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Resultados Neuroconductuales 11 años después del tratamiento neonatal con

cafeína para la apnea de la prematurez

Ines M. Mürner-Lavanchy, Lex W. Doyle, Barbara Schmidt, Robin S. Roberts, Elizabeth V. Asztalos, Lorrie

Costantini, Peter G. Davis, Deborah Dewey, Judy D’Ilario, Ruth E. Grunau, Diane Moddemann, Harvey Nelson,

Arne Ohlsson, Alfonso Solimano, Win Tin, Peter J. Anderson, for the Caffeine for Apnea of Prematurity (CAP) Trial

Group

Abstract

Antecedentes y Objetivos: La cafeína es efectiva en el tratamiento de la apnea de la

prematurez. Pese a que el tratamiento con cafeína tiene beneficio sobre las habilidades

motoras gruesas en niños de edad escolar, los efectos sobre los resultados

neuroconductuales no están completamente aclarados. Quisimos investigar los efectos

de la terapia con cafeína neonatal en infantes muy bajo peso de nacimiento (MBPN)

(500-1250 g) sobre los resultados neuroconductuales en participantes del trabajo

Cafeína para Apnea de la Prematurez (CAP) a los 11 años de edad.

Métodos: Trece hospitales académicos en Canadá, Australia, Gran Bretaña, y Suecia

participaron en esta parte del seguimiento a los 11 años del trabajo doble ciego,

randomizado, placebo-controlado. Se obtuvieron medidas de inteligencia general,

atención, función ejecutiva, integración y percepción visomotora, y comportamiento en

870 niños. Los efectos de la terapia con cafeína fueron determinados utilizando

modelos de regresión.

Resultados: Los resultados neuroconductuales fueron generalmente similares para el

grupo cafeína y el placebo. El grupo cafeína se desempeño mejor que el grupo placebo

en la coordinación motora fina (diferencia media {DM} = 2.9; IC 95%: 0.7 a 5.1; P= .01),

integración visomotora (DM = 1.8; IC 95%: 0.0 a 3.7; P<0.5), percepción visual (MD=

2.0; IC 95%: 0.3 a 3.8; P= .02), y organización visuoespacial (MD= 1.2; IC 95%: 0.4 a 2.0;

P= .003).

Conclusiones: La terapia neonatal con cafeína para apnea de la prematurez mejoró las

habilidades visomotoras, visuoperceptivas, y visuoespaciales a la edad de 11 años. La

inteligencia general, atención, y comportamiento no fueron afectadas adversamente

por la cafeína, los cual resalta la seguridad a largo plazo del tratamiento con cafeína

para apnea de la prematurez en recién nacidos MBPN.

QUÉ SE SABE SOBRE ESTE TEMA: La cafeína es efectiva en el tratamiento de la

apnea de la prematurez. Aumenta la tasa de sobrevida sin discapacidad del

neurodesarrollo, reduce las tasas de parálisis cerebral y defecto cognitivo en

primera infancia, y tiene beneficios sobre habilidades motoras gruesas en niños de

edad escolar.

QUÉ AGREGA ESTE ESTUDIO: La terapia con cafeína neonatal mejoró las

habilidades visomotoras, visoperceptivas, y visoespaciales a la edad de 11 años.

No se observaron resultados adversos para resultados neuroconductuales tales

como inteligencia general, atención, función ejecutiva y comportamiento.

La apnea de la prematurez ocurre en más del 50% de los neonatos prematuros (1) y es

más comúnmente tratada con estimulantes respiratorios tales como la cafeína. Sin

embargo, los efectos a corto y largo plazo de la cafeína sobre el SNC no están

claramente comprendidos, con los efectos neuroprotectores (2) y neurotóxicos (3)

habiendo sido reportados en evidencia experimental. Además, la cafeína puede estar

indirectamente asociada con mejores resultados del desarrollo al reducir la apnea y la

duración de la ventilación mecánica (4, 5).

Los investigadores del trabajo Cafeína para la Apnea de la Prematurez (CAP)

investigaron la seguridad y efectividad del tratamiento con cafeína (6). Este estudio

internacional, randomizado, placebo-controlado ha revelado que la terapia con cafeína

redujo la tasa de DBP y de ROP severa antes del alta (7, 8). A los 18-21 meses de edad

corregida, la terapia con cafeína aumentó la tasa de sobrevida sin déficit del

neurodesarrollo ni cognitivo (8). A la edad de 5 años, la evidencia de la reducción en la

tasa de PC en los tratados con cafeína fue más débil, pero se demostró mejor función

motora (9) y un riesgo reducido de desorden de la coordinación (10). La terapia

neonatal con cafeína no afectó el déficit funcional cuando se evaluó como un

componente de pobre desempeño académico, déficit motor y problemas de

comportamiento en niños de 11 años de edad, pero redujo el riesgo de déficit motor

(4).

Pese a que las tasas de déficit cognitivo no difirieron entre los grupos cafeína y

placebo a los 5 años de edad (9), están aún por determinarse efectos a largo plazo de

la terapia con cafeína sobre resultados específicos tales como inteligencia general,

atención, función ejecutiva, integración visomotora y percepción. Nuestro objetivo en

este estudio fue investigar los efectos de la terapia neonatal con cafeína en infantes

MBPN (500-1250 g) sobre estos resultados neuroconductuales en participantes del

estudio CAP a los 11 años de edad.

MÉTODOS

Infantes con PN de 500 a 1250 g fueron elegibles para el estudio CAP si fueron

considerados candidatos para tratamiento con metilxantinas por sus clínicos en los

primeros diez días de vida; 2006 infantes en 35 hospitales académicos y 9 países fueron

incluídos en este estudio doble-ciego entre Octubre de 1999 y Octubre de 2004. Los

infantes fueron randomizadamente asignados a recibir citrato de cafeína o placebo

(solución salina normal) hasta que no fuera necesario continuar con tratamiento para la

apnea de la prematurez. Los criterios de exclusión, procesos de randomización, y el uso

de la droga de estudio han sido descriptos previamente (7). Resumiendo, los criterios

de exclusión fueron (1) tratamiento previo con metilxantinas, (2) anormalidades

congénitas, y (3) posibilidad de no estar disponible para seguimiento. La randomización

fue estratificada acorde al centro de estudio y fue balanceada en bloques de 2 a 4

pacientes. Una dosis de carga de 20 mg de citrato de cafeína por kg de peso fue

seguido de una dosis diaria de mantenimiento de 5 mg/kg. Si la apnea persistía, la

dosis podía ser incrementada hasta un máximo de 10 mg/kg/d. Los infantes recibieron

su primera dosis de la droga en estudio a una edad mediana de 3 días y fueron

destetados de la droga antes de alcanzar una mediana de EPM de 35 semanas. Los

infantes en el grupo control fueron tratados con un volumen equivalente de solución

salina normal.

El resultado primario del estudio inicial fue muerte antes de los 18 meses de EC o

sobrevida con al menos 1 de las siguientes condiciones: PC, retraso cognitivo, pérdida

auditiva severa, o ceguera bilateral. La cafeína redujo la tasa de resultado combinado

(OR ajustado: 0.77; IC 95% 0.64 a 0.93) (8). A los 5 años de seguimiento, la evidencia

utilizada para apoyar el efecto de de la cafeína sobre el aumento de la tasa de

sobrevida sin discapacidad fue débil, pero análisis secundarios y posteriores revelaron

efectos duraderos beneficiosos de la cafeína sobre el desempeño motor (9, 10).

Catorce centros participaron en el seguimiento de 11 años y proveyeron datos para el

resultado primario (n= 457 participantes en el grupo cafeína, n= 463 participantes en el

grupo placebo), que fue una medida compuesta de déficit funcional en al menos 1 de

los siguientes tres dominios: desempeño académico, conducta, y habilidades motoras.

Un 15 centro en Suecia brindó datos parciales para los componentes del resultado

primario (4). El presente análisis incluye resultados secundarios de inteligencia general,

atención, función ejecutiva, integración visomotora y percepción, y conducta. Dos

centros suministraron sólo las tres medidas de resultado primario, mientras que los

restantes 13 centros suministraron combinaciones de las medidas de resultados

secundarios, dependiendo de los recursos locales. Consecuentemente, los

denominadores varían entre resultados.

El seguimiento de los 11 años fue conducido entre Mayo de 2011 y Mayo 2016, y la

ventana fue para exámenes fue el año entre el cumpleaños 11 y 12 del niño. Los

esfuerzos para ubicar y examinar al niño continuaron más allá de esta edad en caso de

ser necesario.

Cada fase del estudio fue aprobada por los comités de ética institucionales.

Consentimiento informado escrito fue obtenido del padre o tutor de cada niño, y a la

edad de 11 años, se obtuvo asentimiento del niño cuando fue necesario. Los niños, los

clínicos, sus familias, y los investigadores involucrados en el cuidado de los pacientes y

la determinación de los resultados permanecieron sin conocer la asignación neonatal a

cafeína o placebo. Los examinadores fueron cegados al tratamiento en todos los

períodos.

Resultado neuroconductual a los 11 años

La inteligencia general fue estimada con la escala completa de CI de la versión 4-

subtests de la Escala Abreviada de Inteligencia de Weschler II (WASI-II) (11). La escala

también genera un índice de comprensión verbal (una medida de conocimiento verbal

adquirido y habilidades de razonamiento verbal) y un índice de razonamiento

perceptivo (medida de organización viso perceptual y habilidades de razonamiento).

