H Nowotny and others Prenatal dexamethasone in CAH 186:5 K17–K24 Brief Report in Europe Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe Hanna Nowotny1, Uta Neumann 2, Véronique Tardy-Guidollet3, S Faisal Ahmed 4, Federico Baronio5, Tadej Battelino6, Jérôme Bertherat7, Oliver Blankenstein2, Marco Bonomi 8,9, Claire Bouvattier10,11, Aude Brac de la Perrière12, Sara Brucker13, Marco Cappa14, Philippe Chanson 15, Hedi L Claahsen-van der Grinten 16, Annamaria Colao17, Martine Cools18, Justin H Davies19, Helmut-Günther Dörr20, Wiebke K Fenske21, Ezio Ghigo22, Roberta Giordano22, Claus H Gravholt23, Angela Huebner24, Eystein Sverre Husebye25,26, Rebecca Igbokwe27, Anders Juul28,29, Florian W Kiefer30, Juliane Léger31, Rita Menassa3, Gesine Meyer32, Vassos Neocleous33,34, Leonidas A Phylactou33,34, Julia Rohayem 35, Gianni Russo36, Carla Scaroni37, Philippe Touraine 38, Nicole Unger39, Jarmila Vojtková40, Diego Yeste41,42,43, Svetlana Lajic44 and Nicole Reisch 1 1 Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, LMU München, Munich, Germany, 2Centre for Chronic Sick Children, Department of Paediatric Endocrinology and Diabetology, Charité Universitätsmedizin Berlin, Berlin, Germany, 3Laboratoire de Biochimie et Biologie Moléculaire, Hospices Civils de Lyon, Centre National de Référence ‘Développement Génital: du fœtus à l’adulte DEV-GEN’ Université Lyon I, Lyon, France, 4Developmental Endocrinology Research Group, University of Glasgow, Glasgow, UK, 5 Paediatric Endocrinology Unit, Department of Medical and Surgical Sciences, S.Orsola-Malpighi University Hospital, Bologna, Italy, European Journal of Endocrinology 6 Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, University Children’s Hospital, Ljubljana, Slovenia, 7Service d’Endocinologie et Maladies Métaboliques, Hôpitaux Universitaires Paris-Centre, Assistance Publique – Hôpitaux de Paris, Paris, France, 8Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy, 9 Department of Endocrine and Metabolic Diseases and Lab of Endocrine and Metabolic Research, IRCSS Istituto Auxologico Italiano, Milan, Italy, 10Service d’Endocrinologie de l’Enfant, GHU Paris-Sud, Hôpital de Bicêtre, Paris, France, 11Centre National de Référence ‘Développement Génital: du fœtus à l’adulte DEV-GEN’, Paris, France, 12Fédération d’Endocrinologie, de Diabétologie et des Maladies Métaboliques, Hospices Civils des Lyon, Centre National de Référence ‘Développement Génital: du fœtus à l’adulte DEV-GEN’, Lyon, France, 13Department of Women’s Health, University Women’s Hospital, University of Tübingen, Tübingen, Germany, 14Endocrinology Unit, Paediatric University Department, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy, 15Assistance Publique-Hôpitaux de Paris, Université Paris-Saclay, Service d’Endocrinologie et des Maladies de la Reproduction, Centre de Référence des Maladies Rares de Hypophyse, Hôpital Bicêtre, Le Kremlin-Bicêtre, France, 16Department of Paediatric Endocrinology, Amalia Children’s Hospital, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, 17Dipartimento Di Medicina Clinica E Chirurgia, Sezione Di Endocrinologia, Universita’ Federico II di Napoli, Naples, Italy, 18Department of Paediatric Endocrinology, Ghent University Hospital, University of Ghent, Ghent, Belgium, 19Paediatric Endocrinology, University Hospital Southampton NHS Foundation Trust, Southampton, UK, 20Paediatric Endocrinology, Department of Paediatrics, Universitätsklinikum Erlangen, Erlangen, Germany, 21Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany, 22Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Turin, Italy, 23Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark, 24Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Dresden, Technische Universität Dresden, Dresden, Germany, 25Department of Clinical Science and KG Jebsen Centre for Autoimmune Disorders, University of Bergen, Bergen, Norway, 26Department of Medicine, Haukeland University Hospital, Bergen, Norway, 27West Midlands Regional Genetics Laboratory, Birmingham Women’s Hospital NHS Foundation Trust, Birmingham, UK, 28Department of Growth and Reproduction, Copenhagen University Hospital – Rigshospitalet, Copenhagen, Denmark, 29Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark, 30Clinical Division of Endocrinology and Metabolism, Department of Medicine III, Medical University of Vienna, Vienna, Austria, 31Department of Paediatric Endocrinology and Diabetology and Reference Centre for Rare Diseases of Growth and Development, AP-HP Paris Nord Université de Paris, CHU Robert-Debre, Paris, France, 32 Division of Endocrinology, Department of Internal Medicine 1, Goethe University Frankfurt Faculty 16 Medicine, Frankfurt am Main, Germany, 33Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus, 