHD has proven to be successful in significantly reducing genital masculinization in affected females by suppressing excessive adrenal androgen production. Dexamethasone is used because it binds minimally to CBG in the maternal blood, and unlike hydrocortisone, it escapes inactivation by the placental enzyme 11b-HSD 2. Thus, dexamethasone crosses the placenta from the mother to the fetus and suppresses ACTH secretion with longer half life compared to other synthetic steroids.101 Because treatment must start so early in the gestation, it is blind to the disease status and sex of the fetus. If the fetus is later determined to be a male upon karyotype or an unaffected female upon DNA analysis, treatment is discontinued. Otherwise, treatment is continued to term. A simplified algorithm of management of potentially affected pregnancies is shown in Fig. 3. The optimal dosage is 20 mg/kg/ day of dexamethasone per maternal pre-pregnancy body weight, in three divided daily doses.101 It is recommended to start the treatment as soon as pregnancy is confirmed, and no later than 9 weeks after the last menstrual period.102,103 The mother’s blood pressure, weight, glycosuria, HbA1C, symptoms of edema, striae and other possible adverse effects of dexamethasone treatment should be carefully observed throughout pregnancy.104

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Fig. 3. Algorithm of treatment, diagnosis and decision-making for prenatal treatment of fetuses at risk for 21-hydroxylase deficiency congenital adrenal hyperplasia.102 Permission obtained.

According to our most recently analyzed data from 1978 to early 2011, our group has performed prenatal diagnosis in 719 pregnancies at risk for 21OHD, and 63 affected female fetuses have been treated to term (Fig. 4). Treatment was highly effective in preventing genital ambiguity when the mother was compliant until term. In all the female fetuses treated to term, the degree of virilization was on average 1.7, as measured using the Prader scoring system. Late treatment as well as no treatment resulted in much greater virilization, and the average Prader score was 3.73 for those female fetuses not treated,100 (new unpublished data). Not only does prenatal treatment effectively minimize the degree of female genital masculinization in the patients, it also lessens the high-level androgen exposure of the brain during differentiation. The latter is thought to cause a higher tendency to gender ambiguity in some females with CAH.105,106 Genital virilization in female newborns with classical 21OHD CAH has potential adverse psychosocial implications that may be alleviated by prenatal treatment.101 Prenatal dexamethasone treatment has recently been a subject of controversy and heated debate.107 Some uncertainties have been expressed about the long-term safety of prenatal diagnosis and treatment.108,109 Concerns have been raised in regards to the glucocorticoid effects on the fetal brain, which arise from studies of other conditions rather than direct studies on prenatal treatment of 21OHD CAH. These include studies whereby much higher doses of dexamethasone were given to the human subjects at the later part of pregnancy110 or to animals,111,112 and therefore they hold little relevance to using dexamethasone prenatally in CAH. In a small-sample study of children prenatally treated with dexamethasone, Lajic and her colleagues found no effects on intelligence, handedness, memory encoding, or long-term memory, but short-term treated CAH-unaffected children had significantly poorer performance than controls on a test of verbal working memory. These patients also had lower

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Fig. 4. Updated results on prenatal diagnosis and treatment of Congenital Adrenal Hyperplasia from the Adrenal Steroid Disorders Group, Division of Pediatric Endocrinology, Mount Sinai School of Medicine.

questionnaire scores in self-perceived scholastic competence and social anxiety.113 However, parents described these children as more sociable than controls, without significant difference in psychopathology, school performance, adaptive functioning or behavioral problems.114 Compelling data from large cohorts of pregnancies with prenatal diagnosis and treatment of 21-OHD CAH prove its efficacy and safety.115,116 In our studies all the mothers who received prenatal treatment (partial or full-term) stated that they would take dexamethasone again for a future pregnancy.117 Rare adverse events have been reported in treated children, but no harmful effects have been documented that can be clearly attributed to the treatment.118 Another long-term follow-up study in Scandinavia showed that 44 children who were variably treated prenatally demonstrated normal prenatal and postnatal growth compared to matched controls. Furthermore, there was no observed increase in fetal abnormalities or fetal death.119 Although some abnormalities in postnatal growth and behavior were observed among dexamethasone exposed offsprings, none could be explained by the present knowledge of teratogenic effects of glucocorticoids. In our comprehensive published studies of almost 600 pregnancies, 80 of whom were prenatally treated until term and 27 who were male and received dexamethasone for a short period of time, the newborns in the dexamethasone treated group did not differ in weight, length or head circumference from untreated, unaffected siblings. No significant or enduring side effects were noted in either the mothers or the fetuses. Greater weight gain in treated versus untreated mothers did occur, as did the presence of striae and edema. Excessive weight gain was lost after birth. No differences were found regarding gestational diabetes or hypertension.112 No cases have been reported of cleft palate, placental degeneration or fetal death, which have been observed in the rodent model of in utero exposure to high-dose glucocorticoids.120 One explanation for the safety of human versus rodent is that glucocorticoid receptor-ligand systems in human differ from that of rodents.121 Most recently, our group conducted a comprehensive, long-term outcome study looking at 149 male and female patients 12 years of age and older, affected and unaffected with CAH, who were treated with dexamethasone partially or to term. To date, this is the largest study evaluating the long-term effects of dexamethasone. We found no adverse effects such as increased risk for cognitive defects, disorders of gender identity and behavior, sexual function in adulthood, hypertension, diabetes, and osteopenia.122 Advances in genotyping of the CYP11B1 gene have made molecular genetic studies of extracted fetal DNA the ideal method to diagnose 11b-OHD CAH in the fetus.123,124 The established protocol of prenatal diagnosis and treatment in 21OHD CAH can be applied to 11b-OHD CAH. Successful results in prenatal diagnosis and treatment in 11b-OHD CAH have been reported.123,125