Los índices son estandarizados por edad (media= 100; DS=15), con los scores más altos

reflejando mayor inteligencia. Déficit cognitivo fue definido como un CI de escala

completa <85 (<1DS relativo a la media normativa) Los niños que no podían ser

evaluados debido a severo déficit intelectual o autismo severo fueron catalogados

como déficit cognitivo severo.

Integración visomotora, percepción visual, y coordinación motora fina fueron evaluados

con el test de Integración Viso-Motora del Desarrollo de Beery- Buktenica (VMI), sexta

edición (12) (media=100; DS=15). El subtest de dígitos de WISC-IV (13) fue

administrado para determinar la memoria de trabajo (media=7; DS= 3).

La atención fue evaluada utilizando sub-tests del Test de Atención diaria para niños

(TEA-Ch; media= 7; DS= 3) (14), incluyendo Sky Search (atención selectiva), Score!

(atención sostenida), Creature Counting (desvío de atención), y Sky Search Dual Task

(división de atención). La prueba de la figura compleja de Rey (RCF) fue administrada

para determinar los aspectos de planificación y organización de la función ejecutiva

(15), desempeño evaluado acorde a la exactitud y estrategia organizativa (16). El RCF

de memoria demorada fue administrado para determinar la capacidad del niño de

recordar una figura dibujada sin ayuda después de un intervalo de 20 a 30 minutos. Los

scores más altos reflejaron mejor resultado funcional en todas las medidas arriba

mencionadas. Los scores estandarizados por edad fueron empleados con la excepción

del RCF, para el cual no hay disponibles normas confiables. Se definió déficit de

integración motora, percepción visual, coordinación motora fina, memoria de trabajo,

atención, y función ejecutiva como un desempeño < 1DS relativo a la media normativa

del test respectivo.

El Inventario de Rango Conductual de Función Ejecutiva (BRIEF), una escala de

puntuación completada por padres, fue utilizado para determinar las manifestaciones

conductuales cotidianas de las funciones de control ejecutivas de los niños (17). Los

scores del Compuesto Ejecutivo Global (GEC), Índice de Regulación Conductual (BRI), y

del Índice de Metacognición fueron informados. Los padres también completaron el

Índice Conners 3 de Desorden de Déficit de Atención /Hiperactividad (ADHD) (18), que

consiste de 10 ítems que mejor diferencian los niños con ADHD de la población

general. Los scores T estandarizados por edad (media= 50; DS= 10) son generados

para ambos cuestionarios reportados por padres, con lo escores elevados indicando

mayores problemas de conducta. El déficit conductual fue definido como un score >1

DS comparado con la media de la muestra normativa.

Análisis estadístico

Debido a que la randomización se estratificó según cada centro de estudio, los análisis

fueron ajustados utilizando un modelo de regresión linear múltiple que incluía términos

del tratamiento y del centro (los resultados de centros más pequeños fueron

combinados). El coeficiente de regresión asociado con el tratamiento en el modelo

ajustado arrojó un punto estimativo y un IC 95% para el efecto del tratamiento

expresado como la diferencia media (DM) entre los grupos de estudio. Las tasas de

déficit fueron analizadas con modelos de regresión logística, con el efecto ajustado de

tratamiento expresado como OR. El cociente del coeficiente estimado del efecto de

tratamiento y su ES fueron empleados como una estadística de z- test para la hipótesis

nula de no efecto de tratamiento. Después de recibir un comentario de un revisor, se

condujo un análisis posterior para examinar la contribución de la ROP severa al

desempeño visomotor. Un modelo de regresión linear se empleó con un término de

interacción para testear la consistencia del efecto de la cafeína entre niños con y sin

ROP severa. Todos los valores de P tuvieron 2-colas y fueron considerados

significativos si P<.05. No se hicieron ajustes para comparaciones múltiples. Se empleó

SAS versión 9.4 (SAS Institute, Inc, Cary, NC).

RESULTADOS

Participantes en el estudio

En la Fig. 1, se muestran el número de infantes que fueron enrolados en el trabajo

original, el número de niños que fueron elegibles para el estudio actual en 13 sitios, y el

número de niños que completaron cada una de las medidas de resultado. Un total de

870 niños contribuyeron con datas para al menos un instrumento de medición. Las

características de estos niños y sus familias fueron se muestran en la Tabla 1. Los

grupos fueron comparables en edad y asistencia escolar al seguimiento, así como las

características de sus cuidadores primarios y sus familias.

asignados en

asignados

asignados

Resultados Neuroconductuales

Los resultados neuroconductuales fueron ampliamente similares entre los grupos

cafeína y placebo, pese a que los escores medios fueron más altos en la mayoría de las

escalas en el grupo cafeína. La evidencia de diferencias entre grupos fue más fuerte

para integración visomotora (DM= 1.8; IC: 0.0 a 3.7; P< .05), percepción visual (DM=

2.0; IC 95%: 0.3 a 3.8; P= .02), coordinación motora fina (DM=2.9; IC 95%: 0.7 a 5.1; P=

.01), y exactitud de copia de RCF (DM= 1.2; IC 95%: 0.4 a 2.0; P= .003). En los

cuestionarios de padres de conducta, hubo poca evidencia de diferencias de grupo

(Tabla 2).

TABLA 2 RESULTADOS NEUROCONDUCTUALES

Resultado Max na Grupo Cafeína Grupo Placebo MD sin ajustar (95% IC)

MD ajustado por centro 95% IC

n Promedio +/- DE

n Promedio +/- DE

Habilidades Motoras Finas 1065

Beery V, VI 409 90.7 ± 13.1 406 88.9 ± 13.8 1.8 (−0.1 to 3.6) 1.8 (0.0 to 3.7)

Percepción Visual 407 97.7 ± 12.9 397 95.6 ± 13.4 2.1 (0.2 to 3.9) 2.0 (0.3 to 3.8)

Coordinación Motora 406 90.8 ± 15.8 397 88.0 ± 17.0 2.9 (0.6 to 5.2) 2.9 (0.7 to 5.1)

Inteligencia General (WASS I, II) 1041

Escala completa CI 392 97.0 ± 14.9 393 95.5 ± 14.7 1.5 (−0.5 to 3.6) 1.6 (−0.5 to 3.6)

Comprensión Verbal 392 97.8 ± 15.5 394 97.0 ± 14.9 0.9 (−1.3 to 3.0) 0.9 (−1.2 to 3.0)

Razonamiento percepcional 392 96.8 ± 14.9 395 95.2 ± 14.9 1.6 (−0.5 to 3.7) 1.6 (−0.5 to 3.6)

Atención

TEA Ch 1065

Búsqueda selectiva 404 10.8 ± 3.1 400 10.8 ± 3.1 0.0 (−0.4 to 0.4) 0.0 (−0.4 to 0.4)

Puntaje sostenido 402 8.5 ± 3.6 399 8.2 ± 3.6 0.3 (−0.2 to 0.8) 0.3 (−0.2 to 0.8)

Búsqueda dividida 395 6.8 ± 3.3 390 6.5 ± 3.4 0.2 (−0.2 to 0.7) 0.2 (−0.2 to 0.7)

Desplazamiento de Atención 396 9.3 ± 3.2 393 9.2 ± 3.3 0.1 (−0.3 to 0.6) 0.1 (−0.3, 0.5)

TDAH Índices conectores 1114

Puntuación T 429 61.5 ± 18.2 435 60.7 ± 18.4 0.7 (−1.7 to 3.2) 0.6 (−1.8 to 3.0)

Puntuación de probabilidad 429 45.2 ± 33.5 435 43.6 ± 33.5 1.6 (−2.9 to 6.0) 1.3 (−3.1 to 5.8)

Funciones ejecutivas

Prueba de figura compleja RCF 1065

Puntuación copia 405 22.8 ± 5.3 400 21.6 ± 6.1 1.1 (0.4 to 1.9) 1.2 (0.4 to 2.0)

Puntuación memoria 406 12.6 ± 5.1 399 12.0 ± 5.8 0.5 (−0.2 to 1.3) 0.6 (−0.1 to 1.3)

Puntuación estrategia 392 4.0 ± 1.0 387 387 4.0 ± 1.1 0.0 (−0.1 to 0.2) 0.0 (−0.1 to 0.2) BRIEF (inventario de calificación conductual

de la función ejecutiva) puntuación padres. 1114

GEC inventario de calificación conductual de la función ejecutiva

429 55.9 ± 12.5 434 54.8 ± 12.3 1.2 (−0.5 to 2.8) 1.1 (−0.5 to 2.8)

Índice de metacognición 429 55.8 ± 11.7 434 54.7 ± 11.6 1.1 (−0.5 to 2.7) 1.1 (−0.5 to 2.6)

Índice de regulación conductual

431 54.9 ± 13.6 436 53.9 ± 13.2 1.0 (−0.8 to 2.8) 1.0 (−0.8 to 2.7)

WISC-IV

Memoria de trabajo de dígitos en secuenciación anterógrada

405 8.8 ± 3.4 406 406 8.6 ± 3.3 0.2 (−0.2 to 0.7) 0.3 (−0.1 to 0.7)

Memoria de trabajo de dígitos en secuenciación retrógrada

405 8.4 ± 2.9 406 8.2 ± 2.9 0.2 (−0.2 to 0.6) 0.2 (−0.2 to 0.6)

DT, doble tarea.a=Un puntaje de umbral utilizado para definir el deterioro para el instrumento respectivo. Para todas las pruebas, esto correspondía a 1 DE por debajo o por encima de la media de la muestra normativa, dependiendo de la prueba. B= La OR se ajustó para la edad gestacional y el sexo del niño, la administración prenatal de corticosteroides, los partos múltiples y la educación del cuidador principal en el momento de la evaluación.c= Los puntajes de umbral dependen de la edad.

