Prenatal treatment of congenital adrenal hyperplasia by administering dexamethasone to a woman presumed to be carrying an at-risk fetus has been described as safe and effective in several reports. A review of data from animal experimentation and human trials indicates that first-trimester dexamethasone decreases birthweight; affects renal, pancreatic beta cell, and brain development; increases anxiety; and predisposes to adult hypertension and hyperglycemia. In human studies, first-trimester dexamethasone is associated with orofacial clefts, decreased birthweight, poorer verbal working memory, and poorer self-perception of scholastic and social competence. Numerous medical societies have cautioned that prenatal treatment of congenital adrenal hyperplasia with dexamethasone should only be done in prospective clinical research settings with institutional review board approval, and therefore is not appropriate for routine community practice.
Congenital adrenal hyperplasia (CAH) due to steroid 21-hydroxylase deficiency is an autosomal recessive disorder affecting about 1 in 14,500 newborns. Glucocorticoid (cortisol) and mineralocorticoid (aldosterone) synthesis are impaired, and affected females typically have virilized external genitalia. Practice guidelines covering all aspects of the diagnosis and treatment of CAH, from fetus to adult have been published recently. Since the 1980s endeavors have been made to suppress the overproduction of adrenal androgens in female fetuses with CAH by administering prenatal glucocorticoids to the mother. Current knowledge of the molecular genetics of CAH, fetal adrenal physiology, and glucocorticoid actions permits a timely reevaluation of this controversial treatment.
CAH is caused by mutations in the CYP21A2 gene, which encodes steroid 21-hydroxylase. In cortisol synthesis by the adrenal zona fasciculata, 21-hydroxylase converts 17-hydroxyprogesterone to 11-deoxycortisol; in aldosterone synthesis by the zona glomerulosa, 21-hydroxylase converts progesterone to deoxycorticosterone. Increased concentrations of 17-hydroxyprogesterone are used diagnostically because the adrenal makes 100-1000 times more cortisol than aldosterone. The genetics, biochemistry, and disease-causing defects of steroidogenesis have been reviewed in detail recently.
CAH presents as 3 forms, with substantial clinical overlap. In infants with severe, salt-wasting CAH, aldosterone deficiency leads to salt loss, hyponatremia, hyperkalemia, acidosis, and death if not treated. Deficient fetal cortisol production leads to overproduction of adrenocorticotropic hormone, stimulating the disordered fetal adrenal to produce excess androgens, virilizing female fetuses at 7-12 weeks’ gestation. The virilization of a female fetus can lead to incorrect sex assignment, hence CAH must be considered in apparently male infants with bilateral nonpalpable gonads. Affected males have normal external genitalia, but develop life-threatening salt loss during the first month of life. Simple virilizing CAH results from milder mutations that spare overt salt loss, but cortisol remains deficient, adrenocorticotropic hormone levels are high, and affected females are virilized. The anatomically normal males may escape diagnosis until they are older and present with phallic enlargement, premature sexual hair, tall stature, and advanced skeletal maturation. Nonclassic CAH (NCAH) (sometimes termed “late-onset” CAH) may present in adolescent or adult females with irregular menses, infertility, or hirsutism, or may have no symptoms at all; NCAH may be difficult to distinguish from the polycystic ovary syndrome. Males with NCAH are asymptomatic. The incidence of NCAH is about 1:1000, but varies among populations. Newborn screening programs now permit early, life-saving diagnosis of most affected infants; a detailed evaluation by a pediatric endocrinologist is then needed, as false-positive findings are common, and other rare adrenal disorders may also yield positive results.
Sexual differentiation and prenatal virilization
The embryonic structures that develop into male and female internal and external reproductive organs are indistinguishable until about 6-7 weeks after conception, when the fetal testis begins to secrete testosterone and anti-müllerian hormone. Anti-müllerian hormone induces müllerian duct apoptosis; testosterone stabilizes wolffian duct development and induces masculinization of the male external genitalia. Affected males have normal male internal and external genital development, with descended testes at birth. In female fetuses with CAH, the adrenal inappropriately produces androgens during this crucial time, virilizing the external genitalia; however development of the ovaries, uterus, and fallopian tubes remains normal. The degree of external virilization varies, depending on the CYP21A2 mutation and other ill-defined factors. The appearance of the external genitalia can range from isolated clitoromegaly to complete fusion of the labioscrotal folds with a phallic urethra, so that the genitalia appear masculine. The location of the urethral meatus may be anywhere from the base to the tip of the phallus. The urethra may open into the vagina forming a pseudourogenital sinus with a single perineal opening. Androgen exposure after 12-13 weeks’ gestation will cause phallic enlargement, but does not induce labial fusion.
