ESPE Abstracts

Introduction: Prenatal dexamethasone (Dex) therapy in female fetuses with congenital adrenal hyperplasia (CAH) has been conducted for 40 years but the dose given to the pregnant woman has never been fully evaluated in a randomized clinical trial. Prenatal Dex therapy is associated with potential side effects for both mother and child.

Methods: In a study funded by the German Federal Ministry of Education and Research (BMBF), the effect of a pharmacokinetically based low dose of Dex (7.5 ug/kg/day) is compared to the current experimentally used Dex dose (20 ug/kg/day) on reducing intrauterine virilization in female fetuses with CAH. In addition, non-invasive prenatal genetic diagnostics from maternal blood is to be established. Pregnant women with female fetuses and positive CAH genetics who do not receive Dex serve as the control group.

Results: A pharmacokinetic model of maternal Dex concentrations based on an existing Dex dataset from a comparable population was developed and the effective Dex target concentration in fetuses was identified through literature review. Calculations aimed to determine the minimally achievable Dex level in pregnant women with a weight of 55-95 kg which induces suppression of the fetal HPA axis. A pharmacokinetic two-compartment model for Dex was developed and evaluated. Simulations revealed a minimally effective maternal Dex dose of 7.5 µg/kg/d, which ensures exceeding the specified threshold at all time points in >90% of patients, thus aiming for continuous suppression of the fetal hypothalamic-pituitary-adrenal axis. It is planned to treat 22 women carrying a female fetus with CAH, each with either the calculated lower dose of Dex or the conventional Dex dose. Untreated pregnant women with a female fetus with CAH serve as controls. The study is conducted with international collaborators. Recruitment takes place in Germany, France, Italy, Austria, the Netherlands and Sweden. In parallel, prenatal non-invasive genetic diagnostics from maternal blood is established to avoid treatment of unaffected fetuses.

Conclusion: According to pharmacokinetic modeling and simulations, 30% of the currently used dose already produces sufficient suppression of the fetal HPA axis. The current study investigates treatment efficacy and potential side effects in low compared to the conventional dose of Dex used in prenatal treatment of CAH. To reduce the risk of treating unaffected fetuses, prenatal CAH diagnostics from maternal blood is established. The study runs from 2024 to 2031.