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    Home > Active Ingredient News > Endocrine System > Eur J Endocrinol: Prenatal use of dexamethasone for classical 21-hydroxylase deficiency in a European population

    Eur J Endocrinol: Prenatal use of dexamethasone for classical 21-hydroxylase deficiency in a European population

    • Last Update: 2022-04-20
    • Source: Internet
    • Author: User
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    Background: Androgen excess in girls with congenital adrenal hyperplasia (CAH) results in variable degrees of virilization of the external genitalia
    .
    Surgery, such as urogenital correction, may lead to psychosexual problems in adult life, such as impaired genital sensitivity, sexual dysfunction, and urinary incontinence

    .
    Dexamethasone at a dose of 20 g/kg/day, administered before 6 to 7 weeks after conception (the critical window of sexual differentiation), has been shown to be effective in preventing fetal androgen production through the placenta.
    Or reduce prenatal virilization

    .
    It has been in use since 1984, but its use is controversial for several reasons
    .

    Androgen excess in girls with congenital adrenal hyperplasia (CAH) results in variable degrees of virilization of the external genitalia
    .
    Surgery, such as urogenital correction, may lead to psychosexual problems in adult life, such as impaired genital sensitivity, sexual dysfunction, and urinary incontinence

    .
    Dexamethasone at a dose of 20 g/kg/day, administered before 6 to 7 weeks after conception (the critical window of sexual differentiation), has been shown to be effective in preventing fetal androgen production through the placenta.
    Or reduce prenatal virilization

    .

       First, it's an ethical dilemma, as currently unaffected fetuses receive unnecessary treatment during the first trimester of fetal life
    .
    In most countries, genetic diagnosis can only be done by villus sampling at 10-12 weeks of due date
    .
    This means that only one in eight fetuses benefit from prenatal dexamethasone (Pdex), or at least one in four if non-invasive sex determination is performed

    .

    This is an ethical dilemma because currently unaffected fetuses receive unnecessary treatment during the first trimester of fetal life
    .

       Second, and most importantly, there is insufficient evidence for the safety of the treated fetus
    .
    Abnormal fetal programs with effects on the cardiovascular system, metabolism, and cognitive abilities have been described in animal studies and humans

    .
    Clinical outcome studies with Pdex have shown conflicting results

    .
    Several studies have shown no negative effects on neuropsychological function and behavior in non-CAH patients treated with Pdex during the first trimester of fetal life

    .
    A survey based on a parent questionnaire showed no adverse effects on motor and cognitive development in children with CAH who were exposed to Pdex before birth and in children who were not exposed to Pdex compared with children who were not exposed to Pdex

    .
    Other studies have shown that early Pdex treatment affects cognition and behavior in childhood as well as genomic methylation patterns and insulin secretion in individuals without CAH, and that this effect is stronger in girls

    .
    During adulthood, brain structure and insulin secretion also change

    .
    In a small cohort of women with CAH, treatment with dexamethasone throughout pregnancy had a negative effect on cognition compared with a cohort of untreated women with CAH

    .
    During childhood, girls with CAH were observed to have lower intelligence when treated with Pdex

    .
    Another study showed improved cognitive development in girls with CAH disease treated with Pdex, however, in the same report it was found that women who were not affected by CAH disease had poor cognitive function

    .

    And most importantly, there is insufficient evidence for the safety of the fetus undergoing treatment

       Third, so far, there is little data on maternal safety
    .
    The existing literature highlights the side effects of glucocorticoid overdose

    .
    Strong opinions have been raised about this controversial experimental treatment, however only a few countries have systematically assessed the effects and plausible side effects of Pdex in their own populations, but centres in Europe still use Pdex

    .
    Its use is limited to institutional review board-approved research settings, according to the Endocrine Society

    .
    In Sweden, the practice of Pdex has been put on hold due to negative results in non-CAH first trimester treated cases

    .

    So far, little data on maternal safety

    OBJECTIVE: The aim of this study was to reflect current international perceptions of Pdex and practice across Europe at CAH, and to highlight the importance of longitudinal follow-up of treated cases and prospective clinical trials investigating different aspects of the therapy
    .

    Methods: A questionnaire with 17 questions was designed and distributed to collect quantitative and qualitative data
    .
    Thirty-six medical centres from 14 European countries responded, 30 of which are reference centres of the European Rare Endocrine Disease Reference Network

    .

