Prenatal Dexamethasone Treatment Research Articles

Contribution of changes in the orexin system and energy sensors in the brain in depressive disorder - a study in an animal model

BackgroundMaternal elevated glucocorticoid levels during pregnancy can affect the developing fetus, permanently altering the structure and function of its brain throughout life. Excessive action of these hormones is known to contribute to psychiatric disorders, including depression.MaterialsThe study was performed in a rat model of depression based on prenatal administration of dexamethasone (DEX) in late pregnancy (0.1 mg/kg, days 14–21). We evaluated the effects of prenatal DEX treatment on the cognition and bioenergetic signaling pathways in the brain of adult male rats, in the frontal cortex and hippocampus, and in response to stress in adulthood, using behavioral and biochemical test batteries.ResultsWe revealed cognitive deficits in rats prenatally treated with DEX. At the molecular level, a decrease in the orexin A and orexin B levels and downregulation of the AMPK-SIRT1-PGC1α transduction pathway in the frontal cortex of these animals were observed. In the hippocampus, a decreased expression of orexin B was found and changes in the MR/GR ratio were demonstrated. Furthermore, an increase in HDAC5 level triggered by the prenatal DEX treatment in both brain structures and a decrease in MeCP2 level in the hippocampus were reported.ConclusionsOur study demonstrated that prenatal DEX treatment is associated with cognitive dysfunction and alterations in various proteins leading to metabolic changes in the frontal cortex, while in the hippocampus adaptation mechanisms were activated. The presented results imply that different pathophysiological metabolic processes may be involved in depression development, which may be useful in the search for novel therapies.

An update on the long-term outcomes of prenatal dexamethasone treatment in congenital adrenal hyperplasia.

First-trimester prenatal treatment with glucocorticoid (GC) dexamethasone (DEX) in pregnancies at risk for classic congenital adrenal hyperplasia (CAH) is associated with ethical dilemmas. Though effective in reducing virilisation in girls with CAH, it entails exposure to high doses of GC in fetuses that do not benefit from the treatment. The current paper provides an update on the literature on outcomes of prenatal DEX treatment in CAH cases and unaffected subjects. Long-term follow-up research is still needed to determine treatment safety. In addition, advances in early prenatal diagnostics for CAH and sex-typing as well as studies assessing dosing effects of DEX may avoid unnecessary treatment and improve treatment safety.

Impact of different dexamethasone treatment protocols in goats for preterm neonatal outcomes

This study aimed to evaluate metabolic parameters, such as hemogasometric, glycemic, and lactate values of premature newborns from goats subjected to prenatal dexamethasone treatment using different protocols in comparison with those obtained with previous protocols and studies. The protocols were as follows: Group I received 20 mg dexamethasone at 139 days of gestation; Group II received 2 mg dexamethasone from the 133rd to the 136th day of gestation, 4 mg from the 137th to the 139th day, and 20 mg on the 140th day; Group III received 16 mg dexamethasone from the 139th day, with repeated doses every 12 h until elective surgery; and Group IV received 4, 8, 16, and 20 mg dexamethasone on days 137th, 138th, 139th and 140th days of gestation, respectively. The groups whose mothers received 4, 8, 16, and 20 mg dexamethasone at 137, 138, 139, and 140 days of gestation had higher bicarbonate values at 0, 1, and 48 h compared to the other groups. The highest lactate values were observed at birth, with a gradual reduction in all groups. In all groups, there was an increase in glucose levels after birth, with the highest values observed 48 h after birth. The use of antenatal dexamethasone in goats promotes fetal development, and consequently, lung maturation. More extended protocols seem more efficient, resulting in lower mortality rates and less intense metabolic changes. This study will help establish protocols to overcome the mortality and morbidity associated with preterm ruminants.

Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe

ObjectiveTo assess the current medical practice in Europe regarding prenatal dexamethasone (Pdex) treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency.Design and methodsA questionnaire was designed and distributed, including 17 questions collecting quantitative and qualitative data. Thirty-six medical centres from 14 European countries responded and 30 out of 36 centres were reference centres of the European Reference Network on Rare Endocrine Conditions, EndoERN.ResultsPdex treatment is currently provided by 36% of the surveyed centres. The treatment is initiated by different specialties, that is paediatricians, endocrinologists, gynaecologists or geneticists. Regarding the starting point of Pdex, 23% stated to initiate therapy at 4–5 weeks postconception (wpc), 31% at 6 wpc and 46 % as early as pregnancy is confirmed and before 7 wpc at the latest. A dose of 20 µg/kg/day is used. Dose distribution among the centres varies from once to thrice daily. Prenatal diagnostics for treated cases are conducted in 72% of the responding centres. Cases treated per country and year vary between 0.5 and 8.25. Registries for long-term follow-up are only available at 46% of the centres that are using Pdex treatment. National registries are only available in Sweden and France.ConclusionsThis study reveals a high international variability and discrepancy in the use of Pdex treatment across Europe. It highlights the importance of a European cooperation initiative for a joint international prospective trial to establish evidence-based guidelines on prenatal diagnostics, treatment and follow-up of pregnancies at risk for CAH.

Ambulatory Blood Pressure Monitoring in Children and Adults Prenatally Exposed to Dexamethasone Treatment.

ContextThe 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.ObjectiveSince 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.MethodsAmbulatory 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.ResultsParticipants’ 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.ConclusionOur 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.

Sex difference in adrenal developmental toxicity induced by dexamethasone and its intrauterine programming mechanism

Dexamethasone is widely used to treat preterm labor and related diseases. However, prenatal dexamethasone treatment (PDT) can cause multiorgan developmental toxicities in offspring. Our previous study found that the occurrence of fetal-originated diseases was associated with adrenal developmental programming alterations in offspring. Here, we investigated the effects of PDT on adrenal function in offspring and its intrauterine programming mechanism. A rat model of PDT was established to observe the alterations of adrenal steroidogenesis in offspring. Furthermore, we confirmed the sex differences of adrenal steroidogenesis and its molecular mechanism combined with in vivo and in vitro experiments. PDT caused a decrease in adrenal steroidogenic function in fetal rats, but it was decreased in males and increased in females after birth. Meanwhile, the adrenal H3K14ac level and expression of 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2) in PDT offspring were decreased in males and increased in females, suggesting that 11β-HSD2 might mediate sex differences in adrenal function. We further confirmed that dexamethasone inhibited the H3K14ac level and expression of 11β-HSD2 through the GR/SP1/p300 pathway. After bilateral testectomy or ovariectomy of adult PDT offspring rats, adrenal 11β-HSD2 expression and steroidogenic function were both reduced. Using rat primary fetal adrenal cells, the differential expression of AR and ERβ was proven to be involved in regulating the sex difference in 11β-HSD2 expression. This study demonstrated the sex difference in adrenal steroidogenic function of PDT offspring after birth and elucidated a sex hormone receptor-dependent epigenetically regulating mechanism for adrenal 11β-HSD2 programming alteration.

First-Trimester prenatal dexamethasone treatment is associated with alterations in brain structure at adult age

First-Trimester prenatal dexamethasone treatment is associated with alterations in brain structure at adult age

Excess of glucocorticoids during late gestation impairs the recovery of offspring's β-cell function after a postnatal injury.

Since prenatal glucocorticoids (GC) excess increases the risk of metabolic dysfunctions in the offspring and its effect on β-cell recovery capacity remains unknown we investigated these aspects in offspring from mice treated with dexamethasone (DEX) in the late pregnancy. Half of the pups were treated with streptozotocin (STZ) on the sixth postnatal day (PN). Functional and molecular analyses were performed in male offspring on PN25 and PN225. Prenatal DEX treatment resulted in low birth weight. At PN25, both the STZ-treated offspring developed hyperglycemia and had lower β-cell mass, in parallel with higher α-cell mass and glucose intolerance, with no impact of prenatal DEX on such parameters. At PN225, the β-cell mass was partially recovered in the STZ-treated mice, but they remained glucose-intolerant, irrespective of being insulin sensitive. Prenatal exposition to DEX predisposed adult offspring to sustained hyperglycemia and perturbed islet function (lower insulin and higher glucagon response to glucose) in parallel with exacerbated glucose intolerance. β-cell-specific knockdown of the Hnf4α in mice from the DS group resulted in exacerbated glucose intolerance. We conclude that high GC exposure during the prenatal period exacerbates the metabolic dysfunctions in adult life of mice exposed to STZ early in life, resulting in a lesser ability to recover the islets' function over time. This study alerts to the importance of proper management of exogenous GCs during pregnancy and a healthy postnatal lifestyle since the combination of adverse factors during the prenatal and postnatal period accentuates the predisposition to metabolic disorders in adult life.