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Summary Adrenal disorders in pregnancy are not common and may be difficult to diagnose because of the many pregnancy-induced changes. However, a timely diagnosis and treatment are critical because these disorders can lead to significant maternal and fetal morbidity. A diagnostic approach to Cushing’s syndrome and adrenal insufficiency, including laboratory work-up and imaging studies, must be carefully tailored specifically to pregnancy, accounting for the pregnancy-induced changes and the safety and accuracy of radiographic studies. While multiple invaluable case reports and small studies have taught us a great deal about the diagnosis and treatment of these disorders, some questions remain unanswered. Normative values should be established for cortisol levels in pregnancy, particularly for midnight serum and salivary cortisol. Furthermore, studies should be conducted to evaluate the long-range outcome of children born to mothers who were affected with Cushing’s syndrome and adrenal insufficiency during pregnancy. CAH is an important cause of infertility, particularly in the frequent non-classical form owing to 21hydroxylase deficiency. During pregnancy, women with CAH require careful monitoring and treatment. Hydrocortisone, which does not cross the placenta, should be utilized in all pregnant patients with the disorder if the fetus is not at risk for the disease, i.e. if the father does not carry any mutations. Fludrocortisone should be added in those patients who have the salt-wasting form. In those pregnancies where the fetus is at risk for the classical form of 21-hydroxylase deficiency, dexamethasone is used prenatally to prevent genital masculinization should the fetus be an affected female. The new and innovative method of non-invasive prenatal diagnosis, utilizing harvested fetal DNA from maternal blood, should be investigated as a way to establish a genetic diagnosis in fetuses at risk for CAH. This would eliminate invasive diagnostic procedures and unnecessary prenatal treatment with dexamethasone.

Practice points  Adrenal disorders in pregnancy are not common, but a timely diagnosis and treatment are critical because these disorders can lead to significant maternal and fetal morbidity  Adrenal disorders are difficult to diagnose as pregnancy may alter the manifestation of disease, many signs and symptoms associated with pregnancy are also seen in adrenal disorders, and the biochemical profile is altered by pregnancy-induced changes  A careful diagnostic approach to Cushing’s syndrome and adrenal insufficiency, including laboratory work-up and imaging studies, must be tailored specifically to pregnancy, accounting for the pregnancy-induced changes and the safety and accuracy of radiographic studies  Congenital adrenal hyperplasia (CAH) is an important cause of infertility, particularly in the frequent non-classical form due to 21-hydroxylase deficiency  Congenital adrenal hyperplasia in both the classical and non-classical forms requires careful monitoring and treatment of the affected woman during pregnancy. Hydrocortisone should be utilized in all pregnant patients with the disorder if the fetus is not at risk for the disease, and fludrocortisone should be added in those patients who have the salt-wasting form of the disease  In families at risk for having a child with CAH, both parents should be genotyped to determine the risk to the fetus. If the child is at risk for classical CAH, dexamethasone may be administered to the mother prenatally to prevent genital masculinization in an affected female. Because it crosses the placenta, dexamethasone should be avoided in mothers who are affected with CAH and whose fetus is not at risk for the disease, and hydrocortisone should be used instead.

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Research agenda  Normative values should be established for cortisol levels in pregnancy, particularly for midnight serum and salivary cortisol  Normative values should be established for 17-hydroxyprogesterone, androstenedione and testosterone levels in pregnancy for patients affected with CAH to assess the efficacy of treatment  Studies should be conducted to evaluate the long-range outcome of children born to mothers who were affected with Cushing’s syndrome, adrenal insufficiency and CAH  The method of non-invasive prenatal diagnosis, utilizing harvested fetal DNA from maternal blood, should be investigated as a way to establish a genetic diagnosis in fetuses at risk for CAH. This would eliminate invasive diagnostic procedures and unnecessary prenatal treatment with dexamethasone

Acknowledgments We would like to thank Dr. Arun Abraham, Meredith F. Roy and Allison Feldman for their invaluable help with the manuscript.

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