34 Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus, 35Centre of Reproductive Medicine and Andrology, Clinical and Operative Andrology, University of Münster, Münster, Germany, 36Department of Paediatrics, Endocrine Unit, Scientific Institute San Raffaele, Milan, Italy, 37Dipartimento di Medicina, U.O.C. Endocrinologia, Università di Padova, Padova, Italy, 38Department of Endocrinology and Reproductive Medicine, Centre for Rare Endocrine and Gynaecological Disorders, Sorbonne Université, Assistance Publique Hopitaux de Paris, Paris, France, 39Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, Essen, Germany, 40Department of Correspondence Paediatrics, Jessenius Faculty of Medicine, Comenius University in Bratislava, University Hospital in Martin, Martin, should be addressed Slovakia, 41Paediatric Endocrinology Service, Hospital Universitari Vall d’Hebron, Barcelona, Spain, 42Autonomous to N Reisch University of Barcelona, Bellaterra, Spain, 43CIBERER, ISCIII, Madrid, Spain, and 44Department of Women’s and Email Children’s Health, Karolinska Institutet/Karolinska University Hospital, Paediatric Endocrinology Unit (QB83), Nicole.reisch@med. Stockholm, Sweden uni-muenchen.de https://eje.bioscientifica.com This work is licensed under a Creative Commons © 2022 The authors https://doi.org/10.1530/EJE-21-0554 Attribution 4.0 International License. Published by Bioscientifica Ltd. Printed in Great Britain Brief Report H Nowotny and others Prenatal dexamethasone in CAH 186:5 K18 in Europe Abstract Objective: To assess the current medical practice in Europe regarding prenatal dexamethasone (Pdex) treatment of congenital adrenal hyperplasia (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, 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. Conclusions: This 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. European Journal of European Journal of Endocrinology Endocrinology (2022) 186, K17–K24 Introduction Androgen excess in girls with congenital adrenal fetal programming with effects on the cardiovascular hyperplasia (CAH) results in virilization of the external system, metabolism and cognitive performance have genitalia of varying degree (1, 2, 3, 4, 5, 6). Surgeries, such been described in both animal studies and in humans as correction of the urogenital sinus (7, 8, 9), may lead to (24, 25, 26). The clinical outcome studies of Pdex show psychological and psychosexual issues in adult life, such conflicting results. Some studies show no negative effect as impaired genital sensitivity, sexual dysfunction and on neuropsychological functions and behaviour in non- urinary incontinence (10, 11, 12, 13, 14). Dexamethasone CAH patients who have been exposed to Pdex treatment in (15) at a dose of 20 µg/kg/day initiated before 6–7 weeks the first trimester of fetal life (27, 28, 29, 30). A survey based postconception (wpc), that is the critical window of sexual on parental questionnaires of prenatally Pdex-exposed differentiation, traverses the placenta, is able to suppress children with and without CAH compared to unexposed fetal androgen production and hence has been shown to children did not indicate any adverse effects regarding effectively prevent or reduce prenatal virilization (6, 16, 17, motor and cognitive development (31). Other studies 18, 19). It has been in use since 1984 but its use is highly show that early Pdex treatment in individuals without debated for several reasons (20). CAH affects cognition and behaviour during childhood First, it holds an ethical dilemma since unaffected (32, 33, 34, 35, 36, 37) as well as the methylation pattern fetuses currently are treated unnecessarily during of the genome (38) and insulin secretion (26) and that the the first trimester of fetal life. Genetic diagnosis can effects are stronger in girls (26, 33). Altered brain structures in most countries only be established at 1012 weeks (39) and insulin secretion (25, 26) have also been identified wpc by chorionic villous sampling (21, 22, 23). during adulthood. In a small cohort of women with CAH This translates to a risk of only one in eight fetuses treated with dex during the entire gestational period a benefitting from prenatal dex treatment (Pdex) or at negative effect on cognition was observed compared to an least one in four if non-invasive sex determination is untreated female CAH cohort (40). During childhood, lower performed (18). intellectual ability was observed in girls with CAH when Secondly, and most importantly, there is not enough treated with Pdex (36, 41). Another study showed improved evidence for the safety of treated fetuses. Aberrant cognitive development in CAH-affected girls treated with https://eje.bioscientifica.com Brief Report H Nowotny and others