Current clinical practice of prenatal dexamethasone treatment in at risk pregnancies for classic 21‑hydroxylase deficiency in Europe

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Dexamethasone induces an imbalanced fetal-placental-maternal bile acid circulation: involvement of placental transporters

BackgroundThe use of prenatal dexamethasone remains controversial. Our recent studies found that prenatal dexamethasone exposure can induce maternal intrahepatic cholestasis and have a lasting adverse influence on bile acid (BA) metabolism in the offspring. The purpose of this study was to investigate the effects of dexamethasone on fetal-placental-maternal BA circulation during the intrauterine period, as well as its placental mechanism.MethodsClinical data and human placentas were collected and analyzed. Pregnant Wistar rats were injected subcutaneously with dexamethasone (0.2 mg/kg per day) from gestational day 9 to 20. The metabolomic spectra of BAs in maternal and fetal rat serum were determined by LC-MS. Human and rat placentas were collected for histological and gene expression analysis. BeWo human placental cell line was treated with dexamethasone (20–500 nM).ResultsHuman male neonates born after prenatal dexamethasone treatment showed an increased serum BA level while no significant change was observed in females. Moreover, the expression of organic anion transporter polypeptide-related protein 2B1 (OATP2B1) and breast cancer resistance protein (BCRP) in the male neonates’ placenta was decreased, while multidrug resistance-associated protein 4 (MRP4) was upregulated. In experimental rats, dexamethasone increased male but decreased female fetal serum total bile acid (TBA) level. LC-MS revealed that primary BAs were the major component that increased in both male and female fetal serum, and all kinds of BAs were significantly increased in maternal serum. The expression of Oatp2b1 and Bcrp were reduced, while Mrp4 expression was increased in the dexamethasone-treated rat placentas. Moreover, dexamethasone increased glucocorticoid receptor (GR) expression and decreased farnesoid X receptor (FXR) expression in the rat placenta. In BeWo cells, dexamethasone induced GR translocation into the nucleus; decreased FXR, OATP2B1, and BCRP expression; and increased MRP4 expression. Furthermore, GR was verified to mediate the downregulation of OATP2B1, while FXR mediated dexamethasone-altered expression of BCRP and MRP4.ConclusionsBy affecting placental BA transporters, dexamethasone induces an imbalanced fetal-placental-maternal BA circulation, as showed by the increase of primary BA levels in the fetal serum. This study provides an important experimental and theoretical basis for elucidating the mechanism of dexamethasone-induced alteration of maternal and fetal BA metabolism and for exploring early prevention and treatment strategies.

Spatial learning and memory deficits induced by prenatal glucocorticoid exposure depend on hippocampal CRHR1 and CXCL5 signaling in rats

BackgroundPrenatal synthetic glucocorticoid (sGC) exposure increases the susceptibility to cognitive and affective disorders in postnatal life. We previously demonstrated that prenatal sGC exposure results in an increase in corticotropin-releasing hormone (CRH) receptor type 1 (CRHR1) expression in the hippocampus of rats, and CRHR1 is involved in synapse formation via regulation of C-X-C chemokine ligand 5 (CXCL5) in hippocampus. We sought to investigate that the roles of CRHR1 and CXCL5 in learning and memory impairment caused by prenatal sGC exposure.MethodsPregnant rats were administered with saline or dexamethasone (DEX) from gestational day (GD) 14 to GD21. DEX offspring at 2-day old were treated with saline and CRHR1 antagonists (antalarmin and CP154526) for 7 days. Some DEX offspring received intra-hippocampal injection of AAV9 carrying CXCL5 gene. Spatial learning and memory was assessed by Morris water maze test. Immunofluorescence analysis was applied to show synapsin I and PSD95 signals in hippocampus. Synapsin I and PSD95 protein level and CXCL5 concentration were determined by western blotting and ELISA, respectively. Organotypic hippocampal slice cultures were used to investigate the effect of DEX on CXCL5 production in vitro.ResultsBoth male and female DEX offspring displayed impairment of spatial learning and memory in adulthood. Synapsin I and PSD95 signals and CXCL5 levels were decreased in DEX offspring. DEX offspring with antalarmin and CP154526 treatment showed improved spatial learning and memory. Antalarmin and CP154526 treatment increased synapsin I and PSD95 signals and CXCL5 concentration in hippocampus. Bilaterally hippocampal injection of AAV9 carrying CXCL5 gene improved the spatial learning and memory and increased CXCL5 concentration and synapsin I and PSD95 levels in hippocampus. DEX dose-dependently suppressed CXCL5 production in cultured hippocammpal slices, which was prevented by antalarmin treatment.ConclusionCRHR1 and CXCL5 signaling in the hippocampus are involved in spatial learning and memory deficits caused by prenatal DEX exposure. CRHR1 activation contributes to decreased CXCL5 production in hippocampus induced by prenatal DEX treatment. Our study provides a molecular basis of prenatal GC exposure programming spatial learning and memory.

