Concentraciones plasmáticas de cortisol materno secundarias al uso de betametasona para la maduración pulmonar fetal(Maternal plasma cortisol concentrations secondary to betamethasone use for fetal lung maturity)Keibis Jiménez-Castillejo1, Yolima Ruiz-Lopez1, Eduardo Reyna-Villasmil1, Duly Torres- Cepeda1, Joel Santos-Bolívar1, Jhoan Aragón-Charris1, Jorly Mejia-Montilla1, Nadia Reyna-Villasmil 1.1 Servicio de Obstetricia y Ginecología, Maternidad “Dr. Nerio Belloso”, Hospital “Dr. Urquinaona”, Maracaibo - Venezuela.[ARTÍCULO ORIGINAL] Recibido: 24 de Septiembre de 2013. Aceptado: 02 de Febrero de 2014.ResumenEl objetivo de la investigación fue determinar las concentraciones plasmáticas de cortisol materno secundarias al uso de betametasona para la maduración pulmonar fetal. Se realizó una investigación con un diseño tipo cuasi-experimental y una muestra no probabilística intencional de 106 pacientes que acudieron a la consulta pre-natal de alto riesgo del Hospital Central “Dr. Urquinaona". Una vez seleccionadas las pacientes se le administró inyecciones intramusculares de betametasona (12 mg) por dos días consecutivos. Las mediciones se realizaron en tres ocasiones: La primera medición, antes de la administración de la primera dosis de betametasona; la segunda medición, 24 horas después de la segunda y última inyección; y la tercera medición, siete días luego de la administración de la última dosis de betametasona. Se observó que las inyecciones con betametasona producían disminuciones de las concentraciones plasmáticas de cortisol materno, ya que el valor de la primera medición fue de 30,1 +/- 9,4 picogramos/dL, las concentraciones disminuyeron a 5,6 +/- 1,9 picogramos/dL durante la segunda medición y luego aumentaron a 23,2 +/- 4,2 picogramos/dL a la tercera medición. Las variaciones de las concentraciones de cortisol de la segunda y tercera medición se consideraron estadísticamente significativas al compararlas con las concentraciones iniciales (p = 0,001). Se concluye que el uso de betametasona para inducir la maduración pulmonar fetal produce disminución significativa en las concentraciones plasmáticas de cortisol maternoPalabras claveBetametasona, Maduración Pulmonar fetal. Cortisol.AbstractThe objective of research was to determine plasma concentrations of maternal cortisol secondary to betamethasone use for fetal lung maturity. A quasi-experimental type design was done with an intentional non-probabilistic sample of 106 patients who assisted to High Risk Antenatal Consult at Hospital Central “Dr. Urquinaona". Once patients were selected, two intramuscular injections of betamethasone (12 mg) were administered for two consecutive days. Measurements were done in three occasions: first measurement, before first dose of betamethasone; second measurement 24 hours after second and last injection and third measurement, seven days later of last dose of betamethasone. There was observed that betamethasone injections produced decreased plasma concentrations of maternal cortisol, due first measurement value was 30.1 +/- 9.4 picograms/dL, concentrations decreased to 5.6 +/- 1.9 picograms/dL at second measurement and then rised to 23.2 +/- 4.2 picograms/dL at third measurement. Variations of cortisol concentrations at second and third measurement were considered significant when compared with initial values (p = 0.001). It is concluded that betamethasone use for induction of fetal lung maturity produced significant decreased in plasma concentrations of maternal cortisolKeywordsBetametasone, Pulmonar maduration. Cortisol.IntroducciónLiggins y col. (1) fueron los primeros en reportar una disminución del síndrome de dificultad respiratoria entre los recién nacidos prematuros de embarazadas tratadas con corticosteroides antes del parto. Estudios posteriores han confirmado su trabajo y han demostrado beneficios adicionales de la administración de corticosteroides prenatales, incluyendo disminución de la incidencia y severidad de la hemorragia intraventricular, enterocolitis necrotizante y mortalidad perinatal (2). La administración de dos dosis de corticosteroides durante dos días en las embarazadas con riesgo de parto pretérmino es una de las pocas intervenciones perinatales que han demostrado ser beneficiosas para el neonato y se ha convertido en una práctica obstétrica habitual cuando existe el riesgo de parto