Prenatal dexamethasone in CAH 186:5 K19 in Europe Pdex, however, unfavorable cognitive functions in female care centres across Europe, of which 83% (30/36) are CAH-unaffected patients were identified in the same reference centres of EndoERN and all are certified centres report (37). for adrenal conditions. Thirdly, only few data on the mothers’ safety are available so far. The available literature has highlighted the adverse effects of glucocorticoid excess (16, 21, 42, Data extraction and analysis 43). Strong opinions on this controversial experimental Data extraction was performed using Microsoft Excel. treatment (44, 45) have been raised, yet only a few countries Prism version 8 (GraphPad Software) and Adobe Illustrator have evaluated the effect and plausible side effects of Pdex 24.3 2020 (Adobe) were used for statistical analysis and in a systematic way in their own population, but still, graphical presentation of the results. centres in Europe do use Pdex. According to the Endocrine Society its use is to be restricted to institutional review board-approved research settings (5, 46). In Sweden, the Results practice of Pdex has been put on hold due to the negative findings in non-CAH first trimester treated cases (47). Characteristics of study cohort The aim of this study is to offer a current reflection of the international views on and practice of Pdex in CAH across The questionnaire entitled ‘Prenatal dexamethasone Europe and to highlight the importance of longitudinal treatment in CAH across Europe’ was completed by a follow-up of treated cases and prospective clinical trials total of 36 medical centres across 14 different European European Journal of Endocrinology that investigate different aspects of this therapy. countries (Table 1). Currently, 36% (13/36) of the listed medical centres provide Pdex (Fig. 1). As depicted in Table 1, Pdex is applied in 0.5–8.25 cases per country and year. This data mostly depended on individual estimation Methods and is only in the minority of cases generated by hospital This study/survey did not involve patients, thus no patient or disease registries. The median number of pregnant consent was necessary. The study was approved by the women who received Pdex during the first trimester of ethics committee of the Medical Faculty of the Ludwig- pregnancy per centre was ten (n = 197) and a lower median Maximilians-Universität München, Munich, Germany amount of five women per centre received Pdex for the (project no 21-0760). entire gestational period (n = 72). Questionnaire design Current use of Pdex across Europe A questionnaire was designed and distributed using The majority of countries listed Pdex being provided Microsoft Forms (Microsoft Office 365, Windows 10, not by a single, but different specialties (paediatric Microsoft). Seventeen questions were designed including a endocrinologists, endocrinologists and gynaecologists/ mixture of open questions and dichotomous or multiple- obstetricians and in rare cases also by geneticists; Fig. 1B). choice questions with either a single or multiple answer Of all centres using Pdex, there was 100% congruency on possibilities. the recommended dose of 20 µg/kg/day; however, the daily dose distribution varied. Most medical centres (9/13, 69%) use thrice daily (TID) application of dex. Twice daily Study group (BID) application is used by 23% (3/13) of centres and once A total of 45 centres were contacted for completion of the daily (QD) dex application is used by one of the surveyed questionnaire. These comprised all European Reference medical centres (Fig. 1C). Regarding the starting point of Network on Rare Endocrine Conditions (EndoERN) Pdex responses showed at least some congruency with 23% healthcare centres part of the main thematic groups of centres initiating therapy at 4 to 5 wpc, 31% at 6 wpc, and ‘adrenal’ and/or ‘sex development and maturation’. 46% as early as pregnancy is confirmed and before 7 wpc at Additionally, we included a few (n = 6) further tertiary the latest (Fig. 1E). Prenatal diagnostics for CAH in treated care centres with specific expertise in the field but not yet cases are conducted at 72% (26/36) of recruited centres. For certified as an EndoERN reference centre. The questionnaire the question regarding the types of prenatal diagnostics was completed by 80% (36/45) of these endocrine tertiary used at each centre, multiple answers were possible. The https://eje.bioscientifica.com Brief Report H Nowotny and others Prenatal dexamethasone in CAH 186:5 K20 in Europe Table 1 Countries and centres included in the questionnaire ‘Prenatal dexamethasone treatment in CAH across Europe’ and numbers of treated pregnancies per year and per total time since initiation of treatment. Use of pdex