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Context: Prenatal treatment with dexamethasone (DEX) has been used to prevent virilization in females at risk of congenital adrenal hyperplasia (CAH). Both affected and unaffected girls, as well boys, are treated until the genotype and sex of the fetus is known (gestational weeks 10-12). After that, only affected girls are treated until term. Exposure to a high synthetic glucocorticoid dosage may alter the developmental trajectory of the brain, with alterations in resting-state functional connectivity of the brain at adult age., Objective: To investigate resting-state functional connectivity in subjects at risk of having CAH, exposed to DEX treatment during the first trimester of fetal life, both in the whole brain and in 3 regions of interest (amygdala, hippocampus, and superior frontal gyrus)., Design, Setting, and Participants: Eighteen participants (8 females) at risk of having CAH, exposed to DEX treatment, and 38 controls (24 females), age range 16 to 26 years, from a single research institute, underwent functional magnetic resonance imaging of the brain during rest. We used 2 different approaches: an exploratory whole-brain analysis and seed-based analysis. For seed-based analysis, we chose 3 different brain regions (amygdala, hippocampus, and superior frontal gyrus) based on our previous findings and literature evidence., Results: We did not observe any differences in functional connectivity during rest, either in the whole brain nor in seed-based connectivity analyses at this adolescent and young adult age., Conclusions: Our results are reassuring; however, future studies on larger samples and with more sensitive methodologies are needed to confirm these findings., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: The clinical use of dexamethasone (DEX) prenatally to reduce virilization of external genitalia in female fetuses with congenital adrenal hyperplasia (CAH) is efficient but still controversial. It remains challenging to prevent the excessive exposure of DEX in unborn healthy babies during the first trimester of pregnancy., Objective: Since endogenous glucocorticoids contribute to the maintenance of blood pressure (BP) and since events during fetal life may program the fetus and affect future metabolic health, the aim of this study was to analyze ambulatory BP measurements in CAH-unaffected children and adults that were prenatally exposed to DEX treatment., Methods: Ambulatory BP measurements were analyzed in 33 (16 female) DEX-treated participants aged 5.1 to 26.3 years (19 participants aged ≤ 18 years) and in 54 (28 female) age- and sex-matched apparently healthy controls aged 5.5 to 25.3 years (27 participants aged ≤ 18 years) with ambulatory normotension., Results: Participants' age, height, weight, and body mass index were similar between the DEX-treated group and the control group. Heart rate, 24-hour BP, pulse pressure, and nighttime dipping did not statistically significantly differ between DEX-treated participants and controls., Conclusion: Our study suggests that prenatal DEX treatment in CAH-unaffected children and adults does not appear to adversely affect ambulatory BP later in life. Our observations need to be confirmed in larger studies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Context: Prenatal treatment of human disease is rare. Dexamethasone (DEX) is used in pregnancies at risk for congenital adrenal hyperplasia (CAH) to prevent virilization in an affected female fetus. The safety and long-term consequences of prenatal DEX exposure on the brain are largely unknown., Objective: We investigate whether first-trimester prenatal DEX treatment is associated with alterations in brain structure at adult age, and if these alterations are associated with DNA methylation, mood, and cognitive abilities., Design, Setting, and Participants: T1-weighted and diffusion-weighted imaging scans, from a single research institute, are compared between 19 (9 women) first-trimester DEX-treated individuals, at risk of CAH but not having CAH, and 43 (26 women) controls (age range, 16.0-26.4 years)., Results: DEX-treated participants showed bilateral enlargement of the amygdala, increased surface area and volume of the left superior frontal gyrus, and widespread increased radial, mean, and axial diffusivity of white matter, in particular in the superior longitudinal fasciculi and corticospinal tracts. In the DEX-treated group, increased mean and radial diffusivity correlated with increased methylation of the promotor region of the FKBP5 gene. There were no group differences in cognition or in scales assessing depression or anxiety, and the relationship between brain structure and cognition did not differ between DEX-treated and controls., Conclusions: First-trimester prenatal DEX treatment is associated with structural alterations of the brain at adult age, with an accompanying change in gene methylation. The findings add to the safety concerns of prenatal DEX treatment in the context of CAH., (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: High glucocorticoid levels in rodents inhibit development of beta cells during fetal life and lead to insulin deficiency in adulthood. To test whether similar phenomena occur in humans, we compared beta-cell function in adults who were exposed to glucocorticoids during the first part of fetal life with that of nonexposed subjects., Research Design and Methods: The study was conducted in 16 adult participants exposed to glucocorticoids during the first part of fetal life and in 16 nonexposed healthy participants with normal glucose tolerance who were matched for age, sex, and body mass index (BMI). Exposed participants had been born to mothers who were treated with dexamethasone 1 to 1.5 mg/day from the sixth gestational week (GW) to prevent genital virilization in children at risk of 21-hydroxylase deficiency. We selected offspring of mothers who stopped dexamethasone before the 18th GW following negative genotyping of the fetus. Insulin and glucagon secretion were measured during an oral glucose tolerance test (OGTT) and graded intravenous (IV) glucose and arginine tests. Insulin sensitivity was measured by hyperinsulinemic-euglycemic-clamp., Results: Age, BMI, and anthropometric characteristics were similar in the 2 groups. Insulinogenic index during OGTT and insulin sensitivity during the clamp were similar in the 2 groups. In exposed subjects, insulin secretion during graded IV glucose infusion and after arginine administration decreased by 17% (P = 0.02) and 22% (P = 0.002), respectively, while glucagon secretion after arginine increased., Conclusion: Overexposure to glucocorticoids during the first part of fetal life is associated with lower insulin secretion at adult age, which may lead to abnormal glucose tolerance later in life., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Prenatal dexamethasone (DEX) treatment has been proposed since 1984 to prevent genital virilization in girls with congenital adrenal hyperplasia (CAH). DEX is effective in CAH females if initiated before the sixth week of gestation, but its safety in children treated in utero remains controversial regarding cognitive functions., Objective: To avoid prenatal DEX in males and initiate DEX in due time in CAH females, we proposed in 2002 a protocol for fetal sex determination in the maternal serum (SRY test)., Design and Setting: We conducted a retrospective study of the management of 258 fetuses in the period 2002 through 2011 in pregnancies managed in referent medical centers with an institutional practice., Patients: A total of 258 fetuses at risk of CAH (134 males and 124 females) were included., Intervention: DEX was offered after informed consent to pregnant women., Main Outcome Measure: The sensitivity of an early SRY test was evaluated after data collection., Results: The SRY test is sensitive from 4 weeks and 5 days of gestation. It avoided prenatal DEX in 68% of males, and this percentage increased over the years. DEX was maintained until prenatal diagnosis in non-CAH females. Virilization was prevented in 12 CAH girls treated at the latest at 6 weeks gestation and minimized in 3 girls treated between 6 and 7 weeks gestation. Maternal tolerance was correct. No fetal malformations were noted in the 154 children treated in utero., Conclusions: The SRY test is reliable to avoid prenatal DEX in males, but its application must be improved. Prenatal DEX should be maintained to prevent virilization and traumatic surgery in CAH girls after informed consent and information provided to families about the benefit to risk ratio in limiting hyperandrogenism during fetal life. Our large multicentric French cohort has helped to better assess the risks previously reported.

