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Impacto a longo prazo da terapêutica pré-natal com dexametasona no contexto da Hiperplasia Congénita da Suprarrenal
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Advisor(s)
Abstract(s)
Introdução: O excesso de androgénios em fetos do sexo feminino com Hiperplasia
Congénita da Suprarrenal (HCSR) pode culminar em virilização genital. Para a
prevenção da ambiguidade genital, a dexametasona, na posologia de 20 µg/kg/dia, pode
ser administrada durante o período gestacional. No entanto, para ser eficaz, deve ser
introduzida precocemente na gestação, muitas vezes antes da confirmação diagnóstica,
expondo fetos saudáveis a doses excessivas de corticoides. Apesar de eficaz, a segurança
desta terapêutica, principalmente a longo prazo, não se encontra estabelecida e não é
conhecida nenhuma avaliação sistemática da dose utilizada. Como tal, na utilização da
dexametasona para prevenção da virilização fetal feminina no contexto da HCSR
subsistem muitas incertezas e múltiplas questões éticas. Esta dissertação tem como
objetivo esclarecer quais os efeitos multissistémicos, a longo prazo, da exposição prénatal à dexametasona em indivíduos com e sem HCSR. Adicionalmente, pretende-se
também refletir sobre as questões éticas inerentes a esta terapêutica.
Materiais e Métodos: Para a realização desta monografia, realizou-se a pesquisa de
artigos científicos na base de dados “PubMed/MEDLINE” com recurso às palavras-chave
“dexamethasone” AND “prenatal treatment” AND “congenital adrenal hyperplasia”.
Foram incluídos estudos observacionais, estudos retrospetivos e estudos piloto,
realizados em humanos, relevantes para a tema. A pesquisa foi complementada com
recurso à consulta das listas de referências bibliográficos de artigos da área da
dissertação.
Resultados: Foram identificados 24 artigos que, na sua globalidade, analisaram o
impacto da exposição pré-natal à dexametasona em diferentes áreas do desenvolvimento
orgânico e psicológico (psicoemocional, comportamental, cognitivo, neuroimagiológico,
cardiovascular, metabólico e epigenético) em indivíduos com e sem HCSR. O estudo da
função cognitiva é, até ao momento, a área com um maior número de artigos publicados.
Na maioria dos estudos, foi encontrado algum tipo de alteração associada à terapêutica
pré-natal. Tanto indivíduos com HCSR como indivíduos sem HCSR expostos à
terapêutica por um curto período parecem ser afetados. Em algumas das áreas estudas,
em particularmente na análise da função cognitiva, foi encontrada uma interação entre
a terapêutica e o sexo.
Discussão: Os dados disponíveis, apesar de reportarem possíveis efeitos nocivos
associados à terapêutica, são ainda pouco conclusivos devido às reduzidas amostras dos estudos realizados. Em cada uma das áreas estudadas, os resultados são por vezes
incongruentes, mas na sua generalidade alertam para alterações dos parâmetros
analisados associadas ao tratamento/ exposição pré-natal à dexametasona. Os
resultados devem ser validados por estudos com maior poder estatístico para obtenção
de informação mais fidedigna.
Conclusão: Os efeitos reportados devem ser disseminados pela comunidade científica
de forma a garantir que o benefício terapêutico continua a ser superior aos riscos.
Importa manter o seguimento de todos os indivíduos expostos e continuar a apurar qual
o impacto nas funções estudadas e em outros órgãos/sistemas. O ensaio clínico
“PREDICT (Prenatal Dexamethasone in Congenital Adrenal Hyperplasia Treatment)”
surge como um importante contributo na futura elaboração de diretrizes clínicas
otimizadas e mais seguras do ponto de vista médico e ético.