Dexamethasone-induced intrauterine growth restriction modulates expression of placental vascular growth factors and fetal and placental growth.

Prenatal exposure to glucocorticoids (GC) is a central topic of interest in medicine since GCs are essential for the maturation of fetal organs and intrauterine growth. Synthetic glucocorticoids, which are used in obstetric practice, exert beneficial effects on the fetus, but have also been reported to lead to intrauterine growth retardation (IUGR). In this study, a model of growth restriction in mice was established through maternal administration of dexamethasone during late gestation. We hypothesised that GC overexposure may adversely affect placental angiogenesis and fetal and placental growth. Female BALB/c mice were randomly assigned to control or dexamethasone treatment, either left to give birth or euthanised on days 15, 16, 17 and 18 of gestation followed by collection of maternal and fetal tissue. The IUGR rate increased to 100% in the dexamethasone group (8 mg/kg body weight on gestational days 14 and 15) and pups had clinical features of symmetrical IUGR at birth. Dexamethasone administration significantly decreased maternal body weight gain and serum corticosterone levels. Moreover, prenatal dexamethasone treatment not only induced fetal growth retardation but also decreased placental weight. In IUGR placentas, VEGFA protein levels and mRNA expression of VEGF receptors were reduced and NOS activity was lower. Maternal dexamethasone administration also reduced placental expression of the GC receptor, αGR. We demonstrated that maternal dexamethasone administration causes fetal and placental growth restriction. Furthermore, we propose that the growth retardation induced by prenatal GC overexposure may be caused, at least partially, by an altered placental angiogenic profile.

First Trimester DEX Treatment Is Not Associated with Altered Brain Activity During Working Memory Performance in Adults.

ContextPrenatal dexamethasone (DEX) treatment is sometimes used in pregnancies at risk for congenital adrenal hyperplasia (CAH) to prevent virilization in female fetuses with CAH. In boys and in fetuses not having CAH, there is no benefit of early DEX treatment and the risks of this therapy must be thoroughly investigated. High doses of prenatal glucocorticoid might alter the developmental trajectory of the brain into adulthood, even for CAH unaffected subjects treated with DEX for a short term during the first trimester.ObjectiveThe present study investigated brain activation during working memory performance in DEX-treated subjects compared with controls.Design, Setting, and ParticipantsWe tested 18 participants who were exposed to DEX during the first trimester of fetal life but did not have CAH (8 females; mean age 20.78 [standard deviation (SD), 2.67] years) and 40 control participants (24 females; mean age 20.53 [SD, 2.64]) from a single research institute. Participants underwent functional magnetic resonance imaging on a 3T scanner during a verbal and visuospatial working memory task.ResultsWe did not observe any differences in brain activity during working memory performance. However, DEX-treated subjects responded faster during the experimental condition of the verbal WM task.ConclusionsFirst trimester DEX treatment did not seem to result in altered working memory–related brain activity at adult age. Our findings contribute to the risk–benefit assessment of prenatal DEX treatment in the context of CAH.

First-Trimester Prenatal Dexamethasone Treatment Is Associated With Alterations in Brain Structure at Adult Age.

ContextPrenatal 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.ObjectiveWe 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 ParticipantsT1-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).ResultsDEX-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.ConclusionsFirst-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.