Context: The 21-hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia. Pregnant women presenting a risk of genetic transmission may be treated with synthetic glucocorticoids such as dexamethasone (DEX) to prevent female fetus virilization., Objective: The aim of this study was to assess the potential deleterious effects of DEX exposure on fetal ovarian development., Settings: Human fetal ovaries, ranging from 8-11 weeks after fertilization, were harvested from material available after legally induced abortions. They were cultured in the absence or presence of DEX (2, 10, or 50 μm) over 14 d, and histological analyses were performed., Results: The glucocorticoid receptor NR3C1 was present and the signaling pathway active in the fetal ovary as demonstrated by the expression of NR3C1 target genes, such as PLZF and FKBP5, in response to DEX exposure. DEX decreased germ cell density at the 10 and 50 μm doses. Exposure to DEX, even at the highest dose, did not change oogonial proliferation as monitored by 5-bromo-2'-deoxyuridine incorporation and significantly increased the apoptotic rate, detected with cleaved caspase 3 staining. Interestingly, the expression of the prosurvival gene KIT was significantly decreased in the presence of DEX during the course of the culture., Conclusion: We have demonstrated for the first time that in vitro exposure to high doses of DEX impairs human fetal oogenesis through an increase in apoptosis. These data are of high importance, and additional epidemiological studies are required to investigate the female fertility of those women who have been exposed to DEX during fetal life.

