PRENATAL TREATMENT OF CONGENITAL ADRENAL HYPERPLASIA

0022-5347/99/1622-0534/0

Vol. 162,534-536, August 1999 Printed in U.S.A.

THE JOURNAL. OF UROLOGY Copyright 8 1999 by AMERICAN UROLQCICAL ASS~CUTION, INC.

PRENATAL TREATMENT OF CONGENITAL ADRENAL HYPERPLASIA PHYLLIS W. SPEISER From the Division of Pediatric Endocrinology and Metabolism, North Shore University Hospital, Manhasset, New York

ABSTRACT

Purpose: The relevant aspects of congenital adrenal hyperplasia due to 2 1-hydroxylase deficiency (CAH-21),the single most common cause of female pseudohermaphroditism, are reviewed to understand the benefits and risks of prenatal intervention. Timely diagnosis is important, since infants with this condition may suffer adrenal insufficiency which carries a high mortality rate. Materials and Methods: Infants suspected of having CAH-21 should undergo radioimmunoassay of serum 17-hydroxyprogesterone,karyotype and pelvidabdominal ultrasound at a minimum. Treatment with glucocorticoid and mineralocorticoid supplements should be instituted immediately. Surgical correction of genitourinary tract anomalies should be performed by a pediatric urologist experienced in this area. Results: Proper postnatal medical and surgical management of CAH-21 will allow the patient to thrive. Many women with classic CAH-21 have now conceived and delivered healthy children. Prenatal diagnosis, now most often done by molecular genetic techniques, is feasible and often done in conjunction with prenatal treatment of the at risk mother. Conclusions: CAH-2 1 has been well characterized. The benefit of prenatal therapy is t o ameliorate potentially genital ambiguity in affected female subjects. The risks of unnecessarily treating unaffected pregnancies, which now seem small, may not be fully elucidated for many years. Prenatal treatment must be done under careful, centralized and ideally long-term medical supervision. KEY WORDS: adrenal hyperplasia, congenital; hydroxylases; prenatal care

female internal genital structures are formed. Wolfian ducts Patients with congenital adrenal hyperplasia (CAH) due to require high local concentrations of testosterone secreted 21-hydroxylase deficiency (CAH-21) cannot adequately syn- from Leydig cells for stabilization and continued growth.6 thesize cortisol, thus signaling the hypothalamus and pitu- External genital structures differentiate as male under the itary to increase respective production of corticotropin releas- influence of 5-a-dihydrotestosterone7 in the presence of an ing hormone and adrenocorticotropic hormone (ACTH). The intact androgen receptor.8 Although in female subjects affected with CAH levels of adrenal glands become hyperplastic but, rather than secreting cortisol, they produce excess sex hormone precursors circulating adrenal androgens are sufficiently high to pre(androstenedione) which do not require 21-hydroxylation for vent formation of separate vaginal and urethral canals, such synthesis. Once secreted, these hormones are further metab- levels are not high enough to sustain wolffian ducts. Further olized to testosterone and dihydrotestosterone, active andro- interference with normal female genital anatomy occurs as gens and, to a lesser extent, estrogens, estrone and estradiol. adrenal derived androgens interact with genital skin androThe net effect is prenatal virilization of girls and rapid so- gen receptors and induce clitoral enlargement, promote fumatic growth with early epiphyseal fusion in both sexes. sion of the labial folds and cause rostra1 migration of the About three-quarters of patients also cannot synthesize suf- urethraVvagina1 perineal orifice. The net effect in severely ficient aldosterone to maintain sodium balance, predisposing affected girls is a genital appearance resembling a boy with perineal hypospadias, chordee and undescended testes.9 Testo potentially life threatening hyponatremic dehydration. tosterone exposure in utero may also suppress the breast anlage, resulting in poor breast development at adolescence. PRENATAL DEVELOPMENT PATHOPHYSIOLOGY