Number of PDEX cases/year Total number of pregnancies Country (n = 14) Centers/Country (n = 36) (N/N centres) Estimated Reported First trimester Entire pregnancy Austria 1 0 Belgium 1 0 Cyprus 1 0 Denmark 2 0 France 5 3 4 2 64 21 Germany 10 5 8.25 38 27 Italy 7 2 3.5 60 10 Netherlands 1 1 1 10 5 Norway 1 0 Slovakia 1 0 Slovenia 1 0 Spain 1 1 0.5 18 3 Sweden 1 0 UK 3 1 2 7 6 majority (65 % of centres, 41 % of answers) uses chorionic population based. The total number of treated cases in other villus sampling (CVS) including CYP21A2 genotyping European countries can only be estimated. The Swedish (CYP21A2 GT) and sex typing between the gestational week PREDEX database registered 276 treated cases and untreated European Journal of Endocrinology (GW) 1012, whereas 38% of centres (24% of answers) uses controls in Sweden and Italy within 10 years. In Germany, amniocentesis (AC) including CYP21A2 GT and sex typing in a period of 10 years, 148 Pdex treated cases have been in GW 1516. Genotyping of the sex-determining region documented based on voluntary reporting of the treating Y (SRYtyping) from maternal blood (GW 5–7) combined physicians; however, the data has not been published due with CVS+CYP21A2 GT at GW 10–12 is used by 46% of to incomplete documentation. In France, over a period of centres (29% of answers). Early non-invasive prenatal 9 years (2002–2011), a total of 258 fetuses at risk of CAH diagnostics (NIPD) using the combination of SRYtyping were subjected to early non-invasive sex determination and CYP21A2 GT by massively parallel sequencing of cell- (18). After the exclusion of male fetuses, 154 of them were free fetal DNA in maternal blood (cfDNA) is offered by only subjected to Pdex. Currently, in France, a multicentric study one of the surveyed centres (Birmingham, UK). Of the is investigating somatic, neurocognitive and metabolic 13 centres providing Pdex treatment, 11/13 centres offer outcomes of Pdex-treated subjects. Based on these data at SRYtyping+CVS and CYP21A2 GT (Fig. 1D). least 10 prenatal treatments per year can be expected in Germany and France. This highlights the strong need and additional benefit of a European collaborative initiative, Discussion which was expressed by 75% (27/36) of research centres. Our data show that a substantial number of cases This study offers a current cross-sectional status quo of Pdex are treated outside the adrenal endocrine tertiary care in CAH in different tertiary care centres across Europe. centres that were approached in this questionnaire and The data obtained demonstrate that only that treatment is initiated by various disciplines. In such approximately a third of centres included in the study are an ultra-rare and complex condition, this is alarming. actually providing Pdex (Fig. 1A). Follow-up on treated Pdex We propose to channel this experimental treatment by cases for both 21OHD and treated unaffected children with international study protocols to endocrine expert centres a rate of only 42% (15/36) and availability of registries for with adequate long-term follow-up in order to disclose prenatally treated cases at only 46% (6/13) of the centres potential side effects. applying experimental Pdex is unacceptable. Moreover, The critical time point of differentiation of external only a small number of cases are treated at each centre per genitalia is between 8 and 12 wpc or even from 6 wpc year with a minimum of approximately one case per every onwards (6, 7, 48). To safeguard the development of female 4 years to three cases per year (Table 1). National registries genitalia and prevent virilization, dex administration is were reported to be available in Sweden, Italy, France and required as early as from 6 wpc onwards up to at least 16 Germany, however, only in Sweden and France they are wpc (49). Analysis of current practice in Europe indicates https://eje.bioscientifica.com Brief Report H Nowotny and others Prenatal dexamethasone in CAH 186:5 K21 in Europe European Journal of Endocrinology Figure 1 Use of Pdex treatment and prenatal diagnostics to prevent virilization in girls with CAH. (A) Pie chart depicting the percentage of included centres using or not using Pdex treatment (n = 36). (B) Selected disciplines providing Pdex treatment in the corresponding country. Multiple selections were possible (n = 31; 5 NA). (C) Daily dosing distribution of Pdex. Only centres using Pdex treatment were included (n = 13). (D) Types of prenatal diagnostics for CAH used in each corresponding country (n = 25). CVS (CYP21A2 GT + ST): CYP21A2 genotyping and sextyping between 1012 wpc; treatment is discontinued for male foetuses or notaffected females. AC (CYP21A2 GT + ST): CYP21A2 genotyping and sextyping between 1516 wpc; treatment is discontinued