Context and Objective: In Sweden, from 1985 through 1995, 40 fetuses at risk for congenital adrenal hyperplasia (CAH) were treated with dexamethasone (DEX) to prevent virilization of affected females. We report long-term effects on neuropsychological functions and scholastic performance of this controversial treatment., Design and Patients: Prenatally treated children, 7 to 17 yr old, were assessed with standardized neuropsychological tests (A Developmental Neuropsychological Assessment and Wechsler Intelligence Scales for Children) and child-completed questionnaires measuring self-perceived scholastic competence (Self-Perception Profile for Children). A parent-completed questionnaire (Child Behavior Checklist/4-18 School Scale) was used to evaluate whether the treatment had any impact on the children's school performance. In addition, a child-completed questionnaire measuring social anxiety (The Social Anxiety Scale for Children-Revised) was completed by the prenatally treated children aged 8 to 17 yr (n = 21) and age- and sex-matched controls (n = 26)., Results: Of 40 DEX-treated children, 26 (median age, 11 yr) participated in the study. Thirty-five sex- and age-matched healthy children were controls. There were no between-group differences concerning psychometric intelligence, measures of cerebral lateralization, memory encoding, and long-term memory. Short-term treated, CAH-unaffected children performed poorer than the control group on a test assessing verbal working memory (P = 0.003), and they rated lower on a questionnaire assessing self-perception of scholastic competence (P = 0.003). This group also showed increased self-rated social anxiety assessed by The Social Anxiety Scale for Children-Revised (P = 0.026). Prenatally treated, CAH-affected children performed poorer than controls on tests measuring verbal processing speed, although this difference disappeared when controlling for the child's full-scale IQ., Conclusions: This study indicates that prenatal DEX treatment is associated with previously not described long-term effects on verbal working memory and on certain aspects of self-perception that could be related to poorer verbal working memory. These findings may thus question future DEX treatment of congenital adrenal hyperplasia. Therefore, we encourage additional retrospective studies of larger cohorts to either confirm or challenge the present findings.

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) refers to a family of monogenic inherited disorders of adrenal steroidogenesis most often caused by enzyme 21-hydroxylase deficiency (21-OHD). In the classic forms of CAH (simple virilizing and salt wasting), androgen excess causes external genital ambiguity in newborn females and progressive postnatal virilization in males and females. Prenatal treatment of CAH with dexamethasone has been successfully used for over a decade. This article serves as an update on 532 pregnancies prenatally diagnosed using amniocentesis or chorionic villus sampling between 1978 and 2001 at New York Presbyterian Hospital-Weill Medical College of Cornell University. Of the 532 pregnancies, 281 were prenatally treated for CAH due to the risk of 21-hydroxylase deficiency. Follow-up telephone interviews with mothers, genetic counselors, endocrinologists, pediatricians, and obstetricians were performed in all cases. Of the pregnancies evaluated, 116 babies were affected with classic 21-OHD. Of these, 61 were female, 49 of whom were treated prenatally with dexamethasone. Dexamethasone administered at or before 9 wk gestation (in proper doses) was effective in reducing virilization. There were no statistical differences in the symptoms during pregnancy between mothers treated with dexamethasone and those not treated with dexamethasone, except for weight gain, edema, and striae, which were greater in the treated group. No significant or enduring side-effects were noted in the fetuses, indicating that dexamethasone treatment is safe. Prenatally treated newborns did not differ in weight from untreated, unaffected newborns. Based on our experience, prenatal diagnosis and proper prenatal treatment of 21-OHD are effective in significantly reducing or eliminating virilization in the newborn female. This spares the affected female the consequences of genital ambiguity, genital surgery, and possible sex misassignment.

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.

Women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, especially those patients with the salt-losing form, have decreased fertility rates. Pregnancy experience in this population is limited. We report the pregnancy outcomes and serial measurements of maternal serum steroid levels in four women with classic 21-hydroxylase deficiency, three of whom were female pseudohermaphrodites with the salt-losing form. These glucocorticoid-treated women gave birth to four healthy female newborns with normal female external genitalia, none of whom were affected with 21-hydroxylase deficiency. In three women, circulating androgen levels increased during gestation, but remained within the normal range for pregnancy during glucocorticoid therapy. In the fourth patient, androgen levels were strikingly elevated during gestation despite increasing the dose of oral prednisone from 5 to 15 mg/day (two divided doses). Notwithstanding the high maternal serum concentration of androgens, however, placental aromatase activity was sufficient to prevent masculinization of the external genitalia of the female fetus and quite likely the fetal brain, consistent with the idea that placental aromatization of androgens to estrogens is the principal mechanism that protects the female fetus from the masculinizing effects of maternal hyperandrogenism. These four patients highlight key issues in the management of pregnancy in women with 21-hydroxylase deficiency, particularly the use of endocrine monitoring to assess adrenal androgen suppression in the mother, especially when the fetus is female. Recommendations for the management of pregnancy and delivery in these patients are discussed.