When feminizing genitoplasty is performed, complications may include vaginal stenosis interfering with tampon use and penetrative vaginal intercourse. Embarrassment about genital appearance may contribute to poor self-esteem or dissatisfaction with sexual life in some women. However, most retrospective studies report the results with surgical procedures that are no longer routinely used. Feminizing genitoplasty is now preferably performed in the first few months when the infant’s skin is still estrogenized, reducing scarring. The severity of the mutation and surgical procedure appear to correlate with outcome regarding sexual function. With appropriate hormonal replacement therapy, affected females can achieve pregnancy.
Genetics
Over 170 CYP21A2 mutations have been identified, and phenotype generally correlates with genotype: patients with classic salt-losing CAH usually have complete loss-of-function mutations on both alleles; patients with simple virilizing CAH often carry a complete loss-of-function mutation on one allele and a milder mutation on their other allele; individuals with NCAH typically carry the missense mutation V281L on at least one allele. The CYP21A2 locus, which lies within the major histocompatibility locus on chromosome 6p21, is unusually complex. Most individuals have a highly homologous pseudogene, CYP21A1P , adjacent to CYP21A2 on each allele, but individuals can have anywhere from 0-4 copies of CYP21A1P or CYP21A2 . These 2 genes share 98.5% sequence identity, making it difficult to distinguish which gene is being examined. Homologous recombinations between CYP21A2 and CYP21A1P cause most mutations. Duplications, deletions, and rearrangements further complicate genetic analysis. CAH is autosomal recessive: the recurrence risk is 25% for future pregnancies with the same 2 parents. For women with CAH, the risk of having a child with CAH depends on the probability that the father is a carrier; this is typically about 1 in 60, so that the risk of having a CAH fetus is 1:120, and the risk of having a CAH female is 1:240.
Genetics
Over 170 CYP21A2 mutations have been identified, and phenotype generally correlates with genotype: patients with classic salt-losing CAH usually have complete loss-of-function mutations on both alleles; patients with simple virilizing CAH often carry a complete loss-of-function mutation on one allele and a milder mutation on their other allele; individuals with NCAH typically carry the missense mutation V281L on at least one allele. The CYP21A2 locus, which lies within the major histocompatibility locus on chromosome 6p21, is unusually complex. Most individuals have a highly homologous pseudogene, CYP21A1P , adjacent to CYP21A2 on each allele, but individuals can have anywhere from 0-4 copies of CYP21A1P or CYP21A2 . These 2 genes share 98.5% sequence identity, making it difficult to distinguish which gene is being examined. Homologous recombinations between CYP21A2 and CYP21A1P cause most mutations. Duplications, deletions, and rearrangements further complicate genetic analysis. CAH is autosomal recessive: the recurrence risk is 25% for future pregnancies with the same 2 parents. For women with CAH, the risk of having a child with CAH depends on the probability that the father is a carrier; this is typically about 1 in 60, so that the risk of having a CAH fetus is 1:120, and the risk of having a CAH female is 1:240.
Prenatal treatment of CAH
Reported experience with prenatal treatment of CAH has used dexamethasone, 20 μg/kg maternal body weight per day. Because the normal secretory rate of cortisol is 6-7 mg/m 2 /d, and dexamethasone is about 50-80 times more potent than cortisol (hydrocortisone), adult physiologic replacement is about 0.1-0.12 mg dexamethasone/m 2 /d. Thus, physiologic replacement in a 60-kg, 1.6-m 2 woman would be approximately 0.2 mg/d, whereas 20 μg/kg/d used in prenatal therapy is 1.2 mg/d, so that the woman is receiving about 6 times her physiologic glucocorticoid need. Since dexamethasone is not inactivated by placental 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) and midgestation fetal glucocorticoid levels are less than one-tenth those in the mother, the fetus receives about 60 times its usual, physiologic glucocorticoid exposure. Studies of prenatal treatment with lower doses of dexamethasone have not been reported; it is unclear why such high doses would be needed.
Because fetal genital virilization begins 6-7 weeks after conception, treatment must be started as soon as the woman knows she is pregnant. However, genetic diagnosis by chorionic villus biopsy cannot be done until 10-12 weeks, and the testing takes additional time, hence all pregnancies deemed to be at risk for virilizing CAH are treated, even though only 1 in 4 is affected and only 1 in 8 fetuses is predicted to be a female with CAH. The genetic testing is facilitated if the specific mutations carried by each parent are known, increasing the speed of the genetic diagnosis. Determination of fetal sex by examining fetal Y-chromosomal DNA obtained directly from maternal blood can be applied to prenatal treatment of CAH, improving the probability of treating an affected female fetus from 1 in 8 to 1 in 4.
