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
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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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PEDIATRICS Volume 141, number 5, May 2018 5
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.
by guest on April 11, 2018http://pediatrics.aappublications.org/Downloaded from
MÜRNER-LAVANCHY et al6
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.
by guest on April 11, 2018http://pediatrics.aappublications.org/Downloaded from
PEDIATRICS Volume 141, number 5, May 2018 7
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.
by guest on April 11, 2018http://pediatrics.aappublications.org/Downloaded from
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
PEDIATRICS Volume 141, number 5, May 2018 9
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).
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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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