Contents
Contributors
Search

During pregnancy increased steroid hormone production is essential to meet both the maternal demand for increased estrogens and cortisol and the fetal demand for reproductive and somatic growth and development. In addition, alterations in the renin-angiotensin-aldosterone cascade are required to allow for a 50% increase in maternal blood volume without resulting in hypertension. These changes occur through a complex interaction amongst maternal and fetal endocrine systems in the placenta.

CHANGES IN ADRENAL ANATOMY AND PHYSIOLOGY DURING PREGNANCY

The normal adult adrenal gland weighs approximately 5gms and during pregnancy increases only slightly in size. Histologically, the zona fasciculate (glucocorticoids) widens during pregnancy, which is suggestive of increased secretion. The zona glomerulosa (mineralo-corticoids) and zona reticularis (androgens) remain unchanged in width (1,2).

CONTROL OF THE ADRENAL CORTEX DURING PREGNANCY

Hypothalamic-pituitary-adrenal axis; Corticotropin-releasing hormone (CRH) is secreted from the hypothalamus, as well as from lungs, liver, gastrointestinal tract, adrenal glands and the placenta (3). CRH releases pro-opiomelanocortin and its breakdown products, including ACTH from the anterior pituitary gland. Release of CRH from the hypothalamus is stimulated by stress, volume contraction and other factors, and is inhibited by glucocorticoids and ACTH.

During pregnancy, maternal CRH levels increase dramatically, predominantly as a result of placental production (4). Placental CRH enters both the maternal and fetal circulation (5). Placental CRH production is stimulated by circulating glucocorticoids, which is in contrast to the negative feedback on hypothalamic production of CRH. Placental CRH entering the fetal circulation may stimulate the fetal pituitary-adrenal axis and this in turn may play a role in fetal organ maturation and also parturition (6).

During pregnancy, ACTH levels increase approximately twofold after the first trimester (Table 1). This increase is, in part, placental in origin and may be a local paracrine effect of placental CRH production. Placental ACTH is not suppressible by glucocorticoids. The normal circadian rhythm of high morning and low evening ACTH and cortisol levels continues throughout pregnancy (7). The stress of labor causes ACTH levels to increase rapidly and then decrease within two days postpartum. (See Table 1)

Cortisol circulates both bound (primarily to cortisol-binding globulin). Both total cortisol, (as measured by serum cortisol), and free cortisol (as measured by 24 hour urinary free cortisol) increase. Serum cortisol levels increase twofold to threefold during pregnancy, mainly due to the increase in corticosteroid-binding globulin levels (CBG). (8). However, increased free and total cortisol levels in pregnancy may also be related to resetting of the sensitivity of the hypothalamic-pituitary-adrenal axis and not merely to raised CBG, progesterone or CRH levels (8). (See also Table 1)

Exogenous corticosteroids are variably affected by placental enzymatic activity and thus have different rates of placental transfer (Table 2). This is important to consider when these medications are prescribed, because maternal and fetal availability will differ. As glucocorticoids like Dexamethasone increase placental CRH and placental ACTH activity, the Dexamethasone suppression test is unreliable in pregnancy (9). (See Table 2)

Adrenal cortex synthesizes three main androgens: androstenedione, dehydroepiandrosterone (DHEA) and DHEA sulfate. During pregnancy the levels of specific androgens change, because they are dependent on changes in both production rates and metabolic clearance. Androstenedione and total testosterone levels increase in pregnancy, whereas DHEA and free testosterone levels decrease (10).

THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM IN PREGNANCY

The renin-angiotensin-aldosterone system includes a series of factors that regulate blood pressure, circulating blood volume, and sodium-potassium homeostasis. Renin production from the juxtaglomerulus apparatus in the kidney is controlled by renal arteriolar blood pressure, sodium concentration in the distal tubule and beta-adrenergic receptors.

Aldosterone is the major circulating mineralo-corticoid and controls sodium reabsorption and potassium and bicarbonate excretion in the distal renal tubule. Its secretion is primarily controlled by angiotensin II, but hyper-kalemia, ACTH and vasopressin are also stimulants (11).

During pregnancy, the pregnant woman must increase plasma volume, and also thus sodium reabsorption, without increasing blood pressure. In spite of the increase in extra cellular fluid volume, plasma renin activity levels increase fourfold between 8 and 20 weeks of gestation, after which they plateau. (see Table 3)

Angiontensin 2 levels are increased threefold as a result of increased renin and angiotensinogen. However, resistance to the pressure effect of angiotensin 2 develops by seven weeks of gestation and reaches a maximum at 28 weeks. After 30 weeks gestation there is some return of sensitivity. This does not reach the value seen in the non-pregnant state (12, 13).