Las diferencias en las tasas de déficit entre grupos revelaron un patrón similar, con

menores posibilidades de déficit en el grupo cafeína para integración visomotora (OR=

0.74; IC 95%: 0.55 a 0.99; P= .04), percepción visual OR= 0.63; IC 95%: 0.43 a 0.92; P=

.02), y coordinación motora fina (OR= 0.69; IC 95%: 0.52 a 0.92; P= .01) comparado con

el grupo placebo (Tabla 3).

En el examen posterior conducido para examinar la contribución del efecto indirecto de

la cafeína en el dominio visomotor a través de la reducción de ROP severa, los niños

con ROP severa mostraron significativamente peor desempeño en todas las sub-escalas

Beery (Beery IVM: no ROP severa, media= 90.1, ROP severa, media= 84.3). Sin embargo,

cuando la ROP severa fue incluida en el modelo de regresión (Tabla 2), la reducción

observada en la ROP severa asociada con cafeína explicó sólo un pequeño pocentaje

(entre 4.1% y 6.5%, dependiendo de la sub-escala) del efecto cafeína general sobre las

habilidades visomotoras a los 11 años de edad. Cuando un término de interacción fue

incluido en un modelo adicional para testear la consistencia del efecto cafeína entre

niños con y sin ROP severa, no se mostró ninguna interacción de subgrupo significativa.

TABLA 3 RESULTADOS DETERIORO EN EL RESULTADO NEUROCONDUCTUAL

Resultado

Puntaje Umbral

N° /N° total (%) OR (95% IC)

Grupo Cafeína Tasa de

discapacidad

Grupo Placebo Tasa de

discapacidad

Sin ajustar

Ajustado

por centro

Habilidades Motoras Finas

Beery V, VI <85 108/409 (26.4) 133/406 (32.8) 0.74 (0.54 to 1.00) 0.74 (0.55 to 0.99)

Percepción Visual <85 54/407 (13.3) 77/397 (19.4) 0.64 (0.44 to 0.93) 0.63 (0.43 to 0.92)

Coordinación Motora <85 122/406 (30.0) 151/397 (38.0)) 0.70 (0.52 to 0.94) 0.69 (0.52 to 0.92)

Inteligencia General (WASS I, II)

Escala completa CI <85 76/392 (19.4) 86/393 (21.9) 0.86 (0.61 to 1.21) 0.87 (0.61 to 1.23)

Comprensión Verbal <85 72/392 (18.4) 69/394 (17.5) 1.06 (0.74 to 1.53) 1.11 (0.77 to 1.59)

Razonamiento percepcional <85 79/392 (20.2) 95/395 (24.1) 0.80 (0.57 to 1.12) 0.78 (0.55 to 1.10)

Atención

TEA Ch

Búsqueda selectiva <7 36/404 (8.9) 37/400 (9.3) 0.96 (0.59 to 1.55) 0.97 (0.59 to 1.58)

Puntaje sostenido <7 125/402 (31.1) 141/399 (35.3) 0.83 (0.62 to 1.11) 0.84 (0.62 to 1.12)

Búsqueda dividida <7 146/395 (37.0) 152/390 (39.0) 0.92 (0.69 to 1.23) 0.93 (0.69 to 1.24)

Desplazamiento de Atención <7 84/396 (21.2) 86/393 (21.9) 0.96 (0.68 to 1.35) 0.99 (0.70 to 1.41)

TDAH Índices conectores

Puntuación T >80 178/429 (41.5) 170/435 (39.1) 1.11 (0.84 to 1.45) 1.08 (0.82 to 1.41)

Puntuación de probabilidad >80 44/429 (33.6) 143/435 (32.9) 1.03 (0.78 to 1.37) 1.00 (0.75 to 1.31)

Funciones ejecutivas

Prueba de figura compleja RCF

Puntuación copia <1DEc 385/405 (95.1) 383/400 (95.8) 0.85 (0.44 to 1.66) 0.83 (0.43 to 1.62)

Puntuación memoria <1DEc 296/406 (72.9) 296/399 (74.2) 0.94 (0.68 to 1.28) 0.91 (0.67 to 1.25) BRIEF (inventario de calificación conductual de la función ejecutiva) puntuación padres.

GEC inventario de calificación conductual de la función ejecutiva

>60 137/429 (31.9) 130/434 (30.0) 1.10 (0.82 to 1.46) 1.08 (0.80 to 1.45)

Índice de metacognición >60 144/429 (33.6) 125/434 (28.8) 1.25 (0.94 to 1.67) 1.23 (0.92 to 1.65)

Índice de regulación conductual >60 125/431 (29.0) 112/436 (25.7) 1.18 (0.88 to 1.59) 1.18 (0.87 to 1.60)

WISC-IV

Memoria de trabajo de dígitos en secuenciación anterógrada

<7 118/405 (29.1) 125/406 (30.8) 0.92 (0.68 to 1.25) 0.90 (0.65 to 1.23)

Memoria de trabajo de dígitos en secuenciación retrógrada

<7 112/405 (27.7) 126/406 (31.0) 0.85 (0.63 to 1.15) 0.83 (0.61 to 1.14)

DT, doble tarea.a=Un puntaje de umbral utilizado para definir el deterioro para el instrumento respectivo. Para todas las pruebas, esto correspondía a 1 DE por debajo o por encima de la media de la muestra normativa, dependiendo de la prueba. B= La OR se ajustó para la edad gestacional y el sexo del niño, la administración prenatal de corticosteroides, los partos múltiples y la educación del cuidador principal en el momento de la evaluación.c= Los puntajes de umbral dependen de la edad.

DISCUSIÓN

La terapia neonatal con citrato de cafeína es uno de los tratamientos más comunes en

medicina neonatal (20), y es esencial que los beneficios y los riesgos a largo plazo de

este tratamiento sean comprendidos. En este estudio, en el cual examinamos los

efectos de la terapia con cafeína neonatal sobre los resultados neuroconductuales,

demostramos que el tratamiento con cafeína tiene beneficios específicos a largo plazo

para la coordinación motora fina, integración visomotora, percepción visual, y

organización visoespacial. Hubo poca evidencia para las diferencias entre el grupo

cafeína y el grupo placebo en los tests de inteligencia general, atención, función

ejecutiva, y comportamiento. Entonces, encontramos beneficios específicos de la

terapia neonatal con cafeína en el dominio visomotor y ninguna evidencia de efectos

dañinos sobe los resultados neuroconductuales a los 11 años de edad.

El beneficio de la cafeína observado en la coordinación motora fina y la integración

visomotora es consistente con nuestras asociaciones previamente reportadas de terapia

neonatal con cafeína con un riesgo reducido de déficit motor a los 18 meses (8), 5 años

(9), y 11 (4) años, mejor coordinación motora fina a los 5 años (9), y menores tasas de

DCD a los 5 años (10). El efecto positivo del tratamiento con cafeína sobre el desarrollo

motor en infantes MPT y MBPN es importante clínicamente porque esta población es

aproximadamente 10 veces más susceptible de desarrollar PC (21) y 3 a 4 veces más

susceptible de desarrollar DCD que los bebés nacidos a término (22). Está bien

determinado que el déficit motor está asociado a problemas conductuales, baja

autoestima, pobres habilidades sociales, y bajo logro académico (23); sin embargo, no

encontramos evidencia de que la cafeína beneficie la conducta o el logro académico

(4). Es posible que las modestas ganancias observadas en el grupo cafeína no fueran

suficientes para influenciar el logro académico y los resultados conductuales o que

estén involucrados diferentes mecanismos. Las mejoras en otros dominios, tales como

autoestima y habilidades sociales, sean posibles pero necesiten mayor estudio.

Un astuto comentario de un revisor y la evidencia de mejor integración visomotora,

percepción visual, y organización visoespacial en el grupo cafeína nos motivó a

considerar la influencia de la ROP severa. Consistente con otros reportes (24-26), los

niños con ROP severa estuvieron en mayor riesgo de dificultades visomotoras

comparadas con niños sin ROP severa. Sin embargo, en nuestro posterior análisis, se

indicó que sólo una pequeña proporción del efecto beneficioso general de la cafeína

sobre el desempeño motor podía ser atribuido a la reducción de ROP severa por la

cafeína.

Es posible que la mejoría en la percepción y organización visual después del

tratamiento con cafeína esté relacionada con el menor número de niños con DCD en el

grupo cafeína (10) porque DCD ha sido asociado con percepción visual disminuida y

menor integración visomotora (27). Hemos descripto previamente difusión reducida en

la sustancia blanca cerebral en el cerebro del recién nacido en la edad equivalente al

término en niños tratados con cafeína al compararlos con infantes en el grupo placebo

(28), y entonces una posibilidad alternativa es que los cambios en la sustancia blanca

están restringidos a regiones corticales maduras tempranamente y funciones

sensoriales.