pretérmino (3).El cortisol es secretado por las células de la capa fascicular de la corteza suprarrenal. Como son hormonas esteroides, se sintetizan a partir del colesterol, por medio de enzimas de la familia del citocromo P450. La actividad de algunas de estos enzimas, como la colesterol desmolasa, se incrementa por la acción de la corticotropina (ACTH) (4). El ACTH es liberado por la hipófisis anterior en respuesta al estrés, y es el principal estimulador de la síntesis de glucocorticoides. El cortisol puede sufrir la acción de la enzima 11β-hidroxiesteroide deshidrogenasa, en el hígado y otros tejidos periféricos (5).En humanos adultos que reciben tratamiento de reemplazo con glucocorticoides o dosis farmacológicas de corticosteroides sintéticos presentan una disminución (40% - 60%) en las concentraciones de cortisol plasmático (6). Las concentraciones de cortisol van aumentando gradualmente durante el embarazo en humanos (7) y esto es considerado como el reflejo de la estimulación del eje hipotálamo – hipófisis – suprarrenal juntos con los cambios en la síntesis de globulina fijadora de corticosteroides (8). También se ha descrito que las concentraciones de diferentes hormonas lipídicas disminuyen después de una dosis única de corticosteroides de larga duración que atraviesan libremente la placenta y suprimen la glándula suprarrenal fetal (9). Sin embargo, los efectos de los corticosteroides exógenos sobre las concentraciones de cortisol materno para la inducción de la maduración pulmonar fetal en el tercer trimestre son desconocidos.El objetivo de la investigación fue determinar las concentraciones plasmáticas de cortisol materno secundarias al uso de betametasona para la maduración pulmonar fetal.Materiales y MétodosLa investigación con un diseño tipo cuasi-experimental y una muestra no probabilística intencional de 106 pacientes que acudieron a la consulta pre-natal de alto riesgo del Hospital Central “Dr. Urquinaona". El Comité de Ética del hospital aprobó la investigación y se obtuvo el consentimiento informado de todas las pacientes.Se incluyeron embarazadas entre 18 y 40 años de edad, con embarazos de 24 a 34 semanas de gestación, y embarazos de alto riesgo (por ejemplo, cirugías uterinas previas, tumoraciones uterinas) que ameritaron la administración de betametasona para la inducción de la maduración pulmonar fetal.Se excluyeron las pacientes con embarazadas con polihidramnios, hemorragia del tercer trimestre, sospecha de restricción del crecimiento intrauterino del feto (circunferencia cefálica, circunferencia abdominal y longitud del fémur menor del percentil 10 de referencia), síndrome de HELLP, alteraciones de la frecuencia cardiaca fetal, gestaciones múltiples, presencia de infección intrauterina o materna activa, enfermedad hipertensiva crónica o gestacional, enfermedad cardiaca, hepática, renal o sistémica crónica, diabetes mellitus pre o gestacional y hábito tabáquico. También se excluyeron a las pacientes que se negaron a participar en la investigación.Una vez seleccionadas las pacientes se les administraron inyecciones intramusculares de betametasona (12 mg) por dos días consecutivos. Las mediciones plasmáticas de cortisol materno se realizaron en tres ocasiones: La primera medición, antes de la administración de la primera dosis de betametasona; la segunda medición, 24 horas después de la segunda y última inyección; y la tercera medición, siete días luego de la administración de la última dosis de betametasona para la maduración pulmonar fetal. 23211181480820520052Las muestras de sangre para la determinación de cortisol se recolectaron en todas las pacientes en posición supina en las tres ocasiones a las 8 am y luego de 10 horas de ayuno. Se tomaron las muestras (10 ml) de la vena antecubital, se centrifugaron a 3.000 rpm por 10 minutos a 4º C para ser posteriormente fueron almacenadas a – 20º C hasta el momento de la determinación. Se utilizó una prueba de radioinmunoensayo convencional utilizando un tubo cubierto de anticuerpos para determinar las concentraciones de cortisol plasmático. El fabricante aseguró que no existe reactividad cruzada detectable entre el cortisol y la betametasona. La sensibilidad de la prueba fue de 2 picogramos/dL. Todas las mediciones fueron hechas por duplicado y el promedio de las dos mediciones fue el resultado final. Los coeficientes de variación