Aldosterone levels in pregnancy increase fourfold by 8 weeks and continue to increase reaching a tenfold increase by term. This is in response to increased renin and angiotensin 2 levels (12). (See Table 3)

CUSHING'S SYNDROME

Cushing's Syndrome is caused by excess glucocorticoid production of any cause. It may be due to excess ACTH stimulation of the adrenal cortex (ACTH-dependent Cushing's Syndrome). If the ACTH is from a pituitary adenoma, the disorder is known as Cushing's Disease. ACTH may come from ectopic sources. Cushing's Syndrome may be independent of ACTH, as in adrenal adenoma or carcinoma, and glucocorticoid therapy. Cushing's Syndrome in pregnancy is rare, because ACTH dependent cases have a 75 to 95% incidence of menstrual irregularities and anovulation (14). The causes of Cushing's Syndrome in pregnancy are very different from the non-pregnant woman, and adrenal causes of Cushing's Syndrome are over represented relative to ACTH-dependent causes. (See Table 4)

The clinical presentation of Cushing's Syndrome in pregnancy may be difficult to recognize, because several features of hypercortisolemia, such as moon facies, abdominal striae, and glucose intolerance, are common during pregnancy. Clues to diagnosis of Cushing's Syndrome in pregnancy are that the striae tend to be wider, greater than 1cm, and darker, and tend to occur in sites other than the abdominal wall. The presence of proximal myopathy, hypertension, neuro-psychiatric disturbances, hirsutism, acne and spontaneous bruising, are all helpful clues.

Diagnosis

Diagnosis of Cushing's Syndrome is often difficult to make in the non-pregnant state. Diagnosis is even more challenging during pregnancy because of the altered hypothalamic-pituitary-adrenal axis, and placental production of CRH and ACTH. As in the non-pregnant state, investigation should occur in three stages. 1) Screening test for hypercortisolemia. 2) Definitive biochemical diagnosis and 3) Determination of the cause. (See Table 4)

The best screening test in pregnancy is a 24-hour urine collection for free cortisol, since the urinary free cortisol range differs in pregnancy, the higher reference range found in Table 1 should be utilized. The diurnal variation of plasma cortisol may also be used, because it is unaffected by pregnancy. (See Table 1) The 1.0mg overnight Dexamethasone suppression test is not accurate in patients during pregnancy, because placental ACTH is not suppressed by glucocorticoids.

If the urinary free cortisol test suggests hypercortisolemia, a two day low dosage Dexamethasone suppression test should be used (0.5mg every 6 hours). Dexamethasone is safer to use in pregnancy, as the maternal:fetal concentration are 2:1 (15). During pregnancy urinary free cortisol should suppress to less than 55nmol for 24 hours.

After hypercortisolemia is confirmed, its cause must be established. Measurement of ACTH is done to differentiate ACTH dependent from ACTH independent causes. Due to placental production, ACTH dependent cases are increased in pregnancy (See Table 1). If the Cushing's Syndrome is ACTH-dependent then MRI of the pituitary should follow. If the Cushing's Syndrome is ACTH independent, an MRI of the adrenal is indicated. MRI is preferred for both pituitary and adrenal lesions, because of its specificity and lack of ionizing radiation. Bilateral inferior petrosal sinus corticotropin sampling with CRH stimulation may also be helpful in the differential diagnosis of Cushing's Syndrome. An increase of more than 50% in ACTH, or more than 20% in cortisol after 1microgram per kilogram of ovine CRH suggests a pituitary source. Comparison of plasma ACTH levels in the venous drainage of the pituitary gland with peripheral values, allows localization and lateralization within the pituitary. A modified approach through brachial rather than femoral veins is preferred to reduce radiation exposure. However, case reports have demonstrated that the procedure of bilateral simultaneous inferior petrosal venous corticotropin sampling can be safely performed during pregnancy (16).

Treatment

If untreated during pregnancy Cushing's Syndrome has a poor fetal and maternal outcome. The outcome seems to be improved when the hypercortisolemic state is treated. Trans-sphenoidal surgery is preferred for ACTH dependent pituitary adenoma. For adrenal lesions, unilateral adrenalectomy during pregnancy decreases neonatal complications. This should be done unless the diagnosis is made late in pregnancy (17). Cortisol replacement is required after both adrenal and pituitary surgery and should be continued until the hypothalamic pituitary axis has had time to recover. High dose corticosteroid therapy should be utilized at times of stress, such as delivery.

If surgical therapy is contraindicated, medical therapy may be considered. Metyrapone and Ketoconazole have both been used in pregnancy but only in a few cases. The fetal risks of both these agents are not known (18). (See Figure 2)

The optional treatment for adrenal carcinoma in pregnancy has not been established. If the carcinoma is diagnosed in the first trimester, therapeutic termination of pregnancy should be considered with definitive therapy by surgery and chemotherapy following. In the second trimester adrenalectomy may be performed with postoperative Ketoconazole or Metyrapone therapy. Although no adverse fetal/neonatal side effects have been reported with either drug, usage has been very limited. In the third trimester Ketoconazole or Metyrapone can be used until delivery is feasible, followed by definitive surgery and chemotherapy postpartum. Despite the use of surgery and chemotherapy the maternal prognosis remains grim, although fetal prognosis is good.