La cafeína puede tener un efecto neuroprotector (2), que lleva a mejoras funcionales

específicas, pese a que los efectos a corto y mediano plazo de la cafeína sobre el SNC

no están claramente comprendidos (29). Las metilxantinas han sido descriptas como

inhibidoras de los receptores de adenosina, comprometiendo por tanto el rol de la

adenosina como importante neuromodulador (30). Además, estudios en roedores

revelaron astrocitogénesis alterada en recién nacidos después del tratamiento con

cafeína (31). Sin embargo, la cafeína ha mostrado que potencia la plasticidad neural en

el nivel de receptores de N-meti-D-aspartato, resultando en morfología alterada de las

sinapsis y tamaño aumentado de las espinas dendríticas (32, 33). Más aún, la

administración de cafeína en crías neonatales expuestas a hipoxia estuvo asociada con

mielinización favorecida y menor ventriculomegalia (34, 35). Esto es consistente con

nuestro estudio de RNM neonatal en el cual la difusión reducida en la sustancia blanca

cerebral demostrada, reflejó desarrollo microestructural de la sustancia blanca

mejorado (28).

No se ha conducido ningún otro estudio en el cual los investigadores examinaran los

efectos a largo plazo de la terapia con cafeína en la inteligencia general, atención,

función ejecutiva, visopercepción, y conducta. Conducir este seguimiento de 11 años

fue un desafío, dado el gran número de centros en el estudio y las diferentes lenguas

habladas por los participantes. Trece centros proveyeron datos para el presente análisis

secundario agregado al resultado compuesto primario. Esto resultó en una tasa de

consentimiento del 78% (870 de 1114 niños sobrevivientes potencialmente elegibles)

para los resultados neuroconductuales. Pese a esta tasa de consentimiento inferior a la

ideal, las principales características neonatales y resultados de la niñez fueron

comparables entre el grupo que fue evaluado a los 11 años y las cohorte mayor

examinada en períodos más tempranos. Por lo tanto, confiamos que los resultados de

la cohorte total están reflejados en los presentes resultados con suficiente exactitud.

CONCLUSIONES

La terapia neonatal con cafeína estuvo asociada con mejores habilidades visomotoras,

visoperceptiva, y visoespacial a los 11 años de edad en niños nacidos MBPN. Ninguno

de los resultados secundarios reportados en este estudio estuvo adversamente

afectado por la cafeína. Esto resalta la seguridad y eficacia a largo plazo del tratamiento

con cafeína para apnea de la prematurez en neonatos MBPN.

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ARTICLE

Neurobehavioral Outcomes 11 Years After Neonatal Caffeine Therapy for Apnea of PrematurityInes M. Mürner-Lavanchy, PhD, a, b Lex W. Doyle, MD, MSc, b, c, d, e Barbara Schmidt, MD, MSc, f, g Robin S. Roberts, MSc, f Elizabeth V. Asztalos, MD, MSc, h Lorrie Costantini, BA, f Peter G. Davis, MD, c, d, e Deborah Dewey, PhD, i Judy D’Ilario, RN, f Ruth E. Grunau, PhD, j, k Diane Moddemann, MD, MEd, l Harvey Nelson, MSc, f Arne Ohlsson, MD, MSc, h Alfonso Solimano, MD, k Win Tin, MD, m Peter J. Anderson, PhD, a, b, c, d for the Caffeine for Apnea of Prematurity (CAP) Trial Group

BACKGROUND AND OBJECTIVES: Caffeine is effective in the treatment of apnea of prematurity. Although caffeine therapy has a benefit on gross motor skills in school-aged children, effects on neurobehavioral outcomes are not fully understood. We aimed to investigate effects of neonatal caffeine therapy in very low birth weight (500–1250 g) infants on neurobehavioral outcomes in 11-year-old participants of the Caffeine for Apnea of Prematurity trial.METHODS: Thirteen academic hospitals in Canada, Australia, Great Britain, and Sweden participated in this part of the 11-year follow-up of the double-blind, randomized, placebo-controlled trial. Measures of general intelligence, attention, executive function, visuomotor integration and perception, and behavior were obtained in up to 870 children. The effects of caffeine therapy were assessed by using regression models.RESULTS: Neurobehavioral outcomes were generally similar for both the caffeine and placebo group. The caffeine group performed better than the placebo group in fine motor coordination (mean difference [MD] = 2.9; 95% confidence interval [CI]: 0.7 to 5.1; P = .01), visuomotor integration (MD = 1.8; 95% CI: 0.0 to 3.7; P < .05), visual perception (MD = 2.0; 95% CI: 0.3 to 3.8; P = .02), and visuospatial organization (MD = 1.2; 95% CI: 0.4 to 2.0; P = .003).CONCLUSIONS: Neonatal caffeine therapy for apnea of prematurity improved visuomotor, visuoperceptual, and visuospatial abilities at age 11 years. General intelligence, attention, and behavior were not adversely affected by caffeine, which highlights the long-term safety of caffeine therapy for apnea of prematurity in very low birth weight neonates.

abstract

aMonash Institute of Cognitive and Clinical Neurosciences, Monash University, Clayton, Australia; bMurdoch Children’s Research Institute, Melbourne, Australia; Departments of cPaediatrics and dObstetrics and Gynaecology, University of Melbourne, Melbourne, Australia; eThe Royal Women’s Hospital, Melbourne, Australia; fDepartment of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada; gDivision of Neonatology, Children’s Hospital of Philadelphia and University of Pennsylvania, Philadelphia, Pennsylvania; hDepartment of Paediatrics, University of Toronto, Toronto, Canada; Departments of iAlberta Children’s Hospital Research Institute for Child and Maternal Health and Pediatrics and Community Health Sciences, University of Calgary, Calgary, Canada; jBritish Columbia Children’s Hospital Research Institute, Vancouver, Canada; kDepartment of Pediatrics, University of British Columbia, Vancouver, Canada; lDepartment of Pediatrics and Child Health, University of Manitoba, Winnipeg, Canada; and mDepartment of Pediatrics, James Cook University Hospital, Middlesbrough, England

Dr Mürner-Lavanchy contributed to the interpretation of data and drafted the initial manuscript; Prof Doyle conceptualized and designed the study, coordinated and supervised data collection, contributed to the interpretation of data, and drafted the initial manuscript; Profs Schmidt and Anderson conceptualized and designed the study, coordinated and supervised data collection,

PEDIATRICS Volume 141, number 5, May 2018:e20174047

WHAT’S KNOWN ON THIS SUBJECT: Caffeine is effective in the treatment of apnea of prematurity. It increases the rate of survival without neurodevelopmental disability, reduces the rates of cerebral palsy and cognitive impairment in toddlers, and has benefits on gross motor skills in school-aged children.

WHAT THIS STUDY ADDS: Neonatal caffeine therapy improved visuomotor, visuoperceptual, and visuospatial abilities at age 11 years. Adverse outcomes were not shown for neurobehavioral outcomes such as general intelligence, attention, executive function, and behavior.

To cite: Mürner-Lavanchy IM, Doyle LW, Schmidt B, et al. Neurobehavioral Outcomes 11 Years After Neonatal Caffeine Therapy for Apnea of Prematurity. Pediatrics. 2018;141(5): e20174047

by guest on April 11, 2018http://pediatrics.aappublications.org/Downloaded from

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Apnea of prematurity occurs in over 50% of preterm neonates1 and is most commonly treated with respiratory stimulants such as caffeine. However, short- and long-term effects of caffeine on the central nervous system are not clearly understood, with both neuroprotective2 and neurotoxic3 effects being reported in experimental evidence. In addition, caffeine may be indirectly associated with better developmental outcomes by reducing apnea and the duration of mechanical ventilation.4, 5

Researchers of the Caffeine for Apnea of Prematurity (CAP) trial investigated the safety and effectiveness of caffeine therapy.6 This international, randomized, placebo-controlled trial has revealed that caffeine therapy reduced the rate of bronchopulmonary dysplasia and severe retinopathy of prematurity (ROP) before discharge.7, 8 At 18 to 21 months’ corrected age, caffeine therapy increased the rate of survival without neurodevelopmental disability and reduced the rates of cerebral palsy and cognitive impairment.8 At the age of 5 years, evidence for the reduction in the rate of cerebral palsy with caffeine treatment was weaker, but improved motor function9 and a reduced risk of developmental coordination disorder (DCD) were demonstrated.10 Neonatal caffeine therapy did not affect functional impairment when assessed as a composite of poor academic performance, motor impairment, and behavior problems in 11-year-old children, but it reduced the risk of motor impairment.4

Although rates of cognitive impairment did not differ between the caffeine and placebo groups at 5 years of age, 9 long-term effects of caffeine therapy on specific neurobehavioral outcomes such as general intelligence, attention, executive function, visuomotor integration and perception, and

behavior are still to be determined. Our aim in this study was to investigate the effects of neonatal caffeine therapy in very low birth weight infants (500–1250 g) on these neurobehavioral outcomes in 11-year-old participants of the CAP trial.

METHODS

Infants with a birth weight of 500 to 1250 g were eligible for the CAP trial if they were considered to be candidates for methylxanthine therapy by their clinicians during the first 10 days of life; 2006 infants in 35 academic hospitals and 9 countries were enrolled in this double-blind trial between October 1999 and October 2004. Infants were randomly assigned to receive caffeine citrate or normal saline placebo until treatment of apnea of prematurity was no longer needed. Exclusion criteria, randomization procedures, and use of the study drug have been described previously.7 In short, exclusion criteria were (1) previous treatment with methylxanthines, (2) congenital abnormalities, and (3) likely unavailability for follow-up. Randomization was stratified according to the study center and was balanced in random blocks of 2 or 4 patients. A loading dose of 20 mg of caffeine citrate per kilogram of body weight was followed by a daily maintenance dose of 5 mg/kg. If apnea persisted, the dose could be increased to a maximum of 10 mg/kg per day. Infants received their first dose of the study drug at a median age of 3 days and were weaned off the study drug before reaching a median postmenstrual age of 35 weeks. Infants in the control group were treated with an equivalent volume of normal saline.

