Prenatal dexamethasone treatment of children at risk for congenital adrenal hyperplasia: the Swedish experience and standpoint.

Congenital adrenal hyperplasia (CAH) refers to rare ( 1:10,000), recessively inherited disorders of adrenal steroidogenesis. 21-Hydroxylase deficiency, the most common form, results in virilization of external genitalia in severely affected female fetuses. Prenatal treatment of CAH with dexamethasone (DEX) has been administered since the mid-1980s and is effective in reducing virilization in CAH-affected girls (1). The treatment has to be initiated early in pregnancy, before prenatal testing is possible. Consequently, seven of eight fetuses (all boys and CAH-unaffected girls) are treated in early pregnancy without any benefit of the treatment per se, until prenatal testing can determine the sex and diagnostic status at the end of the first trimester. CAH-affected girls are treated until term. Prenatal DEX treatment of fetuses at risk for CAH is controversial. Results from animal studies, as well as studies on prenatal glucocorticoid therapy in other contexts, have raised concerns regarding possible negative effects on behavioral and somatic development (2, 3). Adult corticosteroid-exposed rodent offspring are characterized by hypertension (via reduced nephron number); hyperinsulinemia and hyperglycemia (via permanently increased levels of the hepatic enzyme phosphoenolpyruvate carboxylase); fatty liver but not obesity when given a high-fat diet; and hyperactivity of the hypothalamic-pituitaryadrenal axis and altered affective behavior, reminiscent of anxiety, as well as impaired learning and memory functions. In the rhesus monkey, prenatal DEX during the last trimester resulted in offspring with elevated basaland stress-stimulated cortisol at the age of 10 months as well as smaller hippocampal volume. In the African vervet monkey, high-dose DEX exposure (120–200 g/kg) from midgestation until term resulted in offspring with an exaggerated cortisol response to stress already prepubertally, and adult animals exhibited hypertension, impaired glucose tolerance, and hyperinsulinemia (4). A long-term follow-up of individuals treated prenatally with betamethasone due to a risk of preterm birth shows that 30 yr after exposure the individuals exhibit insulin resistance, particularly in women, and 7% of the adults had elevated basal, morning cortisol levels (5). Other authors consider the prenatal treatment of CAH to be safe (1), but the recent Endocrine Society Guidelines state that such treatment should only be done within the frames of ethically approved clinical studies (6). The prenatal treatment of CAH is considered to be safe in the short-term perspective, although there are few longterm follow-up studies. In Sweden, prenatal treatment of CAH has been administered within the frameworks of a clinical study since 1999. The study, which is ongoing, is designed as a prospective, nonrandomized, multicenter trial in several participating European countries, including both follow-up of the mothers and long-term follow-up of the children. In Sweden, 31 cases have been enrolled during the last 10 yr. Hence, it will take several years before the first results from the long-term follow-up assessments will be available. We have also conducted retrospective follow-up studies of mothers and 43 children treated in Sweden and Nor-