Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe

Abstract

Objective: To assess the current medical practice in Europe regarding prenatal dexamethasone (Pdex) treatment of CAH due to 21-hydroxylase deficiency. Design and Methods: A 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. Results: Pdex treatment is currently provided by 36 % of the surveyed centres. The treatment is initiated by different specialties i.e. paediatricians, endocrinologists, gynaecologists or geneticists. Regarding the starting point of Pdex, 23 % stated to initiate therapy at 4 to 5 weeks post conception (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/d is used. Dose distribution among the centres varies between 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 to 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. Conclusions: This study reveals a high international variability and discrepancy on 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.

Pregnancy and Prenatal Management of Congenital Adrenal Hyperplasia

“…Fetal genetic testing is usually performed around the 10th to 13th gestational week via chorionic villus sampling, but it can also be performed with amniocentesis at later times (15th to 16th gestational week) [ 16 , 50 ]. Given that genitalia formation begins around the ninth gestational week [ 51 ], starting a prenatal therapy after such time may be too late to prevent development abnormalities, posing clinicians and patients the dilemma of whether to undergo prenatal therapy, with a variable but usually substantial risk of inappropriate exposure of non-affected fetuses, or to refuse it, with subsequent risk of virilized female fetuses and related consequences.…”

“…Massively parallel sequencing of cell-free fetal DNA may also allow CYP21A2 genotyping, leading to an earlier diagnosis, so that non-biallelic-mutated and male fetuses may be excluded from (or less exposed to) prenatal therapy [ 49 , 51 ]. Such techniques, however, are still expensive and often unavailable: Nowotny et al reported the use of early sex typing in 11/13 tertiary care European centers and CYP21A2 genotyping in only 1/13 of these centers [ 50 ]. Nonetheless, it is foreseeable that the costs and availability of these diagnostic tests may improve over time, expanding their use, and thus improving the benefit/risk ratio of such therapy [ 53 , 54 ].…”

“…Based on embryology considerations, such therapy should be started by the ninth gestational week to be effective in avoiding hyperandrogenism and subsequent genital development abnormalities in female fetuses. Dexamethasone is usually administered for this prenatal treatment at the dosage of 20 μg/kg/day (based on pre-pregnancy body weight), fractioned in one, two, or usually three daily doses, up to 1.5 mg/day [ 50 , 60 ]. Recently, Stachanow et al proposed a markedly reduced dose of 7.5 μg/kg/day [ 61 ].…”

“…There is a strong need for prospective research on short- and especially long-term effects of prenatal dexamethasone treatment [ 16 , 60 ]. Most of the cited works on this issue have been published by a Swedish research group, carrying out extensive research on these long-term effects [ 50 ]; however, the studied population is often of a small size. Follow-up registries must be implemented in other centers and multicentric studies must be carried out, as internationally advocated.…”

“…Given the uncertainty regarding prenatal therapy fetal safety, some authors strongly oppose it [ 63 , 94 ], with national and international guidelines recommending it to be carried out only as experimental therapy in referral centers with appropriate informed consent and long-term follow-up registries [ 16 , 95 , 96 ]. Nowotny et al performed a survey of 36 centers from 14 European countries to evaluate current practice of prenatal treatment for 21-OHD: 13 of these centers carry out prenatal therapy, with great variability in terms of prenatal diagnostics and therapy starting points, dose fractioning, and the absence of follow-up registries in more than half of the responding centers [ 50 ]. The authors underline how European cooperation may increase scientific data, potentially leading to more conclusive results.…”