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Prenatal dexamethasone (DEX) treatment in congenital adrenal hyperplasia (CAH) is effective in reducing virilization in affected girls, but potential long-term adverse effects are largely unknown. In this report we intended to explore potential side effects of DEX therapy to enhance the adequacy of future risk benefit analyses of DEX treatment. We investigated the long-term effects of first trimester prenatal DEX treatment on behavioral problems and temperament in children and adolescents aged 7-17 years. The study included 34 children and adolescents, without CAH, who had been exposed to DEX during the first trimester and 67 untreated controls. Standardized parent-completed questionnaires were used to evaluate adaptive functioning and behavioral/emotional problems (CBCL), social anxiety (SPAI-C-P), and temperament (EAS) in the child. Self-reports were used to assess the children's perception of social anxiety (SASC-R). No statistically significant differences were found between DEX-treated and control children and adolescents, suggesting that, in general, healthy children treated with DEX during early fetal life are well adjusted., (Copyright © 2017. Published by Elsevier Inc.)

Competing Interests: Interessenkonflikt: Zulassungsstudie (Phase III) für Chronocort an der Med. Klinik IV

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the authors due to technical errors that have called into question the reliability of the data used to inform the author's conclusions. All data on cognitive and behavioral outcomes in CAH and non–CAH cases, treated or not treated with DEX prenatally, were put into a single Excel database. The authors had in total four different patient groups for each age group (5–6 y, 7–17 y and 18-35 y). The database consisted of 237 cases in total and there were multiple columns for the different outcome measures. When the behavioral data for the sub-cohort described in this paper (first trimester treated non-CAH cases and healthy population controls, age 7–17 y) were copied to another sheet and compressed/modified in preparation for statistical analysis in SPSS, an error occurred. This technological issue caused rows to shift and the data from the different groups got mixed up. In particular, the non–CAH group versus the control group were "contaminated" with cases from the wrong patient group. The authors discovered this mistake when they started to analyse the data from the other sub–groups of patients, the CAH cases and the adult cohort, which was after their original results had already been published in Hormones and Behavior in this manuscript "Evaluation of behavioral problems after prenatal dexamethasone treatment in Swedish adolescents at risk of CAH". It then became apparent that the entire data set was unreliable and needed to be re–analysed which is what has motivated the retraction of this article. The authors have recently completed this re–analysis and the results have been published here: https://www.sciencedirect.com/science/article/pii/S0018506X17300752, (Copyright © 2016 Elsevier Inc. All rights reserved.)

Congenital adrenal hyperplasia (CAH) refers to a group of recessively inherited disorders of cortisol production, which in the classical form results in virilisation of female fetuses. Since the 1980s, antenatal treatment with dexamethasone has been recommended in high-risk pregnancies to minimise the risk of virilising the female genitalia of affected fetuses. To be effective, this treatment requires implementation in early pregnancy, prior to the commencement of autonomous fetal adrenal androgen synthesis. Using this approach, seven of eight high-risk pregnancies are treated unnecessarily, prior to establishing the fetal gender or the confirmed diagnosis of a genetically affected pregnancy. In the face of ongoing concerns regarding potential adverse maternal-fetal effects of antenatal dexamethasone exposure, a review of this practice has been advocated by expert advisory groups. In this review, we summarise current controversies, potential improvements and future directions in the management of pregnancies at risk of CAH. In high-risk families, recent genomic advances include early prenatal diagnosis utilising noninvasive genetic techniques to minimise unnecessary dexamethasone exposure to unaffected fetuses. In affected pregnancies when families elect for antenatal treatment, optimal antenatal dosing regimens need to be defined and a standardised treatment and follow-up protocol are recommended. Establishment of a national registry with standardised follow-up will allow future families to be better informed of the risks and benefits of both treated and untreated fetal CAH., (© 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.)