intra e inter-ensayo fueron de 6% y 5%, respectivamente.3249930-1657985Figura 1. Valores promedio de las concentraciones plasmáticas de cortisol materno antes y después del uso de betametasona.00Figura 1. Valores promedio de las concentraciones plasmáticas de cortisol materno antes y después del uso de betametasona.Los resultados se presentan en figuras. Se utilizaron medidas absolutas y relativas. Una vez que se utilizó la prueba de Kolmogorov-Smirnov para evaluar el tipo de distribución de los datos, se confirmó que la distribución de estos era igual a la normal (p = ns). La comparación de las concentraciones plasmáticas de cortisol se realizó utilizando la prueba de ANOVA utilizando la post-prueba de Dunnett utilizando como control los valores de la primera medición (antes del uso de la betametasona). Se consideró p < 0,05 como estadísticamente significativaResultados Se seleccionaron 106 pacientes que fueron sometidas a inyecciones de betametasona para inducir la maduración pulmonar fetal. La edad promedio de las pacientes fue de 22,6 +/- 5,1 años y la edad gestacional al momento del tratamiento fue de 31,8 +/- 3,0 semanas.Se observó que las inyecciones con betametasona producían disminuciones de las concentraciones de cortisol (figura 1), ya que el valor de la primera medición fue de 30,1 +/- 9,4 picogramos/dL, las concentraciones disminuyeron a 5,6 +/- 1,9 picogramos/dL durante la segunda medición y luego aumentaron a 23,2 +/- 4,2 picogramos/dL en la tercera medición. Las variaciones de las concentraciones de cortisol de la segunda y tercera medición se consideraron estadísticamente significativas al compararlas con las concentraciones iniciales (p = 0,001). Discusión3041096010530053-91391086789020000La maduración eje hipotálamo-hipófisis-suprarrenal fetal es un hecho confirmado al final del embarazo en varias especies animales, al igual que en los fetos humanos. El incremento en las concentraciones plasmáticas de cortisol aporta una parte del estímulo para aquellos órganos y sistemas que son necesarios para la vida extrauterina y pueden contribuir a los estímulos que conducen al inicio del parto (10). Los resultados de esta investigación demuestran que la administración materna de betametasona produce una disminución secundaria en las concentraciones de cortisol plasmático en las embarazadas tratadas para acelerar la maduración pulmonar fetal. Diferentes estudios demuestran que en la mitad y en la parte final del embarazo los 17-hidroxiesteroides urinarios y el índice de secreción de cortisol están disminuidos (11-13). Por tanto, la concentración plasmática aumentada de cortisol no es consecuencia de un aumento de la secreción de la hormona. Estos datos corroboran que hay un pequeño aumento del cortisol libre del plasma, puesto que su excreción está en función de la concentración global de cortisol plasmático no ligado. Aunque las mujeres embarazadas no manifiesten signos ni síntomas evidentes del hipercortisolemia, existe coincidencia en que los niveles plasmáticos de cortisol libre o no ligado aumentan durante el embarazo. Dado que el embarazo no se acompaña de modificaciones del índice de secreción de cortisol, es muy probable que exista un reajuste del punto fijo en la retroacción negativa entre el cortisol no ligado y la ACTH (14).Se ha sugerido que la relación entre las concentraciones plasmáticas de cortisol y las de globulina fijadora de corticosteroides permanecen relativamente constantes durante el embarazo pero pueden estar elevadas en las embarazadas con riesgo de parto pretérmino (15). Después de la administración de betametasona, se suprimen las concentraciones de cortisol pero las concentraciones de la globulina se mantienen sin alteraciones; además la relación de las concentraciones plasmáticas de cortisol y las de globulina fijadora de corticosteroides disminuyen en forma marcada. La supresión a largo plazo del eje hipotálamo-hipófisis-suprarrenal fetal por la administración de corticosteroides maternos y la supresión del eje hipotálamo-hipófisis-suprarrenal materno y de las hormona liberadora de corticotropina placentaria y ACTH son mecanismos potenciales para los efectos adversos en el feto y el recién nacido. Los efectos sobre el desarrollo humano a largo plazo de la administración materna de corticosteroides son contradictorios (16,17).Dos estudios han evaluado los efectos de