The primary outcome of the initial study was death before 18 months’ corrected age or survival with at least 1 of the following conditions: cerebral palsy, cognitive delay, severe

hearing loss, or bilateral blindness. Caffeine reduced the rate of the combined outcome (adjusted odds ratio [OR]: 0.77; 95% confidence interval [CI]: 0.64 to 0.93).8 At 5-year follow-up, the evidence used to support a caffeine effect on the rate of survival without disability was weak, but secondary and post hoc analyses revealed lasting benefits of caffeine on motor performance.9, 10

Fourteen centers participated in the 11-year follow-up and provided data for the primary outcome (n = 457 participants in the caffeine group, n = 463 participants in the placebo group), which was a composite measure of functional impairment in at least 1 of the following 3 domains: academic performance, behavior, and motor skills. A 15th center in Sweden provided partial data for components of the primary outcome.4 The present analysis includes secondary outcomes of general intelligence, attention, executive function, visuomotor integration and perception, and behavior. Two centers administered only the 3 primary outcome measures, whereas the remaining 13 centers administered combinations of secondary outcome measures, depending on local resources. Consequently, the denominators vary among outcomes.

The 11-year follow-up was conducted between May 2011 and May 2016, and the target window for assessments was the year between the child’s 11th and 12th birthday. Efforts to locate and examine the children continued beyond this age when necessary.

Each phase of the study was approved by the relevant institutional ethics boards. Written informed consent was obtained from a parent or guardian of each child, and at the 11-year follow-up, assent was obtained from the child when appropriate. The children, their families, and all clinicians and researchers involved in the

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care of the participants and in the assessments of their outcomes remained unaware of the neonatal random assignments to caffeine or placebo treatment. Assessors were blinded to treatment allocation at all stages.

Eleven-Year Neurobehavioral Outcomes

General intelligence was estimated with the full-scale IQ from the 4-subtest version of the Wechsler Abbreviated Scale of Intelligence–II (WASI-II).11 The scale also generates a verbal comprehension index (a measure of verbal acquired knowledge and verbal reasoning abilities) and a perceptual reasoning index (a measure of visual perception organization and reasoning skills). The indices are age standardized (mean = 100; SD = 15), with higher scores reflecting higher intelligence. Cognitive impairment was defined as a full-scale IQ < 85 (<1 SD relative to the normative mean). Children who could not be assessed because of severe intellectual impairment or severe autism were coded as having a severe cognitive impairment.

Visuomotor integration, visual perception, and fine motor coordination were assessed with the Beery-Buktenica Developmental Test of Visual-Motor Integration (VMI), sixth edition12 (mean = 100; SD = 15). The digit span subtest of the Wechsler Intelligence Scale for Children–IV (WISC-IV)13 was administered to assess working memory (mean = 7; SD = 3). Attention was assessed by using subtests from the Test of Everyday Attention for Children (TEA-Ch; mean = 7; SD = 3), 14 including Sky Search (selective attention), Score! (sustained attention), Creature Counting (shifting attention), and Sky Search Dual Task (divided attention). The Rey complex figure test (RCF) was administered to assess planning and organizational aspects of executive function, 15 with

performance assessed according to accuracy and organizational strategy.16 The RCF delayed recall test was administered to assess the child’s capacity to remember a drawn figure without cues after a 20- to 30-minute interval. Higher scores reflected better functional outcome in all of the abovementioned measures. Age standardized scores were used with the exception of the RCF, for which reliable norms are not available. Impairment in visuomotor integration, visual perception, fine motor coordination, working memory, attention, and executive function was defined as a performance <1 SD relative to the normative mean of the respective test.

The Behavior Rating Inventory of Executive Function (BRIEF), a parent-completed rating scale, was used to assess the everyday behavioral manifestations of children’s executive control functions.17 The Global Executive Composite (GEC), Behavioral Regulation Index (BRI), and Metacognition Index scores were reported. Parents also completed the Conners 3 Attention-Deficit/Hyperactivity Disorder (ADHD) Index, 18 which consists of 10 items that best differentiate children with ADHD from the general population. Age-standardized T-scores (mean = 50; SD = 10) are generated for both of these parent-reported behavior questionnaires, with elevated scores indicating greater problematic behaviors. Behavioral impairment was defined as a score >1 SD compared with the mean of the normative sample.

Statistical Analyses

Because randomization was stratified according to study center, the analyses were adjusted with the use of a multiple linear regression model that included terms for treatment and center (results from smaller centers were combined). The regression coefficient associated with

treatment in the fitted model yielded a point estimate and a 95% CI for the treatment effect expressed as the mean difference (MD) between the study groups. Impairment rates were analyzed with equivalent logistic regression models, with the adjusted treatment effect expressed as an OR. The quotient of the estimated coefficient of the treatment effect and its SE were used as a z-test statistic for the null hypothesis of no treatment effect. After a reviewer’s comment was received, a post hoc analysis was conducted to examine the contribution of severe ROP to visuomotor performance. A linear regression model was used with an interaction term to test for the consistency of the caffeine effect between children with and without severe ROP. All P values were 2-sided and considered significant if P < .05. No adjustments were made for multiple comparisons. SAS version 9.4 was used (SAS Institute, Inc, Cary, NC).

RESULTS

Study Participants

In Fig 1, we show the number of infants who were enrolled in the original trial, the number of children who were eligible for the current study in 13 sites, and the number of children who completed each of the outcome measures. A total of 870 children contributed data for at least 1 measurement instrument. Characteristics of these 870 children and their families are given in Table 1. Groups were comparable in age and school attendance at follow-up, as well as the characteristics of their primary caregivers and families.

Neurobehavioral Outcomes

Neurobehavioral outcomes were broadly similar between the caffeine and placebo groups, although mean scores were higher on most scales in the caffeine group. Evidence for group differences was strongest

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for visuomotor integration (MD = 1.8; 95% CI: 0.0 to 3.7; P < .05), visual perception (MD = 2.0; 95% CI: 0.3 to 3.8; P = .02), fine motor coordination (MD = 2.9; 95% CI: 0.7 to 5.1; P = .01), and RCF copy accuracy (MD = 1.2; 95% CI: 0.4 to 2.0; P = .003). For the parent-rated behavior questionnaires, there was little evidence for group differences (Table 2).

Differences of impairment rates between groups revealed a similar pattern, with lower odds of impairment in the caffeine group for visuomotor integration (OR = 0.74; 95% CI: 0.55 to 0.99; P = .04), visual perception (OR = 0.63; 95% CI: 0.43

to 0.92; P = .02), and fine motor coordination (OR = 0.69; 95% CI: 0.52 to 0.92; P = .01) compared with the placebo group (Table 3).

In the post hoc analysis conducted to examine the contribution of the indirect effect of caffeine on the visuomotor domain through the reduction of severe ROP, children with severe ROP showed significantly worse performance in all Beery subscales (Beery VMI: no severe ROP mean = 90.1, severe ROP mean = 84.3). However, when severe ROP was included in the regression model (Table 2), the observed reduction in severe ROP associated with caffeine explained only a small percentage

(between 4.1% and 6.5%, depending on the subscale) of the overall caffeine effect on the visuomotor abilities at 11 years of age. When an interaction term was included in an additional model to test for the consistency of the caffeine effect between children with and without severe ROP, no significant subgroup interaction was shown.

DISCUSSION

Neonatal caffeine citrate therapy is one of the most common therapies in neonatal medicine, 20 and it is essential that the long-term benefits and risks of this therapy are understood. In this study, in which we examined the effects of neonatal caffeine therapy on neurobehavioral outcomes, we demonstrated that caffeine therapy had specific long-term benefits for fine motor coordination, visuomotor integration, visual perception, and visuospatial organization. There was little evidence for differences between the caffeine and placebo groups on tests of general intelligence, attention, executive function, and behavior. Thus, we found specific benefits of neonatal caffeine therapy in the visuomotor domain and no evidence of harmful effects on neurobehavioral outcomes up to 11 years of age.

The caffeine benefit we observed in fine motor coordination and visuomotor integration is consistent with our previously reported associations of neonatal caffeine therapy with a reduced risk for motor impairment at 18 months, 8 5 years, 9 and 114 years, improved fine motor coordination at 5 years, 9 and lower rates of DCD at 5 years.10 The positive effect of caffeine therapy on motor development for very preterm and very low birth weight infants is important clinically because this population is ∼10 times more likely to develop cerebral palsy21 and 3 to 4 times more likely to develop DCD than term

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FIGURE 1Instrument completion rates. aPrimary score available. bCompletion rate by instrument.