Adrenal glands. The adrenal cortex arises from the mesoCLASSIC CAH PHENOTYPES derm at 4 weeks of gestation and begins to secrete steroids by weeks 6 to 7.1 There is controversy as to whether ACTH is the Virilizing CAH is the most common cause of genital ambisole or principal trophic hormone for adrenal growth and guity in genetic female subjects, and about 90 to 95%of CAH steroidogenesis in fetal life.2 The fact that CAH causes a cases are caused by 21-hydroxylase deficiency. Female subfunctional excess of adrenal androgens and ambiguity in jects affected with severe, classic 21-hydroxylase deficiency affected female external genitalia suggests that ACTH influ- are exposed to excess androgens prenatally and are born with ences fetal steroidogenesis. virilized external genitalia. The diagnosis can be confirmed Sexual differentiation. At about the same time the adrenal by a markedly elevated serum 17-hydroxyprogesterone levglands are beginning to secrete steroids, the testes begin to el.1° Differentiation of 21-hydroxylase deficiency from other differentiate under the influence of a cascade of testis deter- forms of CAH may be accomplished by clinical features of the mining genes.3 If there is no anti-miillerian hormone se- disease and complete adrenocortical hormone profile after creted by the testicular Sertoli cells,4~5miillerian ducts and ACTH stimulation. As indicated previously, about three-fourths of classic CAH Presented at the Society for Fetal Urology Panel Discussion on Prenatal Diagnosis of Genital Anomalies, San Francisco, California, cases are "salt-wasters" due to severely impaired 21October 16, 1998. hydroxylation of progesterone.11 Salt wasting may include 534

PRENATAL TREATMENT OF CONGENITAL ADRENAL HWERPLASIA

such nonspecific symptoms as poor appetite, vomiting, lethargy and failure to gain weight. Careful evaluation reveals hyponatremia, hyperkalemia and hypovolemic shock. These adrenal crises may prove fatal if proper medical care is not delivered. This problem is particularly critical in male infants who have no genital ambiguity to alert physicians to the diagnosis of CAH before the onset of dehydration and shock.12 The mortality rate for CAH is still high in such patients, suggested by the discrepancy in the number of male patients identified in case reports versus newborn screening.13 It is for this reason that many states in the United States and a number of countries have adopted newborn screening for CAH. Cases of sufficient aldosterone production and no salt-wasting with signs of prenatal virilization and/or markedly increased production of hormonal precursors of 21-hydroxylase (17-hydroxyprogesterone)are referred to as simple virilizers. THERAPY

Medical treatment. Infants and children with CAH are treated with about 15mg./m.2hydrocortisone daily. This dose and type of glucocorticoid are chosen because they are less likely to cause growth suppression and low bone density compared with higher doses or long acting preparations such as prednisone and dexamethasone.l4,15 Fludrocortisone, an aldosterone analogue, prevents symptoms of salt-wasting. Surgical treatment. Affected female subjects with severe genital ambiguity will often be referred for urological surgery in the newborn period. Most parents are emotionally traumatized by the experience of having an infant with a genital birth defect, and wish to correct the most visible deformity, the enlarged clitoris, as early as possible. At some centers repair of the urogenital sinus is done simultaneously. Because of the variable degree of genital ambiguity, not all female subjects require surgery. Some clinicians favor waiting until an older age to repair the urogenital sinus. One should be aware of an association with upper tract urinary malformations in female subjects with CAH and an increased incidence of urinary tract infections. Prenatal therapy. In pregnancies at risk for a child affected with virilizing adrenal hyperplasia suppression of fetal adrenal androgen production with lessening of genital ambiguity in female subjeds has been achieved by administering dexamethasone to the mother.16-19 The dose is typically 20 pgJkg. daily to a maximum of 1.5 mg. daily in 3 divided doses beginning before weeks 7 to 8 of gestation.20 Several hundred pregnancies have been treated in this manner. Occasional treatment failures, that is affectedfemale subjects requiring genital reconstruction, have been attributed to late onset of treatment, cessation of therapy in midgestation, noncompliance or suboptimal dosing,Z1while a rare few had no ready explanation.22There are no systematically collected data available regarding natural variability in genital virilization among CAH patients with the same CYF'21 genotype but the likelihood of severe genital ambiguity is reduced among those prenatally treated compared to all CAH affeded female subjects. Prenatal therapy is usually coupled with prenatal diagnosis. Since dexamethasone treatment suppresses amniotic fluid adrenocortical hormones, genetic diagnosis must be made in the early second trimester. Whereas the incidence of fetal deaths in treated pregnancies does not appear to exceed that of the general population (9% spontaneous abortion rate a high in treated versus 14% in untreated pregnan~ies),2~ rate of spontaneous abortions has been observed following chorionic villus sampling performed to obtain tissue for genetic diagnosis.24 Either amniocentesis or chorionic villus sampling may be done for diagnostic purposes but the latter should be performed only at experienced centers at 9 to 12 weeks of gestation.25 Future development of robust methods for obtaining and typing fetal cells in the maternal circula-