múltiples dosis de esteroides prenatales sobre el eje hipotálamo – hipófisis - suprarrenal a diferentes edades gestacionales. McKenna y col. (18) demostraron que las embarazadas que reciben múltiples dosis de corticosteroides prenatales tienen insuficiencia adrenal secundaria en la semana siguiente a la última dosis. Helal y col. (19) demostraron una supresión adrenal progresiva en las embarazadas que recibían varias dosis de corticosteroides antenatales. Los datos de ambos trabajos confirman los hallazgos de la presente investigación en el cual las embarazadas en el presente estudio recibieron solo dos dosis de betametasona, lo comúnmente recomendado en la práctica clínica diaria.Otro elemento importante es que en sujetos no embarazados, cuando las concentraciones plasmáticas de cortisol entre las 8 am y las 9 am son menores de 3,0 picogramos/dL son indicadores de insuficiencia suprarrenal (20). En la presente investigación, ninguna embarazada presentó esos valores en la primera y tercera medición comparándolas con 9 embarazadas (8,5%) presentaron valores basales de cortisol menores de 3,0 picogramos/dL en la segunda medición realizadas a las 8 am. Estos datos indican que las determinaciones de cortisol basal a las 8 am durante el tercer trimestre del embarazo pueden indicar la aparición de una insuficiencia adrenal secundaria transitoria en un pequeño grupo de embarazadas que reciben dos dosis de betametasona para la inducción de la maduración pulmonar fetal.Aunque la presente investigación se centra sobre los efectos maternos del esquema comúnmente recomendado de betametasona durante el periodo prenatal, también existen potenciales efectos adversos fetales. El sinciciotrofoblasto y el citotrofoblasto controlan el paso de cortisona materna y la disponibilidad de cortisol biológicamente activo hacia el feto (21). La modulación placentaria del eje hipotálamo-hipófisis-suprarrenal se logra con las hormonan peptídicas placentarias que son homologas a la hormona liberadora de ACTH hipotalámico y la ACTH hipofisario (21). En la rata, el exceso de glucocorticoides durante el embarazo tiene un fuerte efecto inhibitorio sobre la estructura y función de las glándulas suprarrenales fetales (22,23). Sin embargo, un estudio que evaluó los recién nacidos de mujeres a quienes se les administró dosis habituales de dexametasona preparto para la maduración fetal pulmonar, no pudo demostrar ningún efecto de la respuesta de la hormona liberadora de ACTH a los 7 días de nacidos (24). La dexametasona administrada en el periodo post-natal como tratamiento de enfermedad pulmonar crónica ha demostrado que suprime la función suprarrenal y los efectos pueden persistir después de detener el tratamiento con los esteroides (25,26). Son escasas las evidencias de los efectos a largo plazo de la administración de corticosteroides durante el embarazo. Los únicos datos convincentes son los de una investigación que demostró diferencias psicológicas entre los controles y los niños de madres que recibieron corticosteroides durante el embarazo por presentar hiperplasia adrenal congénita (27).Los beneficios y riesgo de dosis repetidas de corticosteroides prenatales debe ser cuidadosamente evaluada. Hasta que exista más evidencia de la eficacia y necesidad de varias dosis de corticosteroides durante el embarazo para disminuir la morbilidad y mortalidad perinatal, los corticosteroides prenatales solo deben ser utilizados en aquellos embarazos con mayor riesgo de parto pretérmino. Más aún, no existen datos suficientes que apoyen el uso de más de dos dosis de corticosteroides por indicación profiláctica. 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Correo electronico sippenbauch@gmail.com Avances en BiomedicinaPublicación Oficial del Instituto de Inmunología ClínicaMérida-VenezuelaVolumen 3(2), May-Ago 2014, p 51-56Copyright: © ULA 2014Depósito Legal: PPI201102ME3935ISSN: 2244-7881-273052921000Avan Biomed. 2014; 3(2): 51-6.2014; 3(2): 51-6. Avan Biomed.Concentraciones de cortisol materno secundarias al uso de betametasona. Jiménez-Castillejo K y col.Jiménez-Castillejo K y col. 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with perinatally acquired HIV: emerging behavioral and health needs forCompu4siham salmen halabi22014-08-23T16:16:00Z2014-08-28T04:18:00Z2014-08-28T04:18:00Z

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