Efficacy
Prenatal dexamethasone can prevent or ameliorate the genital virilization of female infants with classic CAH, reducing the need for feminizing genital reconstructive surgery. A postulated potential benefit is reduced “androgenization” of the fetal female brain, but such effects are difficult to measure and have not been studied in detailed follow-up studies. Available data concerning treatment outcomes are limited to those from 3 groups. The French group that first described prenatal treatment has reported treating 253 pregnancies, indicating that “prenatal therapy is effective in significantly reducing or even eliminating virilization in CAH females,” and that “the success rate is over 80%,” but has not provided specific data describing the outcomes of these cases. The US group assessed 532 pregnancies at risk for carrying a fetus with CAH, initiating prenatal treatment in 281. Among 105 fetuses with classic CAH (61 female, 44 male), 49 received dexamethasone throughout the pregnancy. Among 25 female fetuses receiving dexamethasone before the 9th week of pregnancy, 11 had normal female genitalia, 11 had minimal virilization (Prader stages 1-2), and 3 were virilized (Prader stage 3); the mean Prader score for this group was 0.96 (a wholly normal female score is 0.0). Among 24 female fetuses where treatment was begun after week 9, the genitalia averaged a Prader score of 3.0; among untreated females the score was 3.75. A Swedish group did a small study in which 3 of 6 female fetuses treated to term were unvirilized, 2 had mild virilization (Prader 2), and a poorly compliant mother had a girl with Prader 2-3 genitalia. Thus, the consensus success rate for ameliorating genital virilization is about 80-85%.
Maternal safety
Among 118 women responding to a mailed questionnaire, prenatally treated women experienced more striae ( P = .01), increased edema ( P = .02), and a mean weight gain 7.1 lb greater than that experienced by untreated women ( P < .005), but did not self-report increased hypertension or gestational diabetes. Another study found that 9-30% of treated women reported mild gastric distress, weight gain, mood swings, pedal edema, and mild hypertension that did not require discontinuation of therapy; only 1.5% of 253 treated women reported striae, large weight gain, hypertension, preeclampsia, and gestational diabetes. A study of 44 women receiving prenatal dexamethasone (6 to term) found no differences in maternal weight gain between treated and untreated women, although the treated women gained more weight during the first trimester. No differences were found in maternal blood pressure, glycosuria, proteinuria, length of gestation, or placental weight. However, the treated women reported increased appetite ( P < .01), rapid weight gain ( P < .02), and edema ( P = .04) compared to untreated controls, and 30 of the 44 women indicated they would decline prenatal treatment of a subsequent pregnancy. Other studies have reported Cushingoid effects in small numbers of treated women. Thus prenatal treatment is associated with modest but manageable maternal complications that do not appear to pose a major risk to the mother.
Fetal safety–animal studies
High-dose dexamethasone is teratogenic in animals : it can cause palatal clefting in mice and other species, lowers the threshold for genetic palatal clefting, and lowers the threshold for its induction by other teratogens. In rats, prenatal dexamethasone (100 μg/kg given from day 1 of pregnancy to parturition) reduced the number of kidney cells undergoing mitosis and resulted in postnatal hypertension, albuminuria, sodium retention, and decreased glomerular filtration ; similar doses decreased the number of nephrons and altered expression of genes involved in nephron development in the spiny mouse. Daily administration of dexamethasone (100 μg/kg/d) to pregnant rats during the third week of gestation (which in rats corresponds to human late first trimester and early second trimester) reduced birthweight and altered genes regulating carbohydrate metabolism, resulting in hyperglycemia and insulin resistance. Administration of 6 doses of betamethasone (1 mg/kg) to pregnant guinea pigs between 40-60 days’ gestation (term, 63 days) altered fetal DNA methylation, transgenerationally altering the hypothalamic-pituitary-adrenal axis. Prenatal administration of dexamethasone to African green monkeys from midgestation to term showed that at 1 year of age, a dose of 120 μg/kg, but not 50 μg/kg, reduced pancreatic beta cell numbers, impaired glucose tolerance, increased systolic and diastolic blood pressure, and reduced postnatal growth despite normal birthweight. The number of animals receiving 50 μg/kg was half the number of controls or animals receiving 120 μg/kg, hence subtle effects may not have been detected. Thus, dexamethasone doses of the same order of magnitude as those used in prenatal therapy elicit adverse effects in nonhuman primates.
Placental HSD11B2 inactivates cortisol, corticosterone, and prednisone (but not dexamethasone or betamethasone) protecting the fetus from maternal glucocorticoids. Treatment of pregnant rats with the HSD11B2 inhibitor carbenoxolone resulted in hypertension and predisposition to hyperglycemia in the offspring. These effects were diminished when the mothers were adrenalectomized, confirming the effect is mediated by glucocorticoids. Mice lacking HSD11B2 had lower birthweights and increased anxiety compared to wild-type littermates. High doses of glucocorticoids also exert multiple negative effects on brain development. Maternally administered betamethasone reduced brain weight and neuronal myelinization in fetal sheep given 4 doses of betamethasone, 0.5 mg/kg at 104, 111, 118, and 124 days’ gestation (term, 145 days), and doses of 0.5, 5, or 10 mg/kg of maternally administered dexamethasone administered to pregnant rhesus monkeys at 132-133 days’ gestation (term, 165) disrupted the development of hippocampal neurons in fetal monkeys.
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