Adreno-nodular hyperplasia in pregnancy should be treated by bilateral adrenalectomy.

PRIMARY HYPERALDOSTERONISM IN PREGNANCY (HA)

Primary hyperaldosteronism (HA) is the excess production of aldosterone from the adrenal cortex, and causes hypertension, hypokalemia and bicarbonate retention (metabolic alkalosis). It is a very rare cause of secondary hypertension in pregnancy. In pregnancy between 60 and 70% of cases are due to a unilateral benign adrenal adenoma (19).

Clinical Presentation and Diagnosis

Hypertension in association with hypokalemia is a classic presentation but 7 to 40% of women have normal potassium levels. Very low potassium levels may cause the symptoms of headache, muscle weakness, muscle cramps, and fatigue. Serum sodium levels are high normal and metabolic alkalosis is present. Normally in pregnancy, there is a respiratory alkalosis with a compensatory decrease in bicarbonate of 4mEq/L. Thus in pregnancy one must compare bicarbonate levels to the reference range of 18 to 22mEq/L. If hypokalemia is present, urinary potassium levels greater than 30mmol for 24 hours are required to confirm renal potassium wasting. Before further biochemical testing is done, the hypokalemia should be corrected and the use of any medications that suppress renin, such as beta-blockers and calcium-channel blockers and spironolactone must be discontinued. Aldomet may be used to control the hypertension during investigations (20).

The normal increase in aldosterone into the hyperaldosteronism range during pregnancy makes baseline plasma aldosterone levels difficult to interpret (See Table 3). Plasma renin levels should be decreased in primary hyperaldosteronism and are increased during pregnancy. In pregnant patients with primary hyperaldosteronism renin levels are suppressed and are therefore helpful in diagnosis.

Normally, to confirm autonomous mineralocorticoid secretion, salt-loading studies are done. In pregnancy, however, there is a risk for volume overload, worsening hypokalemia, and a lack of established diagnostic criteria, all of which limit the usefulness of this test in pregnancy. The rennin/aldosterone response to the upright position is maintained in pregnancy, but normal values for renin stimulation have not been established.

Imaging should be done after biochemical confirmation and MRI is the preferred imaging tool.

Treatment

In pregnancy the use of medical therapy to reduce the production or inhibit the action of aldosterone is difficult because of the risk for adverse fetal effects. In the non-pregnant situation spironolactone has been used, but in pregnancy there is concern about the risk of feminization of a male fetus, as the drug is a mild anti-androgen. The ACE inhibitors again are helpful in non-pregnant women but they are contraindicated in pregnancy due to neonatal malformations and the risk of neonatal renal failure. Calcium-channel blockers have a reducing effect on aldosterone synthesis and release, and are safe to use in pregnancy and are more effective than Aldomet or beta blockers (21). Surgical removal of an identified adrenal adenoma is the treatment of choice. Adrenalectomy performed at 15 and 17 weeks of gestation normalized blood pressure in pregnancy and healthy term infants were delivered. Therefore if hypertension or hypokalemia cannot be controlled medically, surgery is definitely warranted during the second trimester (22).

ANDROGEN-PRODUCING ADRENAL ADENOMAS IN PREGNANCY

Virilizing adrenal adenomas are rare during the reproductive years. Some androgen producing adrenal adenomas have been gonadotropin-responsive, but most are associated with amenorrhea and infertility (23). Adrenal androgen-producing adenomas are very rare in pregnancy and only 5 cases have been reported to-date (Figure 3). Virilization of female infants has been reported in each case. This suggests that high maternal-fetal placental transfer of testosterone occurred during the first trimester (7-12 weeks), as this is the time when labial fusion and cliteromegaly can develop. Between the second and third trimesters maternal-fetal transfer of testosterone is minimal due to placental aromatization (24).

Figure 3. Maternal Signs of an Adrenal Adenoma producing androgens presenting during pregnancy. A. Alopecia onset Third Trimester. B. Abdominal Hirsutism. C. Bisected Adenoma 11.8 x 6.7 x 4.9cm weight 239g (Courtesy of Dr. T.C. Ooi).

