Metabolic and cognitive effects after early prenatal dexamethasone treatment

Congenital adrenal hyperplasia (CAH), due to 21-hydroxylase deficiency (21OHD), is a disease with an inborn error of the adrenal steroid synthesis. This enzyme deficiency leads to cortisol shortage and androgen excess. If left untreated, CAH is potentially life-threatening especially in the neonatal period, but girls are also affected in the prenatal period with virilization caused by the surplus of adrenal androgen. Prenatal dexamethasone (DEX) treatment will minimize the androgen levels and reduce virilization. However, because the development of genitalia occurs in early gestation, the treatment must start in gestational week (GW) 6-8 to be efficient. Because of the recessive mode of inheritance and because genotyping of the fetus is not possible until GW 12, statistically, 7 of 8 fetuses will be treated unnecessarily during the first trimester of fetal life. This quandary emphasizes the importance of investigating the potential risks of DEX treatment. Glucocorticoid (GC) exposure during fetal development is known to negatively affect the child (e.g. cognition, behavior and metabolism and altered brain morphology). This thesis is part of a long-term study of children without CAH who were prenatally treated with DEX because of the potential risk of having CAH. Specifically, the thesis investigates the effects of DEX treatment on cognition (study I), behavior (study II), metabolism (study III) and blood pressure (study IV). Forty-two DEX-treated children and young adults without CAH (age range, 4-26 years) and 75 controls from the general population matched for age and sex were included in the studies. We identified a negative effect on cognition in DEX- treated girls but not in boys. Girls did worse on test assessing verbal IQ, non-verbal IQ and verbal working memory. There were no differences in behavioral problems, evaluated by parents and self-rated questionnaires in treated versus non-treated children. We found a lower HOMA-β in girls, but not in boys (another sex-dimorphic effect), suggesting a lower beta-cell function due to prenatal DEX exposure. In the younger age group (<16 years), fasting glucose levels were higher in the treated group in both sexes. In the older age group (≥16 years), total cholesterol and LDL cholesterol levels were higher in the exposed group in both sexes. When we assessed 24-hour ambulatory blood pressure, the only significant finding was higher pulse pressure in the younger age group during nighttime measurements. In conclusion, early prenatal DEX treatment seems to have a sex-dimorphic effect on cognition and glucose metabolism. It also affects blood lipids in both sexes. Owing to these findings, and other negative findings previously shown in this cohort, the safety of prenatal DEX treatment is questionable. New, and an earlier prenatal diagnosis is needed to avoid treating healthy fetuses and males with CAH

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 g irls 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 resear ch 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 DE X may avoid unnecessary treatment and improve treatment safety

The efficacy of hypotonic and near-isotonic saline for parenteral fluid therapy given at low maintenance rate in preventing significant change in plasma sodium in post-operative pediatric patients: protocol for a prospective randomized non-blinded study

<p>Abstract</p> <p>Background</p> <p>Hyponatremia is the most frequent electrolyte abnormality observed in post-operative pediatric patients receiving intravenous maintenance fluid therapy. If plasma sodium concentration (p-Na⁺) declines to levels below 125 mmol/L in < 48 h, transient or permanent brain damage may occur. There is an intense debate as to whether the administered volume (full rate <it>vs. </it>restricted rate of infusion) and the composition of solutions used for parenteral maintenance fluid therapy (hypotonic <it>vs. </it>isotonic solutions) contribute to the development of hyponatremia. So far, there is no definitive pediatric data to support a particular choice of parenteral fluid for maintenance therapy in post-surgical patients.</p> <p>Methods/Design</p> <p>Our prospective randomized non-blinded study will be conducted in healthy children and adolescents aged 1 to 14 years who have been operated for acute appendicitis. Patients will be randomized either to intravenous hypotonic (0.23% or 0.40% sodium chloride in glucose, respectively) or near-isotonic (0.81% sodium chloride in glucose) solution given at approximately three-fourths of the average maintenance rate. The main outcome of interest from this study is to evaluate 24 h post-operatively whether differences in p-Na⁺between treatment groups are large enough to be of clinical relevance. In addition, water and electrolyte balance as well as regulatory hormones will be measured.</p> <p>Discussion</p> <p>This study will provide valuable information on the efficacy of hypotonic and near-isotonic fluid therapy in preventing a significant decrease in p-Na⁺. Finally, by means of careful electrolyte and water balance and by measuring regulatory hormones our results will also contribute to a better understanding of the physiopathology of post-operative changes in p-Na⁺in a population at risk for hyponatremia.</p> <p>Trial registration</p> <p>The protocol for this study is registered with the current controlled trials registry; registry number: <a href="http://www.controlled-trials.com/ISRCTN43896775">ISRCTN43896775</a>.</p