MON-156 Efficacy and Safety of Prenatal Dexamethasone Treatment in Offspring at Risk for Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

Objective: To assess the efficacy and safety of prenatal dexamethasone treatment in offspring at risk for congenital adrenal hyperplasia. Methods: MEDLINE, EMBASE, the Cochrane Library, the clinicaltrials.gov website databases was systematically searched from inception through March 2019. WMD and SMD with 95%CIs were calculated using random or fixed effects models. Results: There was a significant reduction of virilizationin the DEX-treated group (WMD: -2.39, 95%CI: -3.31,-1.47). No significant differences were found in newborn physical outcomes for birth weight (WMD: 0.09, 95%CI: -0.09, 0.27) and birth length (WMD= 0.27, 95%CI: -0.68, 1.21). Concerning cognitive functions, no significant differences in the domains of psychometric intelligence (SMD: 0.05, 95%CI: -0.74, 0.83), verbal memory (SMD: -0.17, 95%CI: -0.58, 0.23), visual memory (SMD: 0.10, 95%CI: -0.14, 0.34), learning (SMD: -0.02, 95%CI: -0.27, 0.22), verbal processing (SMD: -0.38, 95%CI: -0.93, 0.17). Regarding behavioral problems, no significant differences in the domains of internalizing problems (SMD: 0.16, 95%CI: -0.49, 0.81), externalizing problems (SMD: 0.07, 95%CI: -0.30, 0.43), total problems (SMD: 0.14, 95%CI: -0.23, 0.51). With respect to temperament, no significant differences in the domains of emotionality (SMD: 0.13, 95%CI: -0.79, 1.05), activity (SMD: 0.04, 95%CI: -0.32, 0.39), shyness (SMD: 0.25, 95%CI: -0.70, 1.20), sociability (SMD: -0.23, 95%CI: -0.90, 0.44). Conclusions: Prenatal DEX treatment reduced virilization with no significant differences in newborn physical outcomes, cognitive functions, behavioral problems, temperament. The results need to be interpreted cautiously due to the existence of limitations.

Efficacy and safety of prenatal dexamethasone treatment in offspring at risk for congenital adrenal hyperplasia due to 21-hydroxylase deficiency: A systematic review and meta-analysis.

To assess the efficacy and safety of prenatal dexamethasone treatment in offspring at risk for congenital adrenal hyperplasia. MEDLINE, EMBASE, the Cochrane Library, the clinicaltrials.gov website databases were systematically searched from inception through March 2019. WMD and SMD with 95%CIs were calculated using random or fixed effects models. There was a significant reduction in virilization in the DEX-treated group (WMD: -2.39, 95%CI: -3.31,-1.47). No significant differences were found in newborn physical outcomes for birth weight (WMD: 0.09, 95%CI: -0.09, 0.27) and birth length (WMD=0.27, 95%CI: -0.68, 1.21). Concerning cognitive functions, no significant differences in the domains of psychometric intelligence (SMD: 0.05, 95%CI: -0.74, 0.83), verbal memory (SMD: -0.17, 95%CI: -0.58, 0.23), visual memory (SMD: 0.10, 95%CI: -0.14, 0.34), learning (SMD: -0.02, 95%CI: -0.27, 0.22) and verbal processing (SMD: -0.38, 95%CI: -0.93, 0.17). Regarding behavioural problems, no significant differences in the domains of internalizing problems (SMD: 0.16, 95%CI: -0.49, 0.81), externalizing problems (SMD: 0.07, 95%CI: -0.30, 0.43) and total problems (SMD: 0.14, 95%CI: -0.23, 0.51). With respect to temperament, no significant differences in the domains of emotionality (SMD: 0.13, 95%CI: -0.79, 1.05), activity (SMD: 0.04, 95%CI: -0.32, 0.39), shyness (SMD: 0.25, 95%CI: -0.70, 1.20) and sociability (SMD: -0.23, 95%CI: -0.90, 0.44). Prenatal DEX treatment reduced virilization with no significant differences in newborn physical outcomes, cognitive functions, behavioural problems and temperament. The results need to be interpreted cautiously due to the existence of limitations.

Epigenetic alterations associated with early prenatal dexamethasone treatment

Prenatal treatment with dexamethasone (DEX) has been used to avoid virilization in girls with Congenital Adrenal Hyperplasia (CAH). However, it has potential short- and long-term risks and has been associated with cognitive impairments. Here, the authors investigate whether epigenetic modification of DNA during early developmental stages may be a key mediating mechanism by which prenatal DEX treatment could result in poor outcomes in the offspring by comparing genome-wide DNA methylation, from peripheral CD4+ T-cells, between prenatal DEX-treated individuals without CAH and population controls.