Maternal signs of adrenal adenoma producing androgens usually include increasing hirsutism, alopecia and vocal change. However, a definitive diagnosis in all reported cases was undertaken only postpartum after delivery of a virilized female fetus. Surgical therapy at the time of diagnosis is the treatment of choice. (See Figure 3)

ADDISON'S DISEASE IN PREGNANCY

Adrenocorticol insufficiency (ACIS) is a result of inadequate production of adrenocorticosteroid hormones, and may be acute or chronic, and primary or secondary. Primary ACIS (Addison's Disease) is caused by deficient steroid production due to an adrenal lesion, whereas secondary ACIS is a result of the adrenal cortex being under-stimulated by tropic hormones. If the clinical presentation of ACIS is insidious, with a prolonged period of partial hormone deficiency, it becomes chronic ACIS. This may end in an abrupt crisis of acute ACIS when hormone production is below a critical point, or the individual is stressed by intercurrent illness. Hormone deficiency usually is combined due to disease of all the three adrenal zones, with decreased production of aldosterone, glucocorticoids, and androgens. Occasionally ACIS may be a result of isolated steroid deficiency, but only decreased production of aldosterone and cortisol have important clinical sequelae. Autoimmune adrenalitis causes 85% of primary ACIS. All three zones of the adrenal cortex exhibit diffuse mononuclear cell infiltration histologically and adrenal auto-antibodies are found in the serum of two thirds of individuals (25). In addition, more than half of all patients show cell mediated immunity against the adrenal cortex. ACTH receptor blocking antibodies have also been isolated (26).

CHRONIC ACIS IN PREGNANCY

The diagnosis of chronic ACIS (Addison's Disease) presenting in pregnancy may be difficult, because some clinical features, for example, vomiting, weakness, syncope, and hyper-pigmentation may also accompany normal pregnancies. If undiagnosed, chronic ACIS may develop into an acute crisis following stress, such as hyperemesis gravidarum, infection, or delivery. Prior to corticosteroid therapy, maternal mortality was 77% (27). With full corticosteroid replacement therapy, maternal morbidity and mortality no longer are increased.

The clinical diagnosis should be entertained in a pregnancy complicated by excessive vomiting during the first 2 trimesters, or by weakness, hypotension, and hyper-pigmentation during early pregnancy or postpartum. Hyper-pigmentation can be differentiated from the chloasma of pregnancy, when the pigmentation is found in the mucous membranes of the mouth, rectum, or vagina, over non-exposed areas or over extensor surfaces of the body.

Diagnosis

Laboratory diagnosis can be made more difficult by the normal physiological changes that accompany pregnancy. Common findings include hyponatremia, hyperkalemia, eosinophilia, hypoglycemia, hypercalcemia, and elevated BUN. Plasma cortisol levels may be in the normal "non-pregnant" range due to the rise in the corticosteroid binding globulin (CBG) concentrations in pregnancy. Low baseline plasma or urinary corticoid steroid estimations are not adequate for the diagnosis of chronic ACIS. The diagnosis is best made by finding high plasma ACTH levels and low plasma cortisol levels, both for the stage of pregnancy (See Table 1). In chronic ACIS plasma cortisol levels do not respond to Cosyntroprin (Synacthen) 0.25mg given intra-muscularly. Basal plasma cortisol levels normally double within 30 minutes of giving Cosyntroprin (28).

The traditional methods of testing the pituitary-adrenal axis by a Metyrapone test or an insulin-hypoglycemia stress test, should be avoided in pregnancy. CRH stimulation testing has been found to be of value in the diagnosis of primary ACIS in non-pregnant research subjects. Recent reports suggest a hyper responsiveness of ACTH to CRH in primary ACIS but a diminished response in pituitary disease. There are no reports of this test being used in pregnancy to-date.

Demonstration of adrenal antibodies in the plasma confirms an autoimmune etiology, but the concentration of these antibodies may fall during pregnancy. MRI imaging of the adrenals may reveal calcification suggesting a tuberculous or fungal infection as the cause.

Management of Chronic Adrenocortical Insufficiency in Pregnancy

As in the non-pregnant state, replacement of glucocorticoids during pregnancy is carried out with either cortisol (30mgs per day), cortisone (37.5mgs per day), Prednisone (7.5mgs per day), or Dexamethasone (0.75mgs per day). The latter two glucocorticoids have little mineralocorticoid activity. Glucocorticoid therapy in human pregnancy is not associated with an increase in congenital malformations, although cleft palate has been reported in rabbits. There has been a theoretical concern that maternal steroid therapy could suppress the fetal hypothalamic-pituitary-adrenal axis, but this has not been upheld on neonatal ACTH stimulation testing (29). The maternal:fetal concentrations of steroids is shown in Table 2.

Long term follow up of children exposed to glucocorticoids therapy during pregnancy has been undertaken. Neurologic assessment at 3 and 6 years of age is normal and psychometric testing reveals no deficit. Somatic growth is also similar to that of control children of similar age. Maternal glucocorticoid administration should be changed from the oral to the parenteral route at times of stress during pregnancy, such as severe pregnancy emesis, infections, or delivery. A suitable regimen is hydrocortisone sodium succinate 200 to 300mgs daily i.m or by intravenous infusion.