Introduction: Excess androgens in female fetuses with Congenital Adrenal Hyperplasia (CAH) can result in genital virilization. To prevent genital ambiguity, dexamethasone, at a dosage of 20 µg/kg/day, can be administered during pregnancy. However, for this therapy to be effective, it must be initiated early in gestation, often before a definitive diagnosis is confirmed, thereby exposing healthy fetuses to excessive doses of corticosteroids. While effective, the safety of this treatment, particularly its longterm effects, remains unestablished, and no systematic evaluation of the administered dose is available. Consequently, the use of dexamethasone to prevent female fetal virilization in the context of CAH involves numerous uncertainties and raises several ethical concerns. This dissertation aims to clarify the long-term multisystemic effects of prenatal dexamethasone exposure in individuals with and without CAH. Additionally, it seeks to reflect on the ethical issues inherent to this therapy. Materials and Methods: To conduct this dissertation, scientific articles were searched in the “PubMed/MEDLINE” database using the keywords “dexamethasone” AND “prenatal treatment” AND “congenital adrenal hyperplasia.” Observational studies, retrospective studies, and pilot studies conducted in humans and relevant to the topic were included. The search was further supplemented by consulting the reference lists of articles within the dissertation’s scope. Results: A total of 24 articles were identified that collectively examined the impact of prenatal dexamethasone exposure on various aspects of organic and psychological development (psychoemotional, behavioural, cognitive, neuroimaging, cardiovascular, metabolic, and epigenetic) in individuals with and without CAH. Cognitive function is currently the area with the greatest number of published studies. Most studies identified some form of alteration associated with prenatal therapy. Both individuals with CAH and those without CAH exposed to the therapy for a short period appear to be affected. In some of the studied areas, particularly in the analysis of cognitive function, an interaction between therapy and sex was observed. Discussion: Although the available data report possible adverse effects associated with therapy, they remain inconclusive due to the small sample sizes of the studies conducted. In each studied area, results are sometimes inconsistent, but overall, they highlight alterations in analysed parameters associated with prenatal dexamethasone treatment/exposure. The findings should be validated by studies with greater statistical power to obtain more reliable information. Conclusion: The reported effects should be disseminated within the scientific community to ensure that therapeutic benefits continue to outweigh the risks. It is essential to follow up on all exposed individuals and to continue investigating the impact on studied functions and other organs/systems. The “PREDICT (Prenatal Dexamethasone in Congenital Adrenal Hyperplasia Treatment)” clinical trial represents a significant contribution to the future development of optimized clinical guidelines that prioritize medical and ethical safety.
Introduction: Excess androgens in female fetuses with Congenital Adrenal Hyperplasia (CAH) can result in genital virilization. To prevent genital ambiguity, dexamethasone, at a dosage of 20 µg/kg/day, can be administered during pregnancy. However, for this therapy to be effective, it must be initiated early in gestation, often before a definitive diagnosis is confirmed, thereby exposing healthy fetuses to excessive doses of corticosteroids. While effective, the safety of this treatment, particularly its longterm effects, remains unestablished, and no systematic evaluation of the administered dose is available. Consequently, the use of dexamethasone to prevent female fetal virilization in the context of CAH involves numerous uncertainties and raises several ethical concerns. This dissertation aims to clarify the long-term multisystemic effects of prenatal dexamethasone exposure in individuals with and without CAH. Additionally, it seeks to reflect on the ethical issues inherent to this therapy. Materials and Methods: To conduct this dissertation, scientific articles were searched in the “PubMed/MEDLINE” database using the keywords “dexamethasone” AND “prenatal treatment” AND “congenital adrenal hyperplasia.” Observational studies, retrospective studies, and pilot studies conducted in humans and relevant to the topic were included. The search was further supplemented by consulting the reference lists of articles within the dissertation’s scope. Results: A total of 24 articles were identified that collectively examined the impact of prenatal dexamethasone exposure on various aspects of organic and psychological development (psychoemotional, behavioural, cognitive, neuroimaging, cardiovascular, metabolic, and epigenetic) in individuals with and without CAH. Cognitive function is currently the area with the greatest number of published studies. Most studies identified some form of alteration associated with prenatal therapy. Both individuals with CAH and those without CAH exposed to the therapy for a short period appear to be affected. In some of the studied areas, particularly in the analysis of cognitive function, an interaction between therapy and sex was observed. Discussion: Although the available data report possible adverse effects associated with therapy, they remain inconclusive due to the small sample sizes of the studies conducted. In each studied area, results are sometimes inconsistent, but overall, they highlight alterations in analysed parameters associated with prenatal dexamethasone treatment/exposure. The findings should be validated by studies with greater statistical power to obtain more reliable information. Conclusion: The reported effects should be disseminated within the scientific community to ensure that therapeutic benefits continue to outweigh the risks. It is essential to follow up on all exposed individuals and to continue investigating the impact on studied functions and other organs/systems. The “PREDICT (Prenatal Dexamethasone in Congenital Adrenal Hyperplasia Treatment)” clinical trial represents a significant contribution to the future development of optimized clinical guidelines that prioritize medical and ethical safety.
Description
Keywords
Dexametasona Endocrinologia Gravidez Hiperplasia Congénita da Suprarrenal Tratamento Pré-Natal