Prenatal treatment of congenital adrenal hyperplasia by administering dexamethasone to a woman presumed to be carrying an at-risk fetus remains a controversial experimental treatment. Review of data from animal experimentation and human trials indicates that dexamethasone cannot be considered safe for the fetus. In animals, prenatal dexamethasone decreases birth weight, affects renal, pancreatic beta cell and brain development, increases anxiety and predisposes to adult hypertension and hyperglycemia. In human studies, prenatal dexamethasone is associated with orofacial clefts, decreased birth weight, poorer verbal working memory, and poorer self-perception of scholastic and social competence. Numerous medical societies have cautioned that prenatal treatment of adrenal hyperplasia with dexamethasone is not appropriate for routine clinical practice and should only be done in Institutional Review Board approved, prospective clinical research settings with written informed consent. The data indicate that this treatment is inconsistent with the classic medical ethical maxim to 'first do no harm'., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Context: Prenatal treatment with dexamethasone to prevent virilization in pregnancies at risk for classical congenital adrenal hyperplasia (CAH) remains controversial., Objective: To conduct a systematic review and meta-analyses of studies that evaluated the effects of dexamethasone administration during pregnancies at risk for classical CAH because of 21-hydroxylase deficiency (CYP21A2)., Data Sources: We searched MEDLINE, EMBASE, and Cochrane CENTRAL from inception through August 2009. Review of reference lists and contact with CAH experts further identified candidate studies., Study Selection: Reviewers working independently and in duplicate determined trial eligibility. Eligible studies reported the effects on either foetal or maternal outcomes of dexamethasone administered during pregnancy compared to a control group that did not receive any treatment., Data Extraction: Reviewers working independently and in duplicate determined the methodological quality of studies and collected data on patient characteristics, interventions, and outcomes., Data Synthesis: We identified only four eligible observational studies (325 pregnancies treated with dexamethasone). The methodological quality of the included studies was overall low. Meta-analysis demonstrates a reduction in foetus virilization measured by Prader score in female foetuses treated with dexamethasone initiated early during pregnancy (weighted mean difference, -2.33, 95% CI, -3.38, -1.27). No deleterious effects of dexamethasone on stillbirths, spontaneous abortions, foetal malformations, neuropsychological or developmental outcomes were found although these data are quite sparse. There was increased oedema and striae in the mothers treated with dexamethasone. There were no data on long-term follow-up of physical and metabolic outcomes in children exposed to dexamethasone., Conclusions: The observational nature of the available evidence and the overall small sample size of the whole body of the literature significantly weaken inferences about the benefits and harms of dexamethasone in this setting. Dexamethasone seems to be associated with reduction in foetus virilization without significant maternal or foetal adverse effects. However, this review underscores the current uncertainty and further investigation is clearly needed. The decision about initiating treatment should be based on patients' values and preferences and requires fully informed and consenting parents., (© 2010 Blackwell Publishing Ltd.)

In foetuses at risk of virilising congenital adrenal hyperplasia (CAH), prenatal treatment can be offered by administration of dexamethasone (DEX) via the mother, in order to suppress foetal adrenal androgen oversecretion and prevent genital malformations. The first treated cases were described 20 years ago, and several hundred pregnancies have been reported since. There is a consensus that the treatment effectively prevents or reduces virilisation, but opinions regarding its safety differ. Rare adverse events have been reported in treated children, but no harmful effect has been documented that can be clearly attributed to the treatment. However, few treated foetuses have been followed until adolescence. Animal studies and epidemiological data point to various adverse effects of excess glucocorticoids on the developing foetus. In order to prevent virilisation effectively in females affected with CAH, the prenatal treatment needs to be instituted in the early first trimester, before prenatal diagnosis is possible. Thus, a majority of treated foetuses will receive DEX unnecessarily. The PREDEX study was initiated in Stockholm in 1999 as an open, controlled, non-randomised, multicentre trial. Participating centres are Stockholm, Bergen, Kuopio, Warsaw, London, Lyon and Barcelona. The study has been approved by the ethics committees in each country. The purpose of PREDEX is to evaluate prospectively the prenatal treatment regarding efficacy in preventing virilisation as well as to study its safety for both mothers and treated children. Children are followed until 18 years of age and a wide range of physiological, metabolic and developmental parameters are considered. In Sweden, treatment is not offered outside the frames of the trial.

Congenital adrenal hyperplasia (CAH) consists of autosomal recessive disorders of cortisol biosynthesis, which in the majority of cases result from 21-hydroxylase deficiency. Another enzymatic defect causing CAH is 11beta-hydroxylase deficiency. In both forms, the resulting excessive androgen secretion causes genital virilization of the female fetus. For over 10 yr female fetuses affected with 21-hydroxylase deficiency have been safely and successfully prenatally treated with dexamethasone. We report here the first successful prenatal treatment with dexamethasone of an affected female with 11beta-hydroxylase deficiency CAH. The family had two girls affected with 1beta-hydroxylase deficiency born with severe ambiguous genitalia who were both homozygous for the T318M mutation in the CYP11B1 gene, which codes for the 11beta-hydroxylase enzyme. In the third pregnancy in this family, the female fetus was treated in utero by administering dexamethasone to the mother, starting at 5 weeks gestation. The treatment was successful, as the newborn was not virilized and had normal female external genitalia. A second family with two affected sons was also studied in preparation for a future pregnancy. We report a novel 1-bp deletion in codon 394 (R394delta1) in the CYP11B1 gene in this family.