Women with mineralo-corticoid deficiency also should receive Fludrocortisone 0.05-0.10mgs daily in addition to the glucocorticoids. Fludrocortisone usually is not necessary in secondary adrenal insufficiency, as mineralocorticoid secretion is not primarily under pituitary control. In primary adrenal insufficiency, the Fludrocortisone dosage should be decreased in pregnancy if hypertension or hypokalemia occurs. Careful monitoring of electrolyte levels is required if hyperemesis gravidarum or pre-eclampsia complicate the pregnancy.

Effect of Chronic ACIS on Fetal/Neonatal Outcome

Women with undiagnosed chronic ACIS have been found to have suboptimal fetal growth patterns, but this is not a uniform finding. Maternal antibodies to the adrenal cortex do cross the placenta but not in sufficient concentration to cause fetal or neonatal adrenal insufficiency. Neonatal hypoglycemia has been reported rarely but seldom requires intervention and glucocorticoid therapy of the newborn is not indicated (30).

Acute ACIS in Pregnancy

Acute ACIS or addisonian crisis can occur in pregnancy in a woman with chronic ACIS who is stressed or in one who is undiagnosed. It also may result from any obstetric complication that results in DIC, such as eclampsia, amniotic fluid embolus, or postpartum hemorrhage. The resultant bilateral massive adrenal hemorrhage is an acute emergency presenting with nausea, vomiting, abdominal pain, and shock, and it frequently is fatal. Death can be prevented by early recognition and treatment. A similar presentation has been noted in the third trimester of pregnancy or in the postpartum period in association with acute pyelonephritis, gram negative bacillemia, and fulminant meningococcal infection (Waterhouse-Friderichsen Syndrome). The largest series of acute ACIS in pregnancy has been reported by MacGillivray (31).

Emergency treatment of acute ACIS in pregnancy should include cortisol hemisuccinate 200mgs intravenously as a bolus, followed by a 100mgs in each litre of normal saline solution. The first litre should be given over 30 minutes, and hydration may take 5 to 6 litres. Hypoglycemia should be avoided by a 50gm glucose infusion. As the woman will receive up to 600mgs of cortisol by this method, no added mineralocorticoid is required.

CONGENITAL ADRENAL HYPERPLASIA IN PREGNANCY

The congenital adrenal hyperplasias (CAH) are a group of inherited enzymatic defects of adrenal steroid biosynthesis. Deficiencies of each enzyme required in the steroid biosynthesis pathway are known, and these deficiencies are all inherited as autosomal recessive disorders (Figure 4, below). During pregnancy maternal and fetal problems are confined to women who have 21-hydroxylase deficiency (21-OHD), 11-hydroxylase deficiency (11-OHD), and 3-beta-hydroxy steroid dehydrogenase deficiency (3-beta-HSD), because other adrenal enzyme deficiencies are not compatible with fertility. The inter-position of the placenta on the hypothalamic-pituitary-adrenal axis, and other endocrine changes during pregnancy, impact considerably on the clinical evaluation of the congenital adrenal hyperplasias. Successful management of CAH in pregnancy requires a firm knowledge of normal adrenal, anatomic and endocrine changes that occur during gestation. Women with severe forms of CAH have decreased fertility rates because of oligo-ovulation, and successful conception requires a combination of good therapeutic compliance, careful endocrine monitoring, and often ovulation induction. From a fetal and neonatal standpoint, accurate prenatal diagnosis of these three enzyme deficiencies is now possible, which allows for prenatal treatment in an attempt to minimize clinical problems in the neonate. Prevention of masculinization of affected female fetuses by corticosteroid suppression has been attempted in all three enzyme deficiency states with variable degrees of success.

Figure 4. Adrenal steroid biosynthesis pathway ßHSD = ß Hydroxysteroid dehydrogenase; DOC = Deoxycorticosterone. DHEA Dehydroepiandrosterone.

All enzyme defects causing CAH are autosomal recessive conditions. It is a relatively common disease occurring in 1 in 5000 to 1 in 15,000 births in most populations (32). 21-OHD has a particularly high frequency in Yupik Eskimos, and Hispanics. Carrier rates of 21-hydroxylase deficiency vary between 1.2% to 6% of the population. The gene responsible for 21-OHD was isolated in 1984 and since then knowledge of the mutations that cause the different forms of CAH has grown rapidly. Of clinical importance is that the clinical expression of endocrine disease is not always correlated with the mutations of the primary structural gene. Clinicians, therefore, cannot accurately predict the cause of the disease or make therapeutic decisions based on genotype alone (32).