    RESULTS: Pdex treatment is currently offered in 36 % of surveyed centres
    .
    Treatment is initiated by different specialties, i.
    e.
    pediatrician, endocrinologist, gynecologist or geneticist

    .
    Regarding the starting point of Pdex, 23% indicated that treatment was started 4-5 weeks after conception, 31% started treatment at 6 weeks after conception, 46% started treatment at confirmation of pregnancy, and at the latest 7 weeks after conception Start treatment weeks ago

    .
    Use a dose of 20 g/kg/day

    .
    Dosing at each center varied from once to three times a day

    .
    Prenatal diagnosis of treated cases was performed in 72 % of response centers

    .
    Each country treats between 0.
    5 and 8.
    25 cases per year

    .
    Only 46 % of Pdex-treated centers had a long-term follow-up registry

    .

    Figure 1
    .
    Prevention of virilization in girls with CAH using Pdex therapy and prenatal diagnosis

    .
    (A) Pie chart depicting the percentage of included centers treated with or without Pdex (n=36)

    .
    (B) Selected disciplines offering Pdex therapy in corresponding countries

    .
    Multiple selection was possible (n = 315 NA)

    .
    (Daily dose distribution

    of Pdex.
    Only centers treated with Pdex are included (n=13)

    .
    (D) Type of prenatal diagnosis of CAH used in each corresponding country (n=25).

    CVS (CYP21A2 GT + ST): CYP21A2 Genotype and sex between 10-12 wpc; discontinue treatment for male fetuses or unaffected females.

    AC 540 (CYP21A2 GT + ST): CYP21A2 genotype and sex between 15-16 wpc discontinue treatment for male fetuses or unaffected females
    .
    SRY+CVS: SRY-from maternal blood typing (cf DNA); females treated only; CVS between 10-12 wpc for CYP21A2 GT; affected only of women continued treatment.

    NIPD: Massively parallel sequencing using cfDNA from maternal blood; only affected women were treated
    .
    (E) Overview of important time points in female external genital development

    .
    Star marks the start of Pdex treatment, as shown for each center (n=13)

    .

    Figure 1
    .
    Prevention of virilization in girls with CAH using Pdex therapy and prenatal diagnosis

    .
    (A) Pie chart depicting the percentage of included centers treated with or without Pdex (n=36)

    .
    (B) Selected disciplines offering Pdex therapy in corresponding countries

    .
    Multiple selection was possible (n = 315 NA)

    .
    (Daily dose distribution

    of Pdex.
    Only centers treated with Pdex are included (n=13)

    .
    (D) Type of prenatal diagnosis of CAH used in each corresponding country (n=25).

    CVS (CYP21A2 GT + ST): CYP21A2 Genotype and sex between 10-12 wpc; discontinue treatment for male fetuses or unaffected females.

    AC 540 (CYP21A2 GT + ST): CYP21A2 genotype and sex between 15-16 wpc discontinue treatment for male fetuses or unaffected females
    .
    SRY+CVS: SRY-from maternal blood typing (cf DNA); females treated only; CVS between 10-12 wpc for CYP21A2 GT; affected only of women continued treatment.

    NIPD: Massively parallel sequencing using cfDNA from maternal blood; only affected women were treated
    .
    (E) Overview of important time points in female external genital development

    .
    Star marks the start of Pdex treatment, as shown for each center (n=13)

    .

    Table 1
    .
    Countries and centres included in the "Antenatal Dexamethasone Treatment of CAH across Europe" questionnaire, and the number of pregnancies per year and per treatment since the start of treatment

    .

    Table 1
    .
    Countries and centres included in the "Antenatal Dexamethasone Treatment of CAH across Europe" questionnaire, and the number of pregnancies per year and per treatment since the start of treatment

    .

    Conclusions: This study revealed high international variability and variability in the use of Pdex treatment across Europe
    .
    It highlights the importance of the European Collaborative Initiative to unite international prospective trials to develop evidence-based guidelines for prenatal diagnosis, treatment and follow-up of pregnancies at high risk for CAH

    .

    This study revealed high international variability and variability in the use of Pdex treatment across Europe
    .
    It highlights the importance of the European Collaborative Initiative to unite international prospective trials to develop evidence-based guidelines for prenatal diagnosis, treatment and follow-up of pregnancies at high risk for CAH

    .

    Original source: Nowotny H, Neumann U, Tardy-Guidollet V, et al.
    Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe .
    Eur J Endocrinol 2022 Mar 01

    Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe

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