Adrenals

Preface: For this year’s chapter on ‘Adrenals’, we have searched the PubMed for articles on ‘adrenal’ or ‘steroidogenesis’ published in English between June 1, 2018 and May 31, 2019. Our search yielded more than 5,000 citations. We have examined all citations individually and selected the following collection of basic research and clinical articles. Whenever possible, we have avoided topics that have been discussed in the Yearbook 2018, unless progress in the field has been incremental. Emerging themes for this year’s chapter include: i) Endogenous glucocorticoids control host resistance to viral infection through the tissue-specific regulation of PD-1 expression on NK cells; ii) Steroidogenic differentiation and PKA signaling are programmed by histone methyltransferase EZH2 in the adrenal cortex; iii) Associations between adrenarcheal hormones, amygdala functional connectivity and anxiety symptoms in children; iv) An Endocrine Society Clinical Practice Guideline for the diagnosis and management of Congenital Adrenal Hyperplasia Due to Steroid 21-hydroxylase deficiency; and v) Epigenetic alterations associated with early prenatal dexamethasone treatment.

Epigenetic Alterations Associated With Early Prenatal Dexamethasone Treatment.

Prenatal treatment with dexamethasone (DEX) reduces virilization in girls with congenital adrenal hyperplasia (CAH). It has potential short- and long-term risks and has been shown to affect cognitive functions. Here, we investigate whether epigenetic modification of DNA during early developmental stages may be a key mediating mechanism by which prenatal DEX treatment could result in poor outcomes in the offspring. We analyzed genome-wide CD4+ T cell DNA methylation, assessed using the Infinium HumanMethylation450 BeadChip array in 29 individuals (mean age = 16.4 ± 5.9 years) at risk for CAH and treated with DEX during the first trimester and 37 population controls (mean age = 17.0 years, SD = 6.1 years). We identified 9672 differentially methylated probes (DMPs) associated with DEX treatment and 7393 DMPs associated with a DEX × sex interaction. DMPs were enriched in intergenic regions located near epigenetic markers for active enhancers. Functional enrichment of DMPs was mostly associated with immune functioning and inflammation but also with nonimmune-related functions. DEX-associated DMPs enriched near single nucleotide polymorphisms (SNPs) associated with inflammatory bowel disease, and DEX × sex-associated DMPs enriched near SNPs associated with asthma. DMPs in genes involved in the regulation and maintenance of methylation and steroidogenesis were identified as well. Methylation in the BDNF, FKBP5, and NR3C1 genes were associated with the performance on several Wechsler Adult Intelligence Scale–Fourth Edition subscales. In conclusion, this study indicates that DNA methylation is altered after prenatal DEX treatment. This finding may have implications for the future health of the exposed individual.

Prenatal dexamethasone treatment in the context of at risk CAH pregnancies: Long-term behavioral and cognitive outcome

Dexamethasone (DEX) is used to prevent prenatal virilization in female fetuses with congenital adrenal hyperplasia (CAH). Since treatment has to be started before the genotype of the fetus is known, 7 out of 8 fetuses will be exposed to DEX without benefit. Previously, we have observed negative effects on cognition and behavior in DEX treated children. Here we evaluated neuropsychological functions, psychopathology and autistic traits in non-CAH DEX-treated adults exposed during the first trimester of fetal life (duration 6.2 ± 2.2 weeks). Cognitive functions, psychopathology and autistic traits were compared between DEX-treated subjects (n = 23) and non-exposed controls (n = 58). Cognitive outcome was also evaluated longitudinally for DEX-treated participants. We used neuropsychological tests (Wechsler Scales and the Stroop Interference Test) and questionnaires assessing executive functions (the Barkley Deficit in Executive Functioning Scale), psychopathology (the Montgomery Åsberg Depression Ratings Scale, the Hospital Anxiety and Depression Scale, the Liebowitz Social Anxiety Scale) and autistic traits (Autism Quota).We did not observe any significant differences in cognition, psychopathology or autistic traits between DEX-treated individuals and population controls. A significant improvement in verbal working memory (p = 0.038) and in impulse inhibition (p = 0.011) was seen when subjects were evaluated longitudinally.In summary, first-trimester DEX-exposed adult individuals do not show any significant neuropsychological deficits nor an increase in anxiety, depression or autistic traits, compared with a control group from the general population. The results also suggest that the observed deficits in executive functioning during childhood may improve with time.