THE PATHOPHYSIOLOGY OF CONGENITAL ADRENAL HYPERPLASIA

CAH is an abnormality of steroid biosynthesis. Most steroidogenic enzymes belong to the cytochrome P450, group of oxydases (33). These enzymes bind the steroid substrate and mediate steroidal conversion. Most P450 enzymes can act on multiple substrates and can also catalyze many oxidation steps. This accounts in part for the broad clinical spectrum of steroid hormone deficiency seen when associated with a single P450 enzyme defect. Thus the complete absence of a particular adrenal P450 enzyme may not result in total deficiency of a particular adrenal steroid, because each enzyme has multiple activities, and because many other tissues besides the adrenal have enzymes with steroidogenic activity. The P450c21 enzyme is found in the cellular endoplasmic reticulum. The P450c11 enzyme is located in the mitochondria. The 3-beta-OHD enzyme is a non-P450 enzyme and it is found in the endoplasmic reticulum. There are two P450c21 genes (P450c21A and P450c21B) which are located on the short arm of chromosome 6 in the middle of the region of the major histocompatibility (HLA) locus. The P450c21A gene is non-functional and is known as a pseudogene. The P450c21A pseudogene can exert an effect on the active P450c21 B gene by exchanging DNA, which is known as gene conversion. Because the P450c21genes are linked to the HLA locus, this association was used clinically to assess whether the fetus was a CAH carrier or would be affected. However, HLA typing has now been superseded by molecular genetic techniques.

There has been a high rate of genetic crossovers and other changes in the HLA locus and several gene duplications involving the P450c21B gene. Because of this large number of different defects in the P450c21B gene, most subjects affected with this type of CAH are "compound heterozygotes" and will have different genetic lesions found on each of the two 21-B genes. Thus the clinical presentation of this form of CAH is also determined partly by the different genetic lesions of the 21-B gene. Gene conversions are the most common lesions found, but 10% of women with severe forms of CAH have macroconversions, that change the 21-B gene sequence into one that resembles the 21-A sequence. The majority of women with severe disease (75%) have microconversions. Random gene deletions, insertions and point mutations are rare in 21-hydroxylase deficiency CAH (34).

Deficiency of 11-hydroxylase is responsible for 15% of CAH cases in Muslim and Jewish women, but is uncommon in women of European descent. The genes of P450c11 enzyme are located on the long arm of chromosome 8 and are therefore not HLA linked. The gene encoding 3-beta-HSD has been cloned and is located on chromosome 1. Three-beta-HSD is not a P450 enzyme and is not HLA linked.

PREGNANCY CONSIDERATIONS IN 21-HYDROXYLASE DEFICIENCY

Historically, different forms of 21-hydroxylase CAH have been identified clinically. Although practically convenient, terms such as salt wasting, simple virilizing, non-classic, late onset, and cryptic, all refer to different presentations to the same disease. Women with all presentations of the disease should receive pre-pregnancy counseling, which must include reference to fertility concerns, possible pregnancy complications, prenatal diagnosis and prenatal treatment.

Fertility and Abortion

Menarche in girls with CAH may be delayed by up to 2 years compared with normal girls. Women with severe forms of CAH have decreased fertility rates (32%) because of several factors. A recent study from Finland concluded that females with simple virilizing 21-OHD often have irregular menses but their final prognosis for fertility seem to be better than previously reported, when compared with the general population (35).

PREGNANCY OUTCOME IN 21-OHD CAH

Maternal

Women with 21-OHD CAH will be receiving glucocorticoids, usually hydrocortisone or prednisone, or Dexamethasone and a mineralocorticoid (if salt-losing) replacement. In the non-pregnant state 17 alpha hydroxy progesterone levels are measured to assess the effectiveness of this treatment in lowering ACTH levels and, thus, stimulation to the adrenal cortex. However, during pregnancy, 17 alpha hydroxy progesterone measurement is not reliable because the steroid normally increases throughout pregnancy. Free testosterone levels do not change and may be used as a marker for adequate suppression. Blood pressure, edema, and electrolytes should be monitored for adequacy of mineralocorticoid replacement. Most women do not require any change in either mineralocorticoid or glucocorticoid therapy, except at times of stress when parenteral stress doses are required (eg. Hyperemesis, labor, delivery).

Prevention of virilization in an affected fetus

In most situations, fetuses at risk for virilization are discovered when a sibling is diagnosed in infancy or in childhood. This diagnosis confirms that both parents are carriers of the enzymatic defect, of which they were previously unaware. Each subsequent pregnancy carries a 1 in 4 risk for an affected child and 1 in 8 risk for an affected female child.

Prenatal treatment

The purpose of prenatal treatment is to prevent virilization in female fetuses thus, 1 in 8 fetuses may benefit from in utero intervention. The adrenal gland-secreted testosterone from 6 to 12 weeks of gestation can masculinize female genitalia. If one can decrease the excess androgen by reducing ACTH stimulation to the fetal adrenal glands, the need for genital corrective surgery, the potential masculinization of the female brain, incorrect sex assignment at birth, and the psychological trauma of ambiguous genitalia for the parents and child may be avoided. Because of the early development of the external genitalia, treatment must be initiated before anyone knows whether the child is affected, and what sex the child is, thus 8 fetuses will be treated to prevent virilization in one fetus. (Figure 5) (39). New and colleagues have developed an algorithm for prenatal diagnosis and treatment of 21-hydroxylase deficiency (Figure 5). To suppress fetal ACTH, glucocorticoids are given to the mother. Dexamethasone is the agent of choice because it has the greatest transplacental passage. Doses of 0.5mgs three times daily, or 20 micrograms per kilogram per day in 2 to 3 doses are recommended. To obtain the best results, treatment must be started before 10 weeks of gestation and continued throughout the pregnancy. The effect of early Dexamethasone on Prader stage of affected female infants, compared with untreated effective siblings, is seen in Figure 6 (39). Fetal response to Dexamethasone is very variable and although masculinization may be reduced, it is often not eliminated. Two-thirds of treated affected females will still need some reconstructive surgery to the external genitalia.