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TABLE 1 Characteristics of the Children and Their Families

Characteristics Caffeine Group (n = 432) Placebo Group (n = 438) P

Children at birth Mean birth wt (SD), g 967 (181) 956 (182) .39 Mean gestational age (SD), wk 27.3 (1.7) 27.3 (1.8) .48 Female sex, No. (%) 222 (51.4) 199 (45.4) .08 Birth wt <10th percentile for gestational age, No. (%)a 59 (13.7) 67 (15.3) .49 Exposure to antenatal corticosteroids, No. (%) 390 (90.3) 394 (90.0) .95 Singleton birth, No. (%) 297 (68.8) 315 (71.9) .31Outcomes at 18 mo Disability, No./total No. (%)b 122/418 (29.2) 153/424 (36.1) .03 Cerebral palsy, No./total No. (%) 14/427 (3.3) 27/433 (6.2) .04 Moderate cognitive delay, No./total No. (%)c 113/416 (27.2) 133/423 (31.4) .17 Severe cognitive delay, No./total No. (%)d 38/416 (9.1) 52/423 (12.3) .14 Severe ROP, No./total No. (%)e 18/432 (4.2) 26/438 (5.9) .23Outcomes at 5 y Disability, No./total No. (%)f 56/415 (13.5) 72/411 (17.5) .11 Motor impairment, No./total No. (%)g 5/424 (1.2) 13/425 (3.1) .06 Cognitive impairment, No./total No. (%)h 18/417 (4.3) 12/421 (2.9) .25 Full-scale IQ, mean (SD) 100 (16) 99 (15) .10 Behavior problem, No./total No. (%)i 23/415 (5.5) 29/413 (7.0) .3811-y follow-up Median age (IQR), y 11.4 (11.1, 11.8) 11.4 (11.1, 11.8) .88 Schooling Mainstream school (public or private), No. (%) 418 (96.8) 424 (96.8) .63 Special education facility, No. (%) 10 (2.3) 11 (2.5) Homeschool, No. (%) 4 (0.9) 2 (0.5) Hospital or chronic care facility, No. (%) 0 (0.0) 1 (0.2) Primary caregivers and family arrangements at follow-up Relationship to child Biological mother, No. (%) 369 (85.4) 379 (86.5) .23 Biological father, No. (%) 47 (10.9) 51 (11.6) Other or unknown, No. (%) 16 (3.7) 8 (1.8) Race White, No. (%) 350 (81.0) 355 (81.1) .70 Black, No. (%) 14 (3.2) 18 (4.1) Asian, No. (%) 45 (10.4) 44 (10.0) Indigenous, No. (%) 11 (2.5) 14 (3.2) Other or unknown, No. (%) 12 (2.8) 7 (1.6) Level of caregiver education Did not finish high school or Eq, No. (%) 83 (19.2) 89 (20.3) .53 Completed high school or Eq, No. (%) 86 (19.9) 91 (20.8) Some college or university, No. (%) 75 (17.4) 60 (13.7) College or university graduate, No. (%) 188 (43.5) 198 (45.2) Family arrangement Single parent, No. (%) 56 (13.0) 52 (11.9) .44 Single parent with partner closely involved, No. (%) 39 (9.0) 28 (6.4) 2-parent family, No. (%) 319 (73.8) 341 (77.9) Other or unknown, No. (%) 18 (4.2) 17 (3.9) Other children <18 y old living in the household, median (IQR) 1 (1, 2) 1 (1, 2) .61 Family’s main source of financial support Earnings from employment or self-employment, No. (%) 374 (86.6) 390 (89.0) .12 Government benefits (excluding pensions), No. (%) 41 (9.5) 37 (8.4) Other, No. (%) 10 (2.3) 2 (0.5)

These data are for the 870 children who completed data for at least one measurement instrument. Percentages may not sum to 100 because of rounding. Eq, equivalent.a The 10th percentile for gestational age in a normal population was reported by Kramer et al.19

b Disability at 18 mo was defined as at least 1 of cerebral palsy, moderate cognitive delay, deafness, or blindness.c Moderate cognitive delay was defined as a Mental Development Index score of <85 on the Bayley Scales of Infant Development, second edition.d Severe cognitive delay was defined as a Mental Development Index score of <70 on the Bayley Scales of Infant Development, second edition.e Severe ROP was defined as unilateral or bilateral stage 4 or 5 disease or as receipt of retinal therapy in at least 1 eye.f Disability at 5 y of age was defined as at least 1 of motor impairment, cognitive impairment, behavior problems, poor general health, deafness, or blindness.g Motor impairment was defined as a Gross Motor Function Classification System level of >2.h Cognitive impairment was defined as a full-scale IQ of <70 on the Wechsler Preschool and Primary Scale of Intelligence–III.i A behavior problem was defined as a Total Problem T score of >69 on the Child Behavior Checklist.




TABL

E 2

Neur

obeh

avio

ral O

utco

mes

Outc

ome

Max

na

Caffe

ine

Grou

pPl

aceb

o Gr

oup

Unad

just

ed M

D (9

5% C

I)M

D Ad

just

ed fo

r Ce

nter

(95

% C

I)P

MD

Adju

sted

for

Cent

er a

nd P

atie

nt

Char

acte

rist

ics

(9

5% C

I)b

nM

ean

± S

Dn

Mea

n ±

SD

Fine

mot

or s

kills

1065

Be

ery

VMI

409

90.7

± 1

3.1

406

88.9

± 1

3.8

1.8

(−0.

1 to

3.6

)1.

8 (0

.0 to

3.7

)<

.05

1.5

(−0.

3 to

3.3

)

Visu

al p

erce

ptio

n40

797

.7 ±

12.

939

795

.6 ±

13.

42.

1 (0

.2 to

3.9

)2.

0 (0

.3 to

3.8

).0

21.

9 (0

.1 to

3.6

)

Mot

or c

oord

inat

ion

406

90.8

± 1

5.8

397

88.0

± 1

7.0

2.9

(0.6

to 5

.2)

2.9

(0.7

to 5

.1)

.01

2.3

(0.1

to 4

.4)

Gene

ral i

ntel

ligen

ce (

WAS

I-II)

1041

Fu

ll-sc

ale

IQ39

297

.0 ±

14.

939

395

.5 ±

14.

71.

5 (−

0.5

to 3

.6)

1.6

(−0.

5 to

3.6

).1

41.

4 (−

0.6

to 3

.3)

Ve

rbal

com

preh

ensi

on39

297

.8 ±

15.

539

497

.0 ±

14.

90.

9 (−

1.3

to 3

.0)

0.9

(−1.

2 to

3.0

).3

90.

7 (−

1.4

to 2

.7)

Pe

rcep

tiona

l rea

soni

ng39

296

.8 ±

14.

939

595

.2 ±

14.

91.

6 (−

0.5

to 3

.7)

1.6

(−0.

5 to

3.6

).1

31.

4 (−

0.6

to 3

.4)

Atte

ntio

n

TEA-

Ch10

65

Se

lect

ive,

Sky

Sea

rch

404

10.8

± 3

.140

010

.8 ±

3.1

0.0

(−0.

4 to

0.4

)0.

0 (−

0.4

to 0

.4)

.96

0.0

(−0.

5 to

0.4

)

Su

stai

ned,

Sco

re!

402

8.5

± 3

.639

98.

2 ±

3.6

0.3

(−0.

2 to

0.8

)0.

3 (−

0.2

to 0

.8)

.21

0.2

(−0.

2 to

0.7

)

Di

vide

d, S

ky S

earc

h DT

395

6.8

± 3

.339

06.

5 ±

3.4

0.2

(−0.

2 to

0.7

)0.

2 (−

0.2

to 0

.7)

.36

0.1

(−0.

3 to

0.6

)

Ta

sk d

ecre

men

t shi

ftin

g, C

reat

ure

Coun

ting

396

9.3

± 3

.239

39.

2 ±

3.3

0.1

(−0.

3 to

0.6

)0.

1 (−

0.3,

0.5

).6

50.

0 (−

0.4

to 0

.5)

Co

nner

s AD

HD in

dex

1114

T-sco

re42

961

.5 ±

18.

243

560

.7 ±

18.

40.

7 (−

1.7

to 3

.2)

0.6

(−1.

8 to

3.0

).6

11.

2 (−

1.2

to 3

.5)

Prob

abili

ty s

core

429

45.2

± 3

3.5

435

43.6

± 3

3.5

1.6

(−2.

9 to

6.0

)1.

3 (−

3.1

to 5

.8)

.56

2.4

(−1.

9 to

6.7

)Ex

ecut

ive

func

tion

RC

F10

65

Co

py s

core

405

22.8

± 5

.340

021

.6 ±

6.1

1.1

(0.4

to 1

.9)

1.2

(0.4

to 2

.0)

.003

1.1

(0.3

to 1

.8)

Reca

ll sc

ore

406

12.6

± 5

.139

912

.0 ±

5.8

0.5

(−0.

2 to

1.3

)0.

6 (−

0.1

to 1

.3)

.11

0.5

(−0.

3 to

1.2

)

St

rate

gy s

core

392

4.0

± 1

.038

74.

0 ±

1.1

0.0

(−0.

1 to

0.2

)0.

0 (−

0.1

to 0

.2)

.56

0.0

(−0.

1 to

0.2

)

BRIE

F pa

rent

T-sc

ores

1114

GEC

429

55.9

± 1

2.5

434

54.8

± 1

2.3

1.2

(−0.

5 to

2.8

)1.

1 (−

0.5

to 2

.8)

.18

1.4

(−0.

3 to

3.0

)

M

etac

ogni

tion

inde

x42

955

.8 ±

11.

743

454

.7 ±

11.

61.

1 (−

0.5

to 2

.7)

1.1

(−0.

5 to

2.6

).1

91.

2 (−

0.3

to 2

.7)

BRI

431

54.9

± 1

3.6

436

53.9

± 1

3.2

1.0

(−0.