for male foetuses or notaffected females. SRY + CVS: SRYtyping from maternal blood (cfDNA); treatment of females only; CVS for CYP21A2 GT between 1012 wpc; treatment only continued for affected females. NIPD: massively parallel sequencing using cfDNA from maternal blood; only affected females are treated. (E) Overview of important timepoints of development of external genitalia in females. Stars are marking the starting point of Pdex treatment as indicated by each centre (n = 13). that centres conducting Pdex usually start treatment as without compromising treatment efficacy (49). A recent early as pregnancy is confirmed or before 6/7 wpc at the publication even stated the traditional Pdex dose being latest (Fig. 1E). Of the estimated 269 cases treated at all three-fold higher than actually needed and suggested included centres since starting point of Pdex at each TID administration to allow for more stable plasma individual centre, most cases were only treated for the concentrations (50). time period of the first trimester of pregnancy (n  = 197; 73 Another important aspect refers to prenatal %), whereas 72 cases (27 %) received full-term treatment diagnostics in fetuses potentially affected with classic (Table 1). Currently, a dose of 20 µg/kg/day is used by all CAH. Despite the improvement of CVS and AC, which is centres surveyed, however, distribution regarding multiple used in most cases, there is still a small risk of miscarriage doses during the day varies (Fig. 1C). In 2006, the idea was in the first 23 weeks of pregnancy due to diagnostic- promoted of reducing dex dosage after 16 wpc in order to related complications (51). A combinational approach of decrease adverse maternal effects of glucocorticoid therapy early NIPD SRYtyping from maternal plasma (GW5-6) and https://eje.bioscientifica.com Brief Report H Nowotny and others Prenatal dexamethasone in CAH 186:5 K22 in Europe CVS in GW10-12 is offered by 11/13 centres providing Pdex References and therefore preventing boys from unnecessary prenatal 1 Therrell BL. Newborn screening for congenital adrenal hyperplasia. treatment. In France, boys have not been treated anymore Endocrinology and Metabolism Clinics of North America 2001 30 15–30. (https://doi.org/10.1016/s0889-8529(08)70017-3) for several years. Thus SRY-typing is recommended to 2 Reisch N, Willige M, Kohn D, Schwarz HP, Allolio B, Reincke M, reduce the number of treated fetuses but does not solve the Quinkler M, Hahner S & Beuschlein F. Frequency and causes of entire problem. Targeted massively parallel sequencing adrenal crises over lifetime in patients with 21-hydroxylase deficiency. European Journal of Endocrinology 2012 167 35–42. (https://doi. of cell-free DNA from plasma drawn from an expectant org/10.1530/EJE-12-0161) mother (52, 53) and SRYtyping (18) to determine sex and 3 Zetterstrom RH, Karlsson L, Falhammar H, Lajic S & Nordenstrom A. CYP21A2 GT as early as 6 wpc; however, is only provided by Update on the Swedish newborn screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency. International Journal of one of the included centres. This strategy could efficiently Neonatal Screening 2020 6 71. (https://doi.org/10.3390/ijns6030071) prevent needless treatment of unaffected children and 4 Speiser PW. Congenital adrenal hyperplasia owing to 21-hydroxylase discard the risk of miscarriage. deficiency. Endocrinology and Metabolism Clinics of North America 2001 30 31–59, vi. (https://doi.org/10.1016/s0889-8529(08)70018-5) 5 Speiser PW, Azziz R, Baskin LS, Ghizzoni L, Hensle TW, Merke DP, Meyer-Bahlburg HF, Miller WL, Montori VM, Oberfield SE et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase Conclusion deficiency: an Endocrine Society clinical practice guideline. Journal of Clinical Endocrinology and Metabolism 2010 95 4133–4160. (https://doi. Current medical standards regarding Pdex are lacking org/10.1210/jc.2009-2631) 6 Goto M, Piper Hanley K, Marcos J, Wood PJ, Wright S, Postle AD, evidence-based guidelines on the optimal starting Cameron IT, Mason JI, Wilson DI & Hanley NA. In humans, early point, optimal duration and optimal dosing as well as cortisol biosynthesis provides a mechanism to safeguard female sexual European Journal of Endocrinology standardized surveillance and follow-up at specialized development. Journal of Clinical Investigation 2006 116 953–960. (https://doi.org/10.1172/JCI25091) centres. An international collaborative initiative on 7 Hanley NA & Arlt W. The human fetal adrenal cortex and the window a prospective randomized trial is needed to allow for of sexual differentiation. Trends in Endocrinology and Metabolism 2006 sufficient sample sizes in order to answer the key questions 17 391–397. (https://doi.org/10.1016/j.tem.2006.10.001) 