There are several theoretical and actual disadvantages to the use of fetal adrenal corticosteroid suppressive therapy. Glucocorticoid therapy in human pregnancy is not associated with an increase in congenital malformations, although cleft palate has been reported in animals (40).

Suppression of the fetal hypothalamic-pituitary-adrenal axis is a theoretical concern, but neonatal ACTH stimulation testing generally has been normal. Dexamethasone has been assigned a risk factor C by the American Food and Drug Administration. To-date no reports linking the use of Dexamethasone with congenital defects in the fetus have been reported.

Another potential problem of maternal glucocorticoid administration is that of an impaired immune response in the neonate. During the early neonatal period, an increase in neonatal infections has been suggested after maternal steroid usage, but both cellular and humoral immune function are normal in the neonate one year of age. There are also a few long-term follow-up studies of children exposed to glucocorticoid therapy during pregnancy. Neurological assessment at 3 and 6 years of age in children exposed to Dexamethasone appears normal and results of psychometric testing has shown no deficit. Somatic growth is also similar to that of control children of a similar age. Another downside to fetal adrenal suppression by first trimester corticosteroid administration, is that blanket coverage of all "potentially affected" fetuses is required until fetal sex and involvement is known. The fetus is considered potentially affected if both parents are heterozygous or if one parent is heterozygous and the other homozygous. If both parents are heterozygous this will result in prenatal treatment of 7 unaffected fetuses unnecessarily to suppress 1 affected female fetus. No documented increase in congenital anomalies, long-term effects on psychomotor development, or intra-uterine death has been seen. However, there have been reports of low birth weight and a reduction of central nervous system DNA content in animal studies, white matter abnormalities on MRI and impaired fine motor coordination (41). The consequences may not yet be apparent, given the small numbers and early ages of infants exposed to-date. The treatment should, therefore, be still considered experimental and parents must be informed that the risk to benefit ratio has not been clearly established. Controversy over the effectiveness of treatment continues.

Sonographic Prenatal Diagnosis of CAH

An ultrasound scan of the fetal perineum can demonstrate ambiguous genitalia in affected female fetuses. This information can assist in neonatal management and may also allow monitoring of the success of prenatal steroid therapy. Sonographic examination of the adrenal glands of 3 newborns with congenital adrenal hyperplasia demonstrated a cerebriform pattern. This is introduced as a sonographic feature specific to the disease. Ultrasonographic measurements of the female adrenal glands at 12 to 17 weeks gestation have also been undertaken. Measurements of normal fetal adrenal glands show a linear increase with fetal age. In mothers with CAH treated with glucocorticoid steroids, the fetal adrenals are much smaller (42).

MATERNAL COMPLICATIONS

Potential maternal complications of prenatal steroid use of fetal adrenal suppression include steroid-induced-hyperglycemia and hypertension. Both these complications should be monitored carefully as the pregnancy progresses.

11 BETA-HYDROXYLASE DEFICIENCY CAH

Steroid 11 beta-hydroxylase deficiency is the second most common cause of CAH and results in a hypertensive form of this disease. 11 beta-hydroxylase deficiency is inherited as an autosomal recessive condition. The adrenal 11 beta-hydroxylase is a mitochondrial P450 enzyme and is coded by the CYP 11B1 gene, which is situated on chromosome 8Q22 in tandem with the gene for aldosterone synthase. Deficiency of 11 beta-hydroxylase results in the inability to convert 11-deoxycortisol, and this deficiency accounts for 5 to 8% of cases of CAH. 11 beta-hydroxylase deficiency causes a decrease in cortisol production (Figure 4, see above), and virilization develops in affected women. However, in a study of 260 women who complained of hyperandrogenic features, only 0.8% were found to suffer from 11 beta-hydroxylase deficiency CAH, and therefore a systematic search for this deficiency in hyperandrogenic states is probably unwarranted. Salt losing forms are not found, because the substrate for 11 beta-hydroxylase is 11-deoxycortisol (DOC), which has a mineralo-corticoid activity. 1l beta-hydroxylase deficiency CAH can be caused by one of several mutations in the CYP 11B1 gene. Single strand conformation polymorphism (SSCP) analysis has been used for the detection of mutations in the CYP 11B1 gene. Sequence analysis has shown deletions, duplication, mis-sense mutations and nonsense mutations. These findings support the early suggestions that the presence of mutational hot spots in the CYP 11B1 gene, and also show that severe clinical manifestations are associated with complete loss of enzymatic activity (43). The diagnosis of 11 beta-hydroxylase deficiency is made by the finding of elevated plasma DOC levels, and an exaggerated response of plasma DOC to ACTH stimulation. Urinary tetrahydro-deoxy cortisol and tetra-hydro deoxycorticosterone levels are also elevated.