8 to

2.8

)1.

0 (−

0.8

to 2

.7)

.30

1.3

(−0.

5 to

3.0

)

WIS

C-IV

dig

it sp

an10

41

Di

git s

pan

forw

ard

405

8.8

± 3

.440

68.

6 ±

3.3

0.2

(−0.

2 to

0.7

)0.

3 (−

0.1

to 0

.7)

.16

0.2

(−0.

2 to

0.6

)

Di

git s

pan

back

war

d40

58.

4 ±

2.9

406

8.2

± 2

.90.

2 (−

0.2

to 0

.6)

0.2

(−0.

2 to

0.6

).2

70.

2 (−

0.2

to 0

.6)

DT, D

ual T

ask

a Nu

mbe

r of

ran

dom

ly a

ssig

ned

child

ren

not k

now

n to

hav

e di

ed b

efor

e fo

llow

-up

who

wer

e el

igib

le fo

r as

sess

men

t with

the

desi

gnat

ed in

stru

men

t.b

The

MD

was

adj

uste

d fo

r th

e ge

stat

iona

l age

and

sex

of t

he c

hild

, ant

enat

al a

dmin

istr

atio

n of

cor

ticos

tero

ids,

mul

tiple

bir

ths,

and

the

prim

ary

care

give

r’s

educ

atio

n at

the

time

of th

e as

sess

men

t.




TABL

E 3

Rate

s of

Impa

irm

ent i

n Ne

urob

ehav

iora

l Out

com

e

Outc

ome

Thre

shol

d Sc

orea

No./T

otal

No.

(%

)OR

(95

% C

I)

Caffe

ine

Grou

p Im

pair

men

t Rat

ePl

aceb

o Gr

oup

Impa

irm

ent R

ate

Unad

just

edAd

just

ed fo

r Ce

nter

PAd

just

ed fo

r Ce

nter

and

Pa

tient

Cha

ract

eris

ticsb

Fine

mot

or s

kills

Be

ery

VMI

<85

108/

409

(26.

4)13

3/40

6 (3

2.8)

0.74

(0.

54 to

1.0

0)0.

74 (

0.55

to 0

.99)

.04

0.77

(0.

57 to

1.0

4)

Visu

al p

erce

ptio

n<8

554

/407

(13

.3)

77/3

97 (

19.4

)0.

64 (

0.44

to 0

.93)

0.63

(0.

43 to

0.9

2).0

20.

64 (

0.43

to 0

.95)

M

otor

coo

rdin

atio

n<8

512

2/40

6 (3

0.0)

151/

397

(38.

0)0.

70 (

0.52

to 0

.94)

0.69

(0.

52 to

0.9

2).0

10.

73 (

0.54

to 0

.98)

Gene

ral i

ntel

ligen

ce (

WAS

I-II)

Fu

ll-sc

ale

IQ<8

576

/392

(19

.4)

86/3

93 (

21.9

)0.

86 (

0.61

to 1

.21)

0.87

(0.

61 to

1.2

3).4

30.

89 (

0.62

to 1

.27)

Ve

rbal

com

preh

ensi

on<8

572

/392

(18

.4)

69/3

94 (

17.5

)1.

06 (

0.74

to 1

.53)

1.11

(0.

77 to

1.5

9).5

91.

13 (

0.77

to 1

.64)

Pe

rcep

tiona

l rea

soni

ng<8

579

/392

(20

.2)

95/3

95 (

24.1

)0.

80 (

0.57

to 1

.12)

0.78

(0.

55 to

1.1

0).1

60.

80 (

0.56

to 1

.13)

Atte

ntio

n

TEA-

Ch

Se

lect

ive,

Sky

Sea

rch

<736

/404

(8.

9)37

/400

(9.

3)0.

96 (

0.59

to 1

.55)

0.97

(0.

59 to

1.5

8).8

91.

02 (

0.62

to 1

.67)

Sust

aine

d, S

core

!<7

125/

402

(31.

1)14

1/39

9 (3

5.3)

0.83

(0.

62 to

1.1

1)0.

84 (

0.62

to 1

.12)

.23

0.87

(0.

64 to

1.1

6)

Di

vide

d, S

ky S

earc

h DT

<714

6/39

5 (3

7.0)

152/

390

(39.

0)0.

92 (

0.69

to 1

.23)

0.93

(0.

69 to

1.2

4).6

10.

97 (

0.72

to 1

.31)

Shift

ing,

cre

atur

e co

untin

g<7

84/3

96 (

21.2

)86

/393

(21

.9)

0.96

(0.

68 to

1.3

5)0.

99 (

0.70

to 1

.41)

.96

1.08

(0.

75 to

1.5

6)

Conn

ers

ADHD

inde

x

T-s

core

>80

178/

429

(41.

5)17

0/43

5 (3

9.1)

1.11

(0.

84 to

1.4

5)1.

08 (

0.82

to 1

.41)

.60

1.15

(0.

87 to

1.5

3)

Pr

obab

ility

sco

re>8

014

4/42

9 (3

3.6)

143/

435

(32.

9)1.

03 (

0.78

to 1

.37)

1.00

(0.

75 to

1.3

1).9

81.

05 (

0.79

to 1

.40)

Exec

utiv

e fu

nctio

n

RCF

Copy

sco

re<1

SDc

385/

405

(95.

1)38

3/40

0 (9

5.8)

0.85

(0.

44 to

1.6

6)0.

83 (

0.43

to 1

.62)

.59

0.82

(0.

42 to

1.6

1)

Re

call

scor

e<1

SDc

296/

406

(72.

9)29

6/39

9 (7

4.2)

0.94

(0.

68 to

1.2

8)0.

91 (

0.67

to 1

.25)

.57

0.96

(0.

70 to

1.3

1)

BRIE

F pa

rent

T-sc

ores

GEC

>60

137/

429

(31.

9)13

0/43

4 (3

0.0)

1.10

(0.

82 to

1.4

6)1.

08 (

0.80

to 1

.45)

.62

1.11

(0.

82 to

1.5

1)

M

etac

ogni

tion

inde

x>6

014

4/42

9 (3

3.6)

125/

434

(28.

8)1.

25 (

0.94

to 1

.67)

1.23

(0.

92 to

1.6

5).1

61.

29 (

0.95

to 1

.73)

BRI

>60

125/

431

(29.

0)11

2/43

6 (2

5.7)

1.18

(0.

88 to

1.5

9)1.

18 (

0.87

to 1

.60)

.29

1.24

(0.

90 to

1.6

9)

WIS

C-IV

dig

it sp

an

Di

git s

pan

forw

ard

<711

8/40

5 (2

9.1)

125/

406

(30.

8)0.

92 (

0.68

to 1

.25)

0.90

(0.

65 to

1.2

3).5

00.

92 (

0.67

to 1

.28)

Digi

t spa

n ba

ckw

ard

<711

2/40

5 (2

7.7)

126/

406

(31.

0)0.

85 (

0.63

to 1

.15)

0.83

(0.

61 to

1.1

4).2

50.

86 (

0.63

to 1

.18)

DT, D

ual T

ask.

a Th

resh

old

scor

e us

ed to

defi

ne im

pair

men

t for

the

resp

ectiv

e in

stru

men

t. Fo

r al

l tes

ts, t

his

corr

espo

nded

to 1

SD

belo

w o

r ab

ove

the

mea

n of

the

norm

ativ

e sa

mpl

e, d

epen

ding

on

the

test

.b

The

OR w

as a

djus

ted

for

the

gest

atio

nal a

ge a

nd s

ex o

f the

chi

ld, a

nten

atal

adm

inis

trat

ion

of c

ortic

oste

roid

s, m

ultip

le b

irth

s, a

nd th

e pr

imar

y ca

regi

ver'

s ed

ucat

ion

at th

e tim

e of

the

asse

ssm

ent.

c Thr

esho

ld s

core

s ar

e ag

e-de

pend

ent.



newborns.22 It is well established that motor impairment is associated with behavioral difficulties, low self-esteem, poor social skills, and academic underachievement23; however, we found no evidence that neonatal caffeine therapy benefits behavior or academic achievement.4 It is possible that the modest motor gains observed in the caffeine group were not sufficient to influence academic achievement and behavioral outcomes or that different mechanisms are involved. Gains in other domains, such as self-esteem and social skills, are possible but need further study.

An astute comment from a reviewer and the evidence of improved visuomotor integration, visual perception, and visuospatial organization in the caffeine group prompted us to consider the contribution of severe ROP. Consistent with previous reports, 24 – 26 children with severe ROP were at increased risk for visuomotor difficulties compared with children without severe ROP. However, in our post hoc analysis, it was indicated that only a small proportion of the overall beneficial caffeine effect on visuomotor performance could be attributed to the reduction of severe ROP by caffeine.

It is possible that improved visual perception and organization after caffeine therapy is related to the lower number of children with DCD in the caffeine group10 because DCD has been associated with decreased visual perception and visuomotor integration.27 We have previously described reduced diffusion in cerebral white matter in the newborn brain at term-equivalent age in infants treated with caffeine compared with infants in the placebo group, 28 and thus an alternative possibility is that white matter changes are restricted to early mature cortical regions and sensory functions.