535

Lion could obviate these risks. If the sex is male or CYP21 Zenotype indicates the fetus is unaffected, dexamethasone should promptly be discontinued to minimize potential risks 3f glucocorticoid toxicity. GLUCOCORTICOID TOXICITY

Fetus and child toxicity. The risk of major congenital defects in human fetuses appears to be lower compared to complications observed in a rodent model of in utero exposure to high dose glucocorticoids,26which feature frequent cleft palate in addition to fetal growth retardation andlor death. Intrauterine growth retardation and unexplained fetal death have also been observed in about 2% or less of treated pregnancies,23 and these statistics are not significantly different from those found in the general p0pulation.2~Rare risks of prenatal glucocorticoid exposure include congenital malformations, such as cardiac septa1 hypertrophy,2* hydrometrocolpos29 and hydrocephalus.24 More subtle effects of glucocorticoids on the developing brain may go unnoticed during early life. Whereas female subjects with CAH manifest aggressive behavior?" those born after prenatal dexamethasone are unusually shy.31 Newborns subjected to prenatal dexamethasone have not undergone thorough neuropsychological t e ~ t i n g . 3Seckl ~ and Miller cited studies of animal models which showed the dangers of prenatal exposure to glucocorticoids with respect to impairment of somatic growth, brain development and blood pressure regulation.33 It is not clear that human development is similarly at risk with glucocorticoid exposure. In Europe a registry of treated pregnancies has been created to facilitate more detailed long-term studies to answer many of these questions. Maternal toxicity. The incidence of maternal complications has varied among investigators. When evaluating such data it is important to distinguish between types of adverse side effects observed and the duration of therapy. American34and European23 investigators have found a higher incidence of drug intolerance in those women carrying affected female fetuses who have been treated from the first through third trimesters. Cushingoid features, excessive weight gain, severe striae, hypertension and hyperglycemia are seen in this setting. Therefore, it is desirable to monitor closely weight, blood pressure and glucose tolerance in all women treated to term. Serial maternal serum dexamethasone levels, if available, could prevent over treatment and under treatment. It has been proposed that a gradual decrease in the dose of dexamethasone may be advisable in long-term gestational treatment of CAH but there are as yet no data concerning the efficacy of such a regimen. More common maternal side effects in women treated for a shorter duration include edema, gastrointestinal upset, mood fluctuations, acne and hirsutism, 1 or more which have been noted in 1.5 to 10%treated in early pregnancy.lg.23 NEED FOR INFORMED CONSENT

Because of the aforementioned concerns, caution should be exercised in recommending prenatal therapy with dexamethasone, and women must be fully informed of potential fetal and maternal risks, some of which may be as yet unrecognized. Additionally, informed consent should include disclosure of nonuniformity of beneficial outcome to the affected female fetus. Parents should be aware that 7 of 8 treated pregnancies will receive unwarranted drug exposure. These warnings notwithstanding, many parents of affected girls still opt for prenatal medical treatment because of the severe psychological impact of ambiguous genitalia on the child and famiiy.31 Obviously, prenatal treatment can and should only be offered to pregnant women who already have had a child with CAH with the same partner. The diagnosis of classic CAH

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PRENATAL TREATMENT O F CONGENITAL ADRENAL HYF'ERPLASIA

should be clearly established with appropriate studies before embarking on prenatal treatment. Investigations are presently under way to determine the frequency of infants born with classic CAH to mothers affected with the mild, nonclassic form of CAH. Considering the number of classic alleles found in nonclassic cases and the number of heterozygotes for classic alleles in the general population, the frequency of severely affected children born to nonclassic mothers should be about 0.001 or less. The incidence should be about half that for affected female subjects. Since this rate is far less than the 1 to 8 risk of CAH in a daughter of known classic 21-hydroxylase deficiency carriers, prenatal therapy does not appear warranted. It may be prudent to measure 17hydroxyprogesterone in such at risk infants, as several newborn screening programs have reported detection of nonclassic CAH.35.36 SUMMARY

Medical treatment of a pregnant woman at risk for carrying a CAH female fetus can be effective in ameliorating genital ambiguity associated with this condition. Whereas data collected in several hundred treated pregnancies during the last 2 decades show no consistent pattern of major birth defects in these offspring, concern remains over potential subtle disturbances in growth, and neurological and vascular function, perhaps not manifest for many years. Moreover, because of such uncertainties the ethics of treating 7 of 8 unaffected pregnancies t~ prevent genital ambiguity in 1 affected female subject requires further discussion while conducting such studies under scrutiny of a n international registry. REFERENCES

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