This form of CAH is uncommon in North America, but the incidence of the defect is higher in certain populations from Morocco, Tunisia, Turkey, Iran and Israel. There is marked clinical variability in presentation, varying from modest masculinization with clitoromegaly to extreme forms with fused labial scrotal folds. Menstrual disturbance is common, hirsutism and acne are variable. Before pregnancy, if a woman is suspected of having 11 beta-hydroxylase deficiency CAH, she should have definitive testing by ACTH stimulation after Dexamethasone suppression, with measurement of serum 11 DOC and deoxycorticosterone levels (44).

Pregnancy considerations in women with 11 beta-hydroxylase deficiency CAH

Many women with 11 beta-hydroxylase deficiency who are treated with adequate doses of glucocorticoids appear to have normal fertility and uneventful pregnancies have been reported. Spontaneous pregnancies in untreated women can occur with the onset of symptoms occurring after the gestation. Severe forms of 11 beta-hydroxylase deficiency, which show a poor response to glucocorticoid suppressive therapy, have been treated by a laparoscopic bilateral adrenalectomy with marked clinical and biochemical improvement. Therefore, more aggressive management of difficult cases using early bilateral adrenalectomy may be appropriate in selected cases before pregnancy (45). Replacement therapy with a glucocorticoid and a mineralocorticoid will be required if adrenalectomy is used as a treatment for CAH.

In spite of the association of 11 beta-hydroxylase deficiency with hypertension, pregnancies reported do not appear to have been complicated by an increased incidence of any other type of hypertensive disease.

Prenatal Diagnosis of Affected Female Fetuses in -hydroxylase Deficiency CAH

Masculinization of the external genitalia may affect female fetuses during the first trimester, but the extent of the genital ambiguity is extremely variable. Prenatal diagnosis and treatment has met with some success. Initially endocrine diagnosis involved utilization of amniotic fluid levels of 11-deoxycortisol and tetrahydro-11-deoxycortisol, which are elevated in pregnancies with affected fetuses (46). Better discrimination of affected from unaffected fetuses was obtained when sequential maternal urine and amniotic fluid levels were obtained in parallel. More accurate diagnosis can now be achieved by the application of the new molecular genetic techniques. Dexamethasone suppressive therapy has been used in an attempt to prevent genital masculinization of affected female fetuses, but has not always been successful (47).

3 BETA-HYDROXYSTEROID DEHYDROGENASE (3 BETA-HSD) DEFICIENCY AND PREGNANCY

Classical 3 beta-HSD deficiency is a rare form of congenital CAH that impairs steroidogenesis in both the adrenals and gonads, resulting from mutations in the HSD 3B2 gene, causing varying degrees of salt loss in both sexes and incomplete masculinization of the external genitalia in genetic males. 3 beta-HSD deficiency CAH decreases steroid synthesis in 3 pathways; 1. reducing the conversion of pregnenolone to progesterone, 2. reducing the conversion of 17a-pregnenolone to 17a-hydroxyprogesterone, and 3. reducing the conversion of dehydro-epiandrosterone (DHEA) to androstenedione.) The genes encoding 3 beta HSD are located on chromosome 1. The type 1 gene which is expressed in peripheral tissues has not to-date shown any mutations. The type 2 gene which is expressed almost exclusively in the adrenal and gonad has demonstrated to-date a total of 34 mutations. Mutations identified include nonsense, frame shift, and mis-sense mutations (48). The type 1 beta-HSD gene is also expressed in the placenta, as well as peripheral tissues.

3 beta-HSD deficiencies are characterized by varying degrees of salt wasting and normal female sexual differentiation, or mild virilization. Clinically there is a very broad spectrum of the disease, varying from acute severe neonatal presentation to a mild form presenting up to puberty with features suggestive of polycystic ovarian disease (49). Women with mild 3 beta-HSD deficiency often are infertile because of oligo-ovulation, but menstrual regularity occurs after Dexamethasone suppression. 3 beta-HSD deficiency is uncommon in North America but has been found in up to 12% of Israeli women presenting with hyperandrogenism. Successful pregnancies have been reported after both Dexamethasone therapy and in vitro fertilization (50). Affected female fetuses may have variable degrees of labial fusion and clitoromegaly, but masculinization is usually mild because DHEA is a weak androgen. To-date there are no reports of prenatal diagnosis or of glucocorticoid treatment of affected female fetuses.