Caffeine may have a neuroprotective effect, 2 which leads to specific functional improvements, although the short- and long-term effects of caffeine on the central nervous system are not clearly understood.29 Methylxanthines have been described to inhibit adenosine receptors, thereby compromising the role of adenosine as an important neuromodulator.30 In addition, rodent studies revealed altered astrocytogenesis in neonates after caffeine treatment.31 However, caffeine has been shown to potentiate neural plasticity at the level of N-methyl-D-aspartate receptors, resulting in altered morphology of neural synapses and increased size of dendritic spines.32, 33 Moreover, caffeine administration in hypoxia-exposed neonatal pups was associated with enhanced myelination and reduced ventriculomegaly.34, 35 This is consistent with our neonatal MRI study in which reduced diffusion in cerebral white matter was demonstrated, reflecting improved white matter microstructural development.28

No other study has been conducted in which researchers assessed the long-term effects of caffeine therapy on general intelligence, attention, executive function, visuoperception, and behavior. Conducting this 11-year follow-up was challenging, given the large number of centers in the trial and the different languages spoken by participants. Thirteen centers provided data for the present secondary analyses in addition to the primary composite outcome. This resulted in an ascertainment rate of 78% (870 of 1114 potentially eligible surviving children) for the neurobehavioral outcomes. Despite this less than ideal ascertainment rate, the main birth characteristics and childhood outcomes were comparable between the group that was assessed at 11 years and the larger cohort assessed at earlier

stages. Therefore, we are confident that the outcomes of the whole cohort are reflected in the present results with sufficient accuracy.

CONCLUSIONS

Neonatal caffeine therapy was associated with better visuomotor, visuoperceptual, and visuospatial abilities at 11 years of age in children born at very low birth weight. None of the secondary outcomes reported in this study were adversely affected by caffeine. This highlights the long-term safety and efficacy of caffeine therapy for apnea of prematurity in very low birth weight neonates.

ACKNOWLEDGMENTS

The following investigators and research staff contributed to the 11-year follow-up of the CAP trial participants. Study sites are listed according to the number of infants they enrolled. The list comprises authors and nonauthor contributors: McMaster University Medical Centre (Hamilton, Ontario, Canada): Barbara Schmidt, MD, MSc, Judy D’Ilario, RN, Joanne Dix, RN, BScN, MSN, Beth Anne Adams, PhD, and Erin Warriner, PhD, CPsych; The Royal Women’s Hospital (Melbourne, Australia): Lex Doyle, MD, MSc, Peter Anderson, PhD, Catherine Callanan, RN, RM, Noni Davis, MBBS, Marion McDonald, RN, Julianne Duff, B Med Sci, MB, BS, Elaine Kelly, MA, MAPsS, LACST, MAASH, CPSP, and Esther Hutchinson, DPsych; Sunnybrook Health Sciences Center (Toronto, Canada): Elizabeth Asztalos, MD, MSc, Denise Hohn, BScOT, OTReg (Ontario, Canada), Afsheen Ayaz, MSc, MBBS, and Jared Allen, PhD; Women’s and Children’s Hospital, Adelaide, Australia: Ross Haslam, MBBS, Louise Goodchild, RN, and Rosslyn Marie Lontis, RN, RM, NICC, Dip of Nursing (Community Health), BN; Mercy Hospital for Women, Melbourne, Australia: Gillian Opie, MBBS, IBCLC,

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Heather Woods, RN, RM, Elaine Kelly, MA, MAPsS, LACST, MAASH, CPSP, Emma Marchant, RN, Emma Magrath, MBBS, MHth&MedLaw, and Amanda Williamson, MPsy; Children’s & Women’s Health Centre of British Columbia, Vancouver, British Columbia, Canada: Ruth E. Grunau, PhD, Anne Synnes, MDCM, MHSC, Alfonso Solimano, MD, Arsalan Butt, MSc, and Julie Petrie, PhD; Foothills Hospital and Alberta Children’s Hospital, Calgary, Alberta, Canada: Reginald S. Sauve, MD, MPH, Deborah Dewey, PhD, Heather Christianson, BA, Deborah Anseeuw-Deeks, BN, and Sue Makarchuk, MA; St. Boniface Hospital, Winnipeg, Manitoba, Canada: Diane Moddemann, MD, MEd, Valerie Debooy, RN, Naomi Granke, RN, CCRP, and Jane Bow, PhD, CPsych; Astrid Lindgren Children’s Hospital, Stockholm, Sweden: Eric Herlenius, MD, PhD, Lena Legnevall, RN, BSc, Birgitta Böhm, PhD, Britt-Marie BergStröm, BSc, Sofia Stålnacke, BSc, and Stéphanie Sundén-Cullberg, BSc; The James Cook University Hospital, Middlesbrough, United Kingdom: Win Tin, MD; Royal Maternity Hospital Belfast, Northern Ireland, United Kingdom: Clifford Mayes, MD, Christopher McCusker, MSc, PhD CPsych, and Una Robinson, MB BCh BAO; Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom: Nicholas Embleton, MD;

Northern Neonatal Initiatives, Middlesbrough, United Kingdom: Win Tin, MD and Joanna Carnell, PhD; Steering Committee for 11-Year Follow-Up: Barbara Schmidt (Chair), MD, MSc, McMaster University (Hamilton, Ontario, Canada) and University of Pennsylvania (Philadelphia, Pennsylvania), Peter J. Anderson, PhD, University of Melbourne (Melbourne, Victoria, Australia), Elizabeth V. Asztalos, MD, MSc, University of Toronto (Toronto, Ontario, Canada), Peter G. Davis, MD, University of Melbourne (Melbourne, Victoria, Australia), Deborah Dewey, PhD, University of Calgary (Calgary, Alberta, Canada), Lex W. Doyle, MD, University of Melbourne (Melbourne, Victoria, Australia), Ruth E. Grunau, PhD, University of British Columbia (Vancouver, British Columbia, Canada), Diane Moddemann, MD, MEd, University of Manitoba (Winnipeg, Manitoba, Canada), Arne Ohlsson, MD, MSc, University of Toronto (Toronto, Ontario, Canada), Robin S. Roberts, MSc, McMaster University (Hamilton, Ontario, Canada), Alfonso Solimano, MD, University of British Columbia (Vancouver, British Columbia, Canada), and Win Tin, MD, The James Cook University Hospital (Middlesbrough, United Kingdom); Neonatal Trials Group, McMaster University, Hamilton, Ontario, Canada: Robin S. Roberts, MSc, Lorrie

Costantini, BA, Judy D’Ilario, RN, and Harvey Nelson, MSc.

We are indebted to the physicians, psychometricians, psychologists, research coordinators, and all other staff who made this study possible, and most importantly, to the children and their families who participated in this follow-up study.

ABBREVIATIONS

ADHD: attention-deficit/hyperac-tivity disorder

BRI: Behavioral Regulation IndexBRIEF: Behavior Rating

Inventory of Executive Function

CAP: Caffeine for Apnea of Prematurity

CI: confidence intervalDCD: developmental coordina-

tion disorderGEC: Global Executive CompositeMD: mean differenceOR: odds ratioRCF: Rey complex figure testROP: retinopathy of prematurityTEA-Ch: Test of Everyday

Attention for ChildrenVMI: visual-motor integrationWASI-II: Wechsler Abbreviated

Scale of Intelligence–IIWISC-IV: Wechsler Intelligence

Scale for Children–IV


obtained funding, contributed to the interpretation of data, and drafted the initial manuscript; Prof Roberts conceptualized and designed the study, coordinated and supervised data collection, obtained funding, conducted the statistical analyses, contributed to the interpretation of data, and drafted the initial manuscript; Dr Asztalos coordinated and supervised data collection and obtained funding; Ms Costantini coordinated and supervised data collection, contributed to the interpretation of data, and drafted the initial manuscript; Prof Davis and Dr Tin conceptualized and designed the study and coordinated and supervised data collection; Prof Dewey conceptualized and designed the study, coordinated and supervised data collection, obtained funding, and contributed to the interpretation of data; Ms D’Ilario coordinated and supervised data collection; Drs Grunau, Moddemann, and Solimano conceptualized and designed the study, coordinated and supervised data collection, and obtained funding; Prof Ohlsson conceptualized and designed the study and obtained funding; Mr Nelson coordinated and supervised data collection, and contributed to the interpretation of data; and all authors reviewed and revised the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

This trial has been registered at www. clinicaltrials. gov (identifier NCT00182312) and with the ISRCTN Register (http:// isrctn. org) (identifier ISRCTN44364365).

DOI: https:// doi. org/ 10. 1542/ peds. 2017- 4047

Accepted for publication Feb 1, 2018

Address correspondence to Peter J. Anderson, PhD, Monash Institute of Cognitive and Clinical Neurosciences, School of Psychological Sciences, Monash University, 18 Innovation Walk, Clayton Campus, Clayton, VIC 3800, Australia. E-mail: [email protected]

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2018 by the American Academy of Pediatrics


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FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: Supported by the Canadian Institutes of Health Research (MOP 102601).

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.


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originally published online April 11, 2018; Pediatrics (CAP) Trial Group

Solimano, Win Tin, Peter J. Anderson and for the Caffeine for Apnea of Prematurity D'Ilario, Ruth E. Grunau, Diane Moddemann, Harvey Nelson, Arne Ohlsson, Alfonso

Elizabeth V. Asztalos, Lorrie Costantini, Peter G. Davis, Deborah Dewey, Judy Ines M. Mürner-Lavanchy, Lex W. Doyle, Barbara Schmidt, Robin S. Roberts,

of PrematurityNeurobehavioral Outcomes 11 Years After Neonatal Caffeine Therapy for Apnea

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