8 Binet A, Lardy H, Geslin D, Francois-Fiquet C & Poli-Merol ML. of this therapy to allow its future use or to ban it. Should we question early feminizing genitoplasty for patients with congenital adrenal hyperplasia and XX karyotype? Journal of Pediatric Surgery 2016 51 465–468. (https://doi.org/10.1016/j. jpedsurg.2015.10.004) Declaration of interest 9 Elsayed S, Badawy H, Khater D, Abdelfattah M & Omar M. Congenital The authors declare that there is no conflict of interest that could be adrenal hyperplasia: does repair after two years of age have a worse perceived as prejudicing the impartiality of this article. outcome? Journal of Pediatric Urology 2020 16 424.e1–424.e6. (https:// doi.org/10.1016/j.jpurol.2020.06.010) 10 Simpson JL & Rechitsky S. Prenatal genetic testing and treatment for Funding congenital adrenal hyperplasia. Fertility and Sterility 2019 111 21–23. This work was supported by the Deutsche Forschungsgemeinschaft (https://doi.org/10.1016/j.fertnstert.2018.11.041) (Heisenberg Professorship, 325768017 to N R and 314061271-TRR205 to 11 Meyer-Bahlburg HFL, Khuri J, Reyes-Portillo J, Ehrhardt AA & New MI. N R and A H), the European Commission for funding EndoERN CHAFEA Stigma associated with classical congenital adrenal hyperplasia in FPA grant no. 739527, the Eva Luise und Horst Köhler Stiftung & Else women’s sexual lives. Archives of Sexual Behavior 2018 47 943–951. Kröner-Fresenius-Stiftung (2019_KollegSE.03 to H N) and the Stockholm (https://doi.org/10.1007/s10508-017-1003-8) County Council (Senior clinical research fellowship dnr RS 2019-1140 12 Crouch NS, Minto CL, Laio LM, Woodhouse CR & Creighton SM. to S L), Stiftelsen Frimurare Barnhuset i Stockholm and Lisa and Johan Genital sensation after feminizing genitoplasty for congenital adrenal Grönbergs Stiftelse. hyperplasia: a pilot study. BJU International 2004 93 135–138. (https:// doi.org/10.1111/j.1464-410x.2004.04572.x) 13 Gastaud F, Bouvattier C, Duranteau L, Brauner R, Thibaud E, Kutten F & Bougneres P. Impaired sexual and reproductive outcomes in women Author contribution statement with classical forms of congenital adrenal hyperplasia. Journal of S Lajic and N Reisch contributed equally to this work. Clinical Endocrinology and Metabolism 2007 92 1391–1396. (https://doi. org/10.1210/jc.2006-1757) 14 Nordenstrom A, Frisen L, Falhammar H, Filipsson H, Holmdahl G, Janson PO, Thoren M, Hagenfeldt K & Nordenskjold A. Sexual Acknowledgements function and surgical outcome in women with congenital adrenal This work was supported by the European Reference Network on Rare hyperplasia due to CYP21A2 deficiency: clinical perspective and the Endocrine Conditions. We acknowledge the entire French working group on patients’ perception. Journal of Clinical Endocrinology and Metabolism PDex for fruitful discussions and comments on this study and manuscript: 2010 95 3633–3640. (https://doi.org/10.1210/jc.2009-2639) Dr Véronique Tardy-Guidollet, Dr Daniela Gorduza, Dr Rita Menassa, Dr 15 Dexter PM, Caldwell KA & Caldwell GA. A predictable worm: Claire-Lise Gay, Dr Patricia Bretones, Dr Aude Brac de la Perrière, Dr Claire application of Caenorhabditis elegans for mechanistic investigation of Bouvattier, Dr Lise Duranteau, Dr Catherine Pienkowski, Pr Anne Bachelot movement disorders. Neurotherapeutics 2012 9 393–404. (https://doi. and Dr Audrey Cartault. org/10.1007/s13311-012-0109-x) https://eje.bioscientifica.com Brief Report H Nowotny and others Prenatal dexamethasone in CAH 186:5 K23 in Europe 16 Forest MG, David M & Morel Y. Prenatal diagnosis and treatment 30 Hirvikoski T, Nordenstrom A, Lindholm T, Lindblad F, Ritzen EM of 21-hydroxylase deficiency. Journal of Steroid Biochemistry and & Lajic S. Long-term follow-up of prenatally treated children at Molecular Biology 1993 45 75–82. (https://doi.org/10.1016/0960- risk for congenital adrenal hyperplasia: does dexamethasone cause 0760(93)90125-g) behavioural problems? European Journal of Endocrinology 2008 159 17 Forest MG, Betuel H & David M. Prenatal treatment in congenital 309–316. (https://doi.org/10.1530/EJE-08-0280) adrenal hyperplasia due to 21-hydroxylase deficiency: up-date 88 of 31 Meyer-Bahlburg HF, Dolezal C, Baker SW, Carlson AD, Obeid JS the French multicentric study. Endocrine Research 1989 15 277–301. & New MI. Cognitive and motor development of children with (https://doi.org/10.1080/07435808909039101) and without congenital adrenal hyperplasia after early-prenatal 18 Tardy-Guidollet V, Menassa R, Costa JM, David M, Bouvattier-Morel C, dexamethasone. Journal of Clinical Endocrinology and Metabolism 2004 Baumann C, Houang M, Lorenzini F, Philip N, Odent S et al. New 89 610–614. (https://doi.org/10.1210/jc.2002-021129) management strategy of pregnancies at risk