2012/03/31 by Tatja Hirvikoski, Anna Nordenström, Anna Wedell +2 · 3 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Sexual Differentiation and Disorders #Birth, Development, and Health #Growth Hormone and Insulin-like Growth Factors
paper · pdf · doi:10.1210/jc.2012-1222
openalex publication_date 2012/03/31 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/31
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-pituitary-adrenal 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 basal- and 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 μg/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 long-term 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 Norway during 1985–1995 (7–10). In summary, maternal side effects were such as can be expected with glucocorticoid/DEX treatment. Most of the maternal side effects seem to disappear after discontinuation of treatment, but in our experience, approximately 50% of the mothers treated during pregnancy and all mothers treated until term reported some type of discomfort that could be attributed to DEX. In general, treated children were born at term and were not small for gestational age. As a group, they did not exhibit teratogenous effects/gross malformations, although eight severe adverse events were noted in the treated group, compared with one in the control group. Three children failed to thrive during the first year of life; in addition, one of these children had a developmental delay; one had developmental delay and hypospadias; one had hydrocephalus; two girls were born small for gestational age, and one of these girls was later diagnosed with mental retardation; and one child had severe mood fluctuations that caused hospital admission. In the control group, only one child was admitted because of Down's syndrome. In the follow-up studies on the behavioral development of the 40 Swedish children, at a mean age of 11 yr, parent reports indicated good general adaptation, psychological well-being, and school performance in DEX-exposed children compared with nontreated controls. Direct neuropsychological assessments of the children showed normal results on measures of IQ, learning, and memory. However, an adverse effect was observed in the form of impaired verbal working memory in CAH-unaffected short-term-treated cases. The verbal working memory capacity correlated with the children's self-perception of difficulties in scholastic ability, another measure showing significantly lower results in CAH-unaffected, DEX-exposed children. These children also reported increased social anxiety. In the studies on gender role behavior, we found indications of more neutral behaviors in DEX-exposed boys. The small sample size, relatively high refusal rate, and the retrospective study design limited the conclusiveness of the results in our studies. Nevertheless, the results cause concern because no side effects should be tolerated in CAH-unaffected children who do not benefit from the treatment per se. As a consequence of our findings of possible adverse effects, we have addressed the Regional Ethics Committee in Stockholm in November 2010 and stated that we wish to put further recruitment of patients on hold for the ongoing prospective study of prenatal DEX treatment of CAH in Sweden. Hence, until larger and more conclusive studies are published, we do not consider it ethical to initiate further treatment. The patients who have entered the study during 1999–2010 will continue to be followed according to the study protocol. We find it unacceptable that, globally, fetuses at risk for CAH are still treated prenatally with DEX without follow-up. If further treatment is initiated in other centers, we wish to stress that the minimal requirement should be to follow the Paediatric Endocrine Society/European Society for Paediatric Endocrinology consensus statement from 2002 (11) and the more recent guidelines from The Endocrine Society (6), i.e. to perform prenatal DEX treatment of children at risk for CAH only within clinical trials including long-term follow-up of all treated individuals, as well as to give thorough information to the parents about the potential risks and uncertainties, in addition to the benefits of this treatment. Such studies should include appropriate untreated controls. However, we also find it unsatisfactory to only await the results of long-term prospective studies. Because large numbers of individuals have been treated, we urge the scientific community to perform additional retrospective studies, preferably on all treated children and young adults. Multisource assessment methods should be applied, including both direct assessment of the treated individuals and collateral information from parents and possibly teachers. Moreover, the assessment should focus on both behavioral—including cognitive—and somatic outcomes. In this way, our findings can be either confirmed or challenged and we will eventually be able to conclude whether prenatal DEX treatment does or does not have a role in the clinical management of CAH. This work was supported by Karolinska Institutet and Stockholm County Council, the Foundation Frimurare Barnhuset, the Foundation Sällskapet Barnavård, the Jerring Foundation, and the Söderberg Foundation. Disclosure Summary: The authors have nothing to disclose. Congenital adrenal hyperplasia dexamethasone.