Congenital adrenal hyperplasia (CAH) is the common name of a constellation of diseases that impair cortisol synthesis in the adrenal cortex. As defects in each of three steroidogenic enzymes, 21-hydroxylase, 11 beta-hydroxylase, and 3 beta-hydroxysteroid dehydrogenase, promote overproduction of adrenal androgens, affected female fetuses may be virilised. The major cause of CAH is 21-hydroxylase deficiency, the incidence of which is 1:10,000 live births in the Swedish population. Of the 10-15 children born in Sweden each year with 21-hydroxylase deficiency, 3-5 will be virilised girls who must undergo traumatic surgery of the external genitalia. This can be prevented by administration of dexamethasone to the gravida during pregnancy. Prenatal treatment was introduced in Sweden in 1985, prenatal diagnosis being based in most cases on direct mutational analysis using allele-specific PCR on DNA from chorionic villus samples. In our experience, genotype corresponds well to phenotype, and we recommend that all children with 21-hydroxylase deficiency be genotyped in order to prepare the family for rapid and reliable prenatal diagnosis and possible treatment when the next child is awaited. Since 1985, 35 women have received prenatal treatment in Sweden, six of the 35 fetuses being found to be affected females and treated until term. As compared with their older sisters, all of these six girls were characterised by no signs, or only minor signs, of virilisation, and only one required surgery because of labial fusion and recurrent urinary tract infections. As a group, the 35 infants were characterised by normal birth weight and length, and normal growth during the first year of life. Passage of developmental milestones was normal though several adverse events, both in treated mothers and infants, have been reported. Approximately one fourth of the women treated throughout pregnancy reported some side-effect (e.g., excessive weight gain, severe cutaneous striae, mood fluctuations and irritability, acne and hirsutism, or oedema). One unaffected boy, treated for seven weeks, was born with severe hydrocephalus and agenesis of the corpus callosum; two affected sisters and one unaffected girl were characterised by failure to thrive during the first year of life, but later recovered (one of the affected sisters was later diagnosed as suffering from mitochondrial disease). Although in our experience prenatal treatment with dexamethasone is effective in preventing virilisation of girls with 21-hydroxylase deficiency, some adverse events have been noted in treated infants. As it remains unknown whether these events were attributable to the treatment, it must still be regarded as experimental, and its use should be centralised and meticulously monitored until more experience has been gained.

We report two cases of congenital adrenal hyperplasia (CAH) in which administration of chlormadinone acetate (CMA), a substituted progestational agent for prostatic disease, suppressed ACTH hypersecretion and lowered plasma testosterone levels. Case 1 was 83-year-old male with advanced prostatic carcinoma and CAH due to 21-hydroxylase deficiency. His plasma testosterone did not decrease in spite of a bilateral orchiectomy. Case 2 was 40-year-old female with CAH due to 21-hydroxylase deficiency suffering from virilization after the cessation of cortisol supplement therapy because of her breast carcinoma. In these two cases, oral administration of CMA at a daily dose of 75-100 mg suppressed ACTH and cortisol to subnormal levels and reduced testosterone levels. With the suppressive effect on ACTH excess and antiandrogenic action, CMA may be suitable for patients with CAH suffering from symptoms due to overproduced ACTH or adrenal androgen.

Prenatal treatment based on administration of dexamethasone to the mother during pregnancy was initiated early during nine pregnancies with a high risk of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The purpose of this treatment was to prevent fetal virilization by reducing production of androgens by the adrenal glands. Prenatal diagnosis was achieved by comparing amniotic fluid cell HLA genotypes and more recently by subjecting trophoblasts to molecular genetic studies. Together with prenatal determination of fetal sex, this allowed to determine that only two female fetuses were affected. Efficacy of continued prenatal treatment in these two cases was good in one case and mediocre in the other. The treatment was well tolerated by the mothers and fetuses.

A mother at risk for 21-hydroxylase deficiency was treated with oral dexamethasone (0.5 mg 12 hourly) from early pregnancy, in an attempt to prevent in utero virilization in case of a female fetus. Fetal karyotype was 46,XX, and because of a possible intra HLA recombination, treatment was continued to term. The newborn had a modest virilization and hormonal studies confirmed the diagnosis of congenital adrenal hyperplasia (CAH). This observation and review of the literature suggest that efficient prenatal treatment of CAH requires a higher and more frequent dosage of dexamethasone.

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency can result in marked virilization of the external genitalia of affected female subjects. Theoretically, suppression of the fetal pituitary-adrenal axis with glucocorticoid during gestational weeks 9 to 17 should prevent the development of ambiguous genitalia in the female fetus. Prenatal diagnosis of congenital adrenal hyperplasia can be made on elevated amniotic fluid 17-hydroxyprogesterone and adrenal androgen concentrations, and HLA typing of cultured amniotic fluid cells. However, these tests cannot be completed before 16 to 17 weeks of gestation, and maternal therapy would have to be instituted before the exact genetic status of the fetus is known. Chorionic villus sampling during the first trimester provides an alternative to second trimester diagnosis in patients who are at risk for bearing offspring with congenital adrenal hyperplasia. We report the use of dexamethasone suppression at 8 weeks of gestation in a 34-year-old woman whose son had congenital adrenal hyperplasia due to severe salt-losing 21-hydroxylase deficiency and whose biopsy revealed a 46XX chromosomal pattern. Cultured cells from the biopsy confirmed the fetus to be of identical HLA haplotype to the previous affected sibling. At 41 weeks the patient delivered a female neonate with minimal prominence of the clitoris, mildly rugated labia, a single perineal opening and minimal posterior labial fusion. Postnatal tapering of maternal steroids was performed with no long-term sequelae.