of congenital adrenal 32 Hirvikoski T, Lindholm T, Lajic S & Nordenstrom A. Gender role hyperplasia using fetal sex determination in maternal serum: French behaviour in prenatally dexamethasone-treated children at risk for cohort of 258 cases (2002–2011). Journal of Clinical Endocrinology and congenital adrenal hyperplasia – a pilot study. Acta Paediatrica 2011 Metabolism 2014 99 1180–1188. (https://doi.org/10.1210/jc.2013-2895) 100 e112–e119. (https://doi.org/10.1111/j.1651-2227.2011.02260.x) 19 Gorduza D, Tardy-Guidollet V, Robert E, Gay CL, Chatelain P, David M, 33 Wallensteen L, Zimmermann M, Thomsen Sandberg M, Gezelius A, Bretones P, Lienhardt-Roussie A, Brac de la Perriere A, Morel Y et al. Nordenstrom A, Hirvikoski T & Lajic S. Sex-dimorphic effects Late prenatal dexamethasone and phenotype variations in 46,XX of prenatal treatment with dexamethasone. Journal of Clinical CAH: concerns about current protocols and benefits for surgical Endocrinology and Metabolism 2016 101 3838–3846. (https://doi. procedures. Journal of Pediatric Urology 2014 10 941–947. (https://doi. org/10.1210/jc.2016-1543) org/10.1016/j.jpurol.2014.02.003) 34 Hirvikoski T, Nordenstrom A, Lindholm T, Lindblad F, 20 David M & Forest MG. Prenatal treatment of congenital adrenal Ritzen EM, Wedell A & Lajic S. Cognitive functions in children hyperplasia resulting from 21-hydroxylase deficiency. Journal at risk for congenital adrenal hyperplasia treated prenatally with of Pediatrics 1984 105 799–803. (https://doi.org/10.1016/s0022- dexamethasone. Journal of Clinical Endocrinology and Metabolism 2007 3476(84)80310-8) 92 542–548. (https://doi.org/10.1210/jc.2006-1340) 21 New MI, Carlson A, Obeid J, Marshall I, Cabrera MS, Goseco A, 35 Trautman PD, Meyer-Bahlburg HF, Postelnek J & New MI. European Journal of Endocrinology Lin-Su K, Putnam AS, Wei JQ & Wilson RC. Prenatal diagnosis for Effects of early prenatal dexamethasone on the cognitive and congenital adrenal hyperplasia in 532 pregnancies. Journal of Clinical behavioral development of young children: results of a pilot Endocrinology and Metabolism 2001 86 5651–5657. (https://doi. study. Psychoneuroendocrinology 1995 20 439–449. (https://doi. org/10.1210/jcem.86.12.8072) org/10.1016/0306-4530(94)00070-0) 22 Forest MG. Recent advances in the diagnosis and management of 36 Meyer-Bahlburg HF, Dolezal C, Haggerty R, Silverman M & New MI. congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Cognitive outcome of offspring from dexamethasone-treated Human Reproduction Update 2004 10 469–485. (https://doi. pregnancies at risk for congenital adrenal hyperplasia due to org/10.1093/humupd/dmh047) 21-hydroxylase deficiency. European Journal of Endocrinology 2012 167 23 Mercado AB, Wilson RC, Cheng KC, Wei JQ & New MI. Prenatal 103–110. (https://doi.org/10.1530/EJE-11-0789) treatment and diagnosis of congenital adrenal hyperplasia owing to 37 Maryniak A, Ginalska-Malinowska M, Bielawska A & Ondruch A. steroid 21-hydroxylase deficiency. Journal of Clinical Endocrinology Cognitive and social function in girls with congenital adrenal and Metabolism 1995 80 2014–2020. (https://doi.org/10.1210/ hyperplasia – influence of prenatally administered dexamethasone. jcem.80.7.7608248) Child Neuropsychology 2014 20 60–70. (https://doi.org/10.1080/092970 24 Khulan B & Drake AJ. Glucocorticoids as mediators of developmental 49.2012.745495) programming effects. Best Practice and Research: Clinical Endocrinology 38 Karlsson L, Barbaro M, Ewing E, Gomez-Cabrero D & Lajic S. and Metabolism 2012 26 689–700. (https://doi.org/10.1016/j. Epigenetic alterations associated with early prenatal dexamethasone beem.2012.03.007) treatment. Journal of the Endocrine Society 2019 3 250–263. (https://doi. 25 Riveline JP, Baz B, Nguewa JL, Vidal-Trecan T, Ibrahim F, Boudou P, org/10.1210/js.2018-00377) Vicaut E, Brac de la Perriere A, Fetita S, Breant B et al. Exposure to 39 Van’t Westeinde A, Karlsson L, Nordenstrom A, Padilla N & Lajic S. glucocorticoids in the first part of fetal life is associated with insulin First-trimester prenatal dexamethasone treatment is associated secretory defect in adult humans. Journal of Clinical Endocrinology and with alterations in brain structure at adult age. Journal of Clinical Metabolism 2020 105 dgz145. (https://doi.org/10.1210/clinem/dgz145) Endocrinology and Metabolism 2020 105 dgaa340. (https://doi. 26 Wallensteen L, Karlsson L, Messina V, Nordenstrom A & Lajic S. org/10.1210/clinem/dgaa340) Perturbed beta-cell function and lipid profile after early prenatal 40 Karlsson L, Gezelius A, Nordenstrom A, Hirvikoski T & Lajic S. dexamethasone exposure in individuals without CAH. Journal of Cognitive impairment in adolescents and adults with congenital Clinical Endocrinology and Metabolism 2020 105 e2439–e2448. (https:// adrenal hyperplasia. Clinical Endocrinology 2017 87 651–659. (https:// doi.org/10.1210/clinem/dgaa280) doi.org/10.1111/cen.13441) 27 Van’t Westeinde A, Zimmermann M, Messina V, Karlsson L, Padilla N 41 Messina V, Karlsson L, Hirvikoski T, Nordenstrom A & Lajic S. & Lajic S. First trimester DEX treatment is not associated with altered Cognitive function of children and adolescents with congenital brain activity during working memory performance in adults. Journal adrenal hyperplasia: importance of early diagnosis. Journal of Clinical of Clinical Endocrinology and Metabolism 2020 105 e4074–e4082. Endocrinology and Metabolism 2020 105 e683–e691. (https://doi. 28 Karlsson L, Nordenstrom A, Hirvikoski T & Lajic S. Prenatal org/10.1210/clinem/dgaa016) dexamethasone treatment in the context of at risk CAH pregnancies: 42 Pang S, Clark AT, Freeman LC, Dolan LM, Immken L, Mueller OT, long-term behavioral and cognitive outcome. Psychoneuroendocrinology Stiff D & Shulman DI. Maternal side effects of prenatal dexamethasone 2018 91 68–74. (https://doi.org/10.1016/j.psyneuen.2018.02.033) therapy for fetal congenital adrenal hyperplasia. Journal of Clinical 29 Wallensteen L, Karlsson L, Messina V, Gezelius A, Sandberg MT, Endocrinology and Metabolism 1992 75 249–253. (https://doi. Nordenstrom A, Hirvikoski T & Lajic S. Evaluation of behavioral org/10.1210/jcem.75.1.1619017) problems after prenatal dexamethasone treatment in Swedish 43 Lajic S, Wedell A, Bui TH, Ritzen EM & Holst M. Long-term somatic children and adolescents at risk of congenital adrenal hyperplasia. follow-up of prenatally treated children with congenital adrenal Hormones and Behavior 2018 98 219–224. (https://doi.org/10.1016/j. hyperplasia. Journal of Clinical Endocrinology and Metabolism 1998 83 yhbeh.2017.11.004) 3872–3880. (https://doi.org/10.1210/jcem.83.11.5233) https://eje.bioscientifica.com Brief Report H Nowotny and others Prenatal dexamethasone in CAH 186:5 K24 in Europe 44 Miller WL. Fetal endocrine therapy for congenital adrenal hyperplasia 49 White PC. Ontogeny of adrenal steroid biosynthesis: why girls will be should not be done. Best Practice and Research: Clinical Endocrinology girls. Journal of Clinical Investigation 2006 116 872–874. (https://doi. and Metabolism 2015 29 469–483. (https://doi.org/10.1016/j. org/10.1172/JCI28296) beem.2015.01.005) 50 Stachanow V, Neumann U, Blankenstein O, Fuhr U, Huisinga W, 45 Lajic S, Nordenstrom A & Hirvikoski T. Long-term outcome of prenatal Michelet R, Reisch N & Kloft C. Rationale of a lower dexamethasone dexamethasone treatment of 21-hydroxylase deficiency. Endocrine dose in prenatal congenital adrenal hyperplasia therapy based on Development 2011 20 96–105. (https://doi.org/10.1159/000321228) pharmacokinetic modelling. European Journal of Endocrinology 2021 46 Clayton PE, Miller WL, Oberfield SE, Ritzen EM, Sippell WG, 185 365–374. (https://doi.org/10.1530/EJE-21-0395) Speiser PW & ESPE/LWPES CAH Working Group. Consensus 51 Alfirevic Z, Navaratnam K & Mujezinovic F. Amniocentesis statement on 21-hydroxylase deficiency from the European Society and chorionic villus sampling for prenatal diagnosis. Cochrane for Paediatric Endocrinology and the Lawson Wilkins Pediatric Database of Systematic Reviews 2017 9 CD003252. (https://doi. Endocrine Society. Hormone Research 2002 58 188–195. (https://doi. org/10.1002/14651858.CD003252.pub2) org/10.1159/000065490) 52 New MI, Tong YK, Yuen T, Jiang P, Pina C, Chan KC, Khattab A, 47 Hirvikoski T, Nordenstrom A, Wedell A, Ritzen M & Lajic S. Prenatal Liao GJ, Yau M, Kim SM et al. Noninvasive prenatal diagnosis of dexamethasone treatment of children at risk for congenital adrenal congenital adrenal hyperplasia using cell-free fetal DNA in maternal hyperplasia: the Swedish experience and standpoint. Journal of plasma. Journal of Clinical Endocrinology and Metabolism 2014 99 Clinical Endocrinology and Metabolism 2012 97 1881–1883. (https://doi. E1022–E1030. (https://doi.org/10.1210/jc.2014-1118) org/10.1210/jc.2012-1222) 53 Zhang J, Li J, Saucier JB, Feng Y, Jiang Y, Sinson J, McCombs AK, 48 Shapiro E, Huang HY & Wu XR. Uroplakin and androgen receptor Schmitt ES, Peacock S, Chen S et al. Non-invasive prenatal sequencing expression in the human fetal genital tract: insights into the for multiple Mendelian monogenic disorders using circulating development of the vagina. Journal of Urology 2000 164 1048–1051. cell-free fetal DNA. Nature Medicine 2019 25 439–447. (https://doi. (https://doi.org/10.1097/00005392-200009020-00031) org/10.1038/s41591-018-0334-x) European Journal of Endocrinology Received 29 September 2021 Revised version received 1 February 2022 Accepted 2